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The Halogen Bond

Gabriella Cavallo,† Pierangelo Metrangolo,*,†,‡ Roberto Milani,‡ Tullio Pilati,† Arri Priimagi,§
Giuseppe Resnati,*,† and Giancarlo Terraneo†
†
Laboratory of Nanostructured Fluorinated Materials (NFMLab), Department of Chemistry, Materials and Chemical Engineering
“Giulio Natta”, Politecnico di Milano, Via L. Mancinelli 7, I-20131 Milano, Italy
‡
VTT-Technical Research Centre of Finland, Biologinkuja 7, 02150 Espoo, Finland
§
Department of Chemistry and Bioengineering, Tampere University of Technology, Korkeakoulunkatu 8, FI-33101 Tampere, Finland
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ABSTRACT: The halogen bond occurs when there is evidence of a net attractive
interaction between an electrophilic region associated with a halogen atom in a
Downloaded via UNIV ESTADUAL DE CAMPINAS on May 15, 2024 at 17:40:23 (UTC).

molecular entity and a nucleophilic region in another, or the same, molecular entity. In
this fairly extensive review, after a brief history of the interaction, we will provide the
reader with a snapshot of where the research on the halogen bond is now, and, perhaps,
where it is going. The specific advantages brought up by a design based on the use of the
halogen bond will be demonstrated in quite different fields spanning from material
sciences to biomolecular recognition and drug design.

CONTENTS 4.1. Liquid Crystals 2543

4.2. Polymers 2545
1. Introduction 2479 4.3. Gels and Other Soft Systems 2546
1.1. Historical Perspective 2479 5. Biomolecular Systems 2547
1.2. Definition of the Halogen Bond 2482 5.1. Halogen Bond Donors 2548
1.3. Pivotal Role of the Halogen Bond in Ration- 5.2. Halogen Bond Acceptors 2548
alizing Other Interactions 2483 5.3. Geometrical Features 2549
1.4. General Aspects of the Interaction 2485 5.4. Energetical Considerations and Complex
1.4.1. Directionality 2486 Stabilization Effects 2550
1.4.2. Tunability 2487 5.5. Relevance in the Pharmaceutical Field 2551
1.4.3. Hydrophobicity 2489 5.6. Computational Models 2552
1.4.4. Donor Atom Dimensions 2490 6. Functional Systems 2552
2. Nature of the Halogen Bond 2490 6.1. Organic Catalysis 2552
2.1. Modeling and Theoretical Studies 2490 6.2. Optical and Optoelectronic Systems 2556
2.1.1. Electrostatic Component 2490 6.2.1. Light-Emitting Materials 2556
2.1.2. Charge-Transfer Component 2493 6.2.2. Light-Responsive and Nonlinear Optical
2.1.3. Dispersion and Polarization Compo- Materials 2560
nents 2496 6.3. Conductive and Magnetic Materials 2564
2.2. Experimental Studies 2499 6.4. Miscellanea 2567
2.2.1. Microwave Spectroscopy 2499 7. Conclusions 2569
2.2.2. Infrared and Raman Spectroscopies 2502 Author Information 2570
2.2.3. Nuclear Magnetic and Quadrupolar Corresponding Authors 2570
Resonance Spectroscopies 2506 Notes 2570
2.2.4. X-ray Diffraction Techniques 2511 Biographies 2570
3. Crystal Engineering 2518 Acknowledgments 2572
3.1. Structures 2519 Glossary 2572
3.1.1. Zero-Dimensional (0D) Systems 2519 References 2572
3.1.2. One-Dimensional (1D) Systems 2522
3.1.3. Two and Three-Dimensional (2D and
3D) Systems 2525
3.1.4. Interpenetrated Networks 2529
3.2. Applications 2533 Special Issue: Frontiers in Macromolecular and Supramolecular
3.2.1. Porous Systems 2533 Science
3.2.2. Solid-State Synthesis 2539
4. Soft Materials 2543 Received: August 17, 2015
Published: January 26, 2016

© 2016 American Chemical Society 2478 DOI: 10.1021/acs.chemrev.5b00484

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Chemical Reviews Review

1. INTRODUCTION 1.1. Historical Perspective

Halogen atoms in haloorganics are typically considered as sites The beginning of the XB story can be traced back
of high electron density because of their high electronegativity. approximately to two centuries ago, when I2···NH3, probably
Consistent with this well-established understanding, it is the first halogen-bonded complex ever prepared, was
commonly accepted that halogen atoms can form attractive serendipitously synthesized by J. J. Colin while working in
interactions by functioning as electron donor sites (i.e., the laboratory of J. L. Gay-Lussac. In fact, in 1814 Colin
nucleophiles). The ability of halogen atoms to work as reported the formation of a blue-black color upon combination
hydrogen bond acceptors was recognized as early as the of iodine with amilose11 and of a liquid with a somewhat
1920s,1−4 and halogen atoms of halocarbons can function as metallic luster upon reaction of dry iodine and dry gaseous
electron donor sites also to several other elements, e.g., when ammonia.12 The exact molecular composition of this liquid was
coordinating alkali-metal or alkaline-earth-metal cations. established only 50 years later, when F. Guthrie obtained the
However, the electron density in halogen atoms is anisotropi- same material in pure form by adding powdered iodine to
cally distributed whenever the atom is covalently bound to one aqueous ammonia and first proposed the I2···NH3 structure for
or more atoms.5−7 In compounds wherein the halogen atom is the formed liquid.13 Notwithstanding this, it required another
involved in the formation of one covalent bond, by far the most century before pioneering discoveries on charge-transfer
common case, there is a region of higher electron density, interactions by R. Mulliken14 and O. Hassel15 allowed for
where the electrostatic potential is negative in nearly all cases, major advancements in the understanding of the nature of the
which forms a belt orthogonal to the covalent bond, and a interaction driving the formation of such a complex. In the two
region of lower electron density (the so-called σ-hole) where centuries after Colin’s report, many theoretical and exper-
the potential is frequently positive, mainly in the heavier imental studies, performed in quite different contexts, provided
halogens, which generates a cap of depleted electron density on information relevant to XB identification and outlining.
the elongation of the covalent bond. This region can form However, these pieces of information remained long
attractive interactions with electron-rich sites, and the general fragmented, their contextualization was limited to their
ability of halogen atoms to attractively interact with electron respective areas, and a unifying and comprehensive catego-
donor sites (nucleophiles) has been fully recognized and rization was missing. In this section we will mention the
comprehensively understood only recently. experimental and theoretical findings which gave major
In 2009 the International Union of Pure and Applied contributions for the development of the XB concept and
Chemistry (IUPAC) started a project (project no. 2009-032-1- practice. Some of these contributions will be discussed in
100) having the aim “to take a comprehensive look at greater detail and after a different perspective in the following
intermolecular interactions involving halogens as electrophilic sections of this review.
species and classify them”.8 An IUPAC recommendation9 Soon after Colin’s discovery, in 1819 P. Pelletier and J. B.
defining these interactions as halogen bonds was issued in 2013 Caventou16 reported the first experimental evidence revealing
when the project was concluded: This definition states that “A the ability of dihalogens to interact attractively with anions.
halogen bond occurs when there is evidence of a net attractive Specifically, they published the synthesis of strychnine triiodide,
interaction between an electrophilic region associated with a where the I3− anion was formed on interaction of I− with I2.
halogen atom in a molecular entity and a nucleophilic region in The formation of triiodide anions has also been invoked by
another, or the same, molecular entity.” A schematic several other investigators to rationalize the greater solubility of
representation of the halogen bond is given in Figure 1. I2 in different solvents on addition of metal iodides as well as
the reaction between metal halides and I2.17 In 1870 S. M.
Jörgensen proposed that polyiodide alkaloids contain iodide
anions as well as I2 and published the first systematic
investigation on the topic.18
In 1883 O. Rhoussopoulos19 reported the synthesis of the
quinoline/iodoform adduct, showing that halocarbons behave
Figure 1. Schematic representation of the halogen bond. as dihalogens and form adducts with Lewis bases.
The formation of halogen-bonded complexes involving
bromine and chlorine as electron acceptor species was first
reported at the end of the 19th century by I. Remsen and J. F.
The IUPAC definition categorizes unambiguously an Norris, who described the 1:1 dimers formed by Br2 and Cl2
interaction responsible for the formation of adducts prepared with various amines.20 On the other hand, the first XB adduct
as early as 1814 but which had been overlooked for decades. involving F2 was reported only 80 years later21−23 when it was
This interaction developed into a routine and predictable tool possible to isolate the F3− anion by using very extreme
to direct self-assembly phenomena in all phases only after its conditions, and the synthesis of F2···NH3 and F2···OH2 adducts
effectiveness in crystal engineering was demonstrated in the late appeared only in the 1990s.24 These early data were already
1990s.10 suggesting, and today it is well established,25−27 that the XB
This review will focus on supramolecular systems assembled strength scales with the polarizability of the XB donor atom,
via the halogen bond (XB). The practice and concept of the that is, F < Cl < Br < I. In fact, F is the least prone to be
interaction developed through a rather patchy course, and it involved in XB, being the less polarizable halogen atom, and
seems instructive to open this review with a brief historical can act as an XB donor only when attached to particularly
perspective of the topic as it may help the reader to identify strong electron-withdrawing groups.28−31 The polarizability of
Ariadne’s thread which enabled the present situation to come astatine, the heaviest halogen, has been calculated to be higher
about. This perspective may also help in anticipating future than that of iodine,32 and according to the trend described
directions. above, it can be foreseen that it may function as an XB donor
2479 DOI: 10.1021/acs.chemrev.5b00484
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Chemical Reviews Review

too, even better than I. Although computational data support distance was found to be slightly longer than in the isolated Br2
this hypothesis,33,34 astatine is a radioactive element with short- molecule, the Br···O intermolecular distance was shorter than
lived isotopes, little is known about its chemistry,35 and no the sum of their respective van der Waals radii, and the Br−
halogen-bonded adducts involving At have been reported, so Br···O angle was close to 180°.57 These three features are
far. general and distinctive of the XB. The “halogen molecule
The whole 20th century saw a flourishing of the research bridges” observed in the Br2···O(CH2CH2)2O adduct were also
activity in the field. Lots of experimental observations and found in similar systems formed upon reaction of Br2 and Cl2
phenomena, where we are now acknowledging the role played with benzene (Figure 2, bottom). Hassel himself reported in
by the XB, were reported. Albeit not yet named so, XB was at 1958 and 1959, respectively, the crystal structures of the
the core of some important achievements in chemistry, being adducts Br2···C6H6 and Cl2···C6H6, containing endless chains
relevant to the work of R. Mulliken (Nobel Prize in chemistry built up of alternating benzene and dihalogen molecules.58,59
in 1966)36,37 on the chemical bond and central to the These two structures were particularly interesting since they
conformational studies of O. Hassel (Nobel Prize in chemistry showed π-systems working as donors of electron density
in 1969).15 toward dihalogens also in the solid state60 and suggested that
Compilations collecting closely related results began to halogen-bonded adducts are on the reaction pathways of
appear in the mid-20th century;38−48 however, single findings halogenation reactions of aromatics and other unsaturated
were understood within conceptual frames different from each systems. In the successive decades this hypothesis was forcefully
other, and the common features were not recognized until the confirmed,61,62 and J. K. Kochi showed that π-donating
end of the 20th century. The most important discoveries moieties form solid adducts also with halocarbons.54
reported in the past 70 years are described below. A comprehensive discussion of the crystal structures of
It has long been known that when I2 is dissolved in organic halogen-bonded systems known at that time was given by H. A.
solvents, solutions of different colors are formed:49 Brown or Bent in the review he published in 1968 on the chemistry of
red-brown solutions are obtained with acetone, alcohols, ethers, donor−acceptor adducts. In this paper, the most distinctive
amines, and benzene, while violet solutions, resembling the geometric features of the interactions were clearly highlighted,
color of the I2 vapors, are obtained with aliphatic hydrocarbons, i.e., the short interatomic distances and high directionality
carbon tetrachloride, and chloroform. In 1948 H. A. Benesi and mentioned above.64 Bent’s analysis evidenced that in all
J. H. Hildebrand rationalized these phenomena when complexes the distances between the electron donor atom
identifying the first cases of intermolecular donor−acceptor and the halogen atom were shorter than the sum of their
interactions in solution.50,51 Similar complexes involving ethers, respective van der Waals radii and that the two atoms lay nearly
thioethers, and carbonyl derivatives were soon after reported by on a straight line (i.e., the corresponding angles were close to
R. S. Mulliken in 1950,14,52,53 and two years later he 180°). These geometric features were confirmed 20 years later
rationalized them as a subclass of the electron donor−acceptor through statistical analysis of the structures in the Cambridge
molecular complex family.53 UV−vis spectroscopy indicated Structural Database (CSD) by R. Parthasarathy and G. R.
that a charge transfer to the halogen occurs in all of these Desiraju.65 In 1983 J.-M. Dumas, M. Gomel, and M. Guerin66
complexes, even in the weaker ones, such as those involving analyzed the intermolecular interactions involving haloorganics
dihalogens and aromatics54 or perfluorocarbons and amines.55 in solution through a variety of techniques (e.g., UV−vis, IR,
X-ray crystallographic studies reported by O. Hassel in the Raman, NMR, nuclear quadrupole resonance (NQR), dielectric
1950s were crucial in identifying the structural features of the polarization, etc.), and they showed that the interaction features
intermolecular interaction occurring in several complexes in the liquid phase parallel those in the solid phase.
formed by dihalogens or halocarbons with electron donor A. Legon and co-workers24,67 were the first to undertake a
molecules. In particular, in 1954 Hassel described the structure systematic analysis of a wide variety of halogen-bonded adducts
of the Br2···O(CH2CH2)2O adduct56 as an infinite chain formed in the gas phase via microwave spectroscopy. Their
containing “halogen molecule bridges” linking together dioxane results on geometries and charge distributions revealed close
molecules (Figure 2, top). In this adduct the covalent Br−Br similarities between “isolated” adducts and adducts in the
condensed phase, showing that the lattice and solvent effects,
present in the solid and in solution, respectively, have a minor
influence on basic XB features.
In the same period some of us proved systematically that
both anions68−75 and lone-pair-possessing heteroatoms76−87
form with halocarbons adducts showing consistent geometrical
features (Figures 3 and 4). We also expanded the range of
halocarbons which can work as effective XB donors10,88 and
identified the key role of residues close to covalently bound
halogen atoms in determining their strength as electrophilic
sites.
Gradually, it became clear that it was possible to design and
Figure 2. Ball-and-stick representation (Mercury 3.3) of the Br2··· fine-tune the structural and functional features of self-assembled
O(CH2CH2)2O56 (top) and Br2···C6H658 (bottom) adducts. Both
adducts by choosing conveniently the nature and the structure
adducts contain infinite chains formed by dibromine as the bidentate
XB donor and dioxane, or benzene, as the bidentate XB acceptor. of the molecules involved in XB formation. However, it took a
Color code: carbon, gray; oxygen, red; bromine, light brown. XBs are long time before it was recognized that the electrophilic
dotted black lines. Hydrogen atoms are omitted for clarity. CSD behavior of halogen atoms is commonplace and can drive the
Refcodes are reported. Reprinted with permission from ref 63. predictable formation of strong and highly directional
Copyright 2015 Springer. interactions in the solid, liquid, and gas phases. Halogens are
2480 DOI: 10.1021/acs.chemrev.5b00484
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Chemical Reviews Review

among the most electronegative elements in the periodic table,

and their ability to function as electrophilic species appeared
quite strange and counterintuitive. A decisive contribution to
the stereoelectronic understanding of the XB was given by
computational studies on the distribution of the electron
density in halogen atoms which began to appear in the early
1990s. The studies by P. Politzer and J. S. Murray were
particularly significant as they demonstrated the anisotropic
charge distribution on halogen atoms forming one covalent
bond89−91 and paved the way to the definition of the “σ-hole”:
a region of depleted and often positive electrostatic potential on
the surface of halogen atoms.
All these findings and related rationalizations clearly
Figure 3. Ball-and-stick representation (Mercury 3.3) of the halogen- demanded a unification process which was initiated by some
bonded infinite chains containing 1,4-diiodotetrafluorobenzene as the of us with the paper entitled “Halogen Bonding: A Paradigm in
bidentate XB donor and n-Bu4N+Br− (OHOWAQ),72 n-Bu4N+Cl− Supramolecular Chemistry”.10 This paper showed how the
(OHOVUD),72 and n-Bu4N+SCN− (AHAJEZ)73 as XB acceptors.
Quite similar infinite chains are obtained when n-Bu4P+Br−,73
electrophilic behavior of halogen atoms is a general
Me4N+Br−,74 n-Bu4P+Cl−,75 and Me4N+Cl− 74 are used. Cations are phenomenon impacting “all the fields where design and
omitted for clarity. Color code: carbon, gray; nitrogen, blue; bromine, manipulation of aggregation processes play a key role”. Soon
light brown; chlorine, light green, sulfur, dark yellow; fluorine, yellow. after we published a review paper in Accounts of Chemical
XBs are dotted black lines. CSD Refcodes are reported. Research,92 highlighting the main and common features of
adducts formed when dihalogens, halocarbons, or other
halogenated derivatives attractively interact with lone-pair-
possessing atoms, π-systems, or anions and afford adducts in
the gas, liquid, or solid phase.
This unification process boosted the interest of the scientific
community on the topic. Thanks to the strength of the
interaction (section 2) and its intrinsic tunability resulting from
the possibility to span the four halogen atoms as electron
density acceptor sites, in recent years the number of papers on
XB has been growing very rapidly, and the interaction has
quickly evolved from a scientific curiosity to one of the
routinely used tools to direct and control molecular assembly
phenomena (Figure 5).93

Figure 5. Number of papers per year having “halogen bonding” in the

title and/or abstract (source SciFinder, search performed in November
2015).
Figure 4. Ball-and-stick representation (Mercury 3.3) of the halogen-
bonded infinite chains containing 1,4-diiodotetrafluorobenzene as the
bidentate XB donor and neutral Lewis bases as bidentate XB acceptors. A symposium devoted to the XB was organized in the frame
The selected Lewis bases are 4,4′-dipyridine (QUIHBEO),76 of the 238th National Meeting of the American Chemical
N,N,N′,N′-tetramethyl-p-phenylendiamine (MOFFUI),85 dioxane Society (Washington, DC, Aug 16, 2009), and had the seminal
(DIVDAO),77 1,4-benzoquinone (ZARFUV),86 thiourea (NUS- role to allow for the emerging consensus on some features of
BUZ),78 and triphenylphosphine selenide (ZEBJUN).79 Quite similar the interaction to be acknowledged. This consensus was further
infinite chains are obtained when other nitrogen-centered nucleo-
philes,80−83,87 oxygen-centered nucleophiles,84 and sulfur-centered
tuned in the kick-off event of the IUPAC project mentioned
nucleophiles77 are used. Color code: carbon, gray; nitrogen, blue; above (Sigüenza, Spain, Aug 20−21, 2011). At the end point of
oxygen, red; iodine, purple; sulfur, dark yellow; phosphorus, orange; a 200 year long process, the IUPAC definition of the XB9 finally
selenium, dark orange; fluorine, yellow. XBs are dotted black lines. registered the agreement reached by the scientific community
Hydrogen atoms are omitted for clarity. CSD Refcodes are reported. on self-assembly and recognition processes controlled by
electrophilic halogens, a topic that is nowadays well-established,
understood, and used.
2481 DOI: 10.1021/acs.chemrev.5b00484
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Chemical Reviews Review

1.2. Definition of the Halogen Bond named hydrogen bonds,4 and cannot be confused with halogen
In the two centuries of research on phenomena where halogen bonds; otherwise the wrong electronic and geometric
atoms function as electrophilic sites, a remarkably wide variety information is delivered. The IUPAC project 2009-032-1-100
of terms were coined to describe this type of behavior, thus was started in 2009 with the task to give a unified conceptual
pointing out the struggle to understand the phenomenon. frame to interactions involving halogens as electrophilic species
Already in 1968 Bent64 reported a list of 20 descriptive phrases and to finally classify them in an unequivocal way.8 The
used during the “first century” of the XB: “Electron clutching”, definition of the halogen bond reported in the previous section
‘saturation of residual affinities’, “bumps-in hollow”, “pairs-in- was the IUPAC recommendation proposed in 2013 at the end
pocket”, “points-in-holes”, “locks-in-keys”, “exaltation of of the project.9 According to this definition, a typical XB is
valency”, “donor−acceptor interactions”, “charge-transfer inter- denoted as
actions”, and “filling of antibonding orbitals” are just some of R−X···Y (1)
the proposed names. Some of them are quite imaginative and with the three dots representing the bond. R−X is the XB
imply that intermolecular interactions can be described in terms donor, and X is a halogen atom covalently bound to the R
of properties of the starting molecules, i.e., “bumps-in hollow” group and having an electrophilic region, or a potentially
or “pairs-in-pocket”, while others aim at emphasizing different electrophilic region, on its electrostatic potential surface. It may
aspects of the intermolecular interaction, i.e., the saturation of happen that X is covalently bound to more than one group. In
bonding potential and the directional character, the creation of such cases the halogen may also form more than one halogen
formal charges and expanded octets, or the fact that the bond (Figure 6). Y is the XB acceptor (donor of electron
increased nucleus−electron attraction is the driving force
behind the intermolecular interaction. In an attempt to
highlight the differences with respect to the hydrogen bond
(HB), the term “anti-hydrogen bond” has also been used by W.
Klemperer and co-workers94 while considering the intermo-
lecular interaction in the F−Cl···F−H complex, while G. R.
Desiraju and T. Steiner95 and I. Alkorta et al.96 had used the
term “inverse hydrogen bonding” referring to the intermo-
lecular interaction occurring between hydrides and covalently
bonded halogen atoms.
It is difficult to establish exactly when the term halogen bond
was first proposed for interactions formed by electrophilic
halogens and even more difficult to give an exact date for when
the concept was developed and accepted. The concept began to
emerge in the middle of the 20th century when the XB began
to be identified as the cause of a well-defined and relatively
homogeneous set of phenomena. In 1961 R. Zingaro and R.
Hedges,97 while describing the complexes formed in solution by
halogens and interhalogens with phosphine oxides and sulfides,
were probably the first to use the term halogen bond to describe
interactions were halogens act as electrophilic species, in Figure 6. Short and directional XBs existing in halonium salts.
analogy to the behavior of hydrogen in the HB. In 1976 D. E. Phenyl[2,2-dimethyl-4-(diethylphosphono)-2,5-dihydro-3-furyl]-
Martire et al. used the term to describe adducts formed in the iodonium perchlorate (VOYXEM108): one oxygen of the phosphonate
residue and one oxygen of the perchlorate anion work as XB acceptors.
gas phase by haloforms with ethers and amines.98 However, it [2-Ethoxy-2-oxo-1-(triphenyl-λ 5 -phosphanylidene)ethyl]-
was the review of J.-M. Dumas, M. Gomel, and M. Guerin in phenyliodonium tetrafluoroborate (IWUKEQ109): the carbonyl oxy-
198366 that first separated results obtained by using several gen of the carbethoxy residue and a fluorine atom of the fluoroborate
experimental techniques in the gas, liquid, and solid phases anion work as XB acceptors. Bis(pentafluorophenyl)bromonium
from other domains (e.g., other electron donor−acceptor tetrafluoroborate (HOHJUJ110): BF4− works as a bidentate XB
interactions) and organized them under the term halogen bond. acceptor as the XB donor ability of Br is increased by strong
The name began to be used regularly after the concept paper by electron-withdrawing residues. Hydrogen atoms have been omitted,
P. Metrangolo and G. Resnati92 afforded general heuristic XBs are dashed lines, and the numbers are the C−X···nucleophile
principles to correlate the structure of the XB donor and angles (deg) and lengths of the halogen bonds (Å). Color code:
acceptor sites and the strength of the resulting interaction. An carbon, gray; oxygen, red; iodine, purple; chlorine, light green;
phosphorus, orange; fluorine, yellow; boron, pink. XBs are dotted
exponential growth of the interest of the scientific community black lines. Hydrogen atoms are omitted for clarity. CSD Refcodes are
has resulted in the past 15 years or so (Figure 5). The terms reported.
halogen bond and halogen bonding are used interchangeably,
both terms having XB as an acronym.
In 2006 R. Glaser et al.99 suggested to use the term halogen
bond to designate any interaction involving halogen atoms, density) and can be an anion or a neutral species possessing at
regardless of whether they act as electrophiles or nucleophiles. least one nucleophilic region, e.g., a lone-pair-possessing atom
Without a general and univocal criterion for assessing if an or π-system. This IUPAC definition has been framed as simply
interaction is a halogen bond, confusion may arise, as in the and comprehensively as possible to account for all the cases
case when halogens interact with positive hydrogen atoms wherein there is evidence of bond formation involving a
through the belt of higher electron density on their electrostatic nucleophile and a positive region on a halogen atom X from a
potential surface. Clearly these interactions are and have to be molecule or molecular fragment R−X.
2482 DOI: 10.1021/acs.chemrev.5b00484
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Iodine, bromine, chlorine, and in some circumstances also

fluorine can act as XB donors. Occasionally the terms fluorine
bond,100−102 chlorine bond,103,104 bromine bond,105 and iodine
bond106,107 have appeared in the literature to designate the
specific interactions involving one of the four halogen atoms as
an electrophilic site. Clearly, these terms address subsets of the
most general set of interactions named halogen bonds. An
advantage of the term XB, with respect to the aforementioned
subsets, is that it gives the instruments to make a direct and
meaningful comparison among the behaviors of the four
halogens.
With respect to the different expressions suggested over the
years to designate interactions formed by electrophilic
halogens, the term halogen bond presents the advantage to
declare immediately the most characteristic and general aspect
of the interaction, namely, that it involves halogen atoms. A
possible further advantage of this term is that it recalls
immediately the alliterating term hydrogen bond, and by
analogy, halogens are surmised to work as electrophiles as the
hydrogen atoms do in the hydrogen bond. The main similarity Figure 7. Selected examples of σ-hole interactions. Short and
directional chalcogen bonds formed in the solid state by the sulfur
for the two interactions is the role of the positive site (electron
atom of two derivatives of thiamin, a vitamin of the B complex, on the
density acceptor, Lewis acid, electrophile) played by the elongation of one (THIMHC)137 or both (MEMKEU)138 of its
halogen and hydrogen atoms, respectively; the inherent covalent bonds. Pnicogen bonds formed by arsenic atoms in 2-chloro-
difference is that atoms of the XVII and I groups are involved. 1,3-bis(4-methoxyphenyl)-2,3-dihydro-1H-bisthieno[3,2-e:2′,3′-g]-
1.3. Pivotal Role of the Halogen Bond in Rationalizing [1,3,2]benzodiazarsole (BAYREA)139 and arsenic trichloride dipyridyl
Other Interactions (ASCDPY).140 Hydrogen atoms are omitted for clarity, chalcogen and
pnicogen bonds are dotted lines, and the numbers are the angles (deg)
The mindset developed in relation to XB studies favored the and lengths of the chalcogen and pnicogen bonds (Å). Color code:
rationalization of the attractive interactions that elements of carbon, gray; nitrogen, blue; oxygen, red; chlorine, light green; sulfur,
groups XIV−XVI form with nucleophiles after a general dark yellow; phosphorus, orange; arsenic, violet. CSD Refcodes are
framework. In this section it will be described how the reported.
anisotropic distribution of the electron density around
covalently bonded atoms is a general phenomenon and the Examples of attractive intermolecular interactions wherein
presence of positive σ-holes on the extensions of single covalent groups XV and XIV atoms get close to nucleophiles are also
bonds is commonplace and frequently results in attractive known. The ability of PF3 to act as a Lewis acid has been
interactions with incoming nucleophiles.111−119 It will also be known since 1991,126 P···P127 and P···N128 interactions have
described how this rationalization was the basis for the been observed through structural analyses, and Si···N and Ge···
development of a fairly comprehensive nomenclature of N attractive interactions have been determined to be
intermolecular interactions, which helped to clarify the intrinsic responsible for anomalous Si−O−N and Ge−O−N angles in
and extrinsic relationships between names and concepts. some silane and germane derivatives.129,130 Pnicogen···π
Many elements when involved in the formation of covalent interactions (Figure 7) have been found also in many biological
bond(s) show a strong anisotropicity of their electrostatic systems where, for instance, they participate in the inhibition of
Sb-based drugs used for leishmaniasis treatment.131
potential surface. Areas of lower electron density, often positive,
Recent theoretical investigations aimed at understanding the
coexist with areas of higher electron density, often negative.
structural and electronic properties of elements of groups XIV−
This anisotropic charge distribution results in an amphoteric
XVI, when interacting with incoming nucleophiles,132 proved
behavior, which is a common property for many elements, that the amphoteric behavior known for halogen atoms is not at
rather than an exception. For instance, it has been known since all an exception, as it is paralleled by an analogous behavior of
the end of the 1960s that chalcogen atoms (mainly S and Se) chalcogens, pnicogens, and tetrels. A theoretical basis was given
can form highly directional short contacts with both for the attractive interactions that covalently bonded atoms of
nucleophiles and electrophiles, the former entering preferen- groups XVI,120−125 XV,133,134 and XIV6,135,136 can form with
tially on the elongations of the covalent bonds120−123 involving nucleophiles, the strength of such interactions even being
the chalcogen atoms, and the latter lateral to the covalent comparable to that of HBs.132
bonds, above and below the plane that the chalcogen forms Atoms of groups XIV−XVI can have as many σ-holes as the
with the covalently bonded atoms. A survey of the Protein Data covalent bonds they form: There can be two σ-holes on
Bank (PDB) revealed that S···O interactions are common in chalcogen atoms, three on atoms of group XV, and four on
proteins and they can play important roles in their functions, atoms of group XIV,7,141,142 and if the atom is hypervalent, σ-
stability, and folding.124 For instance, F. T. Burling and B. M. holes can even be more numerous than in atoms with the
Goldstein125 demonstrated that S···O and Se···O interactions typical valency of the group.6,112 For example, the positive σ-
stabilize the final molecular conformations of some thiazole and holes on the electrostatic potential surfaces of sulfur, arsenic,
selenazole nucleosides possessing antitumor activity (Figure 7), and silicon in SCl2,143 As(CN)3,133 and SiCl46 are shown as red
and affect their biological activity and their binding to a target areas in parts A, B, and C and D, respectively, of Figure 8. In
enzyme. SCl2, two σ-holes are visible on the sulfur surface and are both
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in the group XVII elements, the size of the σ-holes in elements

of groups XIV−XVI increases, and their potential becomes
more positive when electron-withdrawing substituents are
present on the molecules; for instance, it has been calculated
that when fluorine is the substituent, positive σ-holes typically
develop for carbon,6 nitrogen,133 and oxygen.111
Moreover, in asymmetric molecules where the elements of
groups XIV−XVI bear substituents with different electron-
attracting abilities, σ-holes with different VS,max values are
formed, and their magnitude depends on the nature of the
substituents. In Figure 9 the electrostatic potential calculated at

Figure 8. Calculated B3PW91/6-31G** electrostatic potentials of

SCl2143 (A), As(CN)3133 (B), and SiCl46 (C, D) computed on the
0.001 electron/bohr3 contour of the electronic density. (A) SCl2: the
sulfur is in the foreground, and the chlorines are at the back. Color
Figure 9. Electrostatic potential calculated at the M06-2X/aug-cc-
ranges (kcal/mol): purple, negative; blue, between 0 and 8; green,
pVTZ computational level on the 0.001 au molecular surface of
between 8 and 15; yellow, between 15 and 20; red, more positive than
PF(CH3)(CN). Phosphorus is in the middle facing the viewer, the
20. (B) As(CN)3: the arsenic is in the middle, toward the viewer.
cyano group is to the left, the methyl group is to the top right, and
Color ranges (kcal/mol): red, greater than 45; yellow, between 30 and
fluorine is to the bottom right. Color ranges: red, greater than 1.26 V;
45; green, between 15 and 30; blue, between 0 and 15; purple, less
yellow, from 1.26 to 0.65 V; green, from 0.65 to 0 V; blue, less than 0
than 0 (negative). (C, D) SiCl4: electron density views of different
V (negative). Reprinted with permission from ref 144. Copyright 2015
orientations of the molecule. In the (C) view three chlorine atoms are
Springer.
toward the viewer, and the σ-hole, due to the Cl−Si bond to the fourth
chlorine, is in red in the center and on the extension of that Cl−Si
bond. In the (D) view two chlorine atoms are toward the viewer. the 0.001 au molecular surface for PF(CH3)(CN) is reported.
Color ranges (kcal/mol): purple, negative; blue, between 0 and 8; The phosphorus surface presents three σ-holes and, consistent
green, between 8 and 11; yellow, between 11 and 18; red, more
positive than 18. Panel A adapted with permission from ref 143.
with the different electronegativities of the CN, F, and CH3
Copyright 2008 Springer. Panel B adapted with permission from ref substituents, the most positive electrostatic potentials (red
133. Copyright 2007 John Wiley and Sons. Panels C and D adapted areas) are on the extensions of the P−CN (1.52 V) and P−F
with permission from ref 6. Copyright 2008 Springer. (1.41 V) bonds, while the σ-hole on the extension of the P−
CH3 bond (yellow area on the bottom left) is less positive (0.95
V).
along the extension of a Cl−S bond, the Cl−S−(VS,max) angles While the surface electrostatic potential of group XV or
being 180° (VS,max is the most positive surface electrostatic group XVI elements can have both positive and negative
potential). VS,max on the sulfur surface has been calculated to be regions, if the element is bonded to highly electron-with-
25.1 kcal/mol, while the most negative surface electrostatic drawing partners, its surface electrostatic potential may be
potential, VS,min, is on the sides of the sulfur (VS,min = −5.9 kcal/ completely positive (e.g., As(CN)3 in Figure 8). On the other
mol). In As(CN)3, the entire arsenic surface is positive due to end, if the group XV or group XVII atoms are more
the high electron-withdrawing ability of the CN groups, but the electronegative than the bonded partners, then the surface
potential is most positive (51.4 kcal/mol) at three areas located electrostatic potential will be entirely negative and the σ-hole,
approximately on the extensions of the NC−As bonds (in red the area with the lowest electrostatic potential, will be negative,
in Figure 8B). Silicon in SiCl4 has four σ-holes on the extension although less negative than its surroundings. This is the case for
of each Cl−Si with a VS,max of 20.2 kcal/mol. fluorine in H3C−F and nitrogen in (H3C)3N: Their σ-holes are
Similar to that in halogens, the magnitude of the σ-hole in negative, and they are not expected to behave as electrophiles
elements of groups XIV−XVI is affected by the atom in interactions. The opposite situation typically occurs with
polarizability and electronegativity: The more polarizable and tetravalent group XIV atoms, which have entirely positive
less electronegative the element, the more positive the σ-holes. surfaces in nearly all cases, regardless of the bonding partners.7
The magnitude of the σ-hole in elements of any such groups Nevertheless, interactions do not occur in some cases as σ-holes
thus increases when moving from the lighter to the heavier in the elements of this group are less accessible to nucleophiles
atoms. Similar to what has already been observed for fluorine, than in group XVII elements due to the greater steric
attractive interactions due to the entrance of nucleophiles in the hindrance.
σ-hole are therefore the least common for carbon, nitrogen, and As outlined above, σ-hole features in elements of groups
oxygen, since atoms in the first period of the periodic table are XIV−XVII present numerous and important similarities, but a
the most electronegative and the least polarizable and tend to few differences have also been observed. For instance, the
have relatively weakly positive (typically negative) σ-holes. As origin of σ-holes on halogen atoms has been explained by T.
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Clark et al.145 as the results of an electron deficiency arising in instance, solid Cl2 was reported in 1952 to assume a layered
the outer lobe of a half-filled p orbital involved in a covalent structure155 which differed from the close-packed structure of
bond. It was initially believed that the more positive σ-holes other diatomic molecules such as N2 and H2. This structure is
originate with a pure p orbital, and the minimal mixing of s determined by short contacts between the nonbonded charge
character into the p orbital was considered as a fundamental concentration of one Cl atom and the charge depletion of
condition to have a strong σ-hole. This interpretation can be another Cl atom (Figure 10).156
easily and successfully extended also to atoms of groups XV and
XVI; however, it is not really satisfactory when applied to group
XIV atoms, which are essentially sp3-hybridized and yet in some
cases have been calculated to have very high σ-hole VS,max
values.6 Moreover, Clark et al.112 studied two hypervalent sulfur
derivatives, (H3C)2SO and (H3C)2SO2, and found, respectively,
one σ-hole with VS,max = 26.2 kcal/mol and two σ-holes with
VS,max = 30.2 kcal/mol on the sulfur surface on the extensions of
the O−S bonds. Natural bond orbital (NBO) analysis of these
O−S bonds revealed that they are single, with both electrons
being provided by the sulfur, and the sulfur orbitals involved in
these bonds show a significant s character. The same has been
found for the O−P bond in Cl3PO, where a positive σ-hole is
present on the phosphorus surface on the elongation of the O−
P bond, although the phosphorus orbital involved in the O−P
bond is doubly occupied and shows more than 50% s
character.6 These findings led to an expansion of the σ-hole
concept:6 Although the high p character of bonding orbitals
remains a fundamental condition, a sizable s contribution is not
precluded, and it is possible for the bonding orbital to be
doubly occupied and involved in a coordinate covalent bond.
The understanting of the interactions given by halogen
derivatives had a seminal role in the rationalization of the
interactions given by elements of groups XIV−XVI after a
general and unified mode. Due to the numerous and significant Figure 10. Laplacian distribution for the (100) plane of solid chlorine,
analogies, and the few and minor differences, between the solid contours denoting negative values for the gradient of electron
attractive interactions that nucleophiles form with elements of density. Reprinted with permission from ref 156. Copyright 1995
International Union of Crystallography.
groups XIV−XVI and with elements of group XVII, the
mindset developed in relation to the XB paved the way to the
In 1963 T. Sakurai et al.157 noted that R−X···X−R contacts
development of a systematic and consistent terminology for
(X = halogen atom) occur preferentially according to two
understanding and naming interactions wherein elements of different geometries, which, years later, G. R. Desiraju and R.
groups XIV−XVI are the electrophilic sites. Specifically, the Parthasarathy158 classified as type I (symmetrical interactions
names chalcogen bond,116,146 pnicogen (or pnictogen) where θ1 = θ2) and type II (bent interactions where θ1 ≈ 180°
bond,134,147−149 and tetrel bond135,150−153 have been proposed, and θ2 ≈ 90°) (Figures 11 and 12). This classification is still
and widely accepted, to designate interactions where elements
of groups XVI, XV, and XIV function as the electrophile,
respectively. The XB thus inspired a general terminology for all
interactions wherein it is possible to identify an element, or
moiety, working as the electrophile.154 The resulting classi-
fication of interactions links the name of attractive interactions
to the group of the element at the electrophilic site. This
classification offers the advantage that, paralleling the
classification of elements in the periodic table, periodicities in
noncovalent interactions can be easily anticipated or identified.
1.4. General Aspects of the Interaction Figure 11. Structural scheme for type I (left) and type II (right)
halogen···halogen short contacts. X = halogen atom, and R = C, N, O,
Directionality, strength tunability, hydrophobicity, and donor halogen atom, etc. Type II contacts are XBs.
atom dimensions are unique features of the XB which allowed
the interaction to develop as a routinely used tool in the design used nowadays, and the type I contacts have been further
and preparation of self-assembled systems. These features will subdivided into trans and cis systems159 depending on the
be the focus of this section, and some other general relative positions of the R groups covalently bound to X. There
characteristics of the interaction will be discussed. is a clear geometric and chemical distinction between type I and
At a first approximation, atoms in molecules are frequently type II X···X interactions. Type I interactions are geometry-
considered as interpenetrating spheres, but the distribution of based contacts that arise from close-packing requirements, are
the electron density around the nucleus is not spherical, and the found for all halogens, and are not XBs according to the
XB is a straight consequence of this. The halogen atom IUPAC definition. Type II interactions arise from the pairing
anisotropy in molecules has been noted since early times; for between the electrophilic area on one halogen atom and the
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enters the halogen atom σ-hole which is narrowly confined on

the elongation of the R−X covalent bond axis, and the R−X···Y
angle between the covalent and noncovalent bonds around the
halogen is approximately 180°.26,169 Figure 13 shows the CSD

Figure 13. Scatterplot derived from a CSD search reporting the C−

Figure 12. Histogram of I···I contacts and assignment of type I and X···N angle (deg) versus the X···N distance (Å) for crystal structures
type II geometries. Adapted from ref 160. Copyright 2014 American containing X···N contacts. Color code: blue rhombuses, I···N contacts;
Chemical Society. pink squares, Br···N contacts; green triangles, Cl···N contacts. Only
error-free and nonpolymeric structures containing single-bonded I, Br,
electrophilic area on the other and are true XBs.4 Recently, or Cl atoms and showing no disorder with R < 0.05 are considered.
Desiraju and co-workers160 reanalyzed on a larger data set the
occurrence of halogen···halogen (X1···X2) contacts in the solid (version 5.35) scatterplots of intermolecular C−X···N inter-
state by a CSD161 search. It was found that type II contacts are action versus X···N distance (X = I, Br, and Cl). Clearly, short
most favored in iodinated derivatives, less in brominated and strong XBs are more directional that the long and weak
derivatives, and the least in chlorinated derivatives. ones, and by reducing the polarizability of the XB donor, the
Analyses of the type I and type II I···I contacts in the CSD as linearity slightly drops (mean values for the C−X···N angle are
a function of the interaction distance afforded a further 171.4° for I, 164.1° for Br, and 154.6° for Cl). This trend is
outcome. At distances shorter than the van der Waals contacts, general and has also been observed when XB acceptor sites
the type I interactions were more frequent at the shortest other than nitrogen are used.
distances, while XB were more frequent closer to the van der As far as the interaction directionality from the XB acceptor
Waals limit. This behavior has been explained as a direct site is concerned, it is interesting to note that when the
consequence of the electrostatic nature of the XB, which interaction involves heteroatoms Y possessing n-pairs, the XB is
allowed I···I contacts to be formed at longer distances, while preferentially along the axis of the donated n-pair on Y. For
type I contacts, being dispersive forces, operated preferentially instance, in halogen-bonded adducts where pyridines are the
at shorter distances. The authors also found that unsymmetrical XB acceptors, the C−X group is almost coplanar with the
X1···X2 (X1 ≠ X2) short contacts always had the geometry of pyridyl ring, and the two C−N···X angles are close to
XBs. 120°.170,171 The same geometrical features are observed for
Depending on the interacting partners, XB covers a wide other nitrogen heteroaromatics such as pyrazine or quino-
energy range spanning from 10 kJ/mol for weak XBs (e.g., N··· line.172−174 When carbonyl groups act as XB acceptors, the
Cl contacts)162 to 150 kJ/mol (e.g., the very strong interaction oxygen may function as both a monodentate175 and a
observed in the I2···I− adduct).163 The remarkable strength of bidentate176 site, and the XB donor(s) are pinned in a trigonal
some XBs allows the interaction to often prevail over other planar geometry. Sulfonyl177,178 and phosphoryl179 groups
weak noncovalent interactions (e.g., π−π stacking, dipole− behave similarly to carbonyl moieties, and also imines180 form
dipole interactions, and hydrophobic forces).164 Alternatively, XBs along the respective n-pair axis. XBs around ethers,56,181
during the formation of supramolecular systems, XB can thioethers,182,183 and amines184,185 usually adopt a tetrahedral
cooperate with or surrender to HB, and other interactions arrangement with preferential axial directions for the XBs
when of comparable or lower strength, respectively, and nice around hexacyclic amines186 and equatorial directions for
examples of hierarchical self-assembly processes have been hexacyclic thioethers64 (Figure 14).
reported.80,165,166 When the XB acceptor is an isolated π-system, the axis of the
1.4.1. Directionality. The XB is a particularly directional R−X covalent bond (R = halogen,24,187 carbon;188,189 X = Cl,
interaction,167 more directional than the HB. This peculiar Br, I) lies, in the equilibrium geometry, approximately along the
feature is a consequence of the localization of the σ-hole exactly symmetry axis of the π-bonding orbital of the XB acceptor
on the elongation of the covalent bond(s) the halogen atom is (Figure 15). When two conjugated and equivalent π bonds are
involved in.145 Both theoretical26 and experimental168 studies present on the electron donor system, such as in 1,3-butadiene,
have shown that, in monovalent halogen atoms, the effective R−X lies perpendicular to the plane containing the four carbon
atomic radius along the extended R−X bond axis (R = C, N, atoms of the double bonds and is localized at one π-bonding
halogen atom, etc.) is smaller than in the direction orbital site with no evidence of tunneling. Adducts involving
perpendicular to this axis. This smaller radius, also named aromatic π donors (e.g., benzene) exhibit a C6v-symmetric-top-
polar flattering, corresponds to the region of depleted electron type arrangement, the intersection between the elongation of
density named the σ-hole. The great directionality of the XB is the R−X covalent bond and the plane of the benzene ring being
due to the fact that on interaction formation the nucleophile closer to the carbon atom than to the middle point of the π-
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Figure 14. XBs around hexacyclic amines and thioethers feature axial
(left) and equatorial (right) directions, respectively. XBs are dotted
black lines. Color code: carbon, gray; nitrogen, blue; iodine, purple;
bromine, light brown; sulfur, dark yellow. Hydrogen atoms are omitted
for clarity. CSD Refcodes are reported. In ULOJUA the disorder on
1,2-dibromotetrafluoroethane is omitted.

Figure 16. Molecular electrostatic potential at the isodensity surface

with 0.001 au for CF4, CF3Cl, CF3Br, and CF3I. Color ranges: red,
greater than 27 kcal/mol; yellow, between 20 and 14 kcal/mol; green,
between 12 and 6 kcal/mol; blue, negative. Adapted with permission
from ref 145. Copyright 2007 Springer.

Figure 15. Angular geometries of complexes formed by FCl with

simple π-electron donors (A) FCl···ethyne and (B) FCl···ethene and
with aromatic π-electron donors (C) FCl···benzene and (D) FCl···
furan.

bonding orbital. When both n-pairs and aromatic π-pairs are

present in the XB acceptor, n-pairs are preferentially involved in
XB formation. Furan and thiophene are exceptions where the
π-bonding orbitals prevail over the n-pairs.
1.4.2. Tunability. As already mentioned in section 1.1, the
XB donor ability changes in the order I > Br > Cl > F, and this
scale can be explained through the positive character of the Figure 17. Molecular electrostatic potential at the isodensity surface
with 0.001 au of F2 and CF3SO2OCOF (the CF3 group is on top).
corresponding σ-holes, which increases with the polarizability,
Color ranges: red, greater than 20 kcal/mol; yellow, between 20 and 9
and decreases with the electronegativity, of the halogen atom kcal/mol; green, between 9 and 0 kcal/mol; blue, negative. The black
(Figures 16 and 17).190,191 hemispheres denote the positions of the most positive potentials
A nice example of this trend can be observed in the 3-X- associated with the fluorine atoms. Reprinted with permission from ref
cyanoacetylene series (X = I, Br, Cl): All three compounds 195. Copyright 2011 Royal Society of Chemistry.
work as self-complementary modules, and the N···X distance is
consistent with the scale reported above, being 2.932, 2.978,
and 2.984 Å in the iodo, bromo, and chloro derivatives, OCOF are prototypical cases where fluorine bears a positive σ-
respectively.192,193 The same tendency is exemplified by the 4- hole (Figure 17).
halobenzonitrile series, the iodo derivative displaying a shorter Importantly, the presence of a region of charge depletion on
XB distance than the bromo compound, while the chloro and fluorine atoms was experimentally observed by electron density
fluoro analogues do not show XB contacts.194 studies of the homometric crystal of pentafluorophenyl-2,2′-bis-
The fluorine atom is the poorest XB donor; however, a thiazole, among others.31 Two fluorine atoms are involved in
positive σ-hole is found when fluorine is bound to another XB contacts. One fluorine interacts with the lone pair of the
fluorine atom and sometimes when it is linked to O, N, C, or sulfur atom in the thiazole ring, while the other fluorine atom
other atoms bearing particularly strong electron-withdrawing acts as the XB donor interacting with the negative belt of a
substituents.29,195 CF3C(O)OF, (CF3SO2)2NF, and CF3SO2- closeby fluorine, leading to an F···F XB.
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Figure 18. XB donors and XB acceptor and plot of the N···I separation in the corresponding adducts as a function of the number of fluorine atoms
on the donor. N···I distances are reported in picometers. Adapted from ref 202. Copyright 2009 American Chemical Society.

The XB donor ability of a given compound can thus be easily halogen atom, but the same occurs when a cyano or a nitro
tuned by choosing the most convenient halogen atom as the substitutes for the hydrogen. For instance, it has been shown
donor site. A quite large range of interaction energies can be how increasing the number of fluorine substituents onto a
spanned by single-atom mutation on the XB donor tecton, iodobenzene ring results in a uniform decrease in the N···I
namely, by changing an iodine atom into a bromine atom, or a bond distance (Figure 18).202 A similar effect was described
chlorine atom; usually fluorine introduction precludes the XB earlier by P. Metrangolo and G. Resnati et al.203 and by W. T.
from working as the driving force of the self-assembly process. Pennington et al.,76 who compared the structures and spectral
An alternative approach to tune the σ-hole magnitude, i.e., properties of the three diiodobenzene isomers and correspond-
the XB strength, consists in modifying the hybridization of the ing tetrafluoro analogues when interacting with a variety of N
carbon atom bound to the XB donor site. The greater the s acceptors. In all cases, the N···I bond distances were much
component in an sp-hybridized carbon, the greater its electron- shorter for the perfluorinated iodoarene.76 This fluorine ability
withdrawing ability, and many experimental observations and in tuning the XB strength is corroborated by several
theoretical studies confirm that, for organic XB donors where computational studies, which show very good correlation
no other structural differences are present, the strength order is between the interaction energies, the positive electrostatic
C(sp)−X > C(sp2)−X > C(sp3)−X.25 Haloalkynes, such as potentials on the halogens, and the fluorination degree.204 It is
diiodoacetylene and (bromoethynyl)- or (iodoethynyl)- also shown that aromatic fluorine substitutions affect the
benzene, are very good XB donors.196,197 One example of the optimal geometries of the halogen-bonded complexes, often as
sp-hybridization-based trend is observed in the cocrystallization the result of secondary interactions such as weak F···H or F···F
of diiodoacetylene and tetraiodoethylene with 1,4-dioxane. type I interactions.205
When interacting, these molecules give rise to infinite and Haloheteroarenes offer a further opportunity to modulate the
halogen-bonded chains where the XB donors and acceptors XB. In some cases, in fact, the heteroarene moiety can be made
alternate, the I···O interaction length being shortest in the positively charged, for instance, when a halopyridine is
diiodoacetylene system, 2.668 Å, versus 3.004 Å in the transformed into a halopyridinium derivative via protonation
tetraiodoethylene cocrystal.198,199 The same trend is seen or alkylation. This converts the heterosystem into a strong
when 1,4-diselenane interacts with diiodoacetylene182 and electron-withdrawing group that enhances the XB donor ability
iodoform;200 the I···Se distances are 3.336 and 3.464 Å, of the halogen atom.206,207 Similarly, the Lewis acidity of the
respectively. halogen atom of monohaloalkanes is dramatically boosted by
In general, the strength of the XB can be tuned by any the perfluorination of the hydrocarbon chain208 or when a
compositional or structural modification affecting the electron- positively charged residue is geminal to the halogen (as is the
withdrawing ability of the atom(s), or moieties, covalently case for various iodomethyl onium salts, e.g., Ph3P+−CH2−I),
bound to a given halogen atom. For instance, the presence of where the presence of the positive charge close to the halogen
strong electron-withdrawing moieties strengthens the σ-hole on atom drastically increases its σ-hole and its XB donor ability.
the XB donor atom, leading to strong XBs, and the closer the In summary, the XB interaction strength can be tuned (I) by
electron-withdrawing moiety is to the halogen atom, the greater single-atom mutation, (II) by changing the sp hybridization on
the effect. Haloarenes have been routinely used in XB-based the carbon atom the XB donor is bound to, and (III) by
crystal engineering and, in general, are good XB donors.201 The modifying the electron-withdrawing ability of the moiety the
partial or full substitution of hydrogen atoms with fluorine XB donor is bound to.
atoms on the aromatic ring is a well-established strategy to An aspect related to tunability is the possibility to rank XB
increase the size and positive potential of the σ-hole on the donors according to their effectiveness. This opportunity
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becomes important in XB-based supramolecular synthesis since atom was involved in an iodine···π interaction with the
the classification of the XB donor strength could help in benzimidazole ring of another XB acceptor molecule. These
anticipating the preferred binding patterns in a polydentate two examples, among others presented in the same paper,
module, namely, in the development of general heuristic demonstrated that the best donor−best acceptor pairing, well-
principles for hierarchical supramolecular syntheses. In known to occur in hydrogen-bonded systems,210 also applies to
principle, it may also allow for a multistep and sequential halogen-bonded supramolecular systems (Figure 20).
supramolecular synthesis where a simpler adduct self-assembled
via a stronger interaction (e.g., metal coordination) is the
building block for a successive self-assembly process driven by a
weaker interaction. For instance, C. Aakeröy and some of us209
recently tried to establish an XB donor ability ranking of
various molecules by a combination of infrared spectroscopy
data, structural characterizations by X-rays, and computational
studies, namely, by calculating the molecular electrostatic
potential surfaces. The halogen atom donor site, the sp
hybridization on the carbon atom the XB donor is bound to,
and the presence of fluorine atoms on the donor molecule were
systematically varied to tune the XB strength (Figure 19). The Figure 20. Ball-and-stick representation of the cocrystals of 1-
(iodoethynyl)-4-iodobenzene with 4-phenylpyridine (BISBIQ) and
(bromophenyl)benzimidazole (BISBEM). XBs, type I iodine···iodine
contacts, and iodine···π interactions are represented as dotted black
lines. Color code: carbon, gray; nitrogen, blue; iodine, purple;
bromine, light brown; hydrogen, white. CSD Refcodes are reported.

Similarly, the relative XB acceptor ability of two different XB

acceptor sites could be established when they are simulta-
neously present in the same molecular structure. On self-
assembly of methyl isonicotinate with 1,4-DITFB, both the N
Figure 19. Chemical structures of C(sp)-bonded XB donors (IEIB and and the O atoms of methyl isonicotinate interact with the
BEIB), activated C(sp2)-bonded donors (1,4-DITFB and DBTFB), iodine atoms, giving rise to I···N and I···O interactions. By
and nonactivated C(sp2)-bonded donors (DIB and DBB) cocrystal- varying the composition of the reaction mixture, the hierarchy
lized using a solvent-drop grinding methodology. The six XB donor between these interactions allows for the control of the
molecules are reported in order of decreasing VS,max values (from left composition and thus the structure of the supramolecular
to right) associated with the most positive σ-hole on their halogen complex.211
atoms. VS,max values are the numbers reported near the corresponding 1.4.3. Hydrophobicity. Halogen atoms are typically
atom and are given in kilojoules per mole. Adapted with permission
regarded as hydrophobic residues. In fact, a typical XB donor
from ref 209. Copyright 2013 John Wiley and Sons.
site (e.g., an I or Br atom) is remarkably less hydrophilic than a
typical HB donor site (e.g., an OH or an NH group). This
preferential self-assembly of 21 XB acceptors with iodoethynyl difference between the two donor sites brings about many
donors, iodoperfluorocarbon donors, and iodophenyl donors or consequences and many useful and complementary applica-
with analogous bromine derivatives was assessed by cocrystall- tions. For instance, absorption of a drug and its delivery to the
izing the modules using solvent-drop grinding methodology. 1- target tissue tipically requires the compound to cross cell
(Iodoethynyl)-4-iodobenzene and 1,4-diiodotetrafluorobenzene membranes, and halogen atoms are frequently introduced in a
were the best donors of the series and were found to have lead compound to increase its lipophilicity and its ability to pass
similar σ-hole magnitudes. The tendency of other XB donors to through cell membranes. On the other hand, oral admin-
form cocrystals paralleled the electrostatic potential on the istration of a drug often requires the compound to have a fair
donor halogen atom. water solubility, and the presence of −OH and −NH2
The presence in the same molecular structure of two substituents may be helpful for this purpose.
different XB donor sites complements the competitive cocrystal XB can be considered as a hydrophobic analogue of HB as
formation when an assessment of the relative XB donor abilities XB donor tectons and halogen-bonded adducts are, in nearly all
of the sites is pursued. For instance, in 1-(iodoethynyl)-4- cases, much more lipophilic than the structurally analogous HB
iodobenzene the iodine bound to the sp-hybridized carbon donor tectons and corresponding hydrogen-bonded adducts.
proved to be a stronger donor than the iodine bound to the sp2 For instance, 1,2-diiodotetrafluoroethane and iodopentafluor-
carbon. The crystal structure of the cocrystal with 4- obenzene are insoluble in water, while ethylene glycol is
phenylpyridine (Cambridge Crystallographic Data Centre miscible with water in any ratio, and the phenol solubility is
(CCDC) Refcode BISBIQ) showed the presence of a strong greater than 66 g/L. The thermodynamic aspects of the
XB between the iodoethynyl moiety and the nitrogen atom. recognition events leading to either halogen-bonded or
The second halogen atom on the molecule was, instead, hydrogen-bonded adducts (e.g., solvation free energy, solvation
involved in a type I I···I contact with an adjacent molecule. An shell, and solvophobic effects) are quite different, and the use of
analogous situation was observed in a cocrystal where the same tailored and different procedures becomes pivotal if the
XB donor was interacting with a benzimidazole derivative formation of a given supramolecular complex is pursued. In
(BISBEM). In fact, the iodoethynyl iodine formed a short XB relation to the topic of this review, it may be interesting to
with the nitrogen atom, while the iodine on the sp2 carbon mention that both alcohols and iodoperfluoroalkanes effectively
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enter the first coordination sphere of anions, but only the 2.1. Modeling and Theoretical Studies
second class of compounds work as effective agents for anion 2.1.1. Electrostatic Component. The electrostatic point
transport across lipid bilayers.212−214 This behavior has been of view focuses on the distribution of the electron density in the
related to the very poor hydrophilicity of iodoperfluoroalkane− ground state of the starting, and isolated, modules. Areas of
anion adducts. depleted electron density on the XB donor are identified, and
1.4.4. Donor Atom Dimensions. The van der Waals the XB is interpreted as the outcome of the attraction between
radii215 of halogen atoms (1.47, 1.75, 1.85, and 1.98 Å for F, Cl, these areas as the donor of electron density.
Br, and I, respectively) are bigger than that of hydrogen (1.20 The analysis of crystal structures in the CSD by P. Murray-
Å), and this causes differences in some properties of Rust et al.65,235,236 revealed the amphoteric character of
interactions involving these atoms. For the reason stated covalently bonded halogen atoms by proving that they can
above, XB is, in general, more sensitive to steric hindrance than interact attractively with both nucleophiles and electrophiles,
HB. In the infinite chain formed by 1,4-diiodotetrafluoroben- and electrophiles tend to enter orthogonal to the C−X bond,
zene with 4,4′- and 2,2′-bipyridine, the C−I···N distances are while nucleophiles have a preference for the elongation of the
2.864 and 3.158 Å, respectively;84,216 when 2,4′-bipyridine C−X bond, the angles between the covalent and noncovalent
forms heteromeric crystals with the same XB donor, only the 4- bonds at X spanning the 90−120° and 160−180° ranges,
pyridyl nitrogen is halogen-bonded, and trimers are formed respectively. These experimental data were the starting point
wherein the C−I···N distance is 2.821 Å. In section 5, for extensive computational studies aimed at mapping the
Biomolecular Systems, we will see how, in the formation of electrostatic potential on the surface of covalently bonded
DNA base pairs wherein XB substitutes for HB, the most stable halogen atoms. Through these studies P. Politzer et al.89,90 gave
pairing was given by bromine as the advantage offered by the a rationalization for the ability of electronegative halogens to
greater polarizability of iodine was overwhelmed by the interact attractively with nucleophiles.
disadvantage resulting from its greater size. Similarly, in section It is commonly recognized that the electron density
6.2, Optical and Optoelectronic Systems, it will be shown how distribution around a free halogen atom in its ground state is,
the size of the halogen atoms may significantly influence the on average, spherically symmetrical,237 and the electrostatic
optoelectronic properties of the obtained supramolecular potential V(r) created around the atom is positive every-
complex by promoting singlet-to-triplet intersystem crossing. where,238,239 since the contribution of the nucleus dominates
those of the dispersed electrons. V(r) is a real physical property
2. NATURE OF THE HALOGEN BOND of a system, which turned out to be quite effective in predicting
Although the successful use of XB in the design of self-assembly noncovalent interactions. It can be, in fact, determined
processes is mastered to the point that the forefront of the computationally and experimentally by diffraction techni-
studies on the interaction is moving to its use for the design of ques.240,241 Generally, V(r) is computed on the surface of the
advanced functional systems, some basic features of this molecule, since it is primarily this outer potential (VS(r)) that is
interaction are still debated, and interest in fundamental issues seen by nearby molecules. As suggested by R. F. W. Bader et
remain vibrant. al.,242 V(r) is computed at the 0.001 au (electron/bohr3)
The σ-hole concept, introduced by Politzer,145 elegantly contour of its ρ(r), which encompasses roughly 97% of the
rationalized the behavior of halogen atoms as electrophiles, and molecule’s electronic charge. It has been demonstrated that this
actually it is quite commonly used. However, there are contour is somewhat beyond atomic van der Waals radii
documented examples of halogen-bonded complexes whose (except for hydrogen).243
characteristics cannot be explained on the exclusive basis of the When halogen atoms are involved in covalent bonds, an
σ-hole,217,218 and the profile of the nature of the XB is still at electron density redistribution occurs, and the electrostatic
the center of a heated debate between computational potential becomes anisotropic; a similar behavior is shown by
chemists.26,219−227 Charge-transfer, electrostatic, dispersion, any other element.119,154,156,244−247 An atom’s electron density
and polarization interactions plus a repulsive component diminishes in its outer region along the extension of the
resulting from the Pauli exclusion principle have all been covalent bond and increases in the direction perpendicular to it.
invoked to cooperate in determining the strength and The shape of halogen atoms becomes oblate with the shorter
directionality of XB. Different theoretical methods have been radius always along the covalent bond (Figure 21). The term
suggested for the decomposition of the binding energy into the “polar flattening” has been introduced to describe this
different components and quantify their contribu- phenomenon, which was experimentally proven through a
tions.169,224,225,227−229 However, there is not a universal detailed analysis of the CSD245 and studies of electron density
consensus on this approach. P. Politzer and T. Clark have, via X-ray analyses.29,195,248
for instance, rebutted it,119,144,230 emphasizing that only the As a result, a region of positive electrostatic potential along
total binding energy is a physical observable while the various the C−X covalent bond develops on the outermost portion of
proposed components have just a conceptual significance, are the halogen surface. This positive region has been denoted by
not uniquely defined, and are not independent from each other. Politzer et al.145 as a “σ-hole” because it can be seen as a local
Although all the suggested models are just intellectual deficit of electron charge opposite a σ-bond. The σ-hole is
constructs and the several bonding components are not totally surrounded by a belt which has a negative electrostatic potential
independent quantities, they may help in rationalizing the and is orthogonal to the bond responsible for σ-hole formation.
bonding patterns for a better understanding of the nature of the This model elegantly explains the interaction pattern of
XB. covalently bonded halogen atoms, and their directional
The following sections give an overview of computational preferences, i.e., linear interactions with nucleophiles and
studies on the nature of the XB, and readers are directed to the lateral interactions with electrophiles. The presence of a
specialized literature for a more comprehensive discussion on positive σ-hole accounts for the electrophilic behavior of
the topic.119,144,225,231−234 halogen atoms, while the focused nature of the σ-hole accounts
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Table 1. Most Positive (VS,max) and Most Negative (VS,min)

Electrostatic Potentials (V) on the 0.001 au Surfaces of the
Indicated Halogen Atomsa
bond producing a
molecule atom σ-hole VS,max VS,min ref
Focus on General Trends
H3C−F F C−F −1.07 −1.10 136
H3C−Cl Cl C−Cl −0.04 −0.68 136
H3C−Br Br C−Br 0.25 −0.65 136
H3C−I I C−I 0.56 −0.56 136
F3C−F F C−F −0.06 −0.12 136
F3C−Cl Cl C−Cl 0.86 −0.03 136
F3C−Br Br C−Br 1.10 −0.09 136
F3C−I I C−I 1.38 −0.08 136
Figure 21. Schematic representation of the anisotropic distribution of NC−F F C−F 0.56 0.47 144
the electron density around covalently bound halogen atoms and the
NC−Cl Cl C−Cl 1.56 0.45 144
pattern of the resulting interactions.
NC−Br Br C−Br 1.85 0.37 144
NC−I I C−I 2.11 0.31 144
Dihalogens
for the high directionality of XB, and the magnitude of the σ- F−F F F−F 0.49 −0.11 144
hole can be correlated to the XB strength. Cl−Cl Cl Cl−Cl 1.11 −0.12 142
Such an interpretation of XB has also been supported by Br−Br Br Br−Br 1.26 −0.18 142
computational studies carried out by several other groups, Focus on Bromine
among others P. Auffinger et al.,249 F. F. Awwadi et al.,246 and BrCCBr Br C−Br 1.31 −0.09 144
P. S. Ho et al. These authors also confirmed that, in short H3Si−Br Br C−Br 0.02 −0.51 136
contacts of the R−X···H type, hydrogen atoms tend to enter F3Si−Br Br Si−Br 0.79 0.09 136
the halogen orthogonal to the covalent bond,250 nicely H3Ge−Br Br Ge−Br −0.07 −0.58 136
consistent with the amphoteric character of halogens according H2N−Br Br N−Br 0.77 −0.35 142
to which a (positive) hydrogen enters the negative belt of the F2N−Br Br N−Br 1.48 −0.07 142
halogen. H2P−Br Br P−Br 0.15 −0.62 142
Both the size (the spatial range) and the magnitude (the F2P−Br Br P−Br 0.42 −0.33 142
value of VS,max) of the σ-hole can vary significantly from one HO−Br Br O−Br 1.42 −0.46 142
halogen to the other and, for a given halogen, from one FO−Br Br O−Br 1.99 −0.02 142
compound to the other (Table 1) as they are affected by the HS−Br Br S−Br 0.75 −0.42 142
polarizability and electronegativity of the halogen atom and the FS−Br Br S−Br 0.98 −0.20 142
electron-withdrawing ability of the residue bound to the F−Br Br F−Br 2.31 −0.004 142
halogen.142 As a general trend, the more polarizable the halogen Cl−Br Br Cl−Br 1.54 −0.10 142
atom and the more electron-attracting the covalently bound a
Computational method: M06-2X/6-311G.
residue, the more positive and large the halogen σ-
hole.7,26,142,223
This is exemplified by the VS,max on iodine in CH3−I vs more positive when the electron-withdrawing ability of R
CH3−nFn−I (n = 1−3)204 and NC−I (Table 1), which increases increases.253
in the order CH3−I < CF3−I < NC−I.136,144 Strong electron- It is interesting to note that positive σ-holes appear also in
withdrawing substituents can cause the potential VS(r) of the free halogen atoms if considered in the asymmetric valence
entire surface of the halogen to be positive, as is the case for state configuration s2px2py2pz1, the same that they take when
fluorine in NC−F.144 Indeed, also fluorine can form σ-hole forming a covalent bond.145,223,254 The half-filled pz orbital is
bonds, and this has been demonstrated computation- directly involved in the covalent bonding, and positive σ-holes
ally136,195,251 and, to some extent, also experimentally.29,100 are clearly visible in both the +z and −z directions for this
However, in general, fluorine tends to have negative σ- valence state of chlorine, while the equatorial ring of negative
holes136,145 (see CH3−F and CF3−F in Table 1), although potential is due to the doubly occupied px and py orbitals
less negative than the surroundings, and routinely it is not (Figures 24 and 25). It is worth noting that these σ-holes are
involved in attractive σ-hole interactions. In fact, in most cases not present in a neutral, spherically symmetric halogen atom
the fluorine electronegativity, combined with the significant sp where electrons are equally distributed on the three p orbitals,
hybridization of C in the C−F bond, causes an influx of each of which contains, on average, 5/3 electrons.252
electronic charge on the outermost portion of the halogen that The σ-hole model explains well XBs where a halogen atom in
neutralizes the σ-hole.252 one molecule interacts through its σ-hole with the negative
In Figure 22 the computed electrostatic potentials on 0.001 region of a halogen in another, possibly identical, molecule.143
au molecular surfaces of different halobenzenes are reported to In this context DFT studies carried out by Y. Lu et al.255 on
exemplify how, for a given R in R−X, VS,max becomes more trimers (R−X)3 (R = hydrocarbon or fluorocarbon residue; X =
positive when the polarizability of the halogen X increases; Br or I) predicted that it is possible to obtain triangular
namely, VS,max changes in the order F < Cl < Br < I. In Figure structures (Figure 26) stabilized by intermolecular interactions
23 the analogous potentials of F3C−Br and NC−Br are involving the σ-hole on a Br or I atom and the negative lateral
reported to exemplify how, for a given halogen, VS,max becomes region of a neighboring Br or I. Analogously, F. F. Wang et al.
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Figure 24. Calculated electrostatic potential on the 0.001 au molecular

surface of a chlorine atom in the s2px2py2pz1 valence state configuration.
Color ranges (V): red, greater than 0.43; yellow, from 0.43 to 0.22;
green, from 0.22 to 0; blue, less than 0 (negative). The most positive
potentials on the chlorine surface, shown in red at the left and right,
have a VS,max of 0.95 V. Computational level: M06-2X/aug-cc-pVTZ.
Reprinted with permission from ref 144. Copyright 2015 Springer.

Figure 22. Computed electrostatic potentials on 0.001 au molecular Figure 25. Computed electrostatic potential, B3PW91/6-311G(3d),
surfaces of (A) chlorobenzene, (B) pentafluorochlorobenzene, (C) of the chlorine atom in its valence state, 3s23px23py23pz1, as a function
bromobenzene, (D) pentafluorobromobenzene, (E) iodobenzene, and of the radial distance from the nucleus. The upper and red curve
(F) pentafluoroiodobenzene. Color range (kcal/mol): red, greater corresponds to the z-axis, the lower and blue curve to the x- and y-
than 20; yellow, between 20 and 10; green, between 10 and 0; blue, axes. In this valence state, V(r) is still positive at all radial distances
negative. Black hemispheres denote the positions of the halogen VS,max. along the z-axis, corresponding to the half-filled pz orbital. Along the x-
Adapted with permission from ref 205. Copyright 2011 Springer. and y-axes, however, V(r) is positive near the nucleus but then
becomes negative, reflecting the doubly occupied px and py orbitals.
Reprinted with permission from ref 26. Copyright 2010 Royal Society
of Chemistry.

Figure 26. Triangular structure for the (R−X)3 trimer.

Figure 23. Computed electrostatic potential VS(r) on the 0.001 au
surface of F3C−Br (top) and NC−Br (bottom). For each molecule
bromine is at the right. Color range (kcal/mol): red, more positive predicted through ab initio calculations that the halogen-
than 35; yellow, 20−35; green, 0−20; blue, negative. The position of bonded complex FBr···BrF can be stable in the gas phase
the bromine VS.max is indicated as a black dot. In F3C−Br, the σ-hole is thanks to these halogen···halogen interactions.256
an area of positive (yellow and green) VS(r) on the outer surface of the Several papers document both experimentally and theoret-
bromine; the lateral sides of bromine are negative (blue) because of ically the good correlation between the interaction energy ΔE
the two pairs of electrons in the 4px and 4py orbitals. In NC−Br the of the halogen-bonded adduct and the VS,max of the σ-hole on
presence on bromine of an electron-withdrawing substituent stronger the halogen. For instance, Politzer et al.7 calculated the
than CF3 causes such a polarization of the charge in the doubly interaction energy at the M06-2X/aug-cc-pVTZ level for
occupied 4px and 4py orbitals of Br that the potential VS(r) becomes
several complexes with NH3 and HCN as XB acceptors,
positive over the entire surface of the halogen atom. Adapted with
permission from ref 254. Copyright 2010 John Wiley and Sons. proving that ΔE becomes more negative as VS,max becomes
more positive and that the ΔE/VS,max linear correlation is good.
K. Riley et al.205 quantified the effects of aromatic fluorine
substitution on the XB strength in adducts formed by
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halobenzene donors with acetone as the acceptor. The states.14 R. Mulliken and W. Person36 postulated the existence
interaction energy computed through the MP2 method of two types of charge-transfer complexes based on the extent
correlated well with the magnitudes of the σ-holes on the of charge transfer accompanying complex formation: the “outer
halogens, further confirming the high tunability of the XB. This complexes”, characterized by weak interactions and little charge
is also the case for complexes between substituted bromo- transfer between the components, and the “inner complexes”,
benzene and bromopyrimidine donors with acetone257 as characterized by stronger interactions and a substantial charge
shown in Figure 27. Symmetry-adapted perturbation theory redistribution. Both outer and inner complexes, in Mulliken’s
interaction energy decomposition on the same adducts revealed notation AX···B and [BX]+(sol)A−(sol), respectively, have been
that electrostatics plays the key role in these XBs. invoked in describing halogen-bonded complexes.259,260 It is
worth mentioning that the formation of an inner complex does
not imply a complete transfer of one electron from the Lewis
base B to the halogen X, but simply means that there is a
significant charge transfer.
In 1998, I. Alkorta et al.261 reported a theoretical study on
the charge-transfer complexes formed by dihalogens (F2, Cl2,
and Br2) or interhalogens (FBr, FCl, and ClBr) with Lewis
bases (HF, H2O, NH3, CO, HCN, and C2H2) by using hybrid
Hartree−Fock density functional theory (HF-DFT) B3LYP
and second-order Møllet−Plesset perturbation MP2 methods.
As expected, the interaction energy increased with the halogen
atom polarizability (F2 < Cl2 < Br2); in the case of
interhalogens, the largest interaction energies were associated
with the largest dipole moments (FBr > FCl > ClBr); and
regarding the Lewis base, NH3 afforded the strongest
complexes. The electron distribution was also analyzed using
the atoms in molecules (AIM) methodology. The highest
Figure 27. Interaction energy vs bromine VS,max for 13 ArBr···O
C(CH3)2 complexes, where Ar = substituted benzene or pyrimidine (R charge transfers, related to the formation of highly dipolar
= 0.976). Reprinted from ref 257 Copyright 2009 American Chemical complexes, were observed in NH3-containing complexes
Society. (around 0.16 e− in the complexes with FCl and FBr), .
Microwave spectroscopy has been applied by A. Legon et
The important role of electrostatics in the binding was also al.262 to study the interaction of dihalogen molecules (R−X; R,
revealed by a study of the complexes between a range of X = halogen) with simple Lewis bases (Y) in the gas phase. The
halogenated aromatics and HF as the XB acceptor.258 changes in the halogen nuclear quadrupole coupling constants
Calculation of the size and magnitude of the σ-hole on halogen upon complex formation allowed for the evaluation of the
atoms in the donors allowed also for proving that both in-ring amount of charge transfer from the Lewis bases Y to the
and out-of-ring chemical substitutions affect the σ-hole, which halogen X, as well as the extent of electric charge redistribution
systematically increases in size and magnitude going from Cl to in R−X. It was found that, for a number of small Lewis bases,
I. including NH3 and PH3, the smaller the energy required to
2.1.2. Charge-Transfer Component. Several adducts now remove the most loosely bound electron (n-type or π-type)
considered as formed under XB control have long been from Y, the greater the extent of electron transfer from Y to R−
interpreted as charge-transfer adducts, and this rationalization X on formation of the R−X···Y complex. Moreover, the amount
was strongly motivated by UV−vis observations. Within this of charge transfer increased with the halogen polarizability, and
frame XB directionality was rationalized as a consequence of it was usually less than 0.1 e−, except when Y = NH3 and PH3
donation of electron density to the R−X antibonding orbital and R−X = ClBr and ClI (Figure 28). These results suggest
(e.g., adducts between diiodine and amines were rationalized as that all the studied complexes are Mulliken outer complexes.24
n → σ* interactions). These aspects will be discussed in detail UV−vis spectra of complexes containing the same
in the rest of this section. halocarbon but different electron donors105 revealed a linear
As early as in 1950, R. Mulliken14,52,53 examined in detail the correlation between the absorption energy and the oxidation
nature of intermolecular interactions occurring between potential of the XB acceptor, and this correlation is, according
dihalogens or halogenated compounds and benzene or other to Mulliken,36 the most characteristic feature of charge-transfer
organics containing O, S, or N heteroatoms. The appearance of complexes. A charge transfer to the σ* orbital of the R−X bond
strong and different colors upon dissolution of I2 in organic was confirmed through X-ray analysis which showed that the
solvents was explained by Mulliken in terms of a weak and C−I bond of 1,4-DITFB was elongated, relative to that of the
reversible intermolecular association. In general agreement with pure compound, in a variety of adducts with nitrogen-based XB
considerations advanced by H. A. Benesi and J. H. acceptors.76 Similarly, a lengthening of the C−Br bond was
Hildebrand,50 Mulliken14 suggested, except for the “violet” observed in various bromocarbons involved in XB with
solutions obtained with aliphatic hydrocarbons and other apolar bromide263 and bromometalate218 anions as electron donors.
solvents, the existence of specific 1:1 complexes resulting from In all the crystalline structures of the bromocarbon/
“an acid−base interaction in the electron donor−acceptor bromometalate adducts, the short intermolecular C−Br···Br−
sense” in which iodine functions as the Lewis acid, namely, the M XBs (Figure 29) were influential in determining the packing
electron acceptor. The charge-transfer (CT) theory developed and were always directed toward the bromide ligands where the
by Mulliken explained well the spectroscopic properties and the highest occupied molecular orbitals (HOMOs) of bromome-
dipole moments of these complexes in the ground and excited talates are located, while the analysis of the electrostatic
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Figure 29. (Top) VS(r) (calculated at the B3LYP/6-311+G(dp) level

on the 0.001 electron/bohr3 molecular surfaces) of the XB donors and
acceptors superimposed onto X-ray structures of their complexes: (A)
CBr4/[CuBr2]−; (B) CBr4/[ZnBr4]2−; (C) CBr4/[Pt2Br6]2−. Blue and
red colors depict positive and negative potentials, respectively.
(Middle) The electrostatic potentials of bromometalate anions are
negative everywhere, but noticeable variations of their values are also
observed and depicted with a color gradient from the most negative
(red) to the least negative (blue) values (kcal/mol): (A) [CuBr2]−,
Figure 28. Top: variation of the fraction δi of an electronic charge from −100 (red) to −80 (blue); (B) [ZnBr4]2−, from −170 (red) to
transferred from B to YX on formation of the YX···B complex with the −150 (blue); (C) [Pt2Br6]2−, from −155 (red) to −125 (blue).
ionization energy IB of B for the series YX = Cl2, ClBr, and ClI. Each (Bottom) MO shapes (B3LYP/6-311+G(dp) level) of CBr4 and
set of points can be fitted reasonably well by the function δi = A halometalates, superimposed onto crystal structures of their
exp(−aIB), which is represented as a solid curve on the graph. It is complexes. HOMOs of bromometalates are mostly located on the
evident that there is a family relationship among the curves. Bottom: bromide ligands. Adapted from ref 218. Copyright 2012 American
variation of the fraction δp of an electronic charge transferred from X Chemical Society.
to Y on formation of the YX···B complex plotted against the
intermolecular stretching force constant kσ for the series YX = Cl2, Br2, bromide anions showed a good correlation with the
ClBr, and ClI. The solid line represents the least-squares fit of the combination of electrostatic and orbital components, while
points for each YX···B series for a given YX, and δp is an approximately
linear function of kσ and hence of the strength of the interaction.
the correlation with Vmax was rather poor. As far as the
Moreover, for a given B δp increases with the polarizabilities of the pseudohalides are concerned, the amount of charge transferred
interacting atoms X in YX···B. to the electrophile has been calculated through the natural
bond orbital analysis.265 Its value varies from 0.028 e− for
CH3Br···OCN− in dichloromethane to 0.316 e− for CBr3NO2···
potential revealed that HOMO localization did not necessarily N3− in the gas phase. A linear correlation has been found
coincide with the most negative areas on the surfaces of the between the amount of charge transferred and the elongation of
bromometalates. A purely electrostatic interaction would be the C−Br bonds of the bromocarbons: The C−Br bond length
expected to occur preferably between the most positive areas of increases, and the intermolecular distance between interacting
the bromocarbons and the most negative areas on the surfaces species decreases, as the amount of charge transfer increases. As
of the bromometalates, but this is true only in the CBr4··· a result, in the NO2CBr3···N3− complex, the length of the
[CuBr2]− complex. The experimentally observed directional intermolecular Br···N bond is comparable to that of the
preference suggests that in all complexes there is a significant adjacent intramolecular C−Br bond, suggesting that one
HOMO and LUMO overlap (LUMO is the lowest unoccupied electron is essentially delocalized between the two interacting
molecular orbital) and demonstrates the importance of the species in the C−Br···N fragment. This electron delocalization
covalent component of XB. can be explained considering the orbital mixing266 and the
A further confirmation that also the charge-transfer resulting reduction of the barrier for electron transfer267
component plays a significant role in XB stabilization came between halogenated electrophiles and nucleophiles. This result
from a recent experimental and computational analysis of a further supports the hypothesis that halogen-bonded complexes
series of complexes containing electrophilic bromocarbons are prereactive intermediates in the reactions of halogenated
(CBr3F, CBr3NO2, CBr3COCBr3, CBr3CONH2, CBr3 CN, molecules with nucleophiles,24,61,268 and suggests that XB may
etc.) as XB donors and bromide anions264 or pseudohalide also affect the conducting properties of solid-state materials.
anions265 (N3−, NCO−, and NCS−) as acceptors. The HOMO/LUMO charge transfer and polarization are
interaction energies for a wide range of complexes with suggested as the main factors responsible for XB in a set of
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H3CX···OCH2 and F3CX···OCH2 (X = Cl, Br, I) (ETS) method.270 The obtained results confirmed the role of
molecular complexes when the nature of the interaction is the σ-hole that is responsible for the electrostatic stabilization
investigated by using the Kohn−Sham molecular orbital (MO) of the interaction; however, in each analyzed system, the XB
theory.224 This supports a remarkable covalent component of contained a large degree of covalent component due to a charge
XB in these complexes. This understanding is also supported by transfer from the Lewis base to the empty σ*(C−X) orbital
other studies where the Kohn−Sham MO theory was used (Figure 31).
coupled with energy decomposition analysis and Voronoi
deformation density analysis of the charge distribution to build
a physical model of the XB.219,228 In particular, the structure
and bonding mechanism in trihalides R−X···Y− (R, X, Y = F,
Cl, Br, and I) were compared with those in analogous
hydrogen-bonded complexes R−H···Y−, and it was found that
both XB and HB are characterized by significant charge transfer
from the halide Y− to the antibonding σ* orbital (LUMO) on
the R−X or R−H fragment (Figure 30).

Figure 31. (A) VS(r) of the CF3I molecule and represented in blue the
σ-hole. (B) Visualization of σ-hole formation using the deformation
density contributions originating from NOCV. The contour of the
deformation density contribution Δρ1 describes the formation of the
C−I bond in the CF3I molecule starting from an iodine atom and the
CF3 radical (each carrying one unpaired electron with opposite spin
polarization). A charge accumulation at iodine is observed due to
formation of the C−I bond, which confirms significant charge
anisotropy around this atom. An outflow of electron density emerges
Figure 30. Orbital interaction diagrams for (A) XB and (B) HB arising from the outer area of the iodine atom, which clearly corresponds to
in R−X···Y− and R−H···Y− complexes. Only the σ interactions are the formation of the σ-hole. The corresponding ETS-NOCV-based
shown. Adapted with permission from ref 219. Copyright 2014 John energy is shown. The numerically smallest contour values are ±0.0006
Wiley and Sons. au. (C) Contour of the deformation density contribution Δρ1
describing the formation of the XB in the CF3I···NH3 complex.
An ab initio study of the halogen-bonded complexes between
pyridine and a series of dihalogen and interhalogen molecules The observed trend in the XB strength in adducts involving
(R−X; R, X = halogen) has been performed269 with the aim to CY3−I (Y = F, Cl, Br, I) as XB donors and chloride anions or
gain information about the preferred geometry of these systems trimethylamine as XB acceptors could not be rationalized on
and to clarify the nature of the intermolecular interactions the basis of a purely electrostatic model.217 Specifically, it was
driving their formation. The natural bond orbital analysis found that the XB strength decreases going from CI4 to CF3−I,
suggests that the n(Py) → σ*(R−X) charge transfer plays a key a trend opposite that of the σ-hole on iodine (Figure 32). The
role in the formation of these dimers, while the symmetry- same trends were found also with CY3−Cl and CY3−Br as XB
adapted perturbation theory energy decomposition analysis donors when fluoride, bromide, and iodide anions were the
indicates that the XB in R−X···pyridine complexes is Lewis bases, and it was suggested that these observations were
predominantly inductive in nature. evidence of the importance to consider a charge-transfer
Halogen-bonded systems containing one or two XBs were contribution from the XB acceptor to the XB donor.
analyzed by using the natural orbitals for chemical valence The nature of XB in a series of 55 complexes has been
(NOCV) method combined with the extended-transition-state studied by means of ab initio valence bond theory and block
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does not form XB. On the contrary, the existence of the

complex CH3Cl···OCH2 was also predicted,225 and this
apparent inconsistency led to thoughts about a failure of the σ-
hole theory.276 However, it should be taken into account231,277
that, while in an isolated CH3Cl molecule the chlorine
electrostatic potential is negative everywhere, as soon as the
molecule begins to interact with OCH2, the electron density
of each component is polarized by the electric field of the other,
resulting in a positive σ-hole on the chlorine (Figure 33)

Figure 32. Molecular electrostatic potential at the isodensity surface of

CF3−I (A) and CI4 (C) at the same contour value of 0.001 electron/
bohr3. The red color shows the most negative potential, while the blue
color represents the most positive one. The σ-holes of CF3−I (B) and
CI4 (D) in the presence of a 1.0 point charge are also depicted.
Energies are expressed in atomic units. Reprinted with permission
from ref 217. Copyright 2012 Royal Society of Chemistry.

localized wave function theory.226 The authors found a good

linear correlation between charge-transfer energies and total
interaction energies and concluded that, in most of the studied Figure 33. Molecular electrostatic potential (MEP) calculated at the
complexes, the XB is a charge-transfer interaction. MP2/aug-cc-pVDZ level on the 0.001 au isodensity surface of CH3Cl
2.1.3. Dispersion and Polarization Components. The in the presence of a charge of −0.2692 at a distance of 3.0 Å from the
origin of the attractive interaction occurring in halogen-bonded chlorine atom along the extension of the C−Cl bond. The MEP on the
complexes was originally imputed to charge-transfer phenom- chlorine reflects the polarization caused by the electric field of the
negative charge, and a region of positive electrostatic potential (σ-
ena, possibly as this was the frame within which some of the
hole) appears on the chlorine surface. Reprinted with permission from
earliest studies were performed.14,36,52,53,64,271,272 These studies ref 231. Copyright 2015 Wiley and Sons.
frequently employed strong XB donors, and in the resulting
adducts the net transfer of electron density from the site
entering the halogen atom was indeed nonminor. Then the surface and finally in an attractive interaction.231,277 In general,
emphasis moved to electrostatic forces largely because of the recognizing the role of polarization and dispersion is of
close analogy between halogen and hydrogen-bonded com- paramount importance for a correct interpretation of non-
plexes.24,80,273,274 In fact, it is well established that the major covalent interactions.
contribution to the attraction in hydrogen-bonded systems Decomposition of the total interaction energy into well-
comes from the electrostatic interaction between a positively defined energy terms is becoming a common approach to
charged hydrogen and a negatively charged electron donor, and analyze noncovalent interactions since it can be helpful in
by analogy, it was proposed, and commonly accepted, that rationalizing the bonding patterns. Several decomposition
attraction in halogen-bonded systems comes from the electro- analyses have been applied, producing different bonding models
static interaction between a positively charged halogen and a each describing the XB as a complex mixture of several bonding
negatively charged electron donor. Recently, P. Hobza et al.222 components. All these bonding models are mathematical
established for the iodobenzene···trimethylamine system a constructs, and a universal consensus has not been reached
stabilization energy of 5.8 kcal/mol, comparable to that of yet.144,231,277 Different computational methods and decom-
strong H-bonds. Moreover, stabilization energies of 17.1 and position analyses can produce different results, depending on
15.3 kcal/mol have been calculated for FI···NH3 and FBr··· the weight of each energy component on a given XB system.
NH3, respectively,220 while stabilization energies of 8.0 and 15.0 Nevertheless, they are tools that can help in understanding the
kcal/mol have been reported275 for the crystals of the nature of the XB if great care is taken in their interpretation.
complexes of diiodine, I2, with 1,3-dithiole-2-thione-4-carboxy- Particularly interesting is the symmetry-adapted perturbation
clic acid and 1,4-diazabicyclo[2.2.2]octane, respectively, and it theory (SAPT) and its density functional theory version (DFT-
was considered that these data ask for a further and improved SAPT), which allows for the treatment of extended complexes
analysis of the origin of these large stabilization energies. (up to ∼35 atoms). This method decomposes the total
In halogen-bonded systems, the electrostatic attraction is interaction energy into four components, electrostatics (EES),
important, but since two atoms with high polarizability (the induction or polarization (EI), dispersion (ED), and exchange
halogen and the electron donor) are closer than the sum of repulsion (EER), and its application allows for the contribution
their van der Waals (vdW) radii, polarization and dispersion of each component to the total binding energy to be evaluated.
contributions cannot be overlooked. Neglecting these compo- The DFT-SAPT method was applied to a series of halogen-
nents led to the assertion that the electrostatic interpretation of bonded complexes, including the X2···benzene systems (X = F,
XB is inadequate as in the case of the complexes involving Cl, and Br), the set of HnF3−nCBr···NH3 complexes, and some
CH3Cl as the XB donor. In fact, a completely negative surface complexes containing formaldehyde as the XB acceptor and
around the chlorine atom was found in this molecule252 (see chloroform, halothane, enflurane, or isoflurane as the XB
Table 1), and on this basis, it has been assumed that CH3Cl donor.278 The analysis revealed the mixed dispersion−electro-
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static nature of XB. The dispersion energy was dominant in 8

out of 10 different halogen-bonded complexes investigated by
SAPT, while only in two cases the electrostatic term was
slightly larger than the dispersion one. In particular, it was
found that dispersion plays an important role in stabilizing type
II halogen···halogen contacts where two large and polarizable
halogen atoms are in close proximity. The electrostatic
component, on the other end, is responsible for the
directionality and the tunability of an XB. Figure 34, left,

Figure 35. DFT-SAPT components, electrostatics (E(elec)),

induction or polarization (E(ind)), dispersion (E(disp)), and exchange
(E(exch)), and total binding energies (E(int)T), for the H3CBr···NH3
(solid lines) and F3CBr···NH3 complexes (dashed lines) (kcal/mol).
Potential energy minima are shown as vertical dashed lines. H3CBr···
NH3 is green, and F3CBr···NH3 is light blue. Reprinted with
permission from ref 278. Copyright 2013 Royal Society of Chemistry.

Halogen-bonded complexes involving FCl as the XB donor

were studied using the DFT-SAPT theory with the aim of
understanding the factors responsible for the high linearity of
this interaction.279 In particular, the variation of the total
binding energy and its components was calculated upon tilting
FCl away from its linear orientation (Figure 36). It was found
that the linearity is preferred because it minimizes the exchange
repulsion, and although the electrostatic component is usually
the largest attractive term, in many cases electrostatic energy
alone does not predict the structure, and it is necessary to take
into account induction and dispersion components.
DFT-SAPT calculations by using the aug-cc-pVDZ and aug-
cc-pVTZ basis sets were carried out on 128 halogen-bonded
complexes of different sizes and origins to study a set of
molecules as large as possible.233 For each XB donor, the
magnitude and size of the σ-hole were calculated as well as the
LUMO energy. In perfect agreement with previous results, the
Figure 34. Top: electrostatic potentials of H3C−Br (A), H2FC−Br magnitude and size of the σ-hole correlate well (correlation
(B), HF2C−Br (C), and F3C−Br (D). Color code: lightest blue, <−5 coefficient R = 0.86), and both of them increase with the
kcal/mol; intermediate blue, between −5 and −2.5 kcal/mol; dark atomic number of the halogen atom and with the presence of
blue, between −2.5 and 0 kcal/mol; green, between 0 and 4 kcal/mol; fluorine atoms on the remainder of the molecule. Differently,
yellow, between 4 and 8 kcal/mol; pink, between 8 and 16 kcal/mol; the magnitudes of the σ-hole and LUMO energy anticorrelate
red, >16 kcal/mol. Bottom: potential energy curves calculated at the with R = −0.76. This confirms that strong electron acceptors
CCSD(T)/aug-cc-pVTZ level for the four complexes HnF3−nCBr··· (i.e., molecules with the most negative LUMO energies) have
NH3. Reprinted with permission from ref 278. Copyright 2013 Royal more positive σ-holes. An analysis of the stabilization energy
Society of Chemistry. allowed for the halogen-bonded complexes to be divided into
two groups.
shows the B3LYP/aug-cc-pVDZ electrostatic potentials calcu- The first group comprises the strongest complexes
lated on the 0.001 au molecular surface for the HnF3−nC−Br set (stabilization energy larger than 7 kcal/mol) where the most
of molecules (with n spanning the range from 0 to 3). Here it important terms are polarization and induction, consistent with
can be clearly seen that incremental fluorine substitutions result a strong charge-transfer contribution to the binding. The
in larger bromine σ-holes and stronger XB interactions with second group comprises weaker halogen-bonded complexes
NH3 as the Lewis base.204 In fact, the potential energy minima (stabilization energies below 7 kcal/mol), and in this class of
for the HnF3−nC−Br···NH3 complexes become progressively complexes, the dispersion component provides the greatest
greater on going from H3C−Br to F3C−Br, and the contribution to the total binding energy. In the whole set of
intermolecular separations become shorter (Figure 34, right). 128 halogen-bonded complexes, the polarization (electrostatic)
The intermolecular separation can obviously affect the energy is dominant in 62% of the adducts, while the dispersion
character of the noncovalent interaction in the HnF3−nCBr··· energy is the dominant attractive term in the remaining 38%.
NH3 complexes, i.e., the relative importance of dispersion, The authors conclude that the concerted action of polarization
electrostatics, and induction. DFT-SAPT energy dissection and dispersion energies is responsible for the characteristic
reveals that for these systems the most important contributions properties of the XB.
to stabilization come from the electrostatic and dispersion The Laplacian of the electron density, ∇2ρ, provides
terms, with induction playing a smaller role (Figure 35). information about the regions where electronic charge is
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Figure 36. Variation of energy components with the tilt angle θ of FCl···B complexes away from linearity (B is the electron donor). The angle φ was
held at 55° for FCl···FH, 69° for FCl···OCH2, 0° for FCl···OH2, and 48° for FCl···O2S. The components are (black solid) exchange repulsion,
(red solid) electrostatics, (green dashed) dispersion, and (blue dashed−dotted) induction. The heavy black line represents the total. Reprinted from
ref 279. Copyright 2013 American Chemical Society.

concentrated, discriminating between “lumps” (when ∇2ρ < 0) and coming from electron redistribution (polarization and
or depleted “holes” (when ∇2ρ > 0), and has also been applied charge transfer) to also be taken into account. From a
to describe the XB interaction.280,281 In close analogy with the topological point of view, it is convenient and more intuitive to
σ-hole model, this approach considers the XB as an interaction introduce the function L(r) = −∇2ρ, which is positive in a
between a “hole” in a halogen atom and a “lump” in a Lewis region with higher concentration of electron density and
base.280 However, unlike the σ-hole model, ∇2ρ values depend negative in a region with electron density depletion. The
on both the electrostatic potential V(r) and the kinetic energy Laplacian of electron density has been employed in the
G(r), and its sign determines which of these two contributions description of halogen-bonded complexes formed between
dominates: When the Laplacian is negative, V(r) dominates, ammonia and several halogenated molecules, including CH3F,
while when the Laplacian is positive, the kinetic energy G(r) is CH3Cl, CH3Br, and other chloroorganic molecules.280 In good
the dominant factor.281 The advantage of analyzing the ∇2ρ agreement with the σ-hole model, the distribution of the
function rather than simply the electrostatic potential (V(r)), is Laplacian of electron density predicts the absence of “holes” for
that ∇2ρ allows contributions different from the electrostatics fluorine in CH3F and the presence of a hole on bromine in
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Table 2. Angular Geometries, Intermolecular I···Y Distances (r0, Å), and Intermolecular Stretching Force Constants (kσ, N m−1)
As Derived Experimentally from Rotational Spectroscopy in the Gas Phase for a Series of Halogen-Bonded Complexes with ClI
and CF3−I

a
Cs at equilibrium, C2v in the zero-point state. bThese molecules possess low barriers to internal rotation/other motion. The point group of highest
symmetry achieved during the motion is given.

CH3Br. Therefore, the first halomethane is unable to interact complemented by modeling studies) have also allowed
attractively with ammonia, while CH3Br can, instead, form advancements in the understanding of the fundamental features
stable complexes with NH3. of the XB, such as its geometry and thermodynamic parameters.
2.2. Experimental Studies Giving an account of every single use of these experimental
Long before the “rediscovery” of the XB in the late 1990s, the techniques would be a formidable task encompassing nearly the
ability of chlorine and heavier halogens to be involved in whole XB history. In the next sections we will instead offer
attractive interactions with lone-pair-possessing atoms had been selected examples to describe the main advances in XB
revealed by several analytical techniques such as, among others, characterization brought forth through some of the most useful
microwave, infrared, UV−vis, NMR, NQR, and X-ray and informative techniques.
analysis.64,88 Later on, as XB started to attract increasing 2.2.1. Microwave Spectroscopy. Microwave spectroscopy
interest, the number of studies aimed at identifying the enables measurement under conditions of effective isolation of
fingerprints of the interaction rose significantly, and these same molecules, avoiding perturbations of the ground-state structure
techniques are now used more or less routinely to assess the from either solvent or lattice effects. Thus, it is one of the most
occurrence of XB. Moreover, thanks to technological advance- used techniques to investigate halogen-bonded complexes in
ments in available instrumentation, analytical techniques (often the gas phase, although other notable work has been
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performed, e.g., by using vibrational spectroscopy. As an R−X internuclear axis at equilibrium lies preferably along the
example, J. W. Bevan and co-workers have recently shown high- axis of a nonbonding electron pair (n-pair) carried by Y or, if
resolution vibration−rotation spectroscopic studies on Cl2··· there are no n-pairs available, along the local symmetry axis of a
CO complexes using quantum cascade lasers.282 π orbital of the Lewis base. When modules possessing both n-
Importantly, the observation of the pure rotational spectra in pair(s) and π-pair(s) are used, the former prevail over the latter
the microwave region can provide information on several in function as XB acceptors. The only exceptions were found
fundamental properties of the studied complexes, and it is for complexes with furan and thiophene, in which π orbitals
particularly suitable for a comparison with the results of ab dominated over the n-pairs in the tendency to interact with the
initio calculations. The analysis of ground-state spectra leads to electrophile.24,323,324 These rules also apply to the halogen
the determination of a series of ground-state constants. series of CF3−I···Y complexes, which have geometries very
Rotational constants allow for determining the angular and similar to those of their R−X···Y and R−H···Y counterparts.
radial geometries of complexes from the changes in their zero- However, it should be noted that the presence of CF3−I makes
point moments of inertia, centrifugal distortion constants can the interpretation of spectra more complicated, due to the
be used to derive the intermolecular stretching force constant appearance of vibrational satellites coming from a low-energy
kσ by modeling the R−X···Y complex as a pair of rigid barrier related to the rotation of the CF3 group. The angular
molecules held together by a weak intermolecular bond, and geometries for a number of ClI···Y (representative of the
nuclear quadrupole constants can in certain cases provide interhalogen series) and CF3−I···Y complexes are summarized
insight into the electric charge redistribution of the complexes as examples in Table 2.
through the Townes−Dailey model.283 More detailed informa- Notably, the differences in angular geometry between the
tion on how these properties can be derived from spectroscopic complexes formed with H2O and H2S by a dihalogen,24 an
rotational data has been conveniently collected elsewhere.24,188 iodoperfluoroalkane, 344 and X−H 352 showed a set of
Two techniques have been most frequently used to study the correspondences for all XB donors. In the case of H2O, the
rotational spectra of halogen-bonded complexes. They are complexes were shown to be essentially planar with a rapid
pulsed-jet, Fourier transform microwave spectroscopy (PJ- inversion between equivalent pyramidal geometries at oxygen,
FTMW) in a Fabry−Perot cavity284,285 and chirped-pulse, while for H2S the configurations at S were observed to be
Fourier transform microwave spectroscopy (CP-FTMW).286,287 permanently pyramidal. These findings are in agreement with
In both techniques, a mixture of the two interacting compounds the results of ab initio calculations performed at the
in an inert gas undergoes a supersonic expansion to produce a CCSD(T)(F12c)/cc-pVDZ-F12 level, which found signifi-
short gas pulse (about 1 ms) containing the complex to be cantly wider and higher energy barriers for the inversion of
studied. The mixture then expands into a vacuum chamber in configuration at S in H2S complexes than at O in H2O
essentially collisionless conditions, which allow for studying the complexes187,188,353,354 (Figure 37).
complexes in their vibrational ground state and in their lower The radial geometries, i.e., the distances r0 between XB
energy rotational states. A short pulse of microwave radiation is donor and acceptor atoms, afforded another indication of the
used to electrically polarize rotational transitions, and when the existing parallelism between the halogen- and hydrogen-bonded
polarizing radiation has decayed enough to avoid significant complexes. The experimental distances were found to be below
background radiation, the amplitude of spontaneous coherent the sum of the van der Waals radii of the corresponding atoms,
emission as a function of time is recorded. Finally, a Fourier in agreement with Politzer’s electrostatic model of the σ-hole.26
transform of the time-domain signal is performed to yield The R-X···Y distances were always found to be shorter than the
intensity-versus-frequency spectra. corresponding R-H···Y ones, and this difference was attributed,
The series of halogen-bonded complexes R−X···Y involving at least in part, to the anisotropy of the X atom radius in R−X
dihalogens as Lewis acids (R, X = halogen atoms; Y = Lewis molecules, as also supported by ab initio calculations performed
base) have been extensively characterized by rotational on Cl2 and FCl.355 This shortening was not observed, instead,
spectroscopy. Complexes of F2,288−292 Cl2,293−302 Br2,303,304 for the complexes with F2, probably due to their weakness. The
ClF,305−325 and BrCl326−332 were studied by T. Legon’s group intermolecular bond distances appeared to always be longer in
with a series of systematically varied Lewis bases, and the results complexes with CF3−I when compared to those formed by Cl−
of this comprehensive series of investigations have been I (Table 2).
previously summarized.24 More recently, this body of work Rotational spectra can also afford the intermolecular
was expanded by the same group to include and compare the stretching contant kσ, which can be used as an indication of
gas-phase rotational spectra of new molecular pairs such as the strength of the XB. The values derived for kσ mirrored those
ClI···Y24,67,262,273,333−341 and CF3I···Y.188,189,342−345 obtained for radial geometry, yielding smaller kσ values for
Through a systematic variation of R−X and Y and by longer interatomic distances. The results for the Cl−I and
studying the corresponding changes in the derived properties, it CF3−I series are reported in Table 2.
was possible to draw some generalizations about The study of intermolecular stretching constants highlighted
XB,294,326,346−349 for example, the geometry of complexes and one more similarity between HB and XB. For R−X···Y
principles to predict the intermolecular stretching force complexes, the constant k σ was proportional to the
constant kσ from the nucleophilicity of the Lewis base Y and nucleophilicity of the Lewis base Y,24,347 according to the
the electrophilicity of the XB donors.24,347 The angular expression kσ = cNYERX, where c = 0.25 N m−1, NY is a
geometries for R−X were found to substantially follow a numerical nucleophilicity assigned to the Lewis base Y, and ERX
model based on empirical rules which was originally proposed is the numerical electrophilicity of the interhalogen RX. An
for hydrogen-bonded complexes involving HX mole- analogous expression holds for hydrogen-bonded complexes,
cules188,350−352 and which is derived from electrostatic with RH substituting for RX.356 The plot of kσ versus NY
considerations. In its form extended to R−X···Y halogen- reported in Figure 38A was built from six series of complexes of
bonded complexes in the gas phase, this model states that the the dihalogens F2, FCl, Cl2, ClBr, Br2, and ClI with several
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Figure 37. Potential energy V(φ) of the molecules ClI···OH2 (top)

Figure 38. Intermolecular force constant kσ against the nucleophilicity
and ClI···SH2 (bottom) as a function of the angle φ made by the
NY of Lewis bases Y for six series of halogen-bonded complexes RX···Y
extension of the C2 axis of the H2O and H2S molecules with the I···O
(top) and the two series ClI···Y and CF3−I···Y (bottom). The slope of
and I···S internuclear axes (as defined in Table 2). Reprinted with
each line yields the electrophilicity ERX by means of the expression kσ =
permission from ref 188. Copyright 2015 Springer.
cNYERX, and the value c = 0.25 N m−1. Reprinted with permission from
ref 188. Copyright 2015 Springer.
Lewis bases Y; in this diagram the NY scale was defined by
setting ECl−I = 10 and requiring all points of the corresponding
plot to lie on a straight line.188 trimethylamine. By plotting δi versus the first ionization
The resulting plots for all other dihalogens were substantially energies (IY) of the corresponding Lewis bases (Figure 39),
linear; some deviations were observed for the Lewis base NH3, the charge-transfer fraction appears to increase at lower IY
possibly due to significant charge polarization effects occurring values, as well as with the polarity of the XB donor group (ClI
in the corresponding complexes. Since the slopes of the lines > ClBr > Cl2).262,273
are proportional to ERX, these plots allowed for drawing a scale
of electrophilicity of the dihalogens as F2 < Cl2 < Br2 < ClBr ≈
FCl < ClI. The same linearity principle was shown to apply to
CF3−I···Y complexes (Figure 38, bottom), albeit with a slope
about one-third of that of Cl−I···Y interactions, and somewhat
comparable to that of Cl2···Y interactions.188 The binding
strength scale suggested by these findings is consistent with the
σ-hole model, and is supported by the values of the equilibrium
dissociation energies Dσ obtained by various groups through
theoretical modeling. Ab initio calculations were performed for
a series of R−H···Y, R−X···Y,357 and CF3−I···Y188 complexes at
the CCSD(T)(F12*)/cc-pVDZ-F12 level, for complexes of
C2H2 and C2H4 with CF3I at the MP2/cc-aug-pVTZ level,358
for CF3−I···NH3 at the MP2/DZVP level,204 and for Cl−I···
NH3 at the CCSDT(F12b)/VTZ level.359
Finally, the nuclear quadrupole coupling constants derived
from rotational spectra allowed for an estimate of the fraction δi Figure 39. Fraction δi of an electronic charge transferred from Y to RX
of charge transferred from the XB acceptor to the donor, which upon complexation, plotted versus the ionization energy IY of Y for a
was generally found to be on the order of a few hundredths of series of dihalogen molecules and fitted with negative exponential
an electronic charge; exceptions were observed for stronger curves. Adapted with permission from ref 273. Copyright 2010 Royal
complexes,24 such as those with ammonia and especially with Society of Chemistry.

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A similar kind of plot could not be prepared for complexes stretching (R = halogen or carbon) in the far-IR region,
formed by CF3−I, due to the lack of a second quadrupolar accompanied by a significant intensity increase in the bands of
nucleus.188 However, the results exposed above suggest that it the infrared spectra. These findings were explained with
is reasonable to suppose that CF3−I···Y complexes are Mulliken’s charge-transfer model.52 According to this inter-
significantly weaker than those afforded by Cl−I and possibly pretation, as the R−I···Y weak bond gains in strength due to n
comparable to those formed with Cl2 and thus involving → σ* transfer, the corresponding resonance formula (R−I)− ···
negligible charge-transfer components. Y+ acquires importance.374 Thus, the R−I force constant
Overall, the combination of observed electric charge decreases, and the effective charge on the R atom increases,
redistribution and binding energies in almost all the studied thus leading, respectively, to a red-shifted and higher intensity
R−X···Y complexes has been rationalized as these complexes mode observed in FTIR (Figure 40). This red shift was also
being Mulliken outer adducts, with a simple electrostatic term clearly observed when 1,2-diiodotetrafluoroethane was com-
acting as a dominating contribution to the interaction energy.24 plexed with diazabicyclooctane.375
The complexes of F2292 and FCl325 with trimethylamine were
the most notable exceptions, for which a significant
contribution from the form [(CH3)3NX]+···Y− had to be
invoked in a valence-bond description of the complexes.
2.2.2. Infrared and Raman Spectroscopies. The
observation of vibrational shifts upon complex formation is a
powerful tool to establish the presence of an XB; FTIR
spectroscopy, along with X-ray diffraction and NMR spectros-
copy, is among the techniques most commonly employed to
study the interaction. While slightly less commonly used, the
complementarity of Raman spectroscopy allows vibrational
modes with low FTIR intensity to be observed, and it is
particularly useful at far-IR wavelengths, where C−X modes are
found between 100 and 500 cm−1. In this section we will
discuss specific studies based on vibrational spectroscopies and
allowing for the general features of XB to be established in solid
complexes, and to a minor extent liquid complexes. These Figure 40. Infrared absorption of the C−I fundamental stretching
general features (e.g., the relative effectiveness of different XB frequency for NC−I and its complexes with the compound reported
donors and acceptors and the effect of the structural features of above the respective bands. Reprinted from ref 374. Copyright 1959
interacting modules on the XB profile) largely parallel those American Chemical Society.
established for complexes in the gas phase via microwave
spectroscopy and discussed in section 2.2.1. It results that These early vibrational spectroscopy investigations allowed a
fundamental XB characteristics are poorly affected by solvent wealth of important information on what would later be
and lattice effects if these effects are of generic nature, namely, if recognized as XB to be gathered. A. I. Popov and co-workers
they do not involve specific XB acceptor, or XB donor, sites. highlighted noteworthy features such as (i) the similarity
The rationale for the format adopted in this section is that, far between the spectral changes on formation of R−I···Y
from representing a duplication of the section on microwave complexes and corresponding changes in hydrogen-bonded
spectroscopy, it confirms the general validity of some XB complexes,374 (ii) the appearance upon complexation of new
features, and the same holds for the format in sections 2.2.3 and bands in the infrared spectra of, e.g., pyridine bases due to the
2.2.4. breaking of the charge symmetry distribution,369 and (iii) the
FTIR is most frequently used to monitor C−H and C−F formation of stronger complexes for ClI than BrI, when these
stretching modes in the 2800−3000 and 1000−1200 cm−1 were used as Lewis acids.370 In 1963, the solution infrared
regions, respectively, although far-IR measurements are also studies of adducts between nitriles and ClI363 provided
feasible and afford useful information. Most commonly, the evidence that the interhalogen molecule was situated along
focus is on C−H modes of Lewis bases involved in XBs, while the 3-fold symmetry axis of the nitrile group, and that the
C−F modes are monitored when haloperfluorocarbons are strength of the interaction was dependent on the inductive
used as XB donors. One common assumption for R−X···Y−R′ effect of substituents close to the nitrogen.
complexes (Y = Lewis base; X = I, Br, or Cl) was first expressed The complexes of pyridine371 and picolines and luti-
by N. F. Cheetham and A. D. E. Pullin360 and presumes that dines361,376 with I2, BrI, and ClI were investigated in the
since the X···Y bond is weak, it is reasonable to discuss the 1960s. Infrared studies gave evidence for complex dissociation
spectra of the complexes mainly in terms of modified modes of in a variety of solvents in the presence of excess base, according
R−X and Y−R′; this assumption is generally supported by the to the equilibrium 2(RI·Py) ⇆ Py2I+ + IR2− (R = I, Br, Cl). T.
fact that the vibrational spectra of similar complexes display Tassaing and M. Besnard377,378 later reported an intensity
analogous changes. enhancement of the vibrational bands of I3− and [bis(pyridine)-
The interactions between Lewis base atoms (most often iodine]+ upon increased concentration of acetonitrile in CCl4/
n i t r o g e n ) a n d d ii o d in e , 4 2 , 4 5 , 4 8 , 2 7 1 , 3 6 1 − 3 6 7 d ib r o - acetonitrile solvent mixtures and suggested that the polarity of
mine,45,361,364,365,368 interhalogens,45,48,361,363,364,367,369−373 or the solvent plays a role in favoring dissociation.
pseudohalogens such as NC−I45,361,374 have been extensively I. Haque and J. L. Wood determined that the linear geometry
studied by infrared and Raman spectroscopies since the 1950s. observed in the solid state for bis(pyridine) complexes with
Some common fundamental features were found from the very iodine and bromine is maintained in solution, the solvent
early works; this was the case for a small red shift of the R−I polarity being uninfluential.379 However, more recent infrared
2502 DOI: 10.1021/acs.chemrev.5b00484
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studies performed on dicoordinated complexes of picolines group in dimethylacetamide, which increases the basicity of the
with dihalogens showed a band splitting in the 1030−990 cm−1 carbonyl oxygen and thus leads to a more stable complex.
region, which was interpreted with a steric hindrance-induced The ability of iodoacetylenes to act as Lewis acids in
breaking of symmetry.380 complexes was also first observed in the 1960s by vibrational
On the basis of vibrational spectroscopy investigations, the spectroscopy. Early Raman395 and infrared396 studies gave
structure of trihalide ions in solution was described as slightly evidence for self-association of NCCCI in the solid state,
asymmetric and easily affected by weak forces.44,381 This was occurring by charge transfer between the N and I atoms. The
confirmed also by studies performed on ammonium salt existence of complexes of 1-iodopentyne with carbonyl,
trihalides,47which indicated slightly lower symmetry in solution sulfuryl, and phosphoryl electron donors in apolar solvents
than in the solid state; conversely, the occurrence of both was first shown by means of infrared spectroscopy397 and later
symmetric and asymmetric geometries was demonstrated for confirmed through 13C NMR196,398 and X-ray399 studies. Later
Cl2I−.382 Further surveys were aimed at determining possible on, a systematic study on complexes of substituted 1-
effects of the solvent nature and polarity on the geometry of the iodoacetylenes RCCI with various Lewis bases in apolar
I3− ion. Investigations with UV laser-excited Raman spectros- solvents400,401 allowed the strength of the complexes to be
copy afforded evidence for greater asymmetry in alcohols than obtained from the changes in the infrared spectra of the
in water,46,383 while other studies indicated that the degree of electron donors. The results showed that the studied 1-
symmetry of the same anion varies with the solvent according iodoacetylenes are weaker Lewis bases than NC−I, and that
to the order acetonitrile > ethyl acetate > ethanol, suggesting their acidity increases with the electron-withdrawing power of
that polar protic solvents have a stronger symmetry- the R substituent, according to the order n-Pr < SiEt3 < Ph < I
destabilizing effect;384−386 however, an asymmetric bent ≈ CH2Br < C6H4-p-NO2 < COOEt < CN.
geometry was also recently suggested in dichloromethane.387 The vibrational spectra of CF3−X (X = I, Br) in mixtures
The results of all these experimental investigations have been with several Lewis bases were studied in detail by Cheetham
supported by several computational studies,388−393 which and Pullin.360,402−405 Mixtures were prepared as vapors, CCl4
claimed that the asymmetry observed in polar protic solvents solutions (at room temperature), liquids (at lower temper-
is a result of HB-induced polarization, and that the energy atures), and solid films (at 80 K). These authors observed
barrier for the interconversion between symmetric and several important features, in particular for the trimethylamine
asymmetric species is higher in water than in ethanol, while complexes: (i) the appearance of a low-frequency band at
flat single-well or very low barrier double-well potentials are around 100 cm−1, which was attributed to X···N stretching; (ii)
expected for polar aprotic solvents. a red-shifted C−X band with significantly enhanced intensity
A series of infrared spectra of the complex between around 260 cm−1 (X = I) and 330 cm−1 (X = Br), with a shift
dimethylacetamide and iodine showed the onset of a second magnitude following the electron-donating ability of the used
CO stretching band with a 43 cm−1 red shift, while the C−N base; (iii) a blue shift in the symmetric C−F stretching mode
stretching showed a 70 cm−1 blue shift.394 These results were ν1, accompanied by a red shift of the degenerate C−F
interpreted as an indication of iodine coordination to the stretching mode ν4 in the 1000−1200 cm−1 region; (iv) a
oxygen rather than the nitrogen, and several X-ray structures frequency increase in the C−N−C symmetric bending and C−
confirm this binding mode. The intensities of the complexed H stretching of trimethylamine in the 400 and 2800−3000
and free carbonyl bands increased and decreased, respectively, cm−1 regions, respectively; (v) a dependence of the observed
with the iodine/dimethylacetamide ratio, and an isosbestic shifts on the complex aggregation state, according to the order
point was observed. This suggested the presence of only two solid (80 K) > liquid ≈ CCl4 solution > vapor.
main species, i.e., free amide and a complex (Figure 41). These One further step was taken by P. Metrangolo and G. Resnati
studies also allowed for a measurement of a binding enthalpy of et al., who began in the late 1990s a systematic investigation by
the complex as high as −5.1 kcal/mol. Interestingly, a FTIR of halogen-bonded complexes involving iodoperfluor-
comparative study with an iodine−acetone mixture pointed oalkanes10,28,80,88,190,375,406 and iodoperfluoroarenes.10,80,84,407
out the importance of the inductive effect of the dimethylamino Their observations supported those of Cheetham and Pullin,
particularly regarding C−F, C−X, and C−H stretching shifts,
and confirmed their validity for longer haloperfluoroalkanes as
well as for aromatic systems when used as either XB donors or
XB acceptors. Some important additional observations were (i)
smaller red shifts in longer haloperfluoroalkanes, consistent
with the hypothesis that vibrations of difluoromethylene groups
further away from the XB site are significantly less affected,375
and (ii) lower intensities of C−H stretching bands in FTIR
spectra, consistent with a higher positive charge on the H atoms
as a consequence of the n → σ* character of the established
XB.84,375
Recently, the FTIR spectra of heptafluoro-2-iodopropane
and heptafluoro-1-iodopropane complexed with pyridine in a
variety of solvents were compared,408 and proof was obtained
Figure 41. Infrared spectrum of the dimethylacetamide/iodine for stronger I···N XB with the iso compound consistent with
complex. As the I2 concentration increases, the intensity of the free the greater electron-withdrawing ability of a trifluoromethyl
amide peak (1662 cm−l) decreases, while the intensity of the complex group with respect to a fluorine atom. Particularly small spectral
peak (1619 cm−l) increases. Reprinted from ref 394. Copyright 1960 changes were observed in chloroform, which was attributed to
American Chemical Society. the ability of this solvent to form hydrogen bonds with pyridine
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and fluorocarbons. Interestingly, in the same work a blue-shifting symmetric (ν1) and red-shifting antisymmetric
combination of FTIR and 19F NMR dilution studies gave (ν4) CF3 stretching modes, important new observations were
evidence of the onset of self-halogen bonds for heptafluoro-2- made in the 200−400 cm−1 region, where vibrations were
iodopropane in nonpolar solvents. In concentrated cyclohexane assigned to ν3(CF3X) (with significantly increased intensity
solutions, a broad band was observed at around 900 cm−1, compared to that of the free compounds, e.g., 900-fold for the
attributed to the bending of a Cα−F group geminal to the C−I complex between CF3I and trimethylamine) and to ν6(C−X).
one and directly engaged in XB. At increasing dilutions, a sharp In particular, it was possible to point out clear blue shifts of
absorption appeared at 905 cm−1, which was assigned to the these modes for CF3Br complexes with both methyl and ethyl
same vibration for a free Cα−F (Figure 42). Only free Cα−F fluoride. This is remarkable because these were the first
was observed in acetone and acetonitrile, which are known to experimental evidence of blue-shifting C−X fundamental
form XBs with iodoperfluoroalkanes. vibrations in XBs, which had been only predicted by theoretical
studies418−420 as connected to a shortening of the C−X
distance, but had not been experimentally observed before.
Perhaps even more remarkably, blue shifts were observed also
for complexes with CF3I, while it had been previously suggested
that iodoperfluoroalkanes could be involved only in red-shifting
XBs.418
The vibrational spectra for complexes of halotrifluoro-
methanes and dimethyl ether in cryosolutions are reported as
examples in Figures 43 and 44. The new bands appearing in the
complexes are marked with asterisks in trace a of each panel;
particularly remarkable features include the observation of the
ν3 isotopic doublet close to 350 cm−1 in the infrared spectrum
of the complex with CF3Br (Figure 43B), and the weak, blue-
shifted ν6 (C−I) mode visible in the Raman spectrum of the
complex with CF3I (Figure 44C) at 268.4 cm−1.
From the analysis of the shifts reported in Tables 3 and 4, it
is evident that shift magnitudes follow the well-known XB
strength scale, i.e., I > Br > Cl, and that larger shifts are
Figure 42. FTIR absorbance of Cα−F bending for heptafluoro-2- observed for stronger Lewis bases, with trimethylamine
iodopropane in cyclohexane at various dilutions. Reprinted with dominating the series of studied compounds. One noteworthy
permission from ref 408. Copyright 2013 Hindawi Publishing Corp.
feature is that comparable shifts are observed for dimethyl ether
and dimethyl sulfide, at variance with the observation that, in
One clear problem related to vibrational spectroscopic HB, when a sulfur atom substitutes for an oxygen, the
investigations of weak interactions in solution is the influence interaction is weaker.421 The importance of inductive effects on
of the environment on the complexes, which results in changes the XB acceptor, or donor, can be pinpointed by comparing the
in the observed frequencies. On the other hand, measurements shifts obtained for several of the studied adducts. For
performed on solid matrixes are generally not in thermody- complexes with alkyl halides, it was clearly shown by the shifts
namical equilibrium and thus cannot yield information on the and band intensities that ethyl complexes were more stable than
stability of the complexes. These shortcomings can be avoided methyl ones. Analogous considerations can be made for XBs
by performing FTIR and Raman spectroscopy measurements in involving π-systems, as it could be inferred that complex
cryogenic solutions using liquefied rare gases, which also yield stability followed the order propene > ethene for alkenes, 2-
spectra with sharper bands and thus facilitate assignments. butyne > propyne > ethyne for alkynes, and toluene > benzene
Extensive work has been performed on cryogenic solutions of for aromatics.
complexes of halotrifluoromethanes with trimethylamine,409 In these cryogenic studies, complex stoichiometries were
dimethyl ether,410 dimethyl sulfide,411 alkyl halides,412 and π- determined from the band areas of vibrations in the monomers
systems.358,413,414 These experimental studies were supported and complexes. For a complex formation equilibrium
by a variety of quantum chemical calculations to predict the m A + n B ⇆ A mBn
structural, thermodynamic, and spectroscopic properties of the
studied species, and by Monte Carlo free energy perturbation by combining Lambert−Beer’s law with the expression of the
methods415,416 to simulate solvent effects and predict complex- equilibrium constant, it can be shown that
ation enthalpies. The instrumentation and methodologies
involved in these measurements have been recently described S A mBn = C(SA )m (SB)n
in detail elsewhere417 and will not be reported herein.
The fundamental vibrational modes of halotrifluoromethanes where SZ is the monomer band area for species Z and C is a
and the recorded shifts in cryogenic solutions in the presence of constant related to the equilibrium constant. Therefore, by
several Lewis bases are reported in Tables 3 and 4. plotting SAmBn versus the product (SA)x(SB)y in a series of
One first important result is that these cryogenic FTIR and isothermal studies where concentrations are varied systemati-
Raman investigations allowed for the direct observation of XBs cally, the stoichiometric coefficients can be found by evaluating
involving Cl atoms, although the weakness of these bonds the linearity observed for different integer values of x and y.
usually required the very low temperatures provided by liquid In the series of experiments reported above, 1:1
Ar to provide observable band shifts. Second, while the early stoichiometries were generally found. However, for dimethyl
results of Pullin and co-workers were confirmed with regard to sulfide, propene, 2-butyne, and benzene, coordination with two
2504 DOI: 10.1021/acs.chemrev.5b00484
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Table 3. Experimental Frequencies of the Fundamental Vibrational Modes of CF3−X (X = I, Br, Cl) in Liquid Argon (89 K) and
Shifts Recorded upon Complexation with Different Lewis Bases in Various Cryogenic Solutionsa
Δν
freeb Me3Nc Me2Ob Me2Sd MeFe MeCle EtFe EtCle
CF3I
ν1 1068.9 +15.1 +11.4 +8.9 +5.5 +3.4 +6.1 +3.1
ν2 741.3 −10.7 −4.1 −6.5 −1.3 −1.3 −2.0 −1.7
ν3 286.4b −18.1 −2.3b −12.0 +0.8 −1.0 +0.6 −1.2
ν4 1177.3 −32.9 −18.8 −19.5 −8.8 −7.1 −10.3 −8.2
ν5 539.8 −1.3
ν6 266.2b +2.2b −0.2 +2.2 +1.7 +1.2
CF3Br
ν1 1077.1 +5.1 +7.4 +3.8 +4.5 +4.9 +2.8
ν2 759.9 −8.4 −3.0 −3.8 −1.0 −0.8 −0.9 −1.0
ν3 350.2/348.5b −14.9/−14.4 −1.1/−1.1b −7.8/−6.0 +1.3/+1.3 −0.1/−0.2 +1.5/+1.4 −0.2/−0.3
ν4 1199.7 −22.2 −13.8 −11.1 −6.6 −4.3 −7.7 −5.2
ν5 546.7 −1.3 −1.2 −0.5 −0.2 −0.5 −0.6
ν6 301.3b +2.6b +1.4 +1.8
CF3Cl
ν1 1099.4 +8.1 +7.0
ν2 781.0 −4.5 −1.0
ν3 476.3/468.4 −3.9/−3.9 +2.0/+2.0
ν4 1208.0 −13.8 −10.6
ν5 561.2 −0.8
ν6 348.1
a
All shifts are calculated from the FTIR and Raman spectra of the free and complexed CF3−X recorded at the same temperatures. Frequencies and
shifts are reported in inverse centimeters. bReference 410. Measurements performed in liquid Ar (89 K). For CF3I and CF3Br (both free and in
complex with DME), ν3 and ν6 were obtained in liquid Kr (123 K). cReference 409. Measurements performed in different cryosolutions: for CF3I in
liquid Xe (173 K), for CF3Br in liquid Kr (123 K), for CF3Cl in liquid Ar (96K). dReference 411. Measurements performed in liquid Kr (123 K). For
mixed solutions of CF3Cl and dimethyl sulfide, no features suggesting the formation of a complex were detected. This is not surprising when
considering that the complexes of the same Lewis acid with dimethyl ether and trimethylamine could be observed only at the lower temperatures
provided by the use of liquid Ar. eReference 412. Measurements performed in liquid Kr (123 K).

Table 4. Experimental Frequency Shifts of the Fundamental Vibrational Modes of CF3−X (X = I, Br, Cl) upon Complexation
with π-Systems in Various Cryogenic Solutionsa
Δν
CCb CCCb CCc CCCc CCCCc benzened toluened
CF3I
ν1 +4.8 +4.9 +7.1 +8.1 +2.7 +3.1
ν2 −1.8 −2.4 −1.8 −3.0 −2.1
ν3 −2.6 −3.6 −2.7 −3.4 −0.8 −1.3
ν4 −7.9 −10.0 −6.8 −10.0 −12.4 −10.3 −10.8
ν5 −0.2 +0.7 −1.1 +0.5 −0.8
ν6 +0.4 +0.6
CF3Br
ν1 +2.0 +2.2 +3.4 +3.9
ν2 −1.1 −1.7 −1.4 −2.3 −0.8 −1.4
ν3 −1.0 −1.7 −0.1 −0.6
ν4 −4.4 −6.0 −6.8 −8.7 −7.7 −8.3
ν5 −0.9 −0.5 −0.2 −0.5
ν6 +0.5 +0.5
a
All shifts are calculated from the FTIR and Raman spectra of the free and complexed CF3−X recorded at the same temperatures. Frequencies and
shifts are reported in inverse centimeters. Alkenes and alkynes are identified by their carbon atoms and multiple bonds. bReference 358. The
experimental data refer to a solution in liquid Ar (93 K). No features suggesting the formation of complexes with CF3Cl were detected, suggesting
that the complexes are too weak to be observed. cReference 414. Measurements performed in liquid Kr (120 K). No features suggesting the
formation of complexes with CF3Cl were detected, suggesting that the complexes are too weak to be observed at this temperature. For the solutions
containing ethyne, weak spectral features illustrating the occurrence of halogen-bonded complexes were observed only with CF3I. dReference 413.
Measurements performed in liquid Kr (120 K). No features suggesting the formation of complexes with CF3Cl were detected, suggesting that the
complexes are too weak to be observed at this temperature.

CF3−I molecules could also be observed at lower temperatures By performing measurements at variable temperature, the
and higher XB donor concentrations. complexation enthalpy could also be determined from the van’t
2505 DOI: 10.1021/acs.chemrev.5b00484
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where a and b are temperature-independent constants which

define the dependency of the cryosolvent density on the
temperature and R is the ideal gas constant.
Finally, in more recent times FTIR and Raman investigations
in cryogenic solutions were mostly focused on the evaluation of
systems with competing interactions. A series of systematic
studies were performed using halothane (CF3CBrClH) as an
example of a Lewis acid containing both hydrogen and halogen
bond donor sites;421−425 in all cases, however, only hydrogen-
bonded species were found. Conversely, when iododifluoro-
methane (CHF2I) was used as a Lewis acid, hydrogen- and
halogen-bonded complexes were simultaneously observed with
trimethylamine and dimethyl ether, whereas only HBs formed
with methyl fluoride.426 The competition between XB and lone
pair···π interactions involving an electron-poor double bond
was examined by studying the complexes of C2F3−X (X = F,
Cl, Br, I) with dimethyl ether.427 Interestingly, only the
halogen-bonded and lone pair···π complexes were observed,
respectively, for X = I and X = F, while mixtures of both were
found in the other cases.
2.2.3. Nuclear Magnetic and Quadrupolar Resonance
Spectroscopies. Nuclear magnetic resonance (NMR) spec-
troscopy has been used extensively to assess the presence of
Figure 43. Infrared spectra in the 1225−1050 cm−1 region for XBs and to study the XB features usually in solution; it is also
solutions of mixtures of CF3Cl (A), CF3Br (B), and CF3I (C) with one of the methods of choice for investigatiing the nature of
dimethyl ether dissolved in liquid Ar (89 K). Tracs a in each panel XB. NMR parameters such as chemical shifts and coupling
represents the spectrum of the mixed solutions, while traces b and c constants can yield a wealth of information regarding the
are the spectra of the monomers CF3X and dimethyl ether, occurrence, thermodynamics, and local structure of XBs.
respectively. The new bands assigned to the complex are marked
Similar to vibrational spectroscopy investigations, and in
with an asterisk. Reprinted with permission from ref 410. Copyright
2013 John Wiley & Sons, Inc. many cases presented together with them as a complementary
characterization technique, the earliest NMR studies on XB
typically regarded dihalogen and pseudohalogen complexes
with nitrogen Lewis bases. Solutions of I2 and dimethylpro-
pionamide in CCl4 showed spectral changes similar to those
observed for dimethylacetamide in aqueous HCl,428 thus
suggesting a similarity between interactions occurring in the
two systems. In particular, a broadening of the methyl signals
was observed at increased iodine concentration and for
dimethylacetamide at low pH values. The thermodynamic
parameters and lifetimes of complexes of I2 with para-
substituted phenyl methyl sulfides429 and 2,4,6-trimethylpyr-
idine430 were calculated from 1H NMR shifts of the methyl
groups at variable temperature. It was demonstrated that I2···
Lewis base association is influenced by inductive effects and
both ionic and nonionic complexes exist with trimethylpyridine
(inner and outer complexes after Muilliken’s terminology). The
Figure 44. Infrared (A, C, and E) and Raman (B, D, and F) spectra of ionic form was found to be favored in the more polar
the ν3(CF3X) region for solutions of mixtures of CF3Cl (A, B), CF3Br environment offered by nitromethane in comparison to CCl4.
(C, D), and CF3I (E, F) with dimethyl ether dissolved in liquid Ar (89
K). Trace a represents the spectrum of the mixed solution, trace b is Two shifted peaks with increasing intensity at higher I2
the spectrum of the monomer CF3X, and trace c is the spectrum of the concentration were observed, and these peaks became broader
complex, obtained by subtracting trace b from trace a. The new bands and weaker at higher temperatures. A similar study of
assigned to the complex are marked with an asterisk. Reprinted with complexes of CF3−I with trimethylpyridine431 showed that
permission from ref 410. Copyright 2013 John Wiley & Sons, Inc. this haloalkane forms complexes weaker than I2, association ΔH
values being −5.0 and −7.8 kcal/mol for CF3I and I2,
respectively.
Hoff plot of the logarithm of the complex:monomer intensity A 1H and 13C NMR study on complexes of I2 and ClI with a
ratio versus the inverse of the temperature, according to the series of pyridyl compounds (Figure 45) evidenced the
following equation:417 formation of three species, i.e., a halogen-bonded complex,
X−I···Py, an N-iodopyridinium salt, Py−I+·[XnIn−1]−, and an N-
⎡ IA B ⎤ ⎡ ΔH ° + (n + m − 1)Rb ⎤ 1
ln⎢ mm nn ⎥ = −⎢ iododipyridinium salt, Py2I+·[XnIn−1]− (X = I, Cl). The relative
⎥
⎣ IA IB ⎦ ⎣ R ⎦T proportions of these three species were shown to depend on
the Lewis basicity of the pyridine derivatives and the acidity of
− (constant +a) the iodine atom, on the solvent polarity, and on the
2506 DOI: 10.1021/acs.chemrev.5b00484
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Moving up from dihalogens in the molecular complexity

scale, the presence of hydrogen and carbon atoms in XB donors
allowed for using 1H and 13C NMR as tools to gain further
insight into the nature of XBs and perform a more direct
comparison between HBs and XBs in solution. Complexes of
Figure 45. Pyridyl compounds used in the study of Schuster and trihalomethanes with tetraalkylammonium salts441 were studied
Roberts.432 in acetonitrile and CCl4 solutions. The shifts observed for
CHF3 and CHCl3 suggested decreased proton shielding and
concentration of the two starting compounds.432 The 13C shifts were compatible with HB rather than XB; differently, CHI3
of the α-carbons and α-methyl carbons were proposed as useful showed increased shielding, which was explained through an
indicators to identify the nature of the formed species, as they involvement of the iodine rather than the hydrogen atom in
were found to be shielded with respect to the starting base in interaction formation. This hypothesis was supported by FTIR
the monocoordinated iodine(I) complexes, and deshielded in spectra, which gave evidence for polarization of C−I valence
the dicooordinated iodine(I) cations. Conversely, in halogen- electrons by a nearby anion. CHBr3 was reported to be in a
bonded complexes shielding was observed for the α-carbons somewhat intermediate situation, where both interactions
and deshielding for the α-methyl carbons. occur. An increased shielding in 1H NMR spectra was also
Analogous investigations on the 1H NMR spectra of charged observed for other complexes of CHI3 with organic ammonium
dicoordinated iodine(I) and bromine(I) complexes with iodides,442 and a deshielding effect in the 13C NMR spectra of
pyridine, picoline, and lutidine indicated larger deshielding of certain complexes was also observed. This was attributed to
the pyridine protons in the β and γ positions rather than in the concurrent C−I bond lengthening and reduction of the I−C−I
α position, which was attributed to a redistribution of π angles, which decreases the shielding influence of iodine atoms
electron density, the effect being stronger in bromine rather adjacent to the carbon.
than iodine species.433 A proton NMR98 study of the interaction of CHCl3 and
Further research on dicoordinated halogen(I) systems was CHBr3 with a neutral lone-pair donor (hereinafter n-donor)
carried out by M. Erdelyi’s group, who investigated solvent such as dioctyl ether, dioctyl thioether, and dioctylmethylamine
effects on flexible and restrained [bis(pyridine)halogen]+ allowed the conclusion that the energies of halogen···n-donor
complexes (Figure 46).434−436 By using Saunder’s isotopic interactions in the studied systems were small, with enthalpies
following the order CHBr3 > CHCl3 and N > O > S. It has to
be observed here that the XB enthalpy is determined by the
balance of several contributions which are sometimes coherent
and sometimes contrasting. As a result, the relative strength of
the interactions given by a set of XB acceptors may depend on
the used XB donor (and conversely the relative strength of the
interactions given by a set of XB donors may depend on the
used XB acceptor), or in other words, a scale of XB donors may
depend on the used acceptor and vice versa. For instance, by
Figure 46. Structure of [bis(pyridine)iodine]+ complexes used to using XB donors different from halomethanes, the scale N > S
study the symmetry of halonium XBs in solution. The bis- ≥ O was found (see onward) as the difference in the strength
(pyridinylethynyl)benzene was exploited to introduce a restraint to of the XBs given by sulfur and oxygen sites is usually not so
the complex geometry. large to be independent of the used XB donor and the
employed sulfur and oxygen moieties.
perturbation technique with 13C NMR and deuterium A large variety of n-donor solvents showed deviations in the
substitution,437,438 slightly increased complex stability was linear dependence of the solvent-induced proton shifts of
observed in higher polarity nonprotic solvents, and it was CHX3443 and CH2X2444 (X = I, Br) with respect to CHCl3 and
determined that the charge distribution was unaffected by the CH2Cl2. These deviations were attributed to XB occurring in
solvent polarity, thus suggesting the formation of symmetric competition with HB. For CHBr3, XB was found to occur only
three-center−four-electron complexes. to a small extent in chlorocarbon and amine solutions.
The geometry of dihalogen complexes with nitrogen Lewis Conversely, for CHI3 XB was always clearly visible, increased
bases was also studied by nuclear quadrupole resonance with solvent basicity, and became predominant in amine
(NQR). This technique allowed for measuring the values of solutions. No indication of XB was found for dibromomethane,
the isomer shift and quadrupole interaction at the 129I nucleus while in the case of diiodomethane solutions the predominance
in complexes of BrI and ClI with pyridyl compounds, wherein of one interaction over the other depended on the solvent: XB
the presence of a linear X−I···N bond was observed.439 A was found to prevail in amines, while HB was favored in ethers.
dependence of the isomer shift on the base strength could be Iodoalkynes are a class of well-known and particularly
observed for BrI, but not for ClI. effective XB donors, and their 13C NMR spectra are a sensitive
Recently, 1H NMR titrations and UV−vis spectra showed tool to assess the involvement of these iodine atoms in XB
that the XB between molecular iodine and tetramethylthiourea formation. The 13C NMR signals of the iodinated carbon in
is rather insensitive to the nature of the solvent environment, as several iodoalkynes were found to correlate with signals in the
similar association constants were calculated in media as corresponding hydrogen-terminated alkynes,445 but deviations
different as alkanes and alcohols.440 This may suggest that were observed as early as 1983 for iodoalkynes possessing
charge transfer plays a significant role in this system, at variance electron donor ending groups such as nitrile and ethoxycar-
with HBs where thermodynamic stability is determined by bonyl. In 2000 an initial study of the solvent effect on the 13C
electrostatics. spectrum of iodoalkynes showed that the resonance of the C−I
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carbon was significantly shifted to higher frequencies in determine the XB strength.446 DFT calculations were
electron donor solvents; e.g., a 12−15 ppm shift was observed performed to study the effect of HB and XB interactions on
in DMSO-d6 with respect to chloroform.399 These inves- NQR447 and 17O, 35Cl, and 1H NMR448 parameters by using
tigations were subsequently extended by performing a wider dichloroacetic acid as a model molecule. On the basis of the
study with 1-iodo-1-hexyne and diiodoethyne in a variety of quantum theory of atoms in molecules, a partial covalent
solvents398 (Figure 47). A combination of calculations character was attributed to the O−H···O HBs in dichloroacetic
acid, whereas all C−H···O, Cl···O, and Cl···Cl intermolecular
contacts were found to be essentially electrostatic in nature.
A combined nuclear Overhauser effect (NOE) NMR/DFT
approach based on 1H−19F heteronuclear Overhauser effect
spectroscopy (HOESY) experiments was employed to
discriminate between adducts held together by XB and other
noncovalent interactions.449 The method was tested on
complexes of 1-iodoperfluorohexane, iodopentafluorobenzene,
and bromopentafluorobenzene with 1,4-diazabicyclo[2.2.2]-
octane (DABCO) and trimethylpyridine and allowed for a
rough quantification of the occurrence and relative strength of
XBs with respect to other interactions.
Whenever fluorine is present in the XB donor, 19F NMR
spectroscopy is a particularly powerful and selective tool to
study halogen-bonded complexes thanks to the high sensitivity
and wide chemical shift range of the nucleus. One early study
reported in 1974 that equimolar liquid mixtures of CF3I, C2F5I,
Figure 47. 13C chemical shift of the C−I carbon of 1-iodo-1-hexyne as and C3F7I with trimethylamine showed significant upfield shifts
a function of the concentration of an n-donor compound in hexanes.
The concentrations of the iodohexyne and the n-donor were kept in the 19F NMR resonances of atoms geminal to the iodines.405
approximately equal. Reprinted from ref 398 Copyright 2004 The shifts increased at lower temperatures, thus suggesting a
American Chemical Society. corresponding rise in the concentration of complexed species.
When complexation of C3F7I was studied with other amines,
performed with different methods and experimental studies the magnitude of the 19F NMR shifts changes followed the
led to the conclusion that this is a result of shielding rather than order NMe3 > NEt3 > NPr3 > NH3, and this scale was
spin−orbit effects, due to electron donation from the DMSO considered the result of a combination of steric effects and
oxygen to the iodine.196 It was suggested at first that the alkynyl ionization potentials.
triple bond would absorb a significant portion of the additional It was however in the late 1990s that Metrangolo, Resnati,
charge and thus bring forth the observed chemical shift and co-workers reported the first comprehensive series of
changes, but later observations on very similar or even slightly solution NMR studies10,28,191 of complexes formed by
stronger chemical shift changes for the symmetric diiodoace- haloperfluoroalkanes with a variety of Lewis bases, including
tylene suggested a more complex picture.398 quinuclidine,190 diamines,80,88,375,450 and bipyridines,406 and of
Interestingly, DFT and MP2 calculations on 13C NMR shifts complexes formed by haloperfluoroarenes with pyridyl and
of the C−I carbon in complexes of several iodoarenes and pyridyl oxide moieties.28,80,84,406,407 In the first paper of the
iodoacetylene with DMSO suggested that the nonrelativistic series, 1H and 13C NMR spectra of the complex between 1-
complexation shifts and the change in the spin−orbit-induced iodoperfluoropropane and quinuclidine190 showed chemical
heavy atom effect of iodine compensate and may cancel each shift variations suggesting the onset of a specific interaction. A 7
other so that the onset of XB in solution does not necessarily ppm upfield shift was found in the 14N NMR spectrum for the
translate into observable 13C NMR shifts.201 complex, accompanied by a significant line broadening
While 1H and 13C NMR can be highly informative, further indicative of an increased quadrupolar relaxation associated
data can be obtained by including other nuclei in both NMR with the N···I bond formation. The upfield shifts of −CF2−
and NQR experiments. The use of solvent acceptor numbers resonances in the 19F NMR spectra decreased with increasing
(derived by 31P NMR using triethylphosphine oxide as a probe distance from the iodine atom and varied significantly with the
in a series of XB donor solvents) was suggested as a tool to iodide:amine ratio. A single signal was always observed

Table 5. 19F NMR Chemical Shifts of −CF2X for 1,2-Dihaloperfluoroethanes in Solvents Having Different n-Donor Abilities

solvent I(CF2)2I ΔδCF2I Br(CF2)2Br ΔδCF2Br solvent I(CF2)2I ΔδCF2I Br(CF2)2Br ΔδCF2Br
piperidine 11.03 2.35 1,3-propanediol 4.10 0.85
N-methylpiperidine 9.69 2.02 1,3-propanedithiol 3.25 0.53
morpholine 10.39 1.90 pyridine 7.12 1.07
N-methylmorpholine 8.19 1.66 furan 0.91 0.08
thiomorpholine 9.74 1.57 thiophene 1.21 0.21
tetrahydrofuran 3.93 0.90 acetone 3.43 0.85
tetrahydrothiophene 5.18 0.71 DMSO 7.02 1.98
3,6-dioxaoctane 3.16 0.92 HMPA 8.03 2.71
3,6-dithiooctane 5.30 0.72 acetonitrile 2.54 0.40

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independent of the iodide:amine ratio, indicating the complex

formation−dissociation process was rapid on the NMR time
scale.
A systematic study of the 19F NMR chemical shift variation
of 1-haloperfluoroalkanes, 2-haloperfluoroalkanes, α,ω-dihalo-
perfluoroalkanes,190 and 1,4-dihaloperfluorobenzenes in a series
of n-donor solvents (Table 5) revealed a few important trends.
On the XB donor side, the observed shift changes, namely, the
interaction strengths, followed the halogen polarizability scale
(I > Br > Cl, no appreciable interaction with F) and increased
with the electron-withdrawing ability of the groups close to the
heavy halogen, as demonstrated by the larger shift changes
observed for 2-iodoperfluorobutane in comparison to 1-
iodoperfluorobutane. On the XB acceptor side, the interaction
strength varied with the electron donor heteroatom as N > S ≥
O (see an alternative ranking reported above). The presence of
electron-withdrawing groups close to the XB acceptor site and a
Figure 48. Correlation of the log Ka for the halogen-bonded adducts
greater percentage of s character in the donated lone pair 4-X-C6F4I···OPBu3 with the (A) σpara and (B) σmeta substituent
resulted in weaker complexes. Increased steric hindrance, at constants of X and with the electrostatic potential at the iodine atom,
either the donor or the acceptor site, disfavored the formation calculated with the (C) AM1 and (D) DFT (B3LYP/6-31+G**-
of tightly bound complexes, XB being more sensitive to steric LANLdp) computational methods. Adapted from ref 454. Copyright
hindrance than HB. Stronger interactions were observed for 2010 American Chemical Society.
secondary over primary and tertiary amines, probably as a result
of a balance between inductive and steric effects. All these that HBs and XBs possess consistent similarities but also subtle
trends were consistent with n → σ* electron donation. differences.
The scale of XB donor ability mentioned above (I > Br > Cl) As described in greater detail in the FTIR/Raman section,
was also suggested by an investigation of the 19F NMR evidence for self-halogen bonding of both 1- and 2-
deshielding451 and its temperature coefficients452 for the iodoheptafluoropropane in cyclohexane was obtained by
complexes that 1-haloperfluorooctanes give with partners dilution FTIR and 19F NMR studies. In agreement with most
having different n-electron-donating ability: Strong association published literature, larger C−I···N association constants were
was observed for 1-iodoperfluorooctane with acetone, methyl observed in less polar solvents.408 It should be noted however
acetate, acetonitrile, and hexanenitrile, only a moderate that remarkable differences can be found even among nonpolar
association was found on interaction of 1-bromoperfluorooc- solvents. Considerably stronger C−I···F interaction was found
tane with N-methylpyrrolidine, and no evidence for association in heptane than in toluene when the complex of iodopenta-
could be observed for 1-chloroperfluorooctane. fluorobenzene with trans-(tetrafluoropyrid-2-yl)bis-
1
H, 19F, and 31P NMR spectroscopies have been used to (triethylphosphine)fluoronickel(II) was studied.455 The differ-
study the complexation of 1-iodoperfluorohexane with eight ence as large as almost 1 order of magnitude between the two
Lewis bases in benzene, CCl4, and chloroform. The study Ka values was explained here with a competing π stacking effect
suggested that XBs have many similarities with HBs and that in the aromatic solvent, which could weaken the apparent bond
both interactions can be treated, at least in a first strength. Indeed, the π-system of haloperfluoroarenes can also
approximation, by using a simple electrostatic solvent receive electron density from the heteroatoms of solvents such
competition model.453 However, complexes involving cyclic as methanol, dimethyl sulfoxide, acetonitrile, and acetone;456
amines, such as DABCO and quinuclidine, had significantly this interaction can be even stronger than XBs involving
higher stability than predicted by the electrostatic model, bromo- and chloropentafluorobenzene, and may also have
possibly due to charge-transfer effects. significant effects on the NMR chemical shifts for iodopenta-
A purely electrostatic model was also shown to incur fluorobenzene. 1,2-Aryldiyne-linked haloperfluoroarenes and
significant limitations (when faced with solvent effects and with pyridyl moieties were used as a model system to study
tectons having a wide set of donor and acceptor abilities) by a intramolecular XBs without the influence of entropy effects.457
systematic 19F NMR titration study of the complex formation The observed 19F NMR chemical shifts were solvent dependent
between a variety of electron donors and iodoperfluoroalkanes and decreased according to the order cyclohexane > toluene >
or para-substituted iodoperfluoroarenes.454 The complex benzene > dichloromethane > acetone > pyridine. 15N NMR
association constants were determined, and a linear free energy and 13C NMR signals were also investigated in this study, and
relationship was found with both empirically derived their nonminor changes afforded useful information.
19
substituent parameters and calculated molecular electrostatic F NMR studies on haloperfluoroarenes were also
potentials for several commonly employed XB donors and performed as a part of investigations on XB-based anion
acceptors (Figure 48). On the other hand, DFT-calculated receptors, and provided valuable information on negatively
binding constants yielded moderate correlations with all charged halogen-bonded complexes. Studies on systems
experimental data, except for the strongly bound couples employing halide anions as Lewis bases458 indicated that the
iodoperfluoroalkane−quinuclidine. This study also highlighted affinity of complexes with iodoperfluoroarenes in acetone
that solvents forming HBs are detrimental to XB formation in followed the anion charge density order Cl− > Br− > I−; this
solution and that Lewis basic solvents compete with trimethyl- scale was also recently confirmed for a different set of anion
amine for XBs in a less efficient manner than expected on the receptors based on halo-1,2,3-triazoliums.459 The reverse order
basis of a purely electrostatic approach. Once again, it seems was found by P. Beer for analogous interactions in a mixture of
2509 DOI: 10.1021/acs.chemrev.5b00484
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chloroform, methanol, and water, this difference being possibly

related to the ability of protic solvents to compete with XB460
(see the discussion reported above on the difficulty of filing a
single and general ranking of XB donors and acceptors).
In comparison to solution NMR spectroscopy, solid-state
NMR (SSNMR) offers the advantage to eliminate possible
solvent effects on the chemical shifts of halogen-bonded
complexes, without requiring long-range crystalline order as is
the case for some other solid-state techniques (e.g., X-ray).
Unfortunately, crystal packing can also be influential on the
spectral characteristics. Another possible drawback consists in
the difficulty of studying directly the XB donor sites. SSNMR
spectroscopy of chlorine, bromine, and iodine generally yields
very broad patterns because of the large quadrupole moments
of their NMR-active isotopes.461 One direct observation of
35/37
Cl SSNMR was performed recently by D. L. Bryce and F.
A. Perras for several chlorinated compounds, which however Figure 49. 13C SSNMR chemical shift as a function of the C−I
required an ultrahigh magnetic field and state-of-the art pulse distance for several diiodotetrafluorobenzene complexes with
sequences.462 ammonium and phosphonium salts. The solid line represents the
Nuclear quadrupole resonance (NQR) can be more best exponential fit, while the dashed line represents a linear fit.
informative, thanks to the large quadrupolar interactions of Reproduced with permission from ref 74. Copyright 2013 Royal
heavier halogen atoms involved in covalent bonds. Already in Society of Chemistry.
the early 1970s, the 127I NQR frequencies of α,ω-diiodoper-
fluoroalkanes were reported to change in complexes with Bryce and co-workers also investigated haloanilinium halides,
secondary and tertiary amines, and the effect was attributed to recording 35Cl, 81Br, and 127I SSNMR spectra of the halide
charge-transfer phenomena.463 A series of NQR studies of acceptors.469 They derived information on space group packing
trihalide ions372 and complexes of dihalogens with various of the compounds from quadrupolar data, and observed that for
amines, including 3,5-dibromopyridine,464 3,5-dichloropyri- several compounds of the series the bromine isotropic chemical
dine,465 and trimethylamine,466 afforded conclusions analogous shift and the chemical shift tensor span increased for shorter
halogen−bromide distance. In another recent work, the same
to those discussed above on the role of charge-transfer
authors used multinuclear SSNMR to study complexes of
phenomena in the formation of complexes.
decamethonium diiodides with hydrogenated and perfluori-
Direct SSNMR investigation of carbon atoms covalently
nated p-dihalobenzenes, and found a systematic decrease in the
bound to the heavier halogens is also challenging for several 14
N quadrupolar coupling constant upon XB formation.470
reasons, including residual dipolar broadening caused by the
The slight differences observed in the 15N chemical shifts of
presence of iodine.461 However, Bryce’s group reported 13C
complexes between 1-(2,3,3-triiodoallyl)imidazole and mor-
cross-polarization (CP)/magic angle spinning (MAS) SSNMR
pholinium iodide, morpholine, imidazole, and 1-(3-
spectra from complexes of diiodotetrafluorobenzene with
iodopropargyl)imidazole were attributed to XBs with varying
ammonium and phosphonium halides,74 where weak C−I
strength.471
signals could be studied. By comparing these data with those The 13C and 15N SSNMR analysis of halogen-bonded
obtained from single-crystal X-ray diffraction, it could be complexes involving nitrogen electron donors has been
demonstrated that the related 13C chemical shift increased reported in a fair number of works. One early report is that
along with the C−I distance for different complexes, although a of J. K. Kochi and co-workers, who studied the interaction
clear correlation could not be derived (Figure 49). between tetrahalomethanes and several amines and found a
Nearly all reported SSNMR investigations, however, focus on slightly higher chemical shift when DABCO was halogen
signals belonging to the XB acceptors, which are generally bonded to CBr4.472
much more easily observed. Another work by Bryce’s group CP/MAS 13C NMR was also employed to characterize
reported a systematic study on complexes of thiocyanates and halogen-bonded polymeric systems obtained by interaction of
selenocyanates with diiodotetrafluorobenzenes, using 77Se as a poly(4-vinylpyridine) and α,ω-diiodoperfluoroalkanes.473 In
more attractive alternative to 33S for SSNMR. A clear indication this case, the signals of the carbon atoms in the para position
was obtained of increased chemical shift upon XB formation,467 of the pyridyl ring were observed to undergo a clear line
and these results were also supported by 13C and 15N spectra broadening.
for both thio- and selenocyanate adducts. Importantly, analysis Evidence for self-halogen bonding was also observed through
of the 77Se chemical shift tensor revealed that XB caused SSNMR, as reported in studies of benzylbis(4-iodobenzyl)-
molecular perturbations in the plane perpendicular to the axis amine,474 C-aryl-4-halo-1H-pyrazoles,475 and itraconazole in a
of the anion, in accordance with the crystal structures. cocrystal with succinic acid.476
More recently, the same authors further extended this Pharmaceutical cocrystals of the antimicrobial 3-iodo-2-
approach to iodoperfluorobenzene−triphenylphosphine sele- propynyl-N-butylcarbamate with CaCl2, tetra-n-butylammo-
nide complexes, demonstrating that 77Se chemical shifts nium iodide, and dipyridyl compounds were investigated by
increase with the onset of CI···SeP XBs and correlate Metrangolo, Resnati, Chierotti, and co-workers through 1H
with the PSe distance and the interaction strength.468 MAS and combined rotation and multiple-pulse spectroscopy
Importantly, J(77Se,31P) coupling constants increase in (CRAMPS), 13C and 15N CP/MAS, and NQS spectral
magnitude with the weakening of the XB. editing.477 Larger 13C shifts were observed for complexes
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featuring I···N rather than I···X− interactions, although the also the steric and electronic effects that residues close to the
shifts could not be directly correlated to the XB strength due to XB donor and acceptor sites have on the energetic and
the different crystalline environments experienced by the C geometric features of the interaction are recognized in close
CI moiety. A low-frequency shift was observed in 15N spectra analogy with effects identified through the technicques
when pyridyl derivatives were used as XB acceptors. mentioned above.
Another system comprising an iodoalkynyl XB donor was For these reasons, in the remaining part of this section, rather
studied as a part of ultrafast rotors with a potential use as than using crystalline structures to exemplify and confirm all
crystalline molecular machines. The authors characterized their these XB features, we will itemize and discuss some crystalline
systems by 1H wide-line and 13C CP/MAS SSNMR, and used structures with the aim of filing an inventory of the most
the 1H spin−lattice relaxation and second moment as a commonly used XB donor and acceptor moieties.9,493 X-ray
function of temperature to investigate the rotation dynamics. figures in this section are ball-and-stick representations
Finally, 31P SSNMR can also be a useful tool to characterize prepared with Mercury 3.5, and XBs have been indicated
certain halogen-bonded structures.478,479 The examination of both with solid lines (as covalent bonds) and with dotted lines
diiodophosphoranes by 31P SSNMR suggested a molecular in relation to their length. CSD Refcodes are given, and the
four-coordinate R3P−I−I structure for these compounds, rather numbers reported close to these lines are the “normalized
than a five-coordinate trigonal bipyramidal structure.
contact” (Nc) values, defined as the ratio Dxy/(rXx + rYy), where
2.2.4. X-ray Diffraction Techniques. Single-crystal X-ray
analysis affords detailed information on the geometrical features Dxy is the experimental distance between the XB donor atom X
of single molecules and their relative arrangement in the crystal. and the XB acceptor atom Y and rXx and rYy are the
It is thus no surprise the technique played a key role from the corresponding vdW radius for the XB donor and vdW radius,
very beginning in the identification of the ability of halogen or Pauling ionic radius, for the neutral or anionic XB acceptor,
atoms to attractively interact with electron donor species. O. respectively. Nc is a useful indicator of the interaction strength,
Hassel reported the infinite chains wherein Br2 alternates with more useful than the XB distance itself, because it allows
dioxane56 or benzene58,59 as early as 1954 and 1958, distances between different interacting sites to be compared.
respectively. As outlined, among others,57,64 in his Nobel 2.2.4.1. Inventory of XB Donor Moieties. Dihalogens and
Lecture,15 the technique was central in Hassel’s studies on interhalogens (e.g., I2,494 BrI,495 ClI,496 Br2,497 Cl2,498,499 and
adducts which are now understood as halogen-bonded systems, ClF498), as well as pseudohalogens (e.g., NC−I),500,501 have
and Hassel’s fruitful use of X-ray structural characterization of been extensively involved in adduct formation with lone-pair-
halogen-bonded adducts went on until the 1970s.480 Structural possessing (Figure 50) and anionic (Figure 51) XB acceptors.
studies based on single-crystal X-ray analyses were once again For instance, I3− is probably one of the most frequently
crucial in the “rediscovery” of the XB, which occurred in the occurring halogen-bonded motifs in the CSD (355 entries in
late 1990s, specifically when P. Metrangolo and G. Resnati ConQuest 1.17), and many other polyiodides adopting the
developed XB-based crystal engineering and proved that
iodoperfluorocarbons are particularly versatile and effective
XB donors.10,63,69,70,481−483 Also other X-ray techniques (e.g.,
small-angle X-ray scattering, SAXS)484 were used to study
halogen-bonded systems, and powder X-ray diffraction (PXRD)
was by far the most frequently and profitably em-
ployed.83,477,485−489
The XB donor···XB acceptor separation and the angle
between the covalent and noncovalent bonds around the
halogen atom are two pieces of structural information afforded
by single-crystal X-ray analyses and routinely used to assess the
XB presence. Notwithstanding influences from the overall
crystal packing, the stronger the XB, the shorter the separation
and the more linear the angle.490,491 The R−X bond dinstance
is a more subtle but equally informative indication of XB which
is afforded by X-ray analyses. This distance is typically longer in
the halogen-bonded adduct than in the pure XB donor,84 and
this lengthening has been associated with the n → σ* character
of the XB. X-ray analyses also afford relevant information on
the XB acceptor, and extensive confirmations are available in
the CSD that the σ-hole on the electrophilic halogen atom
enters preferentially along the axis of the lone pair of an n-
donor of electron density and along the local symmetry axis of a
π orbital when double or triple bonds or aromatic systems are Figure 50. Representation of halogen-bonded crystal structures
the electron density donors. In these latter cases it was involving I2 (VUKDIO), BrI (TASPEJ), Br2 (TEYPES), ClI
(GANXAV), Cl2 (YATKIP and ULISAJ), and FCl (YATKOV). XBs
occasionally possible to distinguish among over-the-ring, over-
are represented as solid lines, similar to covalent bonds, when their
the-bond,54,60 and over-the-atom arrangements.492 These and length is as short as a covalent bond, or as dotted black lines, when
other information afforded by X-ray analyses allow a ranking of their length is close to the sum of the vdW radii of the involved atoms.
XB donor sites (I > Br > Cl > F) parallel to those suggested by Hydrogen atoms are omitted for clarity. Color code: carbon, gray;
vibrational, IR, Raman, NMR, and NQR spectroscopies and nitrogen, blue; oxygen, red; iodine, purple; bromine, light brown;
discussed in previous sections. When X-ray techniques are used, chlorine, light green, fluorine, yellow. CSD Refcodes are reported.

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Figure 51. Representation of halogen-bonded crystal structures

involving dihalogen molecules as XB donors and anionic XB acceptors.
XBs are represented as solid lines, similar to covalent bonds, when
their length is as short as a covalent bond, or as dotted black lines,
when their length is close to the sum of the vdW and Pauling radii of
the involved species. Cations are omitted for clarity. Color code:
iodine, purple; bromine, light brown; chlorine, light green. CSD
Refcodes are reported.

convenient geometric requirements are commonly recurring

XB systems. When interacting with weak XB acceptors,
halogens and interhalogens can work as mono- or bidentate
XB donors; when interacting with strong acceptors, the
nonminor charge transfer to the donor makes the σ-hole on
the noninteracting halogen less positive, and the entrance of a
second acceptor becomes exceptional.171,494,502 When interhal-
ogens function as monodentate donors, the heavier halogen,
hosting the more positive σ-hole, is preferentially involved in
XB formation.
Many structures in the CSD show XBs involving halogen
atoms bound to an sp3-hybridized carbon atom, especially if
they are close to strong electron-withdrawing residues or in a
polyhalogenated moiety (Figure 52).
Similar to the inclusion in crystals of hydroxylic solvents
(e.g., water and alcohols), which is favored by the HBs the
solvents form with HB acceptor sites in the crystallized
molecule, the inclusion and tight binding of halogenated
solvents is favored whenever XB acceptor sites are present in
the crystal components. Many solvates wherein CHCl3 and
CH2Cl2503−523 or, less frequently, CCl4 and CCl2CCl2524,525 are
halogen-bonded to a variety of anions have been obtained
serendipitously. The same holds for solvated systems wherein a
lone-pair-possessing XB donor pins the halocarbon. In these
systems, the inherent ability of anions and n-donors to function Figure 52. Library of halogen-bonded cocrystals involving haloalkanes
as XB acceptors works synergistically with the need to fill as XB donors. Color code: carbon, gray; nitrogen, blue; oxygen, red;
potential voids of the crystal packing, and the formation of iodine, purple; sulfur, dark yellow; chlorine, light green; fluorine,
supramolecular and halogen-bonded anions or neutral adducts yellow. XBs are dotted black lines. Hydrogen atoms are omitted for
results (Figure 53). clarity. CSD Refcodes are reported: CETNEW, (2R,6S)-6-phenyl-2-
CBr4472,526,527 and CHBr354,105,267,526 are better XB donors (trichloromethyl)-3-oxa-1-azabicyclo[4.1.0]heptane-2-carbonitrile;
GIDJUY, methyl 4-bromo-4-cyano-6-oxabicyclo(3.2.1)octan-7-one-1-
(namely, they give adducts with smaller Nc values) than carboxylate; QOJROY, N-tribromoacetylhomoserine lactone; LUN-
analogous chlorinated methanes and have been systematically ZOK, 3,3′-bis(trichloromethyl)tetrahydro-5H,5′H-7a,7a′-bipyrrolo-
used, among others, by J. K. Kochi for studies both in the solid [1,2-c][1,3]oxazole-1,1′-dione; PEPCUK, 6-bromo-7-fluoro-2-methyl-
state and in solution. CHI3528 is an even better donor, and 2-azabicyclo[2.2.1]heptan-3-one; TUKGAI, N,N,N′,N′-tetramethyl-
adducts with both neutral and anionic Lewis bases are available benzene-1,4-diamine−1,4-diiodoperfluorobutane; FEGYEV, quinucli-
in the CSD: Interestingly, in the same database no cocrystal can dine carbon tetrabromide; CLMPMO, 5-chloro-6-(dichloromethy-
be found wherein CI4529 is the donor, possibly due to the high lene)-4-methoxy-1-methyl-4-(trichloromethyl)hexahydropyrimidin-2-
reactivity of the compound with electron donor species. The one; PAWHAY, 2-bromo-2-methyl-1-[4-(methylsulfanyl)phenyl]-
engineered use of CH2X2 and CH3X (X = Cl, Br, I) as reliable propan -1-one; A WIFIW, 4-(tri fl u o r o m e t h y l ) -N ′-(2,2 ,2-
XB donor tectons is virtually undocumented in the solid state, trichloroethanimidoyl)benzene-1-carboximidamide; PILLIF, methyl
2-fluoro-4-iodocubane-1-carboxylate; ULOKEL, N-methylmorpho-
consistent with the fact that with nucleophiles these line−1,2-diiodotetrafluoroethane.
compounds tend to afford SN-type products rather than
halogen-bonded adducts. The same holds for RCH2 X
molecules unless the R residue has a strong electron- Indeed, calculations suggest that the σ-hole in these molecules
withdrawing ability (e.g., CN and CO substituents).530,531 is weakly positive or even negative and becomes more and
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Figure 53. Examples of solvates wherein the chlorinated solvents are

pinned by XBs. For the sake of clarity, only the supramolecular anion
is reported. Metal atoms are labeled. Color code: carbon, gray; oxygen,
red; bromine, light brown; chlorine, light green, hydrogen, white. XBs
are dotted black lines. CSD Refcodes are reported: HIDMEN,
trichloro(tripyrazolylmethane-N,N′,N″)rhenium(IV) perrhenate Figure 54. Representation of halogen-bonded crystal structures
chloroform solvate; FIYLEG, [μ2-1,1′-bis[(1,3-dimethylimidazolidin- involving neutral haloarenes and haloperfluoroarenes: HIBENZ11,
2-ylidene)amino]ferrocene]chloropalladium hemi- XB trigonal synthon present in the hexaiodobenzene structure;
(tetrachloropalladium) dichloromethane solvate; VEGTIL, [N,N′- QIHBEO01, repeating unit in the infinite chain where 4,4′-bipyridine
bis(2,6-diisopropylphenyl)triptycenylimidoformamidium]- and 1,4-DITFB alternate; IOBNIT01, repeating unit in the 4-
tetrabromoindium(II) chloroform solvate. iodobenzonitrile infinite chain. Hydrogens are omitted for clarity.
Color code: carbon, gray; nitrogen, blue; iodine, purple; fluorine,
yellow. XBs are dotted black lines. CSD Refcodes are reported.
more negative, or less positive, if the number of CH2 units
between the electron-withdrawing group R and X increases.
As discussed in previous sections, CF3I forms fairly strong electron-donating/withdrawing groups bound to the aromatic
XBs, and CF3Br and CF3Cl give weaker and much weaker moiety and to their relative position respect to the halogen
adducts, respectively, as confirmed, for instance, through FTIR atom. NO2,541,542 CN,194 and halogens543 are some of the
studies of their complexes with trimethylamine in argon, groups more frequently used to enhance the XB donor ability
krypton, and xenon matricxes.422 However, they have quite low in haloarenes. Unfuctionalized haloarenes have been used
boiling points, and less volatile perfluoroalkanes, namely, C3 to occasionally as key tectons in XB-based crystal engineering and,
C8 analogues, have been preferred over trifluorohalomethanes more generally, in supramolecular chemistry, while iodopenta-
for obtaining crystalline and halogen-bonded adducts. The CF3I fluorobenzene and its derivatives are among the most
moiety is present in several hypervalent iodine derivatives (e.g., commonly used XB donor motifs.10 The availability of general
Togni’s reagent, i.e., the electrophilic trifluoromethylating agent synthetic methodologies544 to append in high yields a 4-
3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole and the car- iodotetrafluorophenyl residue onto a hydroxy or amine residue
bonyl analogue 1-(trifluoromethyl)-1,2-benziodoxol-3-(1H)- or onto an aromatic ring had an instrumental role in paving the
one),532−534 and the bonding pattern around the iodine atom way to such common use. The use of brominated arenes and
in these compounds can be rationalized as the result of the their (per)fluorinated analogues in crystal engineering is much
formation of so strong XBs that they are comparable in length less common than that of iodoarenes, and when chloroarenes
to the other bonds involving iodine.535 are tested in systematic studies, the obtained structures typically
Monohaloperfluoroalkanes CF3(CF2)nCF2X (X = I, Br, Cl; n do not show the presence of XBs, while their brominated and
= 1,2,4,5,6) have been frequently used in solution studies,191 iodinated analogues do.
but their employment in the obtainment of crystalline systems The most commonly used classes of haloheteroarenes are
is occasional.214,536 Differently, α,ω-diiodoperfluoroalkanes those containing nitrogen atom(s) in the ring. Both neutral and
ICF2(CF2)nCF2I (n = 0,2,4,6), and to a lesser extent their positively charged haloheteroarenes can function as scaffolds
brominated analogues,186,208 have been extensively employed in for an XB donor site (Figure 55); the cationic form is typically
crystal engineering and gave a major contribution in the obtained by reacting the neutral form with an alkyl halide or a
“rediscovery” of the XB.10,28,92 hydrogen halide, and the released anion works as an XB
As for XB donors where the halogen atom is bound to an sp2 acceptor for the activated XB donor site.545 Indeed, for a given
carbon, both haloarenes and haloheteroarenes have been used halogen and a given heteroaromatic, the cationic form has a
frequently (Figure 54). Structures reported in the CSD prove much greater XB donor ability than the neutral form thanks to
that haloarenes having from one up to six XB donor sites537 the increased electron-withdrawing ability of the positively
have been involved in the formation of adducts so that systems charged scaffold. The 5-iodo-1,2,3-triazole moiety546−549 is a
where haloarenes work as mono-, 538 di-,71 tri-,539 and particularly interesting neutral system due to its easy
polydentate XB donors are all described. For instance, the preparation via click chemistry. Its cationic form also has a
radical cation of hexaiodobenzene functions as a hexadentate good XB donor ability and has been recently used in anion
donor forming short and directional XBs with incoming recognition processes driven by XB in solution.550
fluorine and oxygen anions.540 The XB donor ability of the Halopyridinium551−562 and haloimidazolium563−566 moieties
haloarene varies in relation to the number and strength of the are two other positively charged systems which have been
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structures of only two halogen-bonded 1-chloroalkynes are

reported.192,572 The remarkable ability of 1-iodoalkynes to work
as XB donors, control the structure of solid architectures, and
switch on or tune functional properties has been exploited in
the obtainment of supramolecular liquid crystals573 and organic
conductors and magnets.574−576
Halonium ions (X+, X = Cl, Br, I) are the ultimately polarized
halogen atoms, and a halonium complex is denoted as [XY2]Z,
where X is the XB donor halonium ion (Cl+, Br+, or I+), Y is the
XB acceptor, and Z is any anion. Br+ or I+ halonium ions have
been studied more frequently,436 and they act as extremely
strong XB donors577 when interacting with several Lewis bases
such as nitrogen,578 sulfur,579 or selenium580 atoms. λ3-Iodanes
and -bromanes581 show bonding patterns which can be
rationalized as the formation of halogen-bonded systems, for
instance, when an anion and/or a lone-pair-possessing
heteroatom enters the σ-hole(s) on the halogen of a
Figure 55. Representation of halogen-bonded crystal structures diaryliodonium or (aryl)alkynyliodonium salt (Figure
involving neutral and positively charged haloheteroarenes as XB 56).582−594
donors. Hydrogen atoms are omitted for clarity, escept for acidic ones
In by far the great majority of the described XB donor
in DIQZEI and FEQBIO. Color code: carbon, gray; nitrogen, blue;
oxygen, red; iodine, purple; sulfur, dark yellow; chlorine, light green, moieties, the electrophilic halogen is bound to a carbon atom or
fluorine, yellow. XBs and HBs are dotted black lines. CSD Refcodes to another halogen atom, but crystalline structures are also
are reported: MEFHOW, trimeric unit present in 5,5′-(1,3- available where the electrophilic halogen is bound to
phenylene)bis(3-benzyl-4-iodo-1-methyl-1H-1,2,3-triazol-3-ium) bis- heteroatoms other than halogens, and N-haloimides are
(trifluoromethanesulfonate); DIQZEI, repeating unit in the infinite probably the best known such cases. The electron density on
chain formed by 4-chloropyridinium chloride; FEQBIO, dimer formed the imide nitrogen is depleted by the two carbonyl residues,
by 5-(1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl)-3-methylpent-2-en-1-ol. and N-haloinimides are quite good XB donors and typically
form fairly short contacts with XB acceptors (Figure 56).595−599
commonly used to study XB via crystallographic techniques, to Tetrathiafulvalene (TTF) derivatives are among the most
recognize anions, and to perform chemical catalysis. versatile and better known molecules endowed with out-
The ability of a carbon atom to withdraw electron density standing redox properties and remarkable electron donor
from a bound atom increases with the increased s orbital characters. TTFs have been extensively used to prepare organic
contribution to the atomic orbital used to bind the atom. It is conductors and magnets. Control of the structure of these
no surprise that halogen atoms bound to an sp carbon atom materials plays a key role in the functional property
show particularly positive σ-holes;209 namely, 1-haloalkynes are optimization, and XB has been used, among other interactions,
particularly strong XB donors and form adducts characterized to fine-tune solid arcitectures and maximize the pursued
by quite low Nc values. 1-Iodoalkynes197,398,399,567−569 have properties.576 The first TTF-based complex assembled via XB
been used much more frequently (Figure 56) than brominated was reported by T. Imakubo and R. Kato et al.600 when they
analogues,209,570,571 and to the best of our knowledge, the described the crystalline structure of 2:1 salts between the
cation radical of mono- and diiodinated TFF derivatives (the
XB donor) and halide, sulfide, or cianometalate anions (the XB
acceptor). The oxidation of the TTF moiety to the cation
radical state boosts the σ-hole in the polar region of the iodine
and favors the formation of particularly short, and strong,
iodine···anion interactions (Figure 57). During the years,
several iodine- and bromide-functionalized TTFs601 and their
tetraselena or dithiadiselena analogues have been synthesized,
and their single-crystal structures proved they were very
efficient XB donors toward different anion systems.576,602 A
few other halogenated radical compounds have been shown to
have an XB donor character, among others p-iodophenyl
nitronyl nitroxide603 and tribromo-functionalized trioxotriangu-
lene neutral radical (Figure 57).
2.2.4.2. Inventory of XB Acceptor Moieties. When the
geometric features of crystalline architectures are determined
via X-ray single-crystal analyses, confirmation is obtained that
Figure 56. Representation of halogen-bonded crystal structures the three most common XB acceptor moieties identified in
involving highly polarized halogen atoms. Hydrogen atoms are
previous sections, namely, neutral and lone-pair-possessing
omitted for clarity. Color code: carbon, gray; nitrogen, blue; oxygen,
red; iodine, purple; bromine, light brown; sulfur, dark yellow. XBs are heteroatoms (n-donors), π-systems (π-donors), and anions, can
dotted black lines. CSD Refcodes are reported: DOXIAC, 1,4-dioxane all work as acceptors in the solid.
and diiodoacetylene; AKOXON, bis(2,4,6-collidine)bromonium per- Nitrogen functionalities are the most frequently recurring n-
chlorate; DEJFIH, dibenzoiodolyl pyrrolidinedithiocarbamate; IBIY- donor moieties in molecular crystalline solids. sp3-hybridized
UP, hexamethylenetetramine and N-bromosuccinimide. nitrogen atoms in acyclic or cyclic, aliphatic77 or aromatic483
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Pn = pnicogen atom; X = Cl, Br, I) can be quite diversified, and

three main structural classes can be identified: (i) halogen-
bonded adducts (also called charge-transfer or “spoke” adducts
in the less recent literature), (ii) ionic halide salts, and (iii)
molecular five-coordinate species adopting a trigonal bipyr-
amidal geometry (Figure 58). The pnicogen atom in the first

Figure 58. Three main structural types of R3PnX2 adducts: the

halogen-bonded adduct (left), the phosphonium halide (center), the
pentacoordinated addition product (right).

and second classes of compounds has a tetrahedral geometry,

and ionic halide salts can be considered products where XBs are
so strong that the X−Pn distances are as short as typical
“covalent” bonds, and the charge transfer from Pn to X is so
remarkable that the heterolytic cleavage of the X−X covalent
bonds is enabled and phosphonium halides are formed. The
nature of the pnicogen heavily influences the most common
structure of the product R3PnX2.
sp3-hybridized neutral oxygen atoms (e.g., those in acyclic631
and cyclic77 ethers and alcohols)632,633 form crystalline adducts
with XB donors, but the Nc values are usually larger than those
Figure 57. Representation of halogen-bonded crystal structures of analogous adducts with sp3-hybridized neutral nitrogen
involving radicals as XB acceptors. Hydrogen atoms are omitted for atoms (e.g., those in amines), consistent with the N > O scale
clarity. Color code: carbon, gray; nitrogen, blue; oxygen, red; iodine, of electron donor abilities identified in previous sections. sp2-
purple; bromine, light brown; sulfur, dark yellow; fluorine, yellow. In hybridized neutral O atoms (e.g., those in carbonyl,634
HUKTOW, Ni is green. XBs are dotted black lines. CSD Refcodes are sulfonyl,635 sulfoxide,636,637 and phosphonyl178 groups) can
reported: JEFFUW, (4-amino-2,2,6,6-tetramethylpiperidin-1-yl)oxy function as XB acceptors (Figure 59). The halogen σ-hole
radical, 1,4-DITFB; HUKTOW, bis[3,4-bisiodo-3′,4′-(ethylenedithio)-
tetrathiafulvalene) bis(cis-1,2-dicyanoethylene-1,2-dithiolato-S,S′)-
nickel; LEHYEE, 2,6,10-tribromo-12-hydroxy-4H,8H-dibenzo[cd,mn]-
pyrene-4,8-dione.

amines all give small Nc values. Tertiary amines are the XB

acceptor in most of the adducts, 197,472,595,604−608 but
secondary77,450,609 and primary610,611 amines have also been
occasionally employed.
Pyridines612 and pyridine derivatives,613 pyrimidines,614
pyrazines,615 and triazines616,617 are some of the six-membered
nitrogen heterocycles that most frequently afford crystalline and
halogen-bonded adducts. sp2-hybridized nitrogen atoms in five-
membered rings (e.g., imidazoles,618 triazoles,619 or purines620)
have been used as XB acceptors less frequently than those in six Figure 59. Partial view of the halogen-bonded infinite chains formed
membered analogues. Also the imine functionality attractively by dimethyl sulfoxide with 1,3,5-trifluoro-2,4,6-tris(iodoethynyl)-
interacts with electrophilic halogens, and the XB is formed benzene (IFOHAO) and hexamethylphosphoric triamide with 1,3-
along the expected axis of the nitrogen lone pair.180 dibromotetrafluorobenzene (PASLAY). Hydrogen atoms are omitted
As discussed above, the hybridization state of the halogen- for clarity. Color code: carbon, gray; nitrogen, blue; oxygen, red;
bound carbon influences the XB donor ability of the halogen; iodine, purple; bromine, light brown; sulfur, dark yellow; fluorine,
similarly, the hybridization state of the nitrogen influences its yellow. XBs are dotted black lines. CSD Refcodes are reported.
XB acceptor ability. Also the sp-hybridized nitrogen atom of
cyano groups621,622 works as an XB acceptors, but it tends to be
a weaker acceptor than sp2- and sp3-hybridized nitrogen atoms. typically enters the oxygen atom along its lone pair axis.
Interestingly, both the π73 and the sp622,623 electrons of cyano Oxygen having more than one lone pair, one or two XBs can be
groups can enter the σ-hole.573,623−628 formed; e.g., carbonyl groups may pin one or two halogen
Also the heavier elements of the 15th group of the periodic atom(s) after a trigonal and planar geometry.176
table, specifically P and As, are shown to function as Lewis Sulfur atoms can act as XB acceptors, and the R−X···S
bases in halogen-bonded systems where dihalogens are most synthon is quite abundant in the CSD. Halogen-bonded
frequently the XB donor.629,630 In general, the distribution of complexes typically involve dihalogens as XB donors and
the electron density and the bonding pattern in R3PnX2 thiols,148 thioethers,149 isothiocyanate units,639 and thione
products (R = alkyl, aryl, alkoxy, aryloxy, dialkylamino, etc.; units640 as acceptors.
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Selenium and tellurium analogues of ethers, R2Ch (Ch = Se, formed in solution, and these latter systems are of particular
Te; R = alkyl and aryl), are shown to function as electron relevance as they are prereactive states in addition reaction to
density donor sites toward an electrophilic halogen, most often olefins62,650 and substitution reactions of aromatics.651 In
a dihalogen. The bonding pattern around the heavy chalcogens principle, any systems possessing π-electrons can work as XB
recalls that described above for R3Pn derivatives: Both halogen- acceptors in the solid state; however, they are involved in the
bonded systems (also named charge-transfer or “spoke” interaction formation only in the absence of other more
adducts) and oxidative addition products (having either a see- effective acceptors, e.g., the nitrogen atoms of an amine or a
saw or a T shape) are formed depending on the nature of R, pyridine. This confirms π-systems are less efficient acceptors
Ch, and the incoming halogen. The heavier the chalcogen, the than most lone-pair-possessing heteroatoms, probably due to
less favored the formation of the halogen-bonded adducts, but the minor localization of the electron density in π-clouds.
various such systems have been described for both selenium641 Several anionic species work as effective XB acceptors, and
and tellurium.642 some anion classes, e.g., halides, halometalates, and cyanome-
It is well-known that halogen atoms X in metal halides M−Xn talates, have been extensively used in the anion-driven self-
(M = metal; X = Cl, Br, I) can work as HB acceptors,4,643 assembly of a wide diversity of XB donors, for instance,
consistent with the fact that the low electronegativity of metals iodoperfluorocarbons and 1-iodoalkynes.69,154,491,652 Under
boosts the inherent electron donor ability by the halogen. It is common conditions, HB and XB are competing interactions
thus no surprise that X in M−Xn can funtion as an XB in driving the formation of the first coordination sphere of
acceptor.4 In 2005, Brammer et al.644 demonstrated that the anions. As a result, it seems that the greater the hydrophilicity
electronic differences between organic (C−X) and inorganic of an anion (identified, for instance, via the Hofmeister series),
(M−X′) halogen atoms can be exploited in crystal engineering, the less easy its involvement in the formation of anion-
which enables the C−X···X′−M motif to become a reliable templated assembly of halogen-bonded crystals. This inverse
supramolecular synthon. In fact, the metal-bound halogen atom relation holds independent of the relative strength of the XBs
functions as the electron density donor site toward the carbon- that the more hydrophilic and less hydrophilic anions form.
bound and electrophilic halogen, and the resulting interaction Iodides, perchlorates, and other poorly hydrophilic anions are
presents all the electronic and geometric features of a typical particularly reliable and robust tectons and can easily afford
XB. Interestingly, for a given XB donor halogen, the Nc value is halogen-bonded crystals assembled thanks to anion-driven
smaller for the lighter inorganic halogen M−X, thus suggesting coordination processes. Conversely, the fluoride anion has
that the interaction is stronger.645 served as the XB acceptor in cocrystal formation in quite a few
Also metal hydrides (M−H) are well-established HB cases.653 The anion recognition occurring in solution has also
acceptors,646 and recently it has been shown that they can been used for anion sensing460,654−658 and transport,212−214
work as XB acceptors too. R. N. Perutz et al.647 have which seem to be promising fields for XB exploitation, probably
demonstrated, by solution NMR studies, the formation of as the XB might be tailored to such functions thanks to its
halogen-bonded complexes between a serie of bis(η5-cyclo- hydrophobic character.
pentadienyl)metal hydrides and iodopentafluorobenzene. The Halides form a particularly large number of halogen-bonded
thermodynamic studies showed that the formation of the crystalline adducts. The topology of these systems is heavily
halogen-bonded complex was energetically favored over the influenced by the cation nature and, even more important, by
hydrogen-bonded one given by indole. the number and geometry of the electrophilic halogen(s)
Electrophilic halogens have formed halogen-bonded crystal- present on the XB donor tecton. Due to their spherical shape
line complexes with a variety of π-systems, for instance, double and their high nucleophilic character, halides can form a
or triple bonds485,648 (Figure 60) and aromatic (Figure 2) variable number of XB contacts.161 Generally, a moderate bias
moieties.649 Adducts in the solid state are similar to those toward the formation of two or three XBs is observed, but a
careful crystal engineering or compelling crystal packing
requirements can force halides to adopt other coordination
numbers, and a given halide can form up to eight XBs (Figure
61).
Trihalide anions, such as I3−, Br3−, IBr2−, and ICl2− are
halogen-bonded adducts, as they result from the entrance of a
halide anion on a dihalogen or interhalogen, but can also
function as XB acceptors, and more complex adducts are
formed. Also polyhalometalates can form halogen-bonded
supramolecular anions, and linear,659 tetrahedral,554 square
planar,660 and bipyramidal661 geometries have been obtained
depending on the anion geometry. However, not all of the
halogen atoms bound to a given metal usually work as XB
acceptors, and the geometry of the polyhalometalate anion is
not univocally translated into the geometry of the supra-
molecular anion.
Figure 60. Partial view of the infine chain formed by XBs between
Polycyanometalates are by far the most frequently encoun-
iodine atoms and the π-electrons of the triple bonds in one of the
polymorphs of haloprogin, the active pharmaceutical ingredient used tered anionic and nitrogen-centered XB acceptors. The high
in antimycotic topical drugs. Hydrogens are omitted for clarity. Color delocalization of the negative charge in these anions results in a
code: carbon, gray; nitrogen, blue; oxygen, red; iodine, purple; lengthening of the distance between the XB donor and
chlorine, light green. XBs are dotted black lines. The CSD Refcode is acceptor; namely, these anions do not form strong XBs.
reported. Nevertheless, directional I···NC interactions have been used
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Figure 62. Isomorphous (6,3) networks where perchlorate (UZU-

QOW) and periodate (UZUQUC) anions are the nodes and 1,4-
Figure 61. Bromide anions can form from one to eight XBs: DITFB is the spacer. Cations were omitted for clarity. Color code:
VOQMOD, 2-bromopyridinium bromide; GIXGEZ, part of the carbon, gray; oxygen, red; iodine, purple; chlorine, light green,
infinite chain formed by tetramethylammonium bromide and 1,4- fluorine, yellow. XBs are dotted black lines. CSD Refcodes are
DITFB; TPCBBR, part of the ribbon formed by tetraphenylphospho- reported.
nium bromide and tetrabromomethane; VAPVUE, part of the
adamantanoid network formed by tetraethylammonium bromide and
tetrabromomethane; VAPWEP, supramolecular anion formed by Radical molecules can act as XB acceptors, and three main
tetramethylammonium bromide and tetrabromomethane. For the types of radical species have been identified: nitronyl radicals,
sake of clarity, cations have been omitted, except in the first adduct. paramagnetic metallic complexes, and metal complexes with
Color code: carbon, gray; iodine, purple; bromine, light brown; noninnocent ligands. Nitronyl radicals function as very good
fluorine, yellow. XBs are dotted black lines. CSD Refcodes are XB acceptors,610,668,669 and two paramagnetic metalate systems
reported. worth mentioning are the S = 5/2 FeIII complex FeCl4− and the
S = 3/2 CrIII complex [Cr(isoq)2(NCS)4]−.670,671 Some
dithiolene complexes, such as [M(mnt)2]•− and [M(dmit)2]•−
effectively for the fine-tuning of crystal and electronic structures (M = Ni, Pd, Pt; mnt = maleonitrileditihionate; dmit = 2-
in molecular conductors,194,662−665 an example being bis- thioxo-1,3-dithiole-4,5-dithiolato), are paramagnetic species (S
(diiodo(ethylenedithio)diselenadithiafulvalene) tetracyanoau- = 1/2) with a spin density strongly delocalized on the two
rate.666 dithiolene moieties, and they can act as XB acceptors, either
Oxyanions, by far the most frequently occurring anions in through the CN group in [Ni(mnt)2] − or through the sulfur
organic chemistry, have afforded a large variety of adducts atoms in [Pd(dmit)2]−.672,673
under XB control. The obtained systems involve both organic This brief inventory of XB acceptors is ended with a
and inorganic oxyanions and span over a wide diversity of discussion of studies aimed at filing a ranking of their ability to
electronic and geometric features.162 The perchlorate anion is donate electron density. C. Laurence and J. Graton et al.
the inorganic oxyanion that most frequently affords halogen- formulated an I2 basicity scale (pKBI2 = log Ka) by using
bonded adducts, and it gives one, two, three, or four XBs spectroscopic data for complexes between I2 and different
depending on the number of XB donor sites available and on Lewis bases.101,674 It was found that molecular entities
the overall crystal packing requirements (Figure 62). containing N, P, Se, and S donor sites give rise to stronger
Carboxylate anions are the most represented organic oxyanions XB contacts with I2 than those having O, F, Cl, Br, and I atoms.
in crystalline systems where XB is present. These anions usually This behavior mirrors the evolution of the nucleophilic
act as monodentate XB acceptors. character in the periodic table, which increases moving down
Several other anions occasionally function as XB acceptors. into the group and decreases across the period.
The ability of the thiocyanate anion to interact with XB donors The I2 basicity scale was used to correlate electron density
in the solid state was recently demonstrated.73,667 It was shown donor ability and XB strength in a nitrogen-based XB acceptor
that SCN− is a weaker XB acceptor than I−.68 It is interesting to series. Reduction of the p character of the lone pair of the
observe that the thiocyanate anion can work as a bidentate nitrogen atom results in an elongation of the XB donor−
acceptor, with an electrophilic halogen entering the sulfur and acceptor distance, the distance increasing in the order amine <
another halogen entering the nitrogen,73 or as a monodentate pyridine < nitrile.
acceptor, and in these cases sulfur is preferentially involved in The approach used for the diiodine scale was also adopted by
XB formation.105 the same authors to rank XB acceptors when the XB donors are
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Figure 63. Crystal structures of 1,4-DITFB with various XB acceptors. Nc values and Refcodes are reported. XBs are dotted black lines. Adapted with
permission from ref 674. Copyright 2013 Royal Society of Chemistry.

iodoorganic derivatives. In this case, crystal structures reported based on supramolecular synthesis.675 A great variety of
in the CSD and involving 1,4-diiodotetrafluorobenzene as the different self-assembly strategies has been proposed, and their
XB donor were used (Figure 63). In the nitrogen series, the impact in the construction of new supramolecular systems
lengthening of the C−I bond follows the shortening of the becomes apparent by considering the extensive scientific
interaction, and as expected, aliphatic amines show normalized literature describing the important achievements obtained
contacts just slightly shorter than those of pyridines, but across the years.676−679 Molecular organic frameworks
significantly shorter than those of nitriles. The nature of the (MOFs),680,681 molecular receptors,682 responsive systems,683
groups close to Nsp3 strongly influences the XB contacts. For organogels,684,685 supramolecular polymers,686 and biomimetic
instance, in anilines the conjugation between the nitrogen lone materials687 are only some examples of these outstanding new
pair and the aromatic moiety is probably responsible for the systems.
longer and less linear I···N interactions compared to those of When aimed at the design and synthesis of supramolecular
the corresponding aliphatic amines. Similarly, in the Nsp2 series materials, a self-assembly approach implies that the compo-
the structure and nature of the XB acceptor impact the XB nents (molecular building blocks, i.e., tectons) are programmed
contact, as exemplified by phenanthroline derivatives, which are to create an ordered structure tailored to the pursued function.
weaker XB acceptors than pyridines because in these The intermolecular recognition and self-assembly processes,
compounds the XB interaction is three-centered and the which can occur at any dimensional length scale, are the result
second interaction, involving the second nitrogen atom, leads of the balanced action of steric and electronic factors related to
to a lengthening of the donor−acceptor distances. shape complementarity and size compatibility of the assembled
Laurence and Graton found a quasi-exhaustive diversity of modules and specific anisotropic interactions.
halogen-bonded oxygen bases in the CSD which allowed them Although self-assembly approaches have generated new
to carry out a detailed analysis for the I···O distances. The mean systems in all aggregation states of matter,688,689 the supra-
normalized contacts for the I···O distance increase in the molecular synthesis in the solid state has attracted particular
following order: NO < PO < R−CO−NR′R″ < SO < RO− attention, leading to a well-defined new area named crystal
CO−NR′R″ < R−O−R′ < R−CO−R′ < R−CO−OR′ < R− engineering.690 Specifically, crystal engineering691 is the under-
SO2−R′ < NO2 < Ph−O−R′ < RCO−O−R′. This trend is in standing of intermolecular interactions in the context of crystal
good agreement with the ranking established by the diioidine packing and the way in which such interactions are employed
basicity scale. for controlling the assembly of molecular building blocks into
designed architectures.
3. CRYSTAL ENGINEERING Supramolecular chemists have attempted to assemble
During the second half of the past century, the chemistry molecular modules by using different intermolecular inter-
behind the development of organic functional materials has actions such as HB, π−π stacking, metal−ligand interactions,
progressively shifted its focus from the well-documented electrostatic forces, strong dipole−dipole association, hydro-
methodologies based on covalent synthesis toward approaches phobic forces, etc. Among all these interactions, HB is by far
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the most used one, and many reliable supramolecular structural complexity of the starting building blocks can also
synthons692 have been discovered for the assembly of new produce quite sophisticated discrete systems as is the case for
supramolecular systems.693 The persistent bias resulting from anion receptors, rotaxanes, and catenanes, which will be
the approximation that halogen atoms are neutral entities in exemplified at the end of the section.
dihalogens or fully negative elements in halocarbon moieties Iodopentafluorobenzene (IPFB) is one the most representa-
has long prevented electrophilic halogens from being tive compounds of the class of “minimal” XB donors. IPFB
considered responsible for the frequent formation of strong gives dimers with 2,6-dimethylpyridine (Figure 64, LEZPOW)
attractive interactions, and XB10 has not been explored to the
same extent as HB. Only recently, XB has evolved from a
scientific curiosity to a chemical interaction widely used to
direct and control assembly phenomena.93
This section is focused on the contribution that XB has made
to crystal engineering and, more in general, to the wider field of
supramolecular synthesis. This discussion will serve as an
introduction to successive sections wherein the use of XB to
switch on or tune functional properties in supramolecular
materials will be presented. Herein, the described results will be
organized from the viewpoint of the dimensionality of the
obtained supramolecular architecture. Specifically, the described
structures will be grouped, at least as far as is reasonably
possible, into discrete (zero-dimensional, 0D) aggregates and
mono-, di-, and tridimensional networks (1D, 2D, and 3D nets,
respectively). Discrete and interlocked structures will be
discussed, bringing the focus onto the XB itself and the way
it generates a molecular recognition event. Then some
representative studies will be reported that attempt to combine
multiple recognition events and to result in the formation of
networks and frameworks, either interpenetrated or porous. In
all cases, adducts formed by neutral, lone-pair-possessing
donors will be discussed first, and then attention will be on
aggregates given by anions. Applications in porous systems and
solid-state synthesis will finally be presented at the end of the
section.
3.1. Structures
3.1.1. Zero-Dimensional (0D) Systems. The basic
approach to form discrete halogen-bonded adducts by design
typically involves the self-assembly of a monotopic XB donor
with a mono- or polytopic acceptor (or vice versa). If fairly Figure 64. Crystal structures of selected discrete halogen-bonded
small and strong XB donors and acceptors are used, all the dimers. Color code: carbon, gray; nitrogen, blue; oxygen, red; iodine,
binding sites are paired during the self-assembly process, and purple; bromine, light brown; fluorine, yellow. XBs are shown as
trimeric complexes are obtained starting from a bidentate dotted black lines or as colored solid lines. CSD Refcodes are
donor and two monodentate acceptors (or vice versa), while reported: LEZPOW, 2,6-dimethylpyridine−pentafluoroiodobenzene;
multimeric complexes, such as tetrameric or pentameric N O G Y U F , N ,N , N - D i m e t h y l p y r i d i n - 4 - a m i n e− 1 -fl u o r o - 4 -
systems, are obtained by using multidentate donors capped (iodoethynyl)benzene; MORIPA01, morpholine−1-iodo-2-phenylace-
with an equal number of monodentate acceptors (or vice tylene; XOHWOH, acridine−iodopentafluorobenzene; TMEAMI,
trimethylamine−diiodine; PAQKAT, triphenylphosphineselenido−
versa). However, if the donor and/or the acceptor modules are
diiodine; CUXCON, triphenylarsine−iodine monobromine.
quite large molecules, the overall packing requirements, and the
tendency to avoid the formation of architectures with large
empty volumes, may prevent a saturation of all binding sites, and 2,4,6-trimethylpyridine538 (LEZPIQ), and in both cases,
and the obtained aggregates will contain fewer components, or the activated iodine atom acts as a powerful XB donor and
have a lower dimensionality, than the potential maximum short contacts are formed. Trimethylpyridine gives a shorter
attainable. The same happens when the donor and/or the contact than dimethylpyridine as the extra methyl group further
acceptor sites can give rise only to weak XBs and factors other activates the electron donor ability of the nitrogen and the
than XB formation drive, or influence, the self-assembly presence of a tweezer motif due to HBs between the hydrogen
process. atoms on the 2,6-methyl groups and the negative belt on the
In general, the formation of halogen-bonded 0D systems is iodine atom further promotes the reduction of the donor−
more straightforwardly designed or performed and better acceptor distance.
exemplified when “minimal” donor/acceptor units are used, The dimer between IPFB and 4-(N,N-dimethylamino)-
and several such examples will be presented. This simplification pyridine shows an even shorter N···I distance (2.693 Å, Nc =
of the structural complexity of the modules maximizes the role 0.76),202 further confirming the role of the substituents on the
of the XB and minimizes the possible interferences of other XB acceptor modules in tuning the strength of the formed
noncovalent interactions. However, a careful design of the XB(s). Not surprisingly, medium or weak XB acceptors (e.g.,
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hexamethylenetetramine and 1,3,5-triazine) form even shorter

XBs when giving dimers with very strong XB donors (e.g., N-
iodosuccinimide or other N-haloimides).595,694,695
(N,N-Dimethylamino)pyridine is a potentially ditopic XB
acceptor, but the dimethylamino moiety was not halogen-
bonded to IPFB, and the same happened on crystallization with
4-fluoro-1-(2′-iodoethynyl)benzene where a dimer was ob-
tained (Figure 64, NOGYUF).696 Similarly, morpholine and β-
(iodophenyl)acetylene form a dimer (Figure 64, MORIPA01)
where the iodine atom selectively interacts with the nitrogen
site and not with the oxygen site.697 This behavior where an XB
donor interacts selectively with one XB acceptor is in line with
the general heuristic principle that the best XB donor interacts
preferentially with the best acceptor.
IPFB and acridine form another discrete halogen-bonded
dimer (Figure 64, XOHWOH),698 and when phenazine is used
rather that acridine, a dimer isostructural with XOHWOH is
formed; namely, one of the two nitrogen atoms of phenazine is
not halogen-bonded. Replacing IPFB with bromopentafluor-
obenzene (BrPFB), the obtained dimer was isostructural with
the IPFB−acridine adduct, demostrating that Br and I can be Figure 65. From LEJKUG to WUWMAD: representation of crystal
equivalent in XB-driven self-assembly. structures of 0D dimeric adducts involving halogen atoms activated by
Also molecular iodine has been involved in the formation of positively charged scaffolds and halide anions. CILHIO22: crystal
discrete systems with neutral XB acceptors. Both iodine atoms structure of a TTF derivative containing the triiodide anion. Hydrogen
atoms are omitted for clarity. Color code: carbon, gray; nitrogen, blue;
in I2 have large positive σ-holes in the isolated molecule, and I2 iodine, purple; bromine, light brown; chlorine, light green, sulfur, dark
can function as a bidentate XB donor, but as discussed above, yellow; fluorine, yellow. XBs are dotted black lines and colored solid
when one iodine atom is halogen-bonded to a strong acceptor, lines. CSD Refcodes are reported: LEJKUG, 2-[[4-(5-bromo-3-
the charge-transfer component of the interaction may methyl-2-pyridyl)butyl]amino]-5-(6-methyl-3-pyridylmethyl)-4-pyri-
significantly increase the electron density of the other iodine, midone trihydrobromide; CICRAI, (bromomethyl)-
and its ability to function as an electron density acceptor site is trimethylammonium bromide; HOLLID, 1-(chloromethyl)pyridinium
hampered. The dimer between trimethylamine and I2 is the chloride; ZONXOP, 1-(bromodifluoromethyl)-4-(dimethylamino)-
minimal example of this behavior (Figure 64, TMEAMI).699 pyridinium bromide; WUWMAD, 4-iodoanilinium chloride; WOQ-
Other discrete adducts can be found in solid-state chemistry REB, trans-4-[2-(4-iodophenyl)ethenyl]pyridinium chloride; CIL-
HIO02, bis[bis(ethylenedithio)tetrathiafulvalene] triiodide.
where I2 forms a single XB with sulfur640 and selenium and
arsenic.700 ClI701 and BrI702 give similar 0D systems where in
all of the cases the iodine atom functions as an XB donor polyhalide species and thus the smallest 0D dimeric adduct
(Figure 64, PAQKAT and CUXCON). involving molecular halogens and halide anions is the trihalide
As mentioned in the XB donor/acceptor inventory in section X3−. Depending on the halogen atoms that form the X3−
2.2.4, the halogen atoms of halogenated heteroarenium cations species, these can be homoatomic trihalides X3− [(X1···X2−
are effective XB donor sites, while anions can function as X3)− ; X1 = X2 = X3 = F, Cl, Br, I) or heteroatomic mixed
effective XB acceptor sites, and X-ray structures frequently trihalides X2Y− [(Y1···X2−X3)−; Y1, X2 = X3 = Cl, Br, I). The
show the presence of strong XBs in crystalline haloheter- most common trihalide unit is I3−, where I2 is halogen-bonded
oarenium salts. Anions may potentially accept multiple XB to I− (Figure 65, CILHIO22).17,709
contacts, but the number of XB donor sites on the In the CSD, trimeric discrete systems are quite common,
haloheteroarenium cation becomes the limiting factor for the although less common than infinite chains. Some selected
number of XBs given by the anion in haloheteroarenium salts. examples involving 1,4-DITFB are shown in Figure 66
In the structures of halogenated organic salts, discrete adducts (TOKFEG, ANUQAC, LICBIK). 1,4-DITFB typically func-
are more common than infinite nets, probably not due to an tions as a bidentate tecton, consistent with calculations which
inherent preference of anions to work as monodentate XB show that both the iodine atoms of this module present a
acceptors but, rather, due to the fact that monohalogenated remarkably positive σ-hole. Trimers are thus formed when two
organic cations are much more numerous than di- or equivalents of a monodentate XB acceptor (such as N,211 O,183
polyhalogenated ones. In monohalopyridinium halides703−705 and π-systems710) are available, and similar trimeric complexes
and monohaloanilinium halides706−708 the monodentate cation are obtained by using other analogous tectons, e.g., 1,3-
prevents the anion from functioning as a polydentate unit, and diiodotetrafluorobenzene,711 1,2-diiodotetrafluorobenzene,618or
discrete adducts are formed (Figure 65, LEJKUG, WUWMAD, 1,4-bis(iodoethynyl)benzene573 and its brominated analogue.
WOQREB, VOQMUJ, CICRAI, HOLLID, and ZONXOP). Alternatively, all these tectons afford halogen-bonded systems
Importantly, molecular halogens could interact with anion with higher dimensionality (e.g., infinite chains, honeycomb-
species, yielding polyhalide entities. In general, polyhalide like nets, etc.) when interacting with di- or tridentate acceptors,
chains X2m+nn− (X = F, Cl, Br, or I) give rise to a particularly but not when crystal packing requirements or the formation of
wide variety of structures that are assembled starting from X−, other intermolecular interactions interfere.618,634,712
X2, and X3− building blocks, where X− and X3− may be Discrete and trimeric motifs are also obtained when the code
considered as the XB acceptors (electron donor moieties) and is reverted, namely, when a bidentate XB acceptor self-
X2 as the XB donor (electron acceptor). The simplest assembles with two monodentate donor molecules. 4,4′-
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Figure 67. Representation of the cyclic tetrameric superanions formed

by CHCl3 and the perchlorate anion of bis[μ2-8-[(2-pyridylsulfanyl)-
methyl]quinoline]disilver(I) diperchlorate (INEYIJ) and CCl4 and the
perchlorate anion of (cis-2,6,9,13-tetrathiabicyclo(12.4.0)octadecane)-
nickel(II) diperchlorate (SUGVOF). Representation of the pentameric
superanion assembled thanks to Il···Cl− XBs in tetraphenylphospho-
nium chloride−tetrakis(1-iodo-2-phenylacetylene) (ZOMNAQ). Cat-
Figure 66. Trimeric discrete complexes formed by 1,4-DITFB with ions are omitted for clarity. Color code: carbon, gray; oxygen, red;
phenanthridine (TOKFEG),713 triphenylphosphine oxide (ANU- iodine, purple; chlorine, light green. XBs are dotted black lines. CSD
QAC),183 and methyl(diphenyl)phosphine oxide (LICBIK).710 Refcodes are reported.
Trimeric complexes assembled by N-(4-bromo-2,3,5,6-tetrafluoro-
phenyl)-2,3,5,6-tetrafluoro-4-iodobenzamide with t-BPE (DIM-
TEA)714 and by 3-iodoprop-2-yn-1-ylbutyl carbamate with 4,4′-
the most relevant examples will be discussed. A common
bipyridine (XIDGAU).477 Color code: carbon, gray; nitrogen, blue;
oxygen, red; iodine, purple; bromine, light brown; chlorine, light feature of all these systems is that their molecular structure is
green; phosphorus, orange; fluorine, yellow. XBs are dotted black lines. preorganized to allow for the targeted function to merge, for
CSD Refcodes are reported. instance, the recognition of the guest by eliciting a specific
binding mode relative to all the other possible interaction
modes. This structure-imposed selectivity is also a key feature
Bipyridine and t-BPE are two “minimal” XB acceptors, and in the construction of complex topologies such as catenanes
examples are reported in Figure 66 (DIMTEA and and rotaxanes.
XIDGAU).477,485,638 The first example of a preorganized anion receptor
Anionic XB acceptors can also be involved in trimeric adduct incorporating XB donor groups was reported by P. Metrangolo
formation. However, the well-known ability of these electron and G. Resnati et al. in 2005 (Figure 68).717 The receptor
density donors to accept multiple XB donors makes the design TIPTEA was obtained by appending three p-iodotetrafluor-
and assembly of defined and discrete units quite challenging ophenyl groups to the tris[2-(ethylene glycol)ethyl]amine
and rare. Two interesting examples are the inclusion complexes moiety. The resulting heteroditopic tripodal receptor bound
of 1,4-DITFB in decamethonium diiodide where two iodide separated alkali-metal halide ion pairs. Specifically, the alkali
anions pin the two iodine atoms of the XB donor470 and the metals interacted attractively with the Lewis basic podand
motif between chloride anion and two monoiodoperfluoropro- portion of the receptor, while their counteranions were
pane molecules.214 The latter example was used as structural recognized through XBs to the iodoperfluoroarene groups at
confirmation to explain the ability of monoiodoperfluoroal- the periphery of the receptor. X-ray studies of TIPTEA with
kanes to act as anion transporters through membranes. Several NaI confirmed the binding mode (Figure 68, DAXGIT). The
other examples of trimeric complexes involving ionic species selectivity of the receptor for the halides was evaluated by
are discussed in two review papers on anion coordination under competitive electrospray ionization mass spectrometry (ESI-
XB control.69,70 MS) experiments and followed the trend I− > Br− > Cl−.
The achievement of multimeric discrete systems by design is In 2010, M. S. Taylor and co-workers developed the tripodal
even more demanding if compared with that of dimeric or anionic receptor TIBTM, where three 2-iodoperfluorobenzoic
trimeric adducts. This is also related to limitations or acid units are appended onto a 1,3,5-tris(hydroxymethyl)-
complications experienced during the covalent synthesis of benzene core (Figure 68).458 This unit oriented the XB donor
preorganized starting modules. Some examples of discrete sites to allow a high selectivity for anionic guests. One year
systems involving multiple XBs are discussed in the following later, the same group synthesized another anion receptor
section on porous systems and cages (3.2.1). Some (DIBU) containing one urea and two 2-iodotetrafluorophenyl
others70,523,715,716 are presented in Figure 67 or can be found groups. The presence of both HB and XB donor groups in the
in the CSD. In general, they have been obtained by chance receptor scaffold enhanced the affinity for the halide anion with
rather than by design. respect to that of DIBU.718
Anion receptors could be considered as a functional class of The use of positively charged XB donors as anion receptors
discrete assemblies, and in the final part of this section some of allows for Coulombic attraction to make a major contribution
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ITIPA, an iodotriazolium-based unit, the axle, was assembled

with an isophthalamide-based macrocycle, the ring. The
rotaxane formation was driven by cooperative HB and XB
interactions involving the bromide anion (Figure 70).
Structural details of the binding of the bromide ion in the
cavity of the rotaxane were afforded by X-ray analysis.460
Similar rotaxanes showed strong and selective recognition for
anions in water, demonstrating the superiority of XB over HB
for strong anion binding.657
In 2014 the same group reported the first rotaxane host
system totally based on XB, DITDIT. In this case both the axle
and the macrocycle integrated XB donor units, namely, two
iodotriazole and two iodotriazolium motifs, respectively (Figure
70, top).550 The cooperative and convergent XB interaction
with chloride allowed for the formation of the interlocked
adduct as confirmed by X-ray analysis.
Similar catenate structures were targeted using either an
approach based on HB and XB (CAT1)719 or an approach
based on XB only (CAT2) (Figure 70, bottom).658 These
systems were formed upon interaction with halide anions.
Two other examples where the preorganization of the
structure is instrumental in the recognition phenomena are the
foldamer reported by J. Lin et al. (HTF)720 and the anion
receptor developed by P. Molina et al. (BITN) (Figure 71).721
Figure 68. Top: molecular formula of TIPTEA (left) and In the first case, the intramolecular HBs imposed a
representation of the single-crystal X-ray structure of the complex of preorganized cavity where the tris(iododifluoroacetate) guest
TIPTEA with NaI (right). The I···I− XB is shown as a black dotted was trapped by XB. In the second system, the bidentate HB and
line. Bottom: molecular formulas of TIBTM and of DIBU. Color code:
carbon, gray; nitrogen, blue; oxygen, red; iodine, purple; fluorine,
XB triazolium-based receptors showed a very high affinity for
yellow; sodium, light purple. XBs are dotted black lines. The CSD the hydrogen pyrophosphate (HP2O73−) anion, which was not
Refcodes are reported. observed for the receptor based only on HB.
3.1.2. One-Dimensional (1D) Systems. 1D halogen-
to anion binding. The approach has evolved as a general bonded architectures can be homomeric systems, obtained on
strategy to strengthen the anion recognition process. In this self-assembly of self-complementary modules bearing both XB
context some of us proposed a monodentate 2-iodoimidazo- donor and acceptor sites. Alternatively, they can be heteromeric
lium system (AMII) which showed a good affinity, in solution, systems, obtained on self-assembly of a ditopic XB donor and a
for halide anions and, importantly, a particularly high affinity for ditopic XB acceptor. Several examples of homomeric halogen-
the poorly explored H2PO4− anion (Figure 69). The crystal bonded 1D chains formed by iodotetrafluorophenyl derivatives
bearing different neutral XB acceptor sites (e.g., sp 3-
hybridized,722 sp2-hybridized,723 or sp-hybridized623 nitrogen
atoms, oxygen-centered sites,724 and π-systems725) are shown
in Figure 72.
In all cases, the activated iodine atoms act as powerful XB
donors, and the acceptors provide the complementary link for
1D chain formation. The C−I···XB acceptor angles are close to
linear, consistent with the high directionality of the interaction.
Similar adducts are formed using activated chlorine623 or
bromine725−727 atoms as XB donor sites. Not only iodotetra-
fluorobenzene derivatives give rise to halogen-bonded infinite
chains, but other neutral self-complementary systems are found
Figure 69. Left: molecular formula of AMII. Middle: single-crystal X- in the CSD, such as 3-iodo-propiononitrile193 and 4-
ray structure of the AMII iodide salt. Right: single-crystal X-ray iodonitrobenzene,690 which are two other “minimal” tectons.
structure of the AMII dihydrogen phosphate salt. Color code: carbon, Also charged self-complementary systems can assemble into
gray; nitrogen, blue; oxygen, red; iodine, purple; phosphorus, orange; infinite chains, as is the case for halogen-substituted zwitterions
hydrogen, white. XBs and HBs are dotted black lines. CSD Refcodes where the XB donor and acceptor sites interact to form
are reported.
homomeric crystals (Figure 73).728−730
The heteromeric 1D chain is by far the most common motif
structures of AMII as iodide and dihydrogen phosphate salts among halogen-bonded cocrystals obtained by design. Gen-
revealed short I···I− and I···O− contacts, respectively, and erally, complexes with linear geometry are obtained when the
confirmed the behavior observed in solution.563 axes of the donor and acceptor sites are parallel and coaxial.
Using positively charged modules, P. Beer and co-workers This is the case for 1D chains formed by flat XB donor and
recently reported several interlocked receptors showing acceptor modules (Figure 74, IKUHUR).168,203,731 Differently,
complex supramolecular structures such as self-assembled stepped infinite chains are obtained when the binding sites are
rotaxanes and catenanes. In the first rotaxane reported, parallel, but not collinear, as is the case when α,ω-
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Figure 70. Top: molecular formula of ITIPA, molecular formula of DITDIT hexafluorophosphate salt, and single-crystal X-ray structure of DITDIT
chloride salt. Adapted with permission from ref 551. Copyright 2014 John Wiley and Sons. Bottom: molecular formulas of CAT1 (left) and CAT2
(right). Adapted with permission from refs 719 and 659. Copyright 2014 and 2012, respectively, John Wiley and Sons.

geometry into the supramolecular geometry. Illustrative

examples are the linear chain that 4,4′-bipyridine affords with
DITFB76 and the weavy chains formed by the same acceptor
with 1,3- and 1,2-diiodotetrafluorobenzenes or their dibromo
analogues203,735 (Figure 75, IKUJON and IKUJIH).736 Many
other cases have been described where the XB donor,190,472 the
XB acceptor,399,407,450,544,737or both tectons105,738 present an
angular geometry translated into the chain geometry. A
particularly nice example is the cocrystal between 3,5-
bis(pyrid-4′-yl)-1,2,4-oxadiazole and 1,4-diiodoperfluorobutane
or its analogue with 1,6-diiodoperfluorohexane (Figure 75,
BEWXIM).167
Heteromeric 1D chains can also be obtained via self-assembly
of a ditopic XB donor with a monotopic XB acceptor bearing a
Figure 71. Left: cartoon representing the binding of the tris- functional site with two lone pairs. Examples reported in the
(iododifluoroacetate) guest to the folded structure of HTF by CSD usually involve oxygen727 and sulfur78 atoms, which
multiple I···N XBs, which further fastens the folded state and leads frequently behave as bifurcated sites (Figure 76, FEQVON and
to an increase of the excimer emission of the appended pyrene units. NUSBUZ). This ability of oxygen atoms, discovered thanks to
Adapted with permission from ref 720. Copyright 2012 John Wiley in situ cryocrystallization, allowed for the obtainment of 1D
and Sons. Right: molecular structure of BITN bound to the HP2O73− polymeric architectures between 1,3-dibromotetrafluoroben-
anion. Here, too, the recognition event leads to an increase of the
excimer emission of the appended pyrene units. Adapted from ref 721.
zene,178 or 1,2-dihalotetrafluoroethane,179 and dimethyl sulf-
Copyright 2014 American Chemical Society. oxide (DMSO) or hexamethylphosphoramide (HMPA).
Also XB donor sites can work as bifurcated sites. This
behavior is quite rare and requires pairing with the appropriate
dihaloperfluoroalkanes are used as XB donors (Figure 74, XB acceptors,216 as was the case for a set of tectons where two
QANRUS and LOQBAU).28,85,406,732−734 electron density donor sites were locked in place in such a way
Herringbone supramolecular chains appear when the axes of to favor the formation of a symmetric bifurcated XB with a
the donor sites on the XB donor tecton, or of the acceptor sites single electrophilic halogen atom (Figure 76, EXIFEX).614
on the XB acceptor tecton, are not parallel. Thanks to the high Anionic species, mainly halides, have been frequently used to
directionality of XB, the angle between the axes of the binding build up linear architectures by design. Many chains in the CSD
sites corresponds to the angle along the resulting 1D chain, or are given by chlorides, bromides, and iodides, and only a few
in other words, the XB directionality translates the molecular involve fluoride anions.653 Examples can be found both among
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Figure 74. Partial representation of the 1D chain: linear chain formed

by t-BPE and 1,4-dibromotetrafluorobenzene (IKUHUR), stepped
chains formed on self-assembly of 4,4′-dipyridyl and DIPFH
(QANRUS) and DIPFO (LOQBAU). Hydrogen atoms are omitted
for clarity. Color code: carbon, gray; nitrogen, blue; iodine, purple;
bromine, light brown; fluorine, yellow. XBs are dotted black lines.
CSD Refcodes are reported.

Figure 72. Representation of single-crystal structures of halogen-

bonded 1D infinite chains assembled via self-complementary modules.
Color code: carbon, gray; nitrogen, blue; oxygen, red; iodine, purple;
fluorine, yellow. XBs are dotted black lines. CSD Refcodes are
reported: PAPRIJ, 4-[2-[1-hexyl-5-[2-(tetrafluoro-4-iodophenyl)-
vinyl]-1H-pyrrol-2-yl]vinyl]pyridine; ACOKIM, 4-iodo-2,3,5,6-fluoro-
benzonitrile; PADHUY, 4-iodotetrafluorobenzaldehyde; JALLEO, 1-
iodo-4-(phenylethynyl)tetrafluorobenzene; JEHREU, N,N-dimethyl-4-
(E)-[2-(tetrafluoro-4-iodophenyl)vinyl]aniline.

Figure 75. Representation of a part of the infinite chains between

4,4′dipyridyl and 1,3-dibromotetrafluorobenzene (IKUJIH)) and 1,2-
dibromotetrafluorobenzene (IKUJON) and between 3,5-bis(pyrid-4′-
yl)-1,2,4-oxadiazole and 1,6-diiodoperfluorohexane (BEWXIN). In
BEWXIN the angle between the two pyridyl pendants of the XB
acceptor (149.1°) is quite similar to the angle between the two formed
XBs (141.5°). Hydrogen atoms are omitted for clarity. Color code:
carbon, gray; nitrogen, blue; oxygen, red; iodine, purple; bromine, light
brown; fluorine, yellow. XBs are dotted black lines. CSD Refcodes are
reported.

the heteromeric two-component systems207,739 and among the

heteromeric three-component systems.263 Linear, zigzag, or
helicoidal arrangements are formed as a function of the overall
crystal packing requirements (Figure 77, IKUXER, BOCGAB,
Figure 73. 1D infinite chains of halogen-substituted zwitterions: 4- PAVZIV, and AHULEU).
bromo-3-(3-pyridyl)sydnone (BRPSYD10), (Z)-3-phenylsydnone-4- Finally, unusual 1D architectures have been assembled using
hydroximic acid chloride (FIHTIA), and 7-iodo-8-hydroxyquinolinium
anionic species such as a “rings and sticks” chain740 or a
5-sulfonate (IHQUSO01). Color code: carbon, gray; nitrogen, blue;
oxygen, red; iodine, purple; bromine, light brown; chlorine, light comblike system.741 A supramolecular ribbonlike arrangement
green; sulfur, dark yellow. XBs are dotted black lines. CSD Refcodes is another peculiar assembly formed, for instance, when halide
are reported. anions, working as tridentate and XB acceptor nodes, self-
assemble with bidentate dihalocarbons, functioning as linear
spacers of the nodes (Figure 77, UGULAK, DOXTOA,
GIXGOJ, and NUZKIC).
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Figure 76. Representation of heteromeric 1D chains where 1,4-DITFB

self-assembles with thiourea (NUSBUZ) and Michler’s ketone
(FEQVON), both functioning as monotopic XB acceptors where
the heteroatom is a bifurcated site, and with 1,10-phenanthroline-5,6-
dione (EXIFEX), forcing the iodine atoms of 1,4-DITFB to work as a
bifurcated XB donor. Color code: carbon, gray; nitrogen, blue; oxygen,
red; iodine, purple; bromine, light brown; sulfur, dark yellow; fluorine,
yellow. XBs are dotted black lines. CSD Refcodes are reported.

3.1.3. Two and Three-Dimensional (2D and 3D)

Systems. As discussed in the previous sections of this review,
there is not a single strategy to assemble halogen-bonded
discrete adducts or chains, and thus, there are several protocols
to target 2D or 3D architectures. Increasing the number of XB
donor and/or acceptor sites on the starting molecular modules
is a strategy that has been largely and successfully applied
during the years. The binding sites on the molecular scaffold
should be oriented in such a way to elicit the desired binding
profile of the interacting partners and afford the targeted
network; for example, three, or four XB donor sites should be
placed more or less orthogonal to each other if a 3D structure is Figure 77. Infinite chains produced on C−Br···Cl− XB formation in
pursued. In general, the higher the dimensionality of the bis(2-bromoimidazole)boronium chloride (IKUXER),742 C−Br···Br−
targeted architecture, the more demanding the required design XB formation in (−)-sparteine hydrobromide/1,2-dibromohexafluor-
becomes and the more complex the synthesis of the starting opropane (BOCGAB),263 C−I···Cl− XB formation in bis[bis-
building blocks may be. (ethylenedithio)tetrathiafulvalene] chloride/diiodoacetylene (PAV-
When one or both of the interactive modules form three or ZIV),665 and C−I···Cl− XB formation in tris[bis(ethylenedithio)-
more XBs, two-dimensional (2D) architectures are usually tetraselenafulvalene] chloride/1,4-bis(iodoethynyl)benzene
(AHULEU).743 Cations and hydrogen atoms are omitted for
formed. Some examples involving neutral and anionic XB simplicity. “Rings and sticks” (UGULAK) and comblike (DOXTOA)
acceptors will be discussed in order, but before discussing architectures form when iodide anions (tridentate nodes) self-
examples afforded by structurally complex tectons, it is worth assemble with α,ω-diiodoperfluoroalkanes. Halogen-bonded ribbons
mentioning that dihalogens, the simplest molecules containing form when iodide anions (tridentate nodes) self-assemble with 1,4-
halogen atoms, assume in the solid state a 2D layered DITFB (GIXGOJ), 75 or with a triiodobenzene derivative
structure.244,745 This well-defined assembly is related to the (NUZKIC).744 Color code: carbon, gray; nitrogen, blue; iodine,
electron density distribution around the halogen atoms. I2, Br2, purple; chlorine, light green; boron, pink; fluorine, yellow. XBs are
Cl2, and F2 molecules all possess two XB donor sites, the two σ- dotted black lines. CSD Refcodes are reported.
holes on the extensions of the covalent bonds, and two XB
acceptor sites, the two belts rich in electron density and
orthogonal to the covalent bonds. In solid Cl2, for instance, the another molecule (Figure 50, YATKIP), and on repetition of
belt of one chlorine atom enters the hole of the chlorine of this supramolecular synthon a flat 2D network is formed.
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A notable example of an infinite layer was reported by F. C. square layer (sql). The substitution of 1-hydroxybenzotriazole
Pigge.746 The trigonal molecule 1,3,5-tris[(4-iodophenoxy)- for the axial ligand yielded a crystalline system (POR2)
carbonyl]benzene (TIPB) functions as a self-complementary containing two-dimensional layers wherein the porphyrin units
tecton when crystallized from chloroform and yields a 2D were connected to one another along the four equatorial
supramolecular network assembled thanks to I···O and I···π directions by nearly linear C−I···N (Nc = 0.85) XBs. The
interactions. The bifurcated I···O and I···π XBs assist in the corrugated nature of the layers allowed for their tight stacking
formation of triangular motifs which lead to the construction of in the normal direction, and disordered DMF molecules were
2D hexagonal patterns arranged in a parallel fashion. The accommodated in the interstitial channel voids of the structure
honeycomb-like structure shows nanometer-sized channels (Figure 78D).
filled by chloroform guest molecules (Figure 78A,B). The free-base bis(iodoaryl)dipyridylporphyrin (POR3)
adopts a crystal structure sustained by I···N and I···π XBs,749
and the overall supramolecular arrangement is an open 2D
herringbone pattern of the porphyrin molecules criss-crossed
through XBs (Figure 78E).
A 2D porous framework is also obtained when a porphyrin
with four iodotetrafluorobenzene residues in the meso positions
is cocrystallized with hexamethylenetetramine (HMTA).750 In
the packing of the obtained system POR4 (Figure 78F), eight
crystallographically different iodine atoms are present, and they
are all involved in XBs. In the obtained layers, I···N XBs
identify infinite ladder-type chains, which are connected to each
other via short I···I interactions.
As already observed, anions have a moderate bias toward the
formation of two or three XBs; it is thus not uncommon that
2D or 3D halogen-bonded supramolecular anions were
obtained as a result of a design tailored to elicit a polydentate
binding profile of halide anions. The number and geometry of
the XB donor sites on the halocarbon tecton and the cation
nature and size are also influential on the topology of the
halogen-bonded anionic architecture, and a prediction of the
structural aspects of the final network still remains a challenge.
The (6,3) network (honeycomb-like structure) is a
frequently recurring pattern in 2D architectures formed on
self-assembly of halide anions with a ditopic XB donor.751 For
instance, honeycomb-like structures were formed when Ph4PBr
and (CH3)4NI were cocrystallized with 1,4-DITFB75 and when
potassium iodide and K.2.2.2 were cocrystallized with α,ω-
diiodoperfluoroalkanes such as 1,2-diiodoperfluoroethane, 1,4-
Figure 78. (A) Triangular motif sustained by bifurcated I···O and I···π diiodoperfluorobutane, 1,6-diiodoperfluorohexane, and 1,8-
XBs in the packing of TIPB. (B) Honeycomb-like network in TIPB. diiodoperfluorooctane (Figure 79, TEHRAA).68 In these
Hexagonal channels are filled by chloroform molecules (in green). (C) structures, the halide units occupied the nodes of the (6,3)
Two-dimensional array (sql) of tin tetrakis(iodophenyl)porphyrin arrangement, while the dihalocarbon modules acted as
with nicotinic acid (POR1) aligned parallel to the ac plane of the bidentate XB donors that connected the nodes. The XB
crystal. (D) Square-grid-type network in the crystal of tetrakis- pattern around the halide anions adopted a pyramidal
(iodophenyl)porphyrin assembled with 1-hydroxybenzotriazole arrangement, and corrugated honeycomb-like layers were
(POR2). Every porphyrin unit is involved in eight XB contacts. (E) formed. Notably, in the tricomponent systems, strong
View parallel to the crystal ab plane of bis(iodoaryl)dipyridylporphyrin
free base (POR3). (F) Representative section of the halogen-bonded segregation between the hydrocarbon moieties and perfluor-
layer in POR4, viewed within the crystal ac plane. XBs are dotted lines. ocarbon units took place, and due to the presence of large
Panels A and B reprinted with permission from ref 746. Copyright cavities, some of the complexes showed an interpenetrated
2008 Royal Society of Chemistry. Panels C and D reprinted with arrangement (see the next section for a detailed discussion of
permission from ref 748. Copyright 2013 John Wiley and Sons. Panel interpenetrated networks).
E reprinted from ref 749. Copyright 2015 American Chemical Society. The deliberate construction of (6,3) networks was also
Panel F reprinted with permission from ref 750. Copyright 2014 Royal achieved via XB-driven self-assembly of tetra-n-butylammonium
Society of Chemistry. perchlorate, periodate, and perrhenate with 1,4-DITFB (Figure
62, UZUQOW).71 The mononegative oxyanions sit at network
Porphyrin units functionalized with both XB donor and nodes and work as tridentate XB acceptors, the diiodobenzene
acceptor sites were used to construct 2D networks.747 The tin derivatives space the nodes and function as bidentate XB
tetrakis(iodophenyl)porphyrin with nicotinic acid (POR1) as donors, and the ammonium cations occupy the space encircled
an axial ligand formed in the solid state a layered grid-type by the supramolecular (6,3) frames. Although perchlorate,
arrangement wherein the porphyrin units were bridged by I···N periodate, and perrhenate anions have four XB acceptor sites,
XBs and I···I type I halogen−halogen contacts (Figure 78C). they function as tridentate nodes, and this behavior was
The topology of the two-dimensional porphyrin array was explained in terms of decreasing overall electron density donor
analyzed with TOPOS,748 and the network was described as a ability on the anion upon formation of the multiple XBs.
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observe that Me3S+I− affords a perfectly planar honeycomb-like

anionic network (Figure 79, CIZROT), while on increasing the
cation size (e.g., on moving from Me4N+ to Et4P+ and n-Pr4N+),
the network becomes more and more corrugated (Figure 79,
CIZSIO).
Another fairly common 2D topology afforded by XB tectons
is the tiling where rhombs and octagons are present. Anions,
usually halide anions, and bi- or tridentate XB donors all sit at
the nodes of the rhombic and octagonal networks (Figure 80,
HEDGOM and VAPXAM).442,526

Figure 79. TEHRAA: side view of the (6,3) superanion network in the
halogen-bonded adduct K.2.2.2/KI/DIPFH. Cations are omitted for
clarity. CIZSAG: front view of the (6,3) network of tetraethylphos-
phonium iodide−1,3,5-triodo-2,4,6-trifluorobenzene. Cations are
shown in space-filling style. CIZSIO: side view showing the undulated
(6,3) anionic net of tetra-n-butylammonium iodide−1,3,5-triodo-2,4,6-
trifluorobenzene dichloromethane solvate. Cations and dichloro-
methane are shown in space-filling style. CIZROT, side view showing
the planarity of the (6,3) anionic network of trimethylsulfonium
iodide−1,3,5-triodo-2,4,6-trifluorobenzene. Cations are shown in
space-filling style. Color code: carbon, gray; nitrogen, blue; iodine,
purple; phosphorus, orange; sulfur, dark yellow; fluorine, yellow. XBs
are dotted black lines. CSD Refcodes are reported.

The formation of the (6,3) topology can be alternatively Figure 80. Tilings formed by octagons and rhombs and resulting on
obtained by the self-assembly of tridentate XB donors with self-assembly of iodoform with benzyltrimethylammonium iodide
anions behaving as tridentate XB acceptors. In this case, the (HEDGOM) and carbon tetrabromide with 1-aza-8-
complementary tectons alternate at the nodes of the 2D azoniabicyclo(5.4.0)undec-7-ene bromide (VAXPAM). (4,4) networks
architecture. Such halogen-bonded (6,3) networks are formed are obtained on self-assembly of diiodoacetylene with chloride anions
when CHI3480,752 self-assembles with onium halides and when (ZOMWAZ), 1,4-difluoro-2,3,5,6-tetraiodobenzene with bromide
anions (XERZID), and [bis[[μ2-N,N′-bis(5-bromosalicylaldehyde)-
1,3,5-trifluoro-2,4,6-triiodobenzene (TITFB) is cocrystallized ethylenediamino]methanol]manganese(III)] perchlorate (IDEHOP).
with onium iodides where the cation size matches the space Hydrogen atoms and cations are omitted. Color code: carbon, gray;
encircled by the hexagonal framework.539 For instance, (6,3) nitrogen, blue; oxygen, red; iodine, purple; bromine, light brown;
nets are obtained when Me3SI, Me4NI, Et4PI, and n-Pr4NI are chlorine, light green; fluorine, yellow. Mn atoms in IDEHOP are
employed (Figure 79, CIZROT and CIZSAG), but this is not shown in gray-violet. XBs are dotted black lines. CSD Refcodes are
the case for Ph4PI as the cation is too large. It is interesting to reported.

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Figure 81. (A) (1) Chemical structure of DBTP. (2) Calculated molecular electrostatic potential distribution of DBTP at the isodensity surface
shown in red (positive) and blue (negative). (3) Cartoon of two DBTP molecules with simplified electrostatic potential distributions around H and
Br atoms (same color code as in (2)). Dotted blue lines indicate Br···Br XBs, and dotted red lines indicate Br···H HBs. (B) (1−3) STM topography
images of three porous networks obtained after DBTP was deposited on Ag(111) at 80 K. (4−6) High-resolution STM images from the square-
marked areas in (1), (2), and (3), respectively, with superimposed molecular models of DBTP. Adapted with permission from ref 756. Copyright
2011 Royal Society of Chemistry. (C) (1) Scheme of the self-assembly of tritopic XB acceptor TEPB and XB donor TITFB affording the TITFB/

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Figure 81. continued

TEPB honeycomb-like network where the two modules alternate at the nodes. (2) Large-scale STM image of the TITFB/TEPB honeycomb-like
structure. (3) The STM image shows the coexistence of a TEPB close-packed structure and the TITFB/TEPB honeycomb-like network. (4) High-
resolution STM image of the TITFB/TEPB honeycomb-like structure. Adapted from ref 755. Copyright 2015 American Chemical Society.

Also (4,4) networks have been obtained. In these networks, a electrical manipulation method of STM was a general method
tetradentate XB acceptor self-assembles with ditopic664 or to engineer XB-based structures. In fact, by varying the XB
tetratopic732 XB donors (Figure 80, ZOMWAZ and XERZID). acceptors across various pyridyl derivatives (ditopic, tetratopic),
The organization of the resulting (4,4) layers is dictated by the different XB-based binary supramolecular structures were
arrangement of the XBs around the halide anions. Oxyanions, obtained (Figure 81C).
by far the most numerous class of anions in organic chemistry, Three-dimensional (3D) architectures can be formed when
can also form 2D supramolecular networks with chloro-, one or both of the interactive modules are tetradentate. The
bromo-, and iodocarbons (Figure 80, IDEHOP).69,753 adamantanoid network is a common motif in 3D arrangements.
When starting tectons organize on metal surfaces, the These architectures have been obtained by using neutral self-
formation of halogen-bonded and self-assembled layers is complementary tetradentated building blocks containing two
governed by the same principles exemplified above in the XB donor sites and two XB acceptors, by using neutral or
formation of bulk crystalline adducts. We have already anionic tetradentate XB acceptors sitting at the network nodes
discussed how in crystalline dihalogens the negative belt on and being spaced by bidentated XB donors, or by using
the halogen atom of one molecule enters the positive cap on tetradentated XB donors and acceptors, which alternate at the
the halogen of another molecule and layers are formed (Figure nodes. Detailed discussion of these systems will be presented in
50, YATKIP). Similarly, when 4,4″-dibromo-p-terphenyl the next section on interpenetrated networks. Here we describe
(DBTP) is deposited on Ag(111), the negative belt of any a simple and noninterpenetrated adamantanoid network
bromine enters the positive cap of another bromine (Figure wherein tetrabromomethane and chloride anion function as
81A) and a porous (4,4) network is formed where the sides of the tetradentate XB donor and acceptor, respectively, and
the squares are four terphenyl moieties and the vertexes are alternate at the nodes of the network (VAPVOY, Figure 82).526
four arrays of halogen-bonded bromine atoms (Figure 81B).754 When chloride is replaced by iodide, which functions as an
Any bromine atom behaves as an XB donor (via its positive octadentate acceptor, a rhombododecahedron network is
cap) and attractively interacts with another bromine, which obtained instead (VAPWIZ, Figure 82).
behaves as an XB acceptor (via its negative belt). Once again,
the XB directionality translates the orthogonal arrangement of
the binding sites on the starting module DBTP into the
topology of the self-assembled porous layer, and the rodlike
character of DBTP helps in this translation. H···Br HBs,
involving the negative belt of the bromine, are also present in
the layer and further pin DBTP modules in their position.
However, we have also discussed how the anisotropic
distribution of the electron density around covalently bound
bromine atoms may account for their organization in the bulk
into trigonal and self-complementary supramolecular synthons
(Figure 26).
The same happens when DBTP is deposited on silver: Figure 82. Isomorphous adamantanoid networks formed when
Triangular motifs are assembled and hexagonal pores are tetrabromomethane (the tetradentate XB donor) alternates at the
generated where the sides are terphenyl moieties and the network nodes with chloride (VAPVOY) or iodide (VAPWAL)
anions, which function as tetradentate XB acceptors. Cations at the
vertexes are three halogen-bonded bromine atoms. Scanning center of the cage are shown in space-filling style. Only one
tunneling microscopy (STM) allows for the visualization of (C2H5)4N+ is drawn for clarity. Color code: carbon, gray; iodine,
these arrays (Figure 81B). The formation of square porous purple; bromine, light brown; chlorine, light green; hydrogen, white.
networks on Au(111) by using 4,4″-dibromo-p-quaterphenyl XBs are dotted black lines. CSD Refcodes are reported.
(DBQP) was reported a few years after the results described
above.755 The network had chiral quadrupole nodes that were
explained with four Br···Br XBs and four H···Br HBs. 3.1.4. Interpenetrated Networks. The design and
XB was also applied to drive the self-assembly of a synthesis of entangled supramolecular networks with high
thienophenanthrene derivative (TPA) at the aliphatic acid/ structural complexity have always stimulated the scientific
graphite interface using STM.756 It was found that different curiosity of chemists either due to the aesthetic beauty of these
nanosized structures could be formed by adjusting the TPA sophisticated architectures or due to the unique and useful
concentration. Even in this case the driving force was the functions they may possess, such as robustness or adaptive
formation of short Br···Br XBs. behavior. Interpenetrated networks are among the most
Finally, Wan et al.757 recently demonstrated the formation of intriguing three-dimensional (3D) systems, and the under-
XB-based open porous networks on a highly oriented pyrolytic standing of their topology is a particularly challenging
graphite surface using 1,3,5-tris(ethynylpyridyl)benzene task.748,758
(TEPB) as an XB acceptor and TITFB, or analogous An instrumental strategy for the construction of entangled
diiodinated tectons, as an XB donor. The formation of the networks by rational design is to translate the molecular
2D networks was driven by I···N XBs, and it was found that the geometry into the supramolecular geometry, namely, to
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Figure 83. Structures of starting tectons and schematic views, obtained with TOPOS,748 of the corresponding interpenetrated networks: (A)
DIPFH/TPP (sql, 4-fold interpenetration); (B) DIPFO/TPP (sql, 5-fold interpenetration); (C) DIPFB/TPP (dia, 8-fold interpenetration); (D)
TITFPP/TPP (dia, 10-fold interpenetration).

translate the topological information encoded in the starting characterization of the solid revealed the formation of an
building blocks into the supramolecular topology. This interpenetrated system composed by the combination of 5-fold
becomes feasible when a highly directional interaction is used diamondoid and 3-fold square grid networks both assembled by
to link donor and acceptor modules bearing the binding sites the I···O2N synthon (Nc = 0.94−0.97).
after a convenient geometry. Another possible strategy to A few years later, P. Metrangolo and G. Resnati760 adopted a
influence the formation of interpenetrated systems is the similar strategy and assembled highly interpenetrated archi-
assembly of rigid frameworks having large and uniform tectures starting from XB donor and acceptor units having a
(potential) cavities. Entanglement involves several such frame- tetrahedral core. The tetrakis(4-pyridyl)pentaerythritol (TPP)
works, which mutually interlock to satisfy the close-packing and the tetrakis(4-iodotetrafluorophenyl)pentaerythritol
requirements and to prevent the system from collapsing, as (TITFPP) were the XB acceptor and donor modules used in
might be the case if the lack of interpenetration leaves voids in the study. These modules exhibited a greater flexibility than
the packing.
DIDNTPM due to the presence of the oxymethylene spacer
As shown in previous sections, the XB is a strong and highly
bridging the tetrahedral core and the XB binding sites. The
directional interaction, and thanks to these unique features, it
could be successfully used to build up robust and rigid absence of a bias toward the diamondoid structure allowed for
supramolecular nets for the assembly of interpenetrated the obtainment of a small library of interpenetrated networks
networks. with quite different topologies and connectivities. In all of the
Tectons with a tetrahedral core are often tailored to form 3D cocrystals, TPP functioned as a robust tetradentate XB acceptor
architectures, and if the arms on the core are sufficiently long thanks to its four pyridyl rings, the Nc values for the I···N
and rigid to create large cavities, these motifs usually tend to contacts spanned the 0.82−0.86 range, and all C−I···N angles
interpenetrate. Following this principle, in 2001 G. R. Desiraju were close to linear (160°−178°). When TPP was cocrystal-
et al. used the 4,4′-diiodo-4″,4‴-dinitrotetraphenylmethane lized with 1,6-diiodoperfluorohexane (DIPFH) and 1,8-
(DIDNTPM) as a self-complementary XB module to construct diiodoperfluorooctane (DIPFO), the corresponding adducts
a supramolecular diamondoid network.759 The structural showed a 1:2 stoichiometry and two-dimensional (2D) square
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Figure 84. Structures of starting tectons and schematic views, obtained with TOPOS,748 of the corresponding interpenetrated networks: (A)
DIOFS/TPP adduct (sql, 3-fold interpenetration); (B) DITFB/TPC (sql, 2-fold interpenetration); (C) DAB-2-IPFB/t-BPE (sql, 5-fold
interpenetration); (D) K.2.2.2/KI/DIPFH or DIPFO ((6,3) net, Borromean interpenetration).

44 layers (sql) with 4-fold and 5-fold interpenetrations, ethylene (t-BPE) as the XB acceptor. The construction of the
respectively (Figure 83). supramolecular network was driven by the I···N synthon (Nc ≈
When TPP was cocrystallized with 1,4-diiodoperfluorobu- 0.8), which thanks to its high directionality (C−I···N in the
tane (DIPFB) and TITFPP, adducts with 1:2 and 1:1 range of 173−178°) was able to effectively translate the
stoichiometries were obtained, respectively, and they both tetragonal arrangement of the DAB-dendr tectons into the
showed a diamondoid (dia) interpenetration with a rare 8-fold overall network. Topological analysis showed that the XB
interpenetration of class Ia and a remarkable 5 × 2 = 10-fold donor/acceptor modules were assembled in very large 2D
interpenetration of class IIIa. The tendency of TPP to form square networks and the overall packing was composed of 5-
interpenetrated nets was further confirmed when it was fold interpenetrated and translationally related square 44 layers
cocrystallized with 4,4′-diiodooctafluorostilbene (DIOFS), (Figure 84).
another rigid, linear, and ditopic XB acceptor. The X-ray These examples of interpenetration, although limited in
characterization of the obtained cocrystal revealed that the self- number, may suggest that the use of donor and acceptor
assembled architecture was formed by alternating parallel layers modules with similar geometries and different sizes afford self-
having a square 44 topology, each layer resulting from the assembled networks with similar topologies and different sizes
interpenetration of three different square networks (Figure 84). where the larger modules afford more extended networks and
When tetrakis(4-pyridyl)cyclobutane (TPC), a tetradentate the resulting larger voids allow for a higher interpenetration.
tecton more rigid than TPP, was cocrystallized with 1,4- Also anionic XB acceptors allowed for the obtainment of
diiodotetrafluorobenzene (1,4-DITFB), an entangled network interpenetrated networks as was the case for some nets having
exhibited a 2D square 44 network with a 2-fold interpenetration iodide anions at the nodes of the nets and showing a
of class IIa (Figure 84).761 Borromean entanglement. Borromean rings constitute one of
A further example of halogen-bonded interpenetrated the most fascinating patterns of topological entanglements, and
networks was achieved by the same authors762 by using their distinctive topological features lie in their mode of
poly(propylenimine) dendrimer DAB-dendr-(NHC 6F 4 I) 22 interpenetration: Three mutually disjoint simple closed curves
(DAB-2-IPFB) as the XB donor and trans-1,2-bis(4-pyridyl)- form a link, yet no two rings are linked; thus, if one is cut, the
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Figure 85. Structures of starting tectons and schematic views, obtained with TOPOS,748 of the corresponding interpenetrated networks. (A)
[Co(1IP)(1,4-BIMB)]n (3-fold interpenetration). Adapted from ref 764. Copyright 2011 American Chemical Society. (B) HFTIPB/Ph4PCl or
Ph4PBr (8-fold interpenetrated net of class Ia). Adapted from ref 765. Copyright 2011 American Chemical Society. (C) TITFB/Et3MeN+I− (4-fold
interpenetration of class IIIa). Adapted from ref 766. Copyright 2013 American Chemical Society. (C) [Zn2(BMIB)(TBTP)2·2H2O]n (4-fold
interpenetration dia of class IIIa). Adapted with permission from ref 767. Copyright 2014 Royal Society of Chemistry.

other two fall apart. In 2006, the first halogen-bonded Several interpenetrated coordination polymers (CPs) have
Borromean networks were obtained on self-assembly of the been obtained starting from manganese, zinc, or cobalt ions,
kryptand 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]- different nitrogen ligands (such as t-BPE or 1,4-bis(imidazol-1-
hexacosane (K.2.2.2), potassium iodide (KI), and DIPFH or ylmethyl)benzene (1,4-BIMB) or its 1,3-analogue (1,3-BIMB)),
DIPFO (Figure 84).763 K.2.2.2 chelates K+, and the formed and the rigid ligand 5-iodoisophthalic acid (IIP),764 where the
naked iodide anion behaves as a tridentate XB acceptor, which iodine atom was expected to support the supramolecular
sits at the nodes of the network and binds three different synthons I···O, I···N, I···π, and I···I. The CP [Zn(IIP)(t-
diiodoperfluoroalkanes, which, in turn, behave as bidentate XB BPE)1.5]n featured interesting 3-fold parallel interpenetrated
donor spacers connecting the nodes. The final supramolecular two-dimensional (2D) → 3D network motifs, which were
architectures of K.2.2.2/KI/DIPFH and K.2.2.2/KI/DIPFO stabilized by interlayer I···π, π···π, and C−H···π interactions. In
present infinite and highly undulated honeycomb-like sheets the structure [Co(IIP)(1,4-BIMB)]n, the ligand adopted a μ2-
where each chair-shaped hexagon is defined by six noncoplanar bridge coordination mode through bis-monodentate carbox-
ylate moieties linking two Co centers to form infinite chains
iodide anions (vertexes) and six diiodoperfluoroalkanes
along the a-axis, which were expanded into a 2D system
(connectors). Nc values for I···I− contacts are 0.83 and 0.85
through μ2-bridged 1,4-BIMB ligands. The adjacent layers were
for Borromean systems formed by DIPFH and DIPFO,
connected by I···O contacts (Nc = 0.95−0.97) to form a 3D
respectively. Once again, the strength and directionality of supramolecular structure, and three sets of them are interlocked
XB, along with the stiffness of the perfluorinated modules, with each other to display a 3-fold interpenetrating architecture
allowed the transfer, with great accuracy, of the arrangement of (Figure 85A). The complex [Co(IIP)(1,3-BIMB)]n also
anions in the crystal packing to the XB donor tectons forming showed I···O XBs (Nc = 0.97), which promoted a rare 2-fold
the undulated (6,3) honeycomb-like arrangement, which interpenetrating 3D supramolecular architecture.
remained unmodified when the XB donor was changed. The Interpenetrated and halogen-bonded networks were seren-
fine balance between supramolecular synthon strength and dipitously formed by R. Kato and M. Fourmigué765 during the
module dimensions allowed for the formation of isostructural development of various nanowire crystals where the insulating
halogen-bonded hexagonal grids with large and uniform networks were made of halide anions halogen-bonded to rigid
cavities, which have induced the fluorinated layers to mutually neutral molecules. The authors synthesized an aromatic tecton
interlock in a Borromean fashion. with an extended skeleton, 2,2′,4,4′,6,6′-hexafluoro-3,3′,5,5′-
2532 DOI: 10.1021/acs.chemrev.5b00484
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tetrakis[[(4-(iodoethynyl)phenyl]ethynyl]biphenyl (HFTIPB) relevance in applications such as encapsulation and separation,

and possessing a pseudotetrahedral symmetry. Electrocrystalli- among others. The halogen bond has opened new avenues in
zation experiments of this tecton with a bis(propylenedithio)- this field thanks to its specificity for halocarbons, a class of
tetrathiafulvalene (BPTTF) derivative were performed in the industrially important compounds.
presence of PPh4Cl or PPh4Br. The two corresponding The first example in this field dates back to 1999, when P.
cocrystals adopted a complex structure with mixed radical Metrangolo and G. Resnati used the Lewis base (−)-sparteine
BPTTF cation/Br− (or Cl−) anion layers alternating with the hydrobromide to resolve the racemic 1,2-dibromohexafluor-
neutral HFTIPB molecules. The halide anions behaved as opropane. The resolution occurred as a result of a highly
tetradentate XB acceptors toward four iodine atoms of four specific inclusion of only the (S)-enantiomer in a chiral crystal
different HFTIPB molecules, driving the formation of a square with a halogen-bonded helical arrangement formed by halogen
planar motif. The overall connectivity pattern around one bonds between the C-bound Br atoms of the perfluoropropane
halide anion led to the formation of a complex sublattice, which and the Br− ions of the enantiopure base.263
showed an 8-fold interpenetrated net of class Ia (Figure 85B). Interestingly, in 2005 T. Takeuchi and co-workers768
The strategy to use halide anions and neutral XB tectons to developed an imprinted polymer based on XB to be applied
develop supramolecular structures having conducting proper- as a stationary phase in a separation technique. In general,
ties was further investigated by assembling 1,3,5-tris- molecularly imprinted polymers are host systems synthesized
(iodoethynyl)-2,4,6-trifluorobenzene (TITFB), a tritopic and by copolymerization of functional monomer(s) and cross-
neutral XB donor, with different haloorganic salts. It was linker(s) in the presence of a template guest molecule.769 The
expected that, similar to triiodotrifluorobenzene,539 the resulting polymers have selective binding sites complementary
tridentate XB donor TITFB could afford 2D (6,3) networks to the template guest. In noncovalent imprinting, the functional
with large cavities, which could accommodate guest molecules monomers are selected to establish specific intermolecular
or could form entangled networks. As anticipated, the interactions with the guest molecule. An approach based on
cocrystallization of TITFB with several halide salts having supramolecular assembly has been largely promoted because
different cations in a 1:1 ratio produced (6,3) honeycomb-like (I) it facilitates the preorganization of complexes induced by
networks where the halide anions behaved as tridentate XB the mutual recognition between the monomer(s) and the guest
acceptors connecting three different TITFB units by I···X− and (II) it favors the formation of the host cavities after the
contacts (X = I, Br). Specifically, the adduct between TITFB removal of the templates by washing.
and Bu3S+I− showed a highly corrugated and halogen-bonded The formation of an imprinted polymer host based on
(6,3) system where Nc for I···I− was 0.82 and the (6,3) halogen bonding was achieved by the polymerization of the
networks showed a 2-fold interpenetration. The self-asembly of functional monomer 2,3,5,6-tetrafluoro-4-iodostyrene, the XB
TITFB and Et3MeN+I− afforded architectures with more donor, with divinylbenzene and styrene as cross-linking agents,
sophisticated topologies. Iodide anions were tridentate, but in the presence of 4-(dimethylamino)pyridine as the templating
while bridging three different TITFB molecules, the expected guest. It was expected that the XB acceptor template would
2D (6,3) network was not formed, since one of the three recognize the XB donor sites on the host system, imprinting the
TITFB units was rotated out of the network plane and a molecular shape of the guest into the polymer and creating
complex 3D anionic network was formed where the very large specific binding sites highly selective for the 4-
cavities enabled for a 4-fold interpenetration of class IIIa (dimethylamino)pyridine guest and its structural analogues.
(Figure 85C).766 A very rare example of an entangled halogen- The binding affinity and the imprinted properties of the
bonded system was obtained when TITFB and Et3BuN+Br− resulting system were investigated by competitive experiments
were mixed in a 2:1 ratio. The assembly process driven by XB using different XB acceptors bearing either aliphatic or aromatic
(Nc for I···Br− is 0.83) produced a cubic structure where the nitrogen groups. The 4-(dimethylamino)pyridine guest showed
bromide anion assumed an unprecedented hexadentate one of the highest affinities for the porous polymeric host
octahedral coordination, which, in combination with the among the different XB acceptors used. This behavior was
trigonal nodes provided by the TITFB molecule, generated a rationalized by the fact that a synergistic effect deriving from
hexagonal 3D network with a 2-fold interpenetration of class Ia. the templating process occurred during the polymerization and
Interpenetrated coordination polymers were also assembled the presence of two electron density donor sites on the guest.
by reacting, under solvothermal conditions, tetrabromotereph- However, the XB-imprinted polymer showed an even higher
thalic acid (TBTP) with zinc ion and 1,4-bis(2-methyl-1H- affinity for the less bulky 4-aminopyridine, suggesting that steric
imidazol-1-yl)butane (BMIB), a flexible ligand.767 The single- hindrance sensibly influenced the recognition phenomena
crystal X-ray diffraction analysis of those crystals revealed that (Figure 86).
the [Zn2(BMIB)(TBTP)2·2H2O]n unit was assembled into α,ω-Diiodoperfluoroalkanes (I(CF2)mI, DIPFAm) are a class
single diamondoid networks with huge voids, which allowed of key intermediates in the synthesis of various fluorochemicals
other networks to entangle each other, leading to a 4-fold and fluoropolymers,770 and an elegant method for their
interpenetrated dia net of class IIIa (Figure 85D). The effective separation was reported in 2009 and expanded the
interpenetrated net was reinforced by several hydrogen concept of dynamic recognition of host systems in the solid
bonds, type I halogen−halogen contacts, and Br···Br XBs state. It was observed that when a mixture of α,ω-
occurring between close TBTP molecules belonging to diiodoperfluoroalkanes and a given α,ω-bis-
different diamond networks (Nc for Br···Br is 0.96, and the (trimethylammonium)alkane diiodide ((CH3)3N(CH2)nN-
C−Br···Br angle is 152°). (CH3)3·2I−, BTMAAn) are crystallized from solution, the
BTMAAn organic salt instantaneously forms a cocrystal, driven
3.2. Applications by the I···I− XB, with DIPFAm when m = n − 6. The
3.2.1. Porous Systems. The dynamic behavior of host− preferential molecular recognition of a given DIPFAm was due
guest systems has received a lot of attention for its great to the enhanced electrostatic binding strength in the ionic
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Figure 86. Top: possible structure of the molecularly imprinted

polymer obtained using 2,3,5,6-tetrafluoro-4-iodostyrene as the
monomer and 4-(dimethylamino)pyridine as the template. Bottom:
binding affinities of different XB acceptors for the imprinted polymer.
Adapted with permission from ref 768. Copyright 2005 Elsevier Ltd.

lattice wherein the size of the halogen-bonded superanion I−···

I(CF2)mI···I− matched that of the dicationic alkyl chain in the
diammonium moiety. Several consistent examples proved that
selective recognition occurred only when the “size-matching
rule” was respected, namely, when the separation between the
two iodide anions in the superanions matched the distance
between the two positive N atoms in the cations by around
0.7−1 Å or less. This size complementarity is exemplified by Figure 87. (A) Packing of bis(trimethylammonium)decane diiodide
the single-crystal structure of the complex DIPFA4···BTMAA10 dihydrate (XOVBIU) viewed along the a-axis. (B) Complex
(Figure 87), where four alkyl dications define a rectangular bis(trimethylammonium)decane diiodide/diiodoperfluorobutane
parallelepiped cavity that encapsulates a DIPFA4 molecule (XOVBAM) showing the molecular cavity defined by four alkyl
which is pinned in its position by strong XBs to the two I− ions dications, with encapsulated disordered guest molecules (space-filling
at either end. Here the difference between the intramolecular style). This molecule is halogen-bonded to I− ions at the top and the
bottom. (C) Crystal packing of the same complex viewed along the c-
distance of the N atoms in the cation and the iodide ions’
axis. The α,ω-DIPFA molecules are disordered over two positions. In
spacing is 0.85 Å. (A) only the water H atoms are reported. In (B) no hydrogen atoms
It was found that even microcrystalline powders of the iodide are reported. Color code: carbon, gray; nitrogen, blue; oxygen, red;
organic salts could selectively and reversibly incorporate iodine, purple; fluorine, yellow; hydrogen, white. XBs and HBs are
DIPFAm from the gas phase despite the absence of porosity dotted black lines.
in the starting crystal structures of BTMAAn. The selective
guest adsorption through a solid−gas reaction occurring under
control by the size complementarity of the modules in the The dynamic behavior of bis(trimethylammonium)alkane
host−guest structure proved the dynamic behavior of these diiodide salts was also exploited to trap the shortest and iodine-
materials. Since the starting organic salts are not porous in based XB donor, i.e., diiodine. The crystallization of the
nature, the formation of the size-matched halogen-bonded diiodide salt of 1,6-bis(trimethylammonium)hexane (HMET)
complexes occurred through a remarkable dynamic and with I2 in a 1:1 ratio led to the quantitative formation of the
reversible rearrangement of the BTMAAn crystal lattice, discrete I42− dianion (Figure 88A), a molecular entity that is a
which created the space to accommodate the size-matched shallow minimum in the surface potential of systems
DIPFAm after an allosteric process, which was not observed in compounded by I2 and I−.771 Similarly, the triiodide of
the mismatched complexes. Interestingly, a system where a 2,2,9,9,16,16-hexamethyl-2,9,16-triazoniaheptadecane, a triam-
BTMAAn is halogen bonded to a mismatched DIPFAm (m ≠ n monium cation structurally related to HMET, trapped two I2
− 6) can also be obtained, and when powders of these materials molecules and formed the discrete I73− trianion (Figure
are exposed to vapors of the size-matched DIPFAm (m = n − 88B).772 In both cases, the formation of these unusual
6), the “right” DIPFAm substitutes for the “wrong” one in a polyiodides as isolated species was driven by a combination
gas−solid reaction. This confirms that bis- of two factors: the ability of I− to function as a very efficient XB
(trimethylammonium)alkane diiodide salts are a very promising acceptor toward I2 and the size matching between the
new class of dynamically porous materials. superanion units and the intraatomic N+−N+ separation in
2534 DOI: 10.1021/acs.chemrev.5b00484
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salts, where the superanion was positioned in a cavity and

stabilized by anion···π interactions occurring with the
perfluorinated rings.163 Cation-templated synthesis was more
recently adopted to obtain long and discrete polyiodide species,
as is the case for dicationic N donors based on 1,4-
diazabicyclo[2.2.2]octane, which was able to template discrete
pseudolinear dodecaiodide species (Figure 88D).774
The dynamic response of bis(trimethylammonium)alkane
dihalide salts toward the inclusion of XB donor guests was
further exploited for the isolation of previously unknown mixed
tetrahalides. It has been reported that, on reaction with 2 equiv
of I2, hexamethonium chloride and bromide afford the
corresponding mixed trihalides XI2− (X = Cl, Br),775 which
undergo thermally induced crystal-to-crystal elimination of one
I2 molecule, yielding quantitatively the virtually unknown
tetrahalides [Cl2I2]2− and [Br2I2]2− (Figure 89). In these
tetrahalide dianions, the lighter Cl− and Br− halides double-pin
a single I2 molecule via short XBs, forming the tetrahalide units,
which are selectively encapsulated by the HMET dications as a
consequence of size matching of the self-assembled compo-
nents. The starting units in the HMET·2XI2− trihalides are
preorganized to respond dynamically to heating and eliminate

Figure 88. Partial view (ball-and-stick representation) of the crystal

packing of (A) the discrete I42− anion hosted in a size-matched cavity
formed by four HMET units, (B) the discrete I73− anion surrounded
by four trication units, (C) the discrete I42− anion caged between two
N,N′-bis(tetrafluorobenzyl)-(E)-1,2-bis(4,4′-bipyridinium)ethylene
units (the cations are disordered over two positions), and (D) the
complex containing the discrete pseudolinear dodecaiodide species.
Polyiodide anions are represented in space-filling style. Color code:
carbon, gray; nitrogen, blue; iodine, purple; fluorine, yellow; hydrogen,
white.

the cations. These discrete polyiodide systems were obtained

from both solution and gas−solid reaction, and both the bi- and
the triammonium cations were able to reversibly uptake and
release I2 by external stimuli, demonstrating further their
dynamically porous character.
Some viologen derivatives with structurally different
pendants on the nitrogen atoms of the pyridyl rings showed
a similar uptake of XB donor guests under size-matching
control. The pendants on the nitrogen atoms effectively
hampered catenation of polyiodide species by capping the
compartments of the crystal lattice identified by the dimensions
of the viologen cations. Specifically, N,N′-bis-
(tetrafluorobenzyl)-(E)-1,2-bis(4,4′-bipyridinium)ethylene was
able to stabilize the I42− superanion independently of the I2 Figure 89. Partial view (ball-and-stick representation) of the crystal
stoichiometry used during the crystallization process. The packing of (A, B) the mixed trihalide adducts HMET·2XI2− (A, X =
Br; B, X = Cl) and (C, D) the mixed tetrahalides [Br2I2]2− (C) and
bipyridiniumethylene moieties adopted a nearly planar [Cl2I2]2− (D), obtained upon heating of the corresponding trihalides
conformation, and four of them were the sides of a from (A) and (B). These mixed polyhalides are held together by XBs
parallelepiped cage self-capped by the fluorophenyl rings of and are pinned by HBs in the cavities formed by four dication units.
benzyl pendants (Figure 88C).773 Color code: carbon, gray; nitrogen, blue; iodine, purple; bromine, light
The isolation of discrete halogen-bonded I42− units was also brown; chlorine, light green; fluorine, yellow; hydrogen, white. XBs
achieved using perfluorobenzene-substituted bisphosphonium and HBs are dotted black lines.

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one I2 molecule and afford the tetrahalide. Interestingly, the purposes,681,779 as the directionality and robustness of metal
second I2 molecule was so tightly bound that it could be coordination allows for a careful design of the porosity of the
released only upon melting of the solid supramolecular systems. HB has recently received growing attention for the
system.487 purpose,780 while quite a few reports describe the preparation
The examples reported above showing the ability of via XB of molecular frameworks possessing well-defined cavities
bis(trimethylammonium)alkane dihalide salts to dynamically in their lattice. In 2009 K. Rissanen et al. reported the
and reversibly encapsulate molecular guests demonstrate that successful use of XB for the rational design of porous materials
the behavior is general and may have far-reaching applications obtained by the self-assembly of rigid macrocyclic building
for the encapsulation and separation of other guests of blocks.184 Piperazine cyclophanes, thanks to the structural
industrial relevance, for example the separation of dicarboxylic rigidity of their rings, could in principle accommodate small
acids by engaging the halide ions of BTMAAn in interactions neutral guest molecules and were selected as starting building
other than XB. blocks. They were cocrystallized with 1,4-diiodotetrafluoroben-
As for gas−solid reactions which produce halogen-bonded zene (XB donor) in different molar ratios. The X-ray studies
cocrystals, it has been reported that simple Cu(II) coordination revealed that the cyclophane modules segregated into columns
complexes such as trans-[CuCl2(3-Xpy)2] (X = Cl, Br) react as where the cyclophane cavities were piled up to form infinite
crystalline solids with either hydrated or anhydrous HCl gas to tubular structures, with the different tubes cross-linked by I···N
give rise to the crystalline salts (3-Xpy)2[CuCl4]. The XBs. Chloroform molecules (crystallization solvent) occupied
absorption of the gaseous HCl induced a variation in the the intramolecular cavities of the cyclophanes (Figure 91). The
coordination sphere of the metal sites, which produced drastic calculated void revealed that the roughly cyclindrical voids
solid-state rearrangements of the molecular structures. represented 13% of the unit cell volume.
Crystallographic studies suggested that the reorganization of
the HB and XB patterns present in the starting structures
played a mayor role during the reorganization process.776,777 In
addition, the reactions were reversible, and the Cu(II)
coordination complexes showed a good sensitivity to the HCl
gas in the range of 200−20000 ppm.
The same authors extended the above-mentioned studies on
HCl absorption by exposing the complex trans-[CuBr2(3-
Brpy)2] to vapors of aqueous HBr. The resulting crystalline salt
(3-BrpyH)2[CuBr4] showed the same chemical composition as
above, but a different crystal structure compared to its (3-
BrpyH)2[CuCl4] counterpart. Despite this structural difference
on HX addition, the reverse reaction, i.e., removal of HX,
returned each system to a common structural arrangement
(Figure 90).778
The design of materials with channels or cavities for gas
storage/separation or for reaction catalysis is a relatively recent
and very important research topic. Metal−organic frameworks
(MOFs) are the materials by far most commonly used for these

Figure 91. Top: molecular structures of the used XB donor and

acceptor. Bottom: crystal packing of the halogen-bonded complex
showing the ciclophane tubes. The XB is represented by dotted lines.
The included chloroform molecules are omitted in the left plot and are
shown in space-filling style in the right plot. Reprinted from ref 184.
Copyright 2009 American Chemical Society.

The same group in 2012 reported the formation of molecular

crystals with nanosized channels. These systems showed an
unusual “breathing behavior”, which allowed for the modulation
of the volume and shape of the channels upon induced fit with
the solvent guests. The basic supramolecular unit was
composed by one hexamethylenetetramine (HMTA) unit and
four N-iodosuccinimide (NIS) molecules, which were
assembled by strong and highly directional I···N XBs (Nc ≈
Figure 90. Different structural arrangements observed in the products
of the reaction between crystalline trans-[CuX2(3-Xpy)2] and HCl or
0.8).781 The [NIS]4···[HMTA] complexes crystallized in three
HBr gases. The colors of the arrows and of the chemical formulas are different polymorphic forms by varying the crystallization
associated. Metal and halide ligands are shown in red, organic halogens solvent. All the forms gave columnar assemblies as a primary
in green, and all other atoms in blue (C, H, N). Black dotted lines motif, and the obtained supramolecular pillars, sustained by
represent HBs and XBs. Reprinted with permission from ref 778. internal HB networks, were assembled parallel to each other to
Copyright 2011 Royal Society of Chemistry. optimize the channel space for the selected guest molecules.
2536 DOI: 10.1021/acs.chemrev.5b00484
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Toluene, chloroform, nitromethane, and acetonitrile were of two channels with different shapes and chemical environ-
hosted in the tubular channels. The inclusion of dichloro- ments. The channels hosted various guest solvent molecules
methane and carbon tetrachloride resulted, instead, in the such as dioxane, nitrobenzene, or 1,3-dibromobenzene. The
formation of a very robust crystal lattice with well-defined XB/HB network was robust enough to sustain a single-crystal
square grid channels, which survived guest exchange by single- to single-crystal and reversible exchange of the guest which
crystal to single-crystal transformation (Figure 92). occurred under gas−liquid conditions. Nitrobenzene and 1,3-
dibromobenzene were, in fact, neatly substituted for dioxane
without disrupting the framework topology (Figure 93).

Figure 93. Top left: partial view (stick representation) of one layer of
the ligand···HI adduct assembled by orthogonal HB and XB. I− and H+
ions are shown in space-filling representation. Top right: two adjacent
layers (red and green) stack along the a-axis, resulting in the
partitioning of the void in the rectangular grids. Dioxane molecules
have been omitted for clarity. Bottom: partial views (stick
representation) of the single-crystal X-ray structures of the ligand···
Figure 92. Top: molecular structures of the used XB acceptor and HI adducts containing dioxane (left) and 1,3-dibromobenzene (right).
donor. Bottom: crystal structures of the [NIS]4···[HMTA] complexes The latter system is obtained when a crystal of the former is divided
obtained upon crystallization from different solvents. Crystal structures into 1,3-dibromobenzene at room temperature. Reprinted with
of [NIS]4···[HMTA]@C6H5CH3 and [NIS]4···[HMTA]@CHCl3 as permission from ref 782. Copyright 2012 Royal Society of Chemistry.
well as [NIS] 4 ···[HMTA]@CH 3 CN and [NIS] 4 ···[HMTA]@
CH3NO2 are isomorphs, whereas [NIS]4···[HMTA]@CH2Cl2 and
[NIS]4···[HMTA]@CCl4 are different, but can be interconverted via Two further examples of frameworks constructed by XB are
guest molecule exchange. Adapted with permission from ref 781. the anionic 3D network formed by [4-(benzoyloxy)-2,2,6,6-
Copyright 2012 Royal Society of Chemistry. tetramethylpiperidinyl]-1-oxy, a free radical species, and
molecular iodine783 and the network based on an asymmetri-
cally substituted and self-complementary arylporphyrin (Figure
In the same year, some of us reported the formation of a 94). Notably, in this case, all the halogen-bonded porphyrin
molecular open organic framework which showed 2D channels layers were aligned in the same direction, imparting chirality
and was able to host various guest molecules and interchange upon the entire 3D assembly.784
them in single-crystal to single-crystal reactions.782 The 4,4′- The design and synthesis of molecular containers for guest
[1,2-bis(2,3,5,6-tetrafluoro-4-iodophenoxy)ethane-1,2-diyl]- encapsulation is a very topical area in supramolecular chemistry
dipyridine possessed two pairs of sites (the nitrogen and iodine and after the pioneering work by Cram et al.785 different
atoms of pyridyl and iodotetrafluorophenyl rings, respectively) approaches based on HB or metal−ligand coordination have
for potential chemically and geometrically orthogonal binding been successful employed.
modes and was selected as a molecular building block for The first halogen-bonded capsule was a heteromeric system
framework preparation. Consistent with the adopted design, obtained in 2012 by C. B. Aakeröy, P. Metrangolo, and G.
the obtained framework was assembled via orthogonal and Resnati on self-assembly of a C-pentyltetrakis(4-pyridyl)-
cooperative XB and HB. The inherent tendency of the cavitand (XB acceptor) and a p-tert-butylcalix[4]arene tetrakis-
molecular building block to self-assemble via I···N XBs was [2-(4-iodotetrafluorophenoxy)ethyl ether] (XB donor).786 The
disrupted using hydrogen iodide, which functioned as a source design assumed that the rigidity of the cavitand and the
of both H+, a strong HB donor for the protonation of the calix[4]arene scaffolds allows for the donor and acceptor sites
pyridine moiety, and I−, a strong XB acceptor for the binding of to be preorganized for a multiple binding, and the conforma-
the iodotetrafluorophenyl ring. Both H+ and I− behaved as tional flexibility of the −OCH2CH2O− bridges separating the
bidentate connectors and formed robust and linear I···I−···I and calix[4]arene platform and the iodotetrafluorobenzene pendant
N···H+···N synthons. These synthons translated the cruciform enables an effective partner-induced fitting between the four XB
shape of the starting module, having the four arms fully donor and acceptor sites of the interacting partners. The
extended two-by-two to opposite sides, into the topology of the cocrystallization of the two modules in CH3CN afforded the
obtained network, comprising quasi-rectangular 2D grids. Two halogen-bonded heteromeric capsule in the solid state thanks to
adjacent grid layers gave rise to a biporous network consisting the pairing of one cavitand unit and one tetrakis-
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Figure 94. Top: partial view of a layer formed on assembly of the self-
complementary porphyrin. XBs are in black dotted lines. Bottom:
unidirectional arrangement of two successive layers. Adapted with
permission from ref 784. Copyright 2008 Royal Society of Chemistry.

(iodotetrafluorophenyl)calix[4]arene via four I···N XBs (aver-

age Nc = 0.85 and C−I···N angle in the range of 169−177°). Figure 95. Top: molecular structures of the XB acceptor (left) and
The pyridyl rings were all inwardly oriented and converged donor (right) used for the construction of the capsule. Bottom left:
space-filling representation of the molecular capsule assembled via XB.
toward the same XB donor, and CH3CN solvent molecules
The solvent molecule are omitted to show the cavity inside the
filled the cavities in the capsule (Figure 95). capsule. Bottom right: ball-and-stick representation of the molecular
More recently, N. K. Beyeh et al.787 developed a dimeric capsule where the solvent molecules are shown in space-filling style
capsule which was assembled by connecting molecular iodine and I···N XBs are shown as dotted black lines. Color code: carbon,
with two macrocyclic molecules with a bowl-shaped structure, gray; nitrogen, blue; oxygen, red; iodine, purple; fluorine, yellow;
the N-cyclohexylammonium resorcinarene chloride. Differently hydrogen, white.
from the previous capsule, the construction of this complex was
driven by I···Cl− XBs, which took place between the telechelic the solvent. Differently, in the confined space within a capsule,
XB donor I2 and the chloride anion of the resorcinarene units the lifetime of noncovalent complexes is prolonged thanks to
(Nc = 0.82−0.94). Thanks to the bowl-shaped XB acceptor the isolation from the medium and the preorganization of the
modules, the capsule showed a single cavity (V = 511 Å3) large environment, which favors the self-assembly process. By
enough to encapsulate three 1,4-dioxane guest molecules monitoring with 19F NMR solution systems containing the
(Figure 96, left). Similar ammonium resorcinarene halide modified cavitad modules, the fluorinated XB donor, and the
systems were used by the same group to develop halogen- XB acceptor, Rebek observed a large shift in the 19F spectrum
bonded analogues of deep cavity cavitands.788 The walls of the of the XB donor consistent with the encapsulation of a halogen-
cavitands were formed by CCl3Br molecules fixed in their bonded dimer.
position by Br···X− contacts (X = Br or Cl). The encapsulation of an XB donor was reported by W. M.
Recently, F. Diederich and co-workers789 reported the first Nau et al. in 2012 when the authors isolated the host−guest
case of a halogen-bonded molecular capsule formed in solution complexes between diiodine or dibromine and the barrel-
as verified by NMR studies. The capsule was assembled by shaped cucurbit[6]uril.791 The crystal structures of the
using two resorcin[4]arene cavitands functionalized with assembled systems showed that the encapsulated dihalogens
pyridyl units, as XB acceptors, and with iodotetrafluorobenzene adopted a tilted axial geometry and were held in place by two
rings, as XB donors (Figure 96, middle). different types of XB interactions, one with a water molecule
J. Rebek and co-workers790 used a supramolecular capsule and the other with the ureido carbonyl groups of the molecular
formed via bifurcated hydrogen bonds involving modified container itself (Figure 97).
cavitad modules to encapsulate a halogen-bonded complex. The A more sophisticated cage for molecular iodide encapsulation
cavity was large enough to accommodate the dimer between was constructed by Y.-C. Horng et al. in the same year.792 The
the XB donor and acceptor units (e.g., iodoperfluoropropane XB acceptor was a cylinder-shaped dimer formed by two
and the γ-picoline, Figure 96, right). It is known that weak tripodal trisulfide precursors connected by three dynamic
intermolecular forces are difficult to observe in solution because disulfide bonds. The diiodine molecule was trapped in the
the molecular encounters are short-lived and overwhelmed by cavity formed by the tripodal trisulfide capsule and was located
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Figure 96. Left: molecular structures of the XB donor, XB acceptor, and guest molecule used for the assembly of N. K. Beyeh’s capsule (top) and
ball-and-stick representation of the halogen-bonded dimeric capsule with three 1,4-dioxane molecules in the cavity as space-filling CPK models
(bottom). The XBs are shown in black and HBs as green and red dotted lines. Adapted with permission from ref 787. Copyright 2015 John Wiley
and Sons. Middle: calculated model for the capsule developed by F. Diederich et al. with two 1,4-dioxane guests and four MeOH bridging units to
stabilize intramolecular HB between imidazole walls (nearly optimized at the DFT:B3LYP/cc-pVDZ-LANL2DZ level of theory). Adapted with
permission from ref 789. Copyright 2015 John Wiley and Sons. Right: chemical formula of the cavitand used by J. Rebek and co-workers and its
computer-modeled dimeric capsule (top; HBs are shown as green dotted lines) and calculated model for the capsule with the encapsulated and
halogen-bonded dimer (bottom). Full geometry optimization was carried out, including the capsule; the basis set for all atoms except iodine is 6-
31G(d,p), and that for I is LANL2DZdp ECP. Adapted from ref 790. Copyright 2013 American Chemical Society.

inclusion in the same cage of a halogen-bonded dimer formed

by aniline and 1,3,5-triiodotrifluorobenzene was also reported.
A similar approach was exploited to encapsulate CFCl3, a
banned freon, in a tetragonal cage based on anion
coordination.796 The freon encapsulation was stabilized by
weak Cl···π contacts as confirmed by the crystal structure
(Figure 98 C). NMR studies and high-resolution ESI-MS
Figure 97. Stick-style views of the single-crystal X-ray structure of the experiments showed that the inclusion complex was formed
cucurbit[6]uril−I2 complex. Encapsulated diiodine, in space-filling even in solution.
style (left), is halogen-bonded with a water molecule (middle) and is 3.2.2. Solid-State Synthesis. 3.2.2.1. Mechanochemistry.
bound to the carbonyl oxygen at the upper portal (right).
The syntheses of halogen-bonded adducts via heterogeneous
processes wherein a solid reagent interacts with a gas were
discussed in the previous section. Here we describe
perpendicular to the benzene ring of the tripodal units. I2 heterogeneous processes resorting to mechanochemistry,
encapsulation was driven by a cooperative effect of XBs namely, processes where a mechanical force is used to induce
(between the σ-hole of I2 and the aromaric π-systems) and HBs and/or sustain the chemical reaction between two solid
(between the negative belt of I2 and NH groups of the tripodal reagents.797 An intrinsic advantage of mechanochemistry is its
units). easy scalability to large quantities in a solvent-free and
M. Fujita’s coordination cages have shown the ability to environmentally compliant approach. In a recent review, T.
accommodate different molecular guests, such as DNA Frišcǐ ć highlighted the intimate connection between mecha-
duplexes793 and fluorous aggregates.794 Recently, it was nochemistry and the principles of supramolecular chemistry.798
shown that the XB between iodoperfluorocarbons (XB donors) Mechanochemical methods have been applied, among others,
and NO3− anions or H2O molecules (XB acceptors) is to the synthesis of new polymorphs and cocrystals of active
enhanced if the XB donor is confined inside a self-assembled pharmaceutical ingredients (APIs) as well as to the large-scale
cage.795 Fujita’s cage was able to encapsulate various XB production of porous metal−organic frameworks (MOFs).
donors, and in all of cases the iodine atoms were located at the Mechanochemical methods have been largely exploited for the
portals of the cage, thus allowing for the formation of XBs with synthesis of hydrogen-bonded cocrystals,797 while only a few
either NO3− anions or H2O molecules. Short I···O contacts examples of their use to produce halogen-bonded materials
were observed with both acceptors, and the XB formation was have been reported so far. The first example of mechanosyn-
demonstrated by using single-crystal X-ray diffraction and thesis of halogen-bonded systems appeared in 2008, carried out
NMR techniques (Figure 98A,B). Interestingly, the pairwise by D. Cincic et al.,77 who systematically studied the assembly
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behavior of 1,4-diiodotetrafluorobenzene and 1,4-dibromotetra-

fluorobenzene with a series of structurally similar XB acceptors
involving nitrogen, oxygen, or sulfur atoms. Powder and single-
crystal X-ray diffraction analyses on the solid materials obtained
upon neat grinding of the starting tectons revealed the
formation of seven chemically different but isostructural
cocrystals formed thanks to I···N, I···O, I···S, Br···N, and Br···
O XBs. A few years later the same researchers used one of these
cocrystals (i.e., the 1,4-diiodotetrafluorobenzene/thiomorpho-
line adduct) to perform kinetic studies with the aim of
understanding the competition between different supramolec-
ular interactions during the mechanochemical synthesis. By
varying the grinding times, different stoichiometric ratios of
donor to acceptor modules were obtained in the prepared
halogen-bonded cocrystals. The 1:2 ratio appeared fast at short
grinding times, while the 1:1 ratio was detected when using
longer grinding times. Single-crystal X-ray analysis showed that
the 1:1 adduct was assembled by the occurrence of
simultaneous I···N and I···S XBs, while the 1:2 cocrystal
showed only I···N XBs. This indicated a kinetic effect driven by
the formation of the product based on the strongest XB
possible, i.e., the I···N one (Figure 99).609
An important modification of the mechanochemical synthesis
methodology is the addition of a few drops of a solvent to the
solid-state materials just before grinding. Among others, this
liquid-assisted grinding (LAG) methodology has been used in
exploring the structure-directing (templating) properties of
various guests during the formation of the succinic acid/caffeine
cocrystal.799 It was found that the templating effect of
haloforms on the formation of the (succinic acid)·(caffeine)4
framework was promoted by both C−H···O HBs and Br···N
(or Cl···N) XBs (Figure 100).
In 2010 Frišcǐ ć and co-workers800 explored the possibility of
using mechanochemical reactions to simulateneously form
dynamic covalent bonds, metal coordination bonds, and XBs.
The one-pot reaction between dibenzoylmethanate, morpho-
line or thiomorpholine, nickel(II) or cobalt(II) cations, and 1,4-
diiodotetrafluorobenzene yielded the formation of an extended
structure consisting of metal−organic complexes connected
through XBs. A one-pot “all at once” milling approach was
used, instead, in 2014 to assemble four components, Cu-
(OAc)2·H2O, 4-aminoacetophenone, 2-hydroxy-1-naphthalde-
hyde, and 1,4-diiodotetrafluorobenzene. The mechanochemical
synthesis yielded the formation of a halogen-bonded metal−
organic framework (MOF), where the metal−organic units
were connected by strong I···O bonds (Figure 101).801
Many other examples of halogen-bonded systems obtained
by mechanochemical methods are now reported in the
literature, for example, for the synthesis of polyhalide771 and
interhalide487 species, as well as of new polymorphs and
cocrystals of halogenated APIs.485 One remarkable example
Figure 98. (A) Molecular structure of the self-assembled coordination involving APIs is the CaCl2 cocrystal of 3-iodo-2-propynyl N-
cage by Fujita. (B) Single-crystal X-ray structure of the inclusion butylcarbamate (IPBC), an iodinated antimicrobial product
complex between Fujita’s cage (stick representation) and 1,8- globally used as a preservative, fungicide, and algaecide.477
diiodoperfluorooctane (space-filling representation). Two molecules When ball milling is used, IPBC affords a 4:1 cocrystal with
of the XB acceptor are hosted inside the cage. NO3− anions and H2O CaCl2, and the cocrystal can be easily obtained on a 10 g scale.
molecules halogen-bonded to diiodoperfluorooctane molecules are Notably, this cocrystal shows improved technological properties
shown as space-filling models. H atoms, NO3− anions, and H2O
compared to the pure IPBC, i.e., higher thermal stability and
moleculs that are not involved in XB have been omitted for clarity.
Adapted with permission from ref 795. Copyright 2015 John Wiley improved powder flow properties (Figure 102).802
and Sons. (C) Crystal structure of the inclusion complex between the 3.2.2.2. Topochemical Reactions. The remarkable achieve-
anion-coordination-based tetragonal cage (stick representation) and ments obtained by crystal engineering and the continuous
CFCl3. CFCl3 is shown as a space-filling model. Adapted with efforts in searching for new supramolecular strategies and tools
permission from ref 796. Copyright 2015 John Wiley and Sons. to engineer molecular crystals are strictly linked to the need to
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Figure 99. Schematic representation showing that on griding 1,4-diiodotetrafluorobenzene and thiomorpholine the 1:2 discrete adduct forms
initially, which then evolves into 1:1 infinite chains on further grinding. Adapted with permission from ref 798. Copyright 2012 Royal Society of
Chemistry.

Figure 100. Left: structural formulas of tectons assembled via LAG

methodology. Middle: (succinic acid)·(caffeine)4 host framework with
guests omitted. Right: view of the hydrogen C−H···O and halogen
Br···N bonds involving the bromoform included in the (succinic acid)· Figure 102. Pictures of cones of powders of pure IPBC (A, C) and its
(caffeine)4 host framework. Adapted with permission from ref 798. CaCl2 cocrystal (B, D), taken after flowing the powders through a
Copyright 2012 Royal Society of Chemistry. funnel from 25 mm (A, B) and 50 mm (C, D) heights. The cylindrical
shape of the IPBC cones clearly indicates the high cohesion of the
powders, while the flat cone shape of the CaCl2 cocrystal indicates
improved powder flow properties. Reprinted from ref 477. Copyright
2013 American Chemical Society.

reactions in solution. Topochemical reactions are defined as

reactions “wherein the structure of the products is dictated by
the geometry and proximity of the reactive sites of the
precursors in the lattice”.804 During the years, various kinds of
reactions, such as Diels−Alder or [4 + 4] reactions, have been
explored in the solid state; however, the [2 + 2] photochemical
reactions are by far the most studied in the solid state.805 In
1918, Kohlschutter postulated the general topochemical
principle that reactions in crystals proceed with a minimum
amount of atomic and molecular movement.806 The essential
structural constraints for promoting photocycloaddition re-
actions in the solid state were first identified by Schmidt807
thanks to a systematic study of photochemical reactivity on
variously substituted cinnamic acids. The constraints are as
follows: (I) The distance between centroids of two photo-
reactive double bonds must be within a distance of 3.5−4.5 Å.
(II) The double bonds of the reacting molecules must be
Figure 101. (A) Molecular structures of single compounds (top) aligned in a parallel fashion.
employed in LAG synthesis of a halogen-bonded MOF (bottom). (B) Several supramolecular strategies based on HB, π−π stacking,
Partial representation of the crystal structure resulting from a arene−fluoroarene interactions, or cation···π interactions have
combination of covalent bond formation, coordination bonds, and been exploited to conduct stereo- and regiocontrolled solid-
XBs. I···O XBs are shown as yellow solid lines, and the I···O distance is state [2 + 2] reactions,803 and also XB has recently proven its
reported (Nc = 0.88). Adapted with permission from ref 801. usefulness in this field.
Copyright 2014 Royal Society of Chemistry. The cocrystallization, by slow solvent diffusion, of trans-1,2-
bis(4-pyridyl)ethylene and a pentaerythritol derivative bearing
master organization and reactivity in the solid state.803 four iodotetrafluorobenzene units led to the formation of a
Compared to classical organic reactions performed in solution, cocrystal where the two modules were present in a 1:2 ratio and
solid-state reactions have several advantages that include high formed infinite, 1D, and halogen-bonded ribbons thanks to
regio- and stereoselectivity, high scalability, and high reaction short and directional I···N XBs (the Nc values were 0.79 and
rates. Avoiding the use of solvents, solid-state reactions are 0.80, and the C−I···N angles were around 177°).808 As
cost-effective and have a lower impact on the environment than expected, the pentaerythritol derivative behaved as a tetratopic
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XB donor, while the dipyridyl module acted as a ditopic XB double bonds of the different modules were organized to meet
acceptor (Figure 103). The conformation of the XB donor Schmidt’s requirements for regiocontrolled photocyclization in
the solid state, the centroids’ separation being only 3.76 Å.
Upon photoirradiation in the solid state, the double bonds
underwent a [2 + 2] reaction, yielding the cycloadduct with
complete regio- and stereospecificity. Thanks to the control
exerted by the crystal packing, only the rctt isomer was
obtained, with pairs of iodotetrafluorobenzene and dimethyla-
minobenzene pendants pointing in opposite directions with
respect to the plane of the cyclobutane ring (Figure 104).
Another kind of reaction that may proceed under top-
ochemical control is the thermal polymerization of diacety-
lenes.804 These 1,4-addition reactions occur when specific
structural requirements are met: (I) The maximum distance
Figure 103. Schematic representation of the infinite, 1D, and halogen- between the reactive C atoms of the monomeric diacetylene
bonded ribbons (top), which upon light irradiation in the solid state
molecules is approximately 3.8 Å. (II) The diacetylene
yield quantitatively the rctt-tetrakis(4-pyridyl)cyclobutane (bottom).
molecules are aligned linearly with an approximate repeat
molecules was determined by intramolecular π···π stacking distance from 4.7 to 5.2 Å.809 XBs was exploited for this kind of
interactions between pairs of fluorophenyl rings which pointed reaction by N. Goroff and co-workers, who targeted the 1,4-
outward at either side of the molecule in an almost parallel polymerization reaction of diiododiacetylenes in the solid
manner. The high directionality of the XB transferred this state.810 The cocrystallization of 1,4-diiodo-1,3-butadiyne (XB
topochemical information to the olefins that were pinned in the donor) with bis(3-picolyl)oxalamide (XB acceptor) led to the
ribbons in a parallel fashion with a distance of less than 4.5 Å formation of a 2D supramolecular network thanks to a
between the olefins’ centroids, nicely meeting Schmidt’s combination of XB and HB (Figure 105). Infinite 1D chains
requirements. A powdered crystalline sample of the above-
described cocrystal was irradiated at 300 nm and readily
underwent a photochemical cycloaddition reaction under
topochemical control, yielding stereospecifically the corre-
sponding rctt-tetrakis(4-pyridyl)cyclobutane in quantitative
yields (Figure 103).
XB played a major role also in the convenient preorganiza-
tion of a photoactive, heteroditopic, and self-complementary
tecton (Figure 104). Specifically, the tecton possessed an
Figure 105. Top: schematic representation of XB donor and acceptors
used for the photochemical polymerization of diacetylene modules.
Bottom: partial views (ball-and-stick representation) of the 2D
supramolecular architecture given by diiodobutadiyne and bis(4-
cyanobutyl)oxalamide (left) and of the related photoreacted cocrystal
between poly(diiododiacetylene) and bis(4-cyanobutyl)oxalamide
(right). Color code: carbon, gray; nitrogen, blue; oxygen, red; iodine,
purple; fluorine, yellow; hydrogen, white. XBs and HBs are dotted
black lines.

are formed thanks to I···N bonds between the iodine atoms of

the diyne molecules and the nitrogen atoms of the dipyridine
Figure 104. Top: schematic representation of the solid-state molecules. These chains are then cross-linked into layers thanks
photoreaction of an XB-based self-complementary tecton to yield a to geometrically orthogonal HBs between the oxalamide
tetratopic self-complementary cyclobutane derivative. Bottom: views residues of adjacent chains. These HBs also allow for the
of the crystal packing of two infinite and halogen-bonded chains stacking of the dipyridyl units, and the information is
formed in the solid state by the starting olefin (left, XBs as dotted transferred to the diyne molecules by the directional XBs, so
black lines), and of the cyclobutane derivative obtained after UV
irradiation (right). Color code: carbon, gray; nitrogen, blue; iodine, that the requirements for polymerization are met. The 1,4-
purple; fluorine, yellow; hydrogen, white. XBs are dotted black lines. polymerization reaction was tried by applying high external
pressure, and the formation of the polymer was evidenced with
solid-state Raman scattering and magic angle spinning solid-
electron-poor aromatic terminal XB donor group connected by
a double bond to an electron-rich aromatic terminal XB state NMR. When the pyridyl-substituted XB acceptor was
acceptor group.722 Upon crystallization from chloroform, this replaced by a structurally analogous oxalamide containing a
self-complementary molecule organized into 1D infinite polar nitrile group rather than a pyridyl group, the polymerization
chains thanks to the expected I···N XB (Nc was 0.82, the C−I··· reaction took place spontaneously during the crystallization
N angle was 170°, and the I···N−C angle was 97.4°). As a result process, leading to the formation of the expected poly-
of the heterodipolar π···π stacking between adjacent chains, the (diiododiacetylene).811
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4. SOFT MATERIALS constituents, or modifying the LC behavior of the pair as

compared to its building blocks.
The use of XB in soft materials engineering is much less
It is stated by C. M. Paleos and D.Tsiourvas831 that “For the
common than in crystalline solids engineering, and examples
formation of liquid-crystalline materials through HB inter-
are especially scarce on polymeric and gel-phase materials.
actions, complementarity of the interacting components
However, the same characteristics rendering the XB a first-class
coupled with the directionality of HBs are the main factors
tool in crystal engineering (e.g., directionality and tunable
contributing to the exhibition of liquid crystallinity.” Single HBs
interaction strength) motivate its use also in the context of being able to form LC phases, it should be even more so in the
supramolecular soft matter. Moreover, HB and XB present case of the more directional XBs. This indeed turned out to be
many similarities,92 and many of the concepts in materials the case, as first shown in 2004.837 Motivated by their earlier
design elaborated with the former interaction can also be work on similar hydrogen-bonded LCs,838−840 the authors of
extended to the latter. A gradually increasing number of reports the paper used a series of alkoxystilbazoles and para-substituted
on halogen-bonded liquid crystals (LCs), polymers, and gels is tetrafluoroiodobenzenes as XB acceptors and donors, respec-
appearing in the literature, and this section demonstrates the tively (Figure 106A). These starting components are non-
vast potential of XB in the design of these new types of soft
matter. The three classes of soft materials mentioned above are
rather interwoven. Many polymeric complexes exhibit liquid
crystallinity,812−814 and both polymeric gels815,816 and liquid-
crystal gels817,818 have been widely studied. As a consequence,
inclusion of a study in a given section may sometimes be a
matter of presentation rather than topic.
Several issues remain to be studied also in the context of
halogen-bonded LCs, the less unexplored area. Halogen-
bonded discotic LCs have not been demonstrated, albeit
hydrogen-bonded discotic LCs were among the first supra-
molecular LCs reported in 1989. Interesting opportunities
might also be provided by ionic LCs,819 in which fluorination Figure 106. (A) Chemical structures of the halogen-bonded LCs
has been reported to enhance lamellar phase segregation, reported in ref 837 and corresponding hydrogen-bonded analogues.
thereby providing anisotropic conduction pathways and (B) Crystal structure of the (octyloxy)stilbazole/iodopentafluoroben-
interesting charge-transport properties.488,820 In supramolecular zene dimer evidencing the presence of I···N XB (shown as black
polymers and block copolymers, XB is foreseen to bring dotted lines) and the coplanarity of the aromatic rings. Color code:
additional benefits in preparation of nanotechnology template gray, carbon; yellow, fluorine; purple, iodine; sky blue, nitrogen; white,
materials due to its reversibility and the easy removal of the hydrogen. (C) Polarized optical micrograph of the smectic A texture of
the (hexyloxy)stilbazole/iodopentafluorobenzene dimer at 69° upon
bond donor components from the system.484 However, general cooling. Reprinted from ref 837. Copyright 2004 American Chemical
guiding principles for XB-driven polymeric self-assembly should Society.
first be comprehensively understood. Therefore, several new
openings and breakthroughs in regard to halogen-bonded soft
matter are to be expected in the near future. liquid-crystalline as pure species, and X-ray crystallographic
4.1. Liquid Crystals studies (Figure 106B) proved that the XB connecting these
components is responsible for the appearance of the liquid-
Liquid crystals bear an immense technological potential crystalline phases, quadrupolar interactions, which play a
because they combine the anisotropy of crystalline solids and central role in some other supramolecular LCs,841−843 being
the mobility of isotropic liquids in a unique manner. Liquid- absent. XB also gave rise to a color change of the material.
crystal alignment can be modulated with external fields, which While stilbazoles themselves are colorless, their absorption
has a profound influence on how light propagates through the maximum red-shifted upon XB formation, and the formed
liquid crystal. Therefore, LCs are particularly promising for adduct was yellow. The LC phase was dependent on the length
applications in display technology and photonics,821−823 but of the alkoxy chain, progressing from nematic (short chains) to
they also constitute a unique template for designing complex smectic A (long chains) (Figure 106C).837 Attempts were also
self-assemblies824 and have received increasing attention in made to use bromopentafluorobenzene as the XB donor, but
applications related to biotechnology,825,826 organic elec- no evidence of compex formation was obtained. Probably the
tronics,827,828 and sensing.829,830 The existence of thermotropic Br···N interaction is too weak to exist at the temperatures
LC phases is inherently connected to noncovalent forces enabling liquid crystallinity (LC phases occurred at temper-
between anisotropic, typically rodlike or disklike, molecular atures typically >70 °C). Importantly, the crystal-to-LC
constituents. HB is by far the most established noncovalent transition temperature was lower in halogen-bonded complexes
interaction in the creation of supramolecular liquid crystals, and than in hydrogen-bonded analogues. Since for many
the topic was comprehensively reviewed by C. M. Paleos and applications it is beneficial to have an operating temperature
D. Tsiourvas in 2001.831 Herein, we restrict ourselves to (i.e., the temperature at which the liquid crystallinity occurs) as
mention the seminal work of T. Kato and J. M. Frechet,832−836 low as possible, this may be a benefit of halogen-bonded as
who were the first to demonstrate that new types of LC species compared to hydrogen-bonded supramolecular liquid crystals.
can be created by coupling, via single HBs, components bearing J. Xu et al. reported on high molecular weight supramolecular
pyridyl and carboxyl moieties. In this context, HB effectively LCs845,846 obtained on self-assembly of bis-
elongates the rigid-rod segment, thus either generating liquid (iodotetrafluorophenoxy)alkanes (bidentate XB donors) with
crystallinity into systems built from non-liquid-crystalline various mono- and bidentate XB bond acceptors (Figure
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107A). The occurrence of XB in many of the studied complexes melting points and to increase the mesophase range of LC
was proven by detecting changes in the binding energies of the materials, yet this was the first successful use of the approach in
the context of halogen-bonded and supramolecular LCs.
Concerted use of XB and HB to induce liquid crystallinity
was demonstrated by forming 2:1 complexes of alkoxystilba-
zoles and iodotetrafluorophenols.852 In the same study and by
using 1:1 complexes, it was shown that stilbazoles interact
preferentially via HB. The synergistic use of XB and HB is
particularly useful in LC polymers built from difunctional low
molecular weight XB donors and acceptors. The quite narrow
LC temperature ranges of halogen-bonded polymeric com-
plexes845 were attributed to the rigidity and high directionality
of the XBs; by also introducing the less directional HBs into the
polymeric supramolecular complex, the rigidity constraints are
alleviated and the mesophase stability is significantly
increased.853 XB-driven chiral LC phases have also been
reported. C. Präsang et al. observed spontaneous symmetry
breaking and chiral nematic phases on self-assembly of
nonchiral starting compounds, i.e., 1,3-diiodotetrafluoroben-
zenes and alkoxystilbazoles.711 To account for their exper-
imental observations, the authors argue that the nematic-to-
isotropic transition is actually accompanied by XBs breaking.
Figure 107. Chemical structures of high molecular weight polymeric Upon cooling, a 1:1 complex is formed first (exhibiting a
(A, top) and trimeric (A, bottom) LCs,845,846 trimeric LCs formed by nematic phase), and shortly after that, the 2:1 complex re-forms
diiodoperfluoroalkanes (B),847 and dimeric systems formed by (giving rise to the bent chiral nematic structure).
dihalogens (C, top).850,851 (C) Representation of the crystal structure The studies described above report on several interesting
of two I2···(octyloxy)stilbazole dimers interacting via type I I···I
contacts. Color code: carbon, gray; nitrogen, blue; oxygen, red; iodine,
findings, but they hardly afford conclusive design principles for
purple; hydrogen, white. halogen-bonded supramolecular mesogens. To address this
issue, the Milano and York teams joined forces and carried out
a systematic and comprehensive investigation using a series of
1s orbitals at nitrogen and 3d orbitals at iodine via X-ray XB donors and acceptors (some of them are shown in Figure
photoelectron spectra,846 and since then, this technique has 108A). By reporting 90 new dimeric halogen-bonded LC
become a commonly used tool to verify XB formation. The LC
temperature range of these halogen-bonded LCs is generally
narrower than that of hydrogen-bonded LCs based on
carboxyl−pyridine binding. The authors attributed the temper-
ature range of hydrogen-bonded LCs to a weak secondary C
O···HC HB (between the carbonyl oxygen and a hydrogen
adjacent to the nitrogen atom in pyridine) which directs the
complex to be planar and stabilizes the mesophase.
Corresponding halogen-bonded complexes lack such a
stabilizing secondary interaction due to the large size of iodine,
and the mesophase range is narrower.
Low molecular weight supramolecular LCs were obtained by
P. Metrangolo and G. Resnati et al. on XB-driven self-assembly
of α,ω-diiodoperfluoroalkanes (bidentate XB donors) and
alkoxystilbazoles (monodentate XB acceptors) (Figure
107B).847 Long fluoroalkyl chains typically drive segregation Figure 108. (A) A selection of XB donors and acceptors used in ref
of the fluorinated and nonfluorinated segments into lamellar 854. (B) Birefringent textures of complexes formed by an (S)-
smectic A phases (fluorophobic effect),848,849 which most often citronellyl-substituted stilbazole with a butoxy-substituted iodotetra-
fluorostilbene, obtained upon cooling from the isotropic state. (C)
precludes the appearance of nematic phases. Surprisingly,
Molecular structures of halogen-bonded (top) and hydrogen-bonded
although such segregation was observed in the crystal structures (bottom) stilbazole−azobenzene complexes. The halogen-bonded
of the complexes formed by α,ω-diiodoperfluoroalkanes, all the complex is liquid-crystalline; the hydrogen-bonded complex is not.489
observed LC phases were monotropic nematic, even when the
relatively long diiodoperfluorohexyl spacers separated the two
XB donor sites. The same group also studied the halogen- species,854 they were able to provide new insights into their
bonded trimers formed by 1,4-DITFB with alkoxystilbazoles.844 structure−property relationships and to demonstrate that XB is
Monotropic nematic phases in a narrow temperature range a reliable tool for the systematic construction of supramolecular
were observed for the pure trimers, and upon mixing several LCs.
alkoxystilbazoles bearing alkoxy pendants of different lengths, Many of the reported complexes displayed enantiotropic LC
the material exhibited enantiotropic liquid crystallinity with an phases with significantly broader LC temperature ranges (>20
extended LC temperature range. Mixing differently sized °C) than those in previous reports. By using chiral citronellyl
components is a rather common method to suppress the pendants on either the XB donor or the XB acceptor,
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enantiotropic chiral nematic mesophases were obtained with

typical focal conic fan textures (Figure 108B, top), which
changed after shear stress into planar textures with oily streaks
(Figure 108B, bottom).
A particularly interesting observation was recently made
using azobenzene-containing complexes,489 which could be
anticipated to exhibit no liquid crystallinity as they are devoid
of flexible aliphatic chains. However, the halogen-bonded
stilbazole−azobenzene complex (Figure 108C, top) shows a
monotropic nematic phase with an isotropic-to-nematic
transition at ca. 132 °C and a mesophase temperature range
of ca. 18 °C. Most interestingly, the corresponding hydrogen-
bonded complex (Figure 108C, bottom) was not liquid-
crystalline. This difference highlights that XB not only parallels Figure 109. (A) Chemical structures of the XB donors and acceptors
but can also override the performance of HB in LC materials. used in ref 573 and the general structures of the halogen-bonded
All the aforementioned studies used iodotetrafluorobenzene complexes. Birefringence textures of the crystal G phase of the p-BIB/
moieties as XB donors (iodoperfluoroalkanes in ref 847). The p-(decyloxy)pyridine complex (at 86 °C) (B), the smectic B phase of
first reports on the use of alternative XB motifs were published the p-BIB/p-[[p-(tetradecyloxy)benzoyl]oxy]stilbazole complex (at
in 2013.573,850 Complexes between alkoxystilbazoles and 108 °C) (C), and the smectic AP phase of the m-BIB/p-
molecular iodine (Figure 107C, top left) exhibited unusually tetradecyloxy)stilbazole complex (at 131 °C) (D). Reprinted from
large mesophase stability and clearing points above 200 °C.850 ref 573. Copyright 2013 American Chemical Society.
Interestingly, some of the complexes exhibited tilted SmC
mesophases, and X-ray crystallographic studies showed that this halogen-bonded LCs, which clearly points out the promise of
phase was driven by the coupling of 1:1 dimers thanks to type I iodoethynyl units in the design of highly ordered supra-
iodine···iodine contact. When replacing I2 with Br2, no liquid molecular LCs and motivates further studies.
crystallinity was detected, and stilbazolium bromide in which 4.2. Polymers
one of the ethylenic hydrogens was replaced with bromine was Polymeric self-assemblies driven by XB have also been studied
formed. In another study,851 the alkoxystilbazole was replaced in parallel to LC dimers, trimers, and polymers built up from
with an azopyridine, to yield photoresponsive liquid crystals. In mono- and bidentate low molecular weight starting com-
this case, both I2 and Br2 XB donors gave rise to liquid- pounds. The preparation of fluorinated comb-shaped polymers
crystalline complexes. This work demonstrated that not only driven by XB between poly(4-vinylpyridine) (P4VP) and α,ω-
can bromine-based XB donors be used in the successful design diiodoperfluoroalkanes (DIPFAs) was published as early as
of supramolecular LCs, but, more surprisingly, dibromine 2002.473 The polymeric 2:1 P4VP/DIPFA complexes self-
significantly stabilized the mesophase compared to diiodine. assembled into anisotropic comb-like structures, probably due
For example, the complexes formed by I2 and Br2 with the to the high tendency of the polymer backbone and the
azostilbazole bearing a dodecyloxy pendant both exhibited fluorinated side chains to phase segregate. This study parallels
smectic A phases, and the respective temperature ranges were the work of O. Ikkala and co-workers on phenol-based
119−135 and 70−158 °C. The reason for this unprecedented, surfactants interacting by HB with comblike homopolymers
bromine-induced stability remains unclear. Another interesting and block copolymers containing a pyridine residue.856,857
feature of the dihalogen-based LC complexes is that only These early studies by the Milan group on the first example of
smectic phases were observed, irrespective of the alkyl chain halogen-bonded supramolecular assemblies involving polymers
lengths on the XB acceptor units. point to (i) finding optimal halogen-bonded side chains to
Iodoethynyl moieties are gaining in popularity as XB donors drive the comblike self-assembly of these systems and (ii)
in general,209,568,855 and a detailed study was recently reported controlling the morphology and self-assembly of block
on the use of 1,3- and 1,4-bis(iodoethynyl)benzenes (p-BIB copolymers using halogen-bonded side chains. Studies on
and m-BIB, Figure 109A) to form trimeric LC complexes with neither have been undertaken to date, but the complementarity
benzonitrile and various pyridine acceptors.573 The most between the perfluoroiodobenzene and pyridyl moieties has
important conclusion of this paper was that the use of XB been used as a driving force for the formation of layer-by-layer
donor mesogens bearing two iodoethynyl residues gives rise to polymeric films.858 The resulting halogen-bonded multilayer
mesophases with a higher degree of ordering compared to the polymer films were less stable than the corresponding
use of the 1,4-DITFB donor. For instance, the 1:2 complex hydrogen-bonded assemblies, yet the stability was improved
between p-BIB and p-(decyloxy)pyridine showed a crystal G by using hybrid films containing both halogen-bonded and
mesophase, while the 1:2 complex between the same XB donor hydrogen-bonded multilayers.
and a p-(benzoyloxy)pyridine showed a smectic B mesophase Recently, noncovalent interactions between a P4VP host
(parts B and C, respectively, of Figure 109). The former matrix and azobenzene derivatives bearing XB donor sites have
mesophase consists of tilted molecular layers with long-range been used in the design of polymeric nonlinear optical and
three-dimensional order, while the latter has molecules photoresponsive materials.855,859,860 These materials are
exhibiting in-plane hexagonal ordering. On the other hand, amorphous, their functionality is provided by XB, and they
m-BIB yielded liquid-crystalline complexes (Figure 109D) only will be treated separately in the section of this review devoted
when XB acceptors with three phenyl rings were used to optical materials.
(specifically p-(benzoyloxy)stilbazoles). A polar SmAP phase, One of the most interesting recent studies on XB-driven self-
which is characteristic of bent-shaped molecules, was observed. assembly of polymers is the work of N. Houbenov et al. on
None of these phases have been previously observed in spontaneous large-scale organization of halogen-bonded
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complexes between star-shaped polyethylene glycol (PEG) use of the monodomain-oriented nanostructure as a nano-
polymers and iodoperfluoroalkanes (Figure 110A).484 Rapid technology template.
M. S. Taylor and A. Vanderkooy studied the solution self-
assembly of complementary, multivalent XB donor and
acceptor linear polymers, obtained from a methacrylate bearing
iodoperfluoroarene residues and a 2-(dimethylamino)ethyl
methacrylate, respectively.861 They observed a variety of
structures under relatively dilute conditions, ranging from
spheres to wormlike nanotubes or more complex mixtures of
the two (Figure 111). The structures appeared to be under

Figure 110. (A) Chemical structures of the PEG−iodoperfluoroalkane Figure 111. Cartoon representing complementary halogen-bonded
complexes used in ref 484. (B) Small-angle X-ray scattering patterns polymers (A) and self-assembly in solution into vesicle (B) and
for iodoperfluorodecane (graph 1), PEG (graph 2), indicating poor wormlike (C) structures, as observed by TEM micrographs. Adapted
self-assembly by segregation of the ionic end groups from the PEG from ref 861. Copyright 2015 American Chemical Society.
core, and the supramolecular complex (graph 3), showing highly
ordered self-assembly. (C) An illustration of the self-assembly
mechanism of the halogen-bonded complex. (D) TEM micrographs kinetic control and depended on a variety of factors such as the
at various locations of pure PEG showing a lack of macroscale block length and polydispersity, the presence or absence of a
alignment. (E) TEM micrographs of the halogen-bonded complex solubilizing poly(ethylene oxide) segment in either polymer,
between PEG and 1-iodoperfluorododecane, showing exceptionally
and the assembly conditions, such as switching between
well-ordered lamellar nanostructures with overall macroscale order on
the millimeter scale. The scale bars correspond to 100 nm. Reprinted different solvent systems.
with permission from ref 484. Copyright 2014 Nature Publishing 4.3. Gels and Other Soft Systems
Group. Supramolecular gel-phase materials are another important class
of self-assembled soft matter, relevant for applications as diverse
as regenerative medicine, drug delivery, and responsive optical/
and cost-effective protocols to achieve macroscopically aligned, electronic materials.862−864 The fibrous networks that provide
nearly single-crystal, globally ordered, and self-assembled supramolecular gels their solidlike rheological properties arise
nanostructures remains a challenge. Importantly, the interplay from complex hierarchical self-assemblies which are often
between XB and the fluorophobic effect spontaneously leads to initiated by HB-directed growth of one-dimensional fibrils. The
this goal in the model system of Figure 110A. The PEG dynamic self-association that nucleates the gel formation is very
polymers themselves give rise to nanoscale periodic structures sensitive to competing noncovalent interactions; hence, such
(Figure 110B, graph 2) due to clustering of the charged end- interactions can be used to control the gel strength, or in
group ammonium moieties, yet the material is macroscopically extreme cases to inhibit (or alternatively to “turn on”) the
isotropic and exhibits poor overall alignment. Upon complex- gelation process altogether.59−61 Recently, XB has also been
ation with iodoperfluoroalkanes, highly ordered lamellar added to the family of supramolecular interactions for
structures are obtained as demonstrated by the higher order controlling gelation.83 Various bis(urea) compounds (Figure
peaks visible in the small-angle X-ray scattering pattern of the 112A) are nongelators in polar organic solvents or water−
complexes (Figure 110B, graph 3). The increased ordering is organic solvent mixtures. Conversely, an equimolar solution of
driven by a combination of (i) XB between the chloride ions of 1,4-DITFB and 1,4-bis(3-pyridylureido)butane (BPUB) or 1,3-
the ammonium chloride end-capped PEG chains and the bis[(1-methyl-1-(3-pyridylureido)ethyl]benzene (DPUB) was
iodoperfluoroalkanes and (ii) the tight lateral packing of the found to gelate polar organic solvent−water mixtures. The
fluorinated segments into phase-segregated layers. A model for single-crystal structure of the 1:1 complex between 1,4-DITFB
the self-assembly mechanism is given in Figure 110C. The and BPUB (Figure 112B) revealed that XB is present and
delicate balance between the different intermolecular inter- probably turns on supramolecular gelation by preventing gel-
actions required to drive long-range self-assembly is evident inhibiting pyridyl−urea interactions. The generality of the role
from the fact that, like the starting polymer that exhibits no of XB in turning on supramolecular gelation was confirmed by
long-range alignment (Figure 110D), complexes with iodoper- the reversed system involving 4,4′-dipyridine (4,4′-DP) and
fluoroalkane chains with less than 10 carbon atoms are only 1,4-bis[(4-iodotetrafluorophenyl)ureido]butane (BIPUB),
locally ordered. Conversely, Figure 110E presents transmission wherein the bis(urea) moiety was within the same molecule
electron microscopy (TEM) micrographs from several containing the XB donor sites (the iodine atom) and 4,4′-DP
positions for a complex with iodoperfluorododecane, and the probably functioned as the XB acceptor and cross-linked the
monodomain alignment spontaneously extends here into the tapes formed by urea−urea interactions. Such a complex
millimeter length scale. As an additional benefit, the resulted in a network of fibers (Figure 112D) gelling various
iodoperfluoroalkanes can be removed from the systems by DMSO−water mixtures. Even a 1:1 mixture of BPUB and
combined vacuum/thermal treatment, which enables further BIPUB provided a supramolecular gel consisting of an intricate
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The former case was particularly informative as the high

resolution of the structure allowed for the study of the
geometry of the complex with a very low experimental error. It
was thus possible to clearly observe how the Br of the inhibitor
and the hydroxyl O of the Thr113 protein residue formed a
short contact with a distance of 2.97 Å and a C−Br···O(γ)
angle of 152.8°, thus substantially satisfying the requisites for an
XB (Figure 113). This interaction was suggested to be the

Figure 112. (A) Chemical structures of the compounds used in ref 83

to obtain supramolecular low molecular weight gels. (B) X-ray crystal
structure of the 1:1 adduct between 1,4-DITFB and BPUB, which
confirms the presence of gel-forming urea tapes cross-linked by XBs
involving the pyridyl groups. (C, D) Scanning electron micrographs of
dried 1:1 cogels formed by 4,4′-DP with BIPUB, and by BPUB with
BIPUB, respectively. (E) Photograph of the 1,4-bis(3-pyridylureido)-
butane/1,4-bis[(4-iodotetrafluorophenyl)ureido]butane cogel. Reprin-
ted with permission from ref 83. Copyright 2013 Nature Publishing
Group. Figure 113. (A) XB (dotted black line) between the Br of IDD594
and the O(γ) of Thr113 in human aldose reductase. (B) Atomic
structure of d(CCAGTACBr5UGG), with bromine atoms rendered as
network of thin, homogeneous fibers showing some coalign- spheres and the deoxyribose backbones as solid ribbons. Panel A
ment on the tens of micrometers scale, and linked by a more reprinted with permission from ref 27. Copyright 2011 Royal Society
disordered secondary mesh of material (Figure 112D). These of Chemistry. Panel B reprinted from ref 878. Copyright 2003
very thin fibers are consistent with the optical transparency of American Chemical Society.
the gel. The results described above were the first
demonstration that XB can play a role in driving the self-
assembly of gel-phase materials even in polar media. Clearly,
XB is sufficiently strong to interfere with competing gel- reason underlying the specificity of IDD594 for AR over
inhibitory HB interactions in a manner similar to that of metal aldehyde reductase, in which Thr113 is replaced by a Tyr
coordination by bis(pyridylurea) gelators.868 This provides new residue. Interestingly, when a single-atom mutation was
opportunities in the development of sophisticated gel-based performed by replacing Br with Cl, the IC50 value increased
functional materials and their supramolecular manipulation. from 500 to 1300 nM, consistent with a decisive role of an XB
in the recognition and binding event associated with enzyme
5. BIOMOLECULAR SYSTEMS inhibition. A similar situation was also found in the 2.1 Å
XB can now be considered a rather established interaction in resolution structure of aldose reductase with the inhibitor
supramolecular and material chemistry, while the presence and statil,879 where a Br···O(γ) distance of 3.11 Å was recorded.
relevance of the interaction in biomolecular systems have begun Holliday junctions are four-stranded intermediates associated
to be studied only very recently. In general, halogen atoms are with genetic recombination and recombination-dependent
scarce in biomolecules, and this may account for the disparity mechanisms such as DNA repair and integration. As part of a
mentioned above. The iodinated thyroid hormones T4 study on nucleotide sequences which stabilize Holliday
(thyroxine, 3,5,3′,5′-tetraiodothyronine) and T3 (3,5,3′-triio- junctions, P. S. Ho and co-workers reported the first evidence
dothyronine) are probably the best known examples of for a significant effect of the XB on a polynucleotide
naturally occurring halogenated compounds, and in the context structure.880 To help phase in X-ray diffraction data, they
of this review, it is important to observe that they work as XB introduced the sequence CCAGTACBr5UGG by substituting a
donors in biomolecular systems.27,249,869,870 However, halogen thymine with a 5-bromouracil,878 which led to a four-stranded
introduction is a traditional tool in drug optimization, for Holliday junction. Conversely, both the native sequence with
example, to increase the membrane permeability and half-life in thymine and the analogous HB sequence with a non-
vivo, and the recent years registered an ever growing interest in halogenated uracil led to standard B-DNA duplexes. A short
halogenated drugs.871 Moreover, halogenated persistent organic contact compatible with XB geometry was observed between
pollutants are raising the attention on the biological relevance the Br atom and a phosphodeoxyribose oxygen and replaced an
of halocarbons, and this is particularly the case for chlorinated analogous HB in the native junction.881
and brominated diphenyls and diphenyl ethers, which are These studies prompted Ho and his group to perform a
raising the highest concerns,872−875 probably as their structural search in the Protein Data Bank (PDB)249 with the goal of
and chemical resemblance to thyroid hormones increases the identifying short halogen−Lewis base (O, N, S) contacts which
impact of their presence in the biosphere. It can thus be might have been previously overlooked, by defining two
anticipated that the interest in the role of XB in biological necessary prerequisites: a donor−acceptor distance lower than
systems will increase in the future. the sum of their respective van der Waals radii and a minimum
The first clear accounts on short Br···O contacts in biological angle of acceptor-to-donor approach of 120°. This first search
systems were the 0.66 Å resolution structure of the inhibitor yielded 113 hits, which were mostly complexes between
IDD594 with aldose reductase (AR)876,877 and the structure of proteins and halogenated ligands. Further surveys have been
a four-stranded Holliday junction containing a bromouracyl performed since then, and this number is now well above
unit.878 700.27,871,882−884
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Figure 114. (A) Chemical formulas of the thyroid hormones T4 and T3. (B) HBs formed by T3 and (C) XBs formed by T4 with TTR. Reprinted
with permission from ref 885. Copyright 2015 Springer.

5.1. Halogen Bond Donors cils878,882,912−914 and iodocytosine: A. Takénaka and co-
In most halogen-bonded biomolecular complexes, the donor is workers observed that the introduction of an iodocytosine to
represented by a small halogenated molecule, while one or obtain the sequence GICGAAAGCT changes the structure
more specific sites of a biomacromolecule (typically a protein) from a parallel intercalated duplex to a hexameric com-
act as acceptors. plex.915,916
The most important naturally occurring bioactive XB donors In proteins, halogenation of amino acids (particularly Tyr) is
are the thyroid hormones T4 and T3, which contain four and known to occur naturally as a result of oxidative stress,
three iodine atoms, respectively (Figure 114). catalyzed by enzymes such as myeloperoxidases917 and
In humans and other backboned animals, proper develop- eosinophil peroxidases.918 Myeloperoxidase catalyzes the
ment of the brain, skeleton, and organs is guaranteed by thyroid reaction of hydrogen peroxide and halide (Cl−, Br−, I−) or
hormones, and is mediated by thyroid hormone receptors pseudohalide (SCN−) ions, generating hypohalous acids
(THRs). Several I···O short contacts play a crucial role in the (HOX), which react rapidly with different targets in proteins
thyroid hormone recognition process,886 and it was proposed including the sulfur atoms of cysteine or methionine, the
that the higher T3 selectivity toward THRα in comparison to nitrogen atoms of α-amino acids or histidine, lysine, and
THRβ would be due to a shorter contact involving iodine.887 In arginine side chains, and the aromatic rings of tyrosine and
the blood, only a very small fraction (0.03−0.3%) of thyroid tryptophan.919 Elevated levels of halogenated tyrosine residues
hormones is present in the biologically active free form, with have been detected in proteins isolated from patients with
the rest bound to transporter proteins such as transthyretin atherosclerosis, asthma, and cystic fibrosis.920,921 While the
(TTR),869,870 which has a higher selectivity for T4 over T3. It occurrence of XBs involving such halogenated protein variants
was shown that the iodines in the phenolic ring of T4 engage in has not yet been proven, the fact that they can be recognized by
two XBs with the TTR backbone, while this is not the case for polyclonal antibodies922 suggests that XB may indeed be at
the single iodine present on the phenol ring of T3.888 work. Furthermore, recent studies on amyloidogenic short
The activation of thyroid hormones, i.e., the conversion of peptide fragments of human calcitonin showed an amplification
T4 to T3 through cleavage of one C−I bond, is mediated by of their fibribillation ability upon halogenation of Phe residues,
the selenoenzymes iodothyronine deiodinases; it was suggested with an effectiveness which follows the known XB strength
that XB would be involved in their activity, through lengthening scale Cl < Br < I.923
and activating the carbon−iodine covalent bonds.889 By 5.2. Halogen Bond Acceptors
mimicking these systems, G. Mugesh and D. Manna have
proposed a series of naphthalenes bearing thiol and selenol In biologically relevant systems, the role of the XB acceptor is
groups in the peri-position, which catalyze the deiodination of almost invariably played by biological macromolecules. In the
thyroid hormones through the combination of halogen and recent survey by W. Zhu and co-workers,871 it was shown that
chalcogen bonds.890 778 short contacts involved halogens in high-quality structures
As mentioned above, most of the known XB donors involved of the PDB, and in 211 of them delocalized π electron systems
in biomolecular systems are non-naturally occurring small were the interacting partner (halogen lone pair···π interactions
molecules, e.g., the volatile anesthetic halothane,891,892 the were possibly included in these short contacts). Such
antibacterial triclosan,893−896 several nonsteroidal anti-inflam- delocalized π electron systems were, for instance, the guanidino
matory drugs (NSAIDs),897−899 kinase inhibitors,900−908 and groups in Arg residues882,924 and other aromatic derivatives,925
several other drugs. Examples where the XB donor site is part notable examples being Phe residues in protein kinases900 and
of a biological macromolecule are understandably much more Tyr in the serine protease factor Xa (fXa).926−930 Of the
limited. Halogens are purposefully introduced into polynucleo- remaining 567 C−X···Y contacts, 430 are formed with protein
tides and proteins to facilitate structure determinations and can residues. About 84% of these involve O atoms as XB acceptors,
sometimes affect the obtained structure.909−911 This was the while N atoms are involved in only 10.4% of the cases (Figure
case, for instance, for site-specific introduction of p-iodo-Phe to 115); this distribution is remarkable when compared to the
aid in protein structure determination.911 For polynucleotides, predominance of nitrogen compounds in halogen-bonded small
examples include the introduction of halogenated ura- molecular complexes. While being a relatively minor fraction,
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Figure 116. Diclofenac−cytochrome P450 complex showing that a

water molecule forms at the same time an XB with one Cl atom of
diclofenac (shown in pale green) and an HB with a carboxyl oxygen of
the Glu297 side chain. Reprinted with permission from ref 27.
Copyright 2011 Royal Society of Chemistry.

Figure 115. XBs in the PDB, divided as (A) C−X···Y and (B) C−X···π
contacts (X = Cl, Br, I). Reprinted from ref 871. Copyright 2013
5.3. Geometrical Features
American Chemical Society. Similar to other fields, radial and angular geometric require-
ments are frequently employed to identify XBs in the
biomolecular context. The radial requirement consists in the
identification of a short contact between the halogen atom and
XBs with S or Se atoms in the side chains of amino acids are the associated Lewis base atom, with an interatomic distance
also well documented.890,892,899,931 lower than the sum of their respective van der Waals radii.
A more in-depth analysis reveals that 64.5% of C−X···Y Solely on the basis of the σ-hole model, the angular
contacts are formed with the protein backbone rather than requirement would be for a linear C−X···B angle. However, a
amino acid side chains, possibly due to steric and solvent separate model has been proposed which takes into account the
entropic costs in forming XBs with the latter.885 The vast available surface area in halogen atoms for contact.938
majority of these backbone XBs are established with the According to this model, the interaction probability is
carbonyl oxygen rather than the amide nitro- maximized for a C−X···B angle close to 170°, which
gen.249,250,871,882,884,932 This was ascribed to two reasons, corresponds nicely to the most common values found for
namely, (i) in CO groups both oxygen lone pairs and the small molecular complexes in the Cambridge Database169,939
double bond can act as electron donors, whereas the nitrogen and to the distribution of short halogen contacts found in the
possesses only one electron lone pair, and (ii) accessing PDB. This agreement is more strict for heavier halogens, such
backbone nitrogens is a sterically more demanding phenom- as Br and I, which form stronger XBs, while significant
enon.933 Interestingly, the peptide bond itself is also a potential deviations are often observed when Cl atoms are involved885
XB acceptor.249,934 (Figure 117).
The only known cases of biomolecular XBs where the An interesting comparative study was performed for the
binding of halogen-substituted benzenes into an internal
acceptor is not part of a biomacromolecule are when water
nonpolar cavity of the Leu99 Ala bacteriophage T4 lysozyme
molecules act as XB acceptors, most often with the ability for a
mutant.931 The I of iodopentafluorobenzene formed a 2.86 Å
single water molecule to be simultaneously involved both in XB
I···S contact with Met102 and a C−I···S angle of 166.3°, thus
and in HB.935−937 Quantum chemical calculations suggested corresponding to a 0.5 Å shift and a 30° rotation with respect to
that XBs with water are thermodynamically more stable than the geometry found for benzene. A rather similar binding
other interactions involving water,935 and it was shown in the geometry was found for one of the two binding modes of the
most recent PDB survey that these interactions are around weaker XB donor iodobenzene, although with a significantly
16.6% of known biomolecular XBs.871 The complexes of longer I···S contact (3.3 Å). Interestingly, the energy difference
diclofenac with cytochrome P450936 and lactoferrin937 feature measured by isothermal titration calorimetry between these two
good examples of water molecules acting as bridges between complexes was 0.5−0.7 kcal/mol in favor of iodopentafluor-
halogen and hydrogen bonds. In the former case, XB with a obenzene; however, it should be noted that a difference in XB
water molecule featuring a Cl···O distance of 2.85 Å and a C− was likely only one of the differences responsible for this value.
Cl···O angle of 158.1° was observed together with an HB An XB was also found for one of the multiple binding modes
involving the same water molecule and a carboxyl oxygen of the displayed by bromopentafluorobenzene, which engaged a S
side chain of Glu297 (Figure 116). In the latter case a rather atom of Met102 (Br···S distance 2.8 Å, C−Br···S angle 167°).
similar structure was observed, albeit with a slightly longer Cl··· Another interesting example is the complex of the NSAID
O distance, with a somewhat less linear angle, and involving 3,5-diiodosalicylic acid with human serum albumin (HSA),899
Val591 in the HB. where one iodine was observed to form a contact with the
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Figure 118. (A) Distribution of the relative angle of approach of HBs

and XBs to a common Lewis base, subdivided by the halogen involved.
Representations of the orthogonality of XBs and HBs in β-sheets (B)
and α-helices (C); the white sphere represents the van der Waals
radius of a Br atom. Reprinted with permission from ref 250.
Copyright 2009 Nature Publishing Group.

Figure 117. Number of short contacts involving halogens as a function between the two interactions has also been shown on small
of the angles: (A) C−X···B (θ1) and (B) C−B···X (θ2). π-BXB and n- molecular peptide models by both theoretical calculations250
BXB indicate biomolecular halogen bonds of the type C−X···π and and experimental studies.634 Orthogonality is not only
C−X···Y, respectively. Reprinted with permission from ref 885. geometrical, but also chemical, in the sense that the formation
Copyright 2015 Springer. of XBs does not alter the HB-driven assemblies.
5.4. Energetical Considerations and Complex Stabilization
carbonyl oxygen of Arg257, featuring an I···O distance of 3.46 Effects
Å and a C−I···O angle of 169.4°. Due to the difficulty of separating neatly the contributions of
As mentioned above, far less ideal geometries are often XBs from other contributions to adduct stabilization in systems
observed for weaker XBs where chlorine atoms act as Lewis as complex as those involving biomolecules, there are to date
acids. In the complex of diclofenac, another NSAID, with the very few experimental measurements of XB binding energies in
cyclooxygenase enzyme COX-2,897 the main contributions to these systems. However, available data suggest contributions
stabilization come from HB. However, in two out of the four falling in the 1−5 kcal/mol range, which are rather consistent
independent complexes, short contacts were observed between with what is observed in small molecular complexes.
a Cl atom and the hydroxyl oxygen of Ser530, with Cl···O The previously mentioned DNA Holliday junction system
distances of 3.23 and 3.18 Å, which are slightly shorter than the was used by P. S. Ho’s group to study the competition between
sum of the vdW radii of O and Cl, and C−Cl···O angles of XBs and HBs. A junction was constructed containing two
147.5° and 140.7°, respectively. These deviations from linearity strands, each able to form either type of bond in competition
are likely the result of geometrical constraints. Somewhat with each other by using a 5-bromouracil or a cytosine,
similarly, in the complex of COX-1 with (S)-indomethacin respectively. The relative stability of the two forms could be
ethanolamide, a Cl···S contact is found with a distance of 3.29 Å observed by means of a crystallographic titration assay912,913,940
and a C−Cl···S angle of 146.5°.898 (Figure 119). On the basis of the observed isomer ratios, the
The X···Y−C angle (X = XB donor; Y = XB acceptor) halogen-bonded structure was found to be more stable by about
essentially depends on the distribution of electron-rich orbitals 2 kcal/mol when the system was designed for competition of
on the Lewis base Y atom. Among the XBs found in the PDB, one XB versus two HBs, and by about 5 kcal/mol in a 2:2
an X···Y−C angle close to 120° is the most commonly found, competition.
which is consistent with an involvement of the nonbonding n The same assay was extended to include 5-halouracils
orbitals of CO groups. However, a local maximum occurs containing different halogen substituents,914 and the results
around 90°, particularly for the heavier halogen atoms,249,885 confirmed that the bond stability increased on going from
which may be associated with interactions involving π orbitals lighter to heavier halogens, at the same time also displaying
of the Lewis base. This geometry is typically observed when XB more ideal geometries in terms of both radial and angular
and HB donors share a common acceptor, resulting in a strong requirements of XB.
X···O···H orthogonal arrangement, which is observed in both β- The DNA junctions were used to compare XB energies not
sheets and α-helices250 (Figure 118). The orthogonality only in crystals but also in solution. Differential scanning
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5.5. Relevance in the Pharmaceutical Field

About 40% of drugs in clinical trials or on the market are
halogenated; at present about 25% of drugs in the launch phase
and about 34% of those in the discovery phase are
organohalogens. These numbers are a clear indication of the
key role of halogen substituents in pharmaceuticals.871
Furthermore, the presence of heavier organohalogens with
respect to organofluorines shows a clear rising trend along the
various phases of the drug discovery process, thus implying a
strategic role of XB in the search for new lead compounds. In
Figure 119. Competition between hydrogen-bonded (cyan strand) the National Cancer Institute’s Diversity Set IV, which is a list
and halogen-bonded (magenta strand) structures in a four-stranded of potential lead small-molecule compounds for high-
DNA junction. Reprinted with permission from ref 885. Copyright throughput screening for cancer research, about 20% of the
2015 Springer. molecules contain I, Br, or Cl.885,944 Standard docking
algorithms cannot account for XB, potentially leading to a
loss of viable lead compounds. On the other hand, halogens are
incorporated into screening libraries used to search lead
calorimetry (DSC) was used to measure the heat required to compounds as potential inhibitors against relevant therapeutic
melt DNA junctions involving Br and I as XB donors.914,940 targets,900,945−948 and the presence of an XB may affect
The results showed that while in these systems iodine allowed protein−drug affinity to an extent significant enough to make
the most favorable enthalpic contribution (−5.9 versus −3.6 the difference in a “go/no go” decision for a lead molecule.
kcal/mol), it also brought forth a significant entropic cost, Many of the reported small-molecule−protein complexes
which made bromine favored in terms of overall free energy involve inhibitors with potential pharmaceutical and therapeutic
(−2.3 kcal/mol for I, −4.8 kcal/mol for Br). interests. A noncomprehensive list of examples is reported
C. D. Tatko and M. L. Waters conceived a study to measure below for illustration purposes; several entries have already
the solution energy of biomolecular XBs involving aromatic been briefly described above in this section.
groups as acceptors.941 The thermal melting of β-hairpin There is a particularly intense interest in protein kinases for
peptides containing halogenated and nonhalogenated Phe their potential usefulness in the treatment of chronic
residues was monitored by NMR, and the results showed inflammatory, cardiovascular, and neurodegenerative diseases,
that a single iodination of the aromatic Phe ring yielded a viral infections, and possibly even cancer; several complexes
stabilization of −0.54 kcal/mol, while a double iodination could wherein XB is responsible for the binding of small molecules to
achieve a value of −1.01 kcal/mol. these proteins have been reported.900−908,947 Aldose reduc-
Since a large number of the reported biomolecular XBs tase876,877,882 and cathepsins942,949 may have implications in a
involve protein inhibitors, on a first degree of approximation, number of pathologies, including diabetic hyperglycemia and
the stabilizing effect of XBs may be described in terms of several cancers, and various halogen-bonded complexes
dissociation constants and IC50 values, although a role is played involving them are available. XB has been a key factor in the
by several other factors, such as dynamic structure differences, design of potent and bioavailable inhibitors of the enzyme fXa,
interactions with solvents, and accessibility of the active sites. a serine protease factor, which has an important role in the
The structures and IC50 values of cathepsin L complexes with a blood coagulation cascade, and which was mentioned earlier as
series of systematically selected halogenated, methylated, and an example of biological XBs involving Cl/Br···π interac-
hydrogenated inhibitors have been determined by F. Diederich tions.926−930
and co-workers.942 The replacement of a methyl group with NSAIDs are used to reduce inflammation, pain, and fever. XB
different halogen atoms able to form short contacts with the has been shown to occur, e.g., in the complexes of the NSAIDs
carbonyl oxygen of Gly61 brought forth an IC50 reduction from diclofenac and (S)-indomethacin ethanolamide with cyclo-
oxygenases,897,898 as well as in that between 3,5-diiodosalicylic
130 nM for the methyl to 22, 12, and 6.5 nM for Cl, Br, and I,
acid and HSA.899 The latter is another example of the relevance
respectively, which roughly corresponds to a stabilizing effect of
of XBs in the biomolecular context, since nonspecific drug
1−2 kcal/mol. The same study also demonstrated the
complexation with the overly abundant HSA is a well-known
possibility to finely tune the stabilization effect by using possible cause of reduced drug effectiveness.
electron-withdrawing groups able to increase the XB donor Of course, this issue does not regard only NSAIDs. In the
ability of the halogens. same study, a Cl···S XB was also found in the complex of HSA
Several structures of tetrahalobenzimidazole inhibitors with with diazepam. In the structure of cocrystals of the anesthetic
the CK2 kinase are reported in the literature, where binding halothane (CF3CHClBr) with HSA, the Br atom was found to
energies were calculated in the range of −8 to −11 kcal/ interact with several protein sites, the sulfur of a cysteine
mol.901−905 As a rough comparison, the binding energy of the residue among others.892 The physiological binding sites for
corresponding complex with 1H-indazole is reported to be halothane are presumed to be cavities within transmembrane 4-
−5.16 kcal/mol,943 but the lack of a systematic study with α-helix bundles of neurotransmitter receptors; while an exact
closely related halogenated and nonhalogenated analogues structural determination of these sites remains elusive, similar
makes it difficult to suggest a value for the specific stabilization motifs are found in ferritin, where hydrophobic cavities are
induced by XB. A comparison of the binding energies found for formed between two protein monomers. In this system, the Br
4,5,6,7-tetrahalobenzimidazoles903,905 suggests a stronger stabi- atom of halothane forms a 3.10 Å contact with the O of Leu24
lization by about 0.8 kcal/mol per established XB for the at a C−Br···O angle of 144.9°, while the Cl forms a C−X···π
iodinated over the brominated analogue. XB with Tyr28, with the closest ring carbon at 3.3 Å.891
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One further particularly interesting example is offered by the One viable approach consists in hybrid quantum mechanical/
HIV-1 reverse transcriptase (RT, a key enzyme used by HIV to molecular mechanics calculations (QM/MM),947 as a reason-
form a new viral particle) and its complex with the inhibitor able compromise between the accuracy of QM and the speed of
R221239.950 In this complex, a 3.4 Å contact is formed between MM methods. This approach consists in using MM or
an iodine atom of the inhibitor and the backbone oxygen of Tyr molecular dynamics (MD) to model most of the biomacro-
188, with a C−I···O angle of 161.6°. The special interest in this molecule, while using QM for those parts which are of higher
case comes from the fact that the inhibitor does not form interest (e.g., a drug binding site) or which cannot be treated
relevant contacts with Tyr181, one of the amino acids involved properly by MM or MD. This method could successfully model
in the most common mutations, which give rise to drug- the geometry of XBs involving backbone carbonyl oxygens,
resistant viruses. although its accuracy in calculating interaction energies proved
A halogen-enriched library for molecules able to reactivate to be more on a qualitative level.
the functionality of the Y220C mutant of the p53 tumor The positive extra point (PEP) approach953,954 can be used
suppressor has been designed and screened. These molecules to account for XBs in MM or MD methods used to evaluate the
could bind to the destabilizing surface crevice induced by the energies of biomacromolecules, such as OPLS-AA955 or
mutation, and thus shift the folding−unfolding equilibrium of AMBER.956 Since these methods assign by default an isotropic
the protein back toward the folded state.946 The best binders negative charge distribution to halogens, in the PEP the σ-hole
displayed XBs between the iodine atom of the drug and the is introduced by adding a positive pseudoatom at or near the
carbonyl oxygen of Leu145, with I···O distances of about 3.0 Å halogen atom surface. This method, for example, allowed
and C−I···O angles between 169° and 173° (Figure 120). A calculation of the binding energies of CK2 kinase complexes
clear reduction in binding capability was observed by with several halogenated ligands, yielding values in good
substituting bromine and chlorine for the iodine. agreement with the experimental dissociation constants and
IC50 values.957 One drawback of this approach is that it tends to
overestimate interatomic X···B distances; however, more
accurate results could be achieved by careful positioning of
the positive pseudoatom closer to the center of the XB.958
P. S. Ho and co-workers approached the issue by deriving a
set of MM/MD force field equations based uniquely on the
physical properties of covalently bound halogen atoms. They
found functions for the Coulombic and Lennard-Jones
potentials which describe the effective charge and shape of Br
atoms as a function of the C−Br···Y angle.938 This method was
successfully used to model the structure−energy relationships
relative to the DNA junction models studied by the same
group.
To help identify XBs in biomolecular complexes, one
knowledge-based approach has been devised by W. Zhu and
co-workers to derive a set of scoring functions based on
statistical distributions of XB geometries.959 While such an
Figure 120. Crystal structure of the complex between the binder approach is clearly influenced by the number and type of
PhiKan5196 and the p53 mutant Y220C. The iodine atom is shown in already available data (for example, there are currently very few
magenta and forms an XB with the carbonyl oxygen of Leu145. structures including iodine atoms, mostly involving thyroid
Adapted from ref 946. Copyright 2012 American Chemical Society. hormones), different binding modes may still show significant
environmental similarities and thus be related.
The interest in biomolecular XBs also extends beyond the
therapeutic field. For example, triclosan is an antibacterial 6. FUNCTIONAL SYSTEMS
which acts as an inhibitor of bacterial fatty acid synthesis.951 In
the complex with the enoyl-acyl reductase (ENR) enzyme from 6.1. Organic Catalysis
Plasmodium berghei,893 a 3.25 Å Cl···O contact is found with
In the field of noncovalent organocatalysis, HB plays an
Gly204, bearing a C−Cl···O angle of 162.4°. A shorter and
important role,960,961 and several examples of HB donor
more linear XB can be observed with the Ala97 of ENR from
catalysts have been reported.210,962−968 Taking into account the
Bacillus anthracis, where a Cl···O distance of 3.08 Å and a C−
similarities between HB and XB, in particular for their effective
Cl···O angle of 166.2° are observed.894
use in anion recognition,69,70,741,967,968 many researchers started
Pseudilins are highly halogenated marine natural products
to investigate the possible use of XB donor molecules as
and have been recently shown as promising herbicide
catalysts in organic synthesis. However, it appeared immedi-
compounds. XBs involving both Br and Cl atoms with protein
ately clear that the potential of the XB in this field may arise
backbone oxygens were found to contribute to the inhibition of
mainly from the peculiarities of halogen-bonded systems
IspD enzymes involved in the nonmevalonate pathway for
compared to related systems based on HB.969 First, the higher
isoprenoid biosynthesis, which is used by plants and many
directionality of XB26 can be exploited in the design of
human pathogens, but not by animal organisms.952
multidentate XB donors with higher selectivity toward different
5.6. Computational Models substrates.970 Second, halogen atoms being involved and
From the findings and considerations reported above, the particularly strong XB donors being associated with fluorinated
potential of XB in drug design is apparent; adequate modeling backbones, XB can be considered as a hydrophobic alternative
tools might nevertheless help in optimization. to HB. Accordingly, XB donors are more soluble in apolar
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solvents than their HB counterparts, which, on the other hand, The electrophilic activation of the carbonyl group of L-lactide
often suffer from the competition of more polar HB donor/ by ICl3 was shown by a blue shift of the CO vibrational band
acceptor solvents.971 Furthermore, since I, Br, Cl, and in some and the downfield shift split of the 13C NMR signals of L-
cases also F atoms can all be involved in XB, the interaction lactide, both consistent with a transfer of electron density from
strength can be easily tuned by changing the halogen atom.205 the oxygen toward the iodine. On the other hand, a large
Finally, halogens are more polarizable and bigger in size than downfield shift of the OH resonance of 11-BU suggested the
hydrogen, and XB donors can be classified as “softer” Lewis formation of OH···Cl HBs. In the suggested polymerization
acids than those based on HB, with important consequences for pathway, XB and HB act in concert to accelerate the reaction
the substrate preference of the final XB-based organocatalysts. (Figure 122). However, traces of HCl and HIO3 deriving from
Halogen-bonded adducts have been invoked as transient the ICl3 hydrolysis could be present in the reaction mixture,
species on the reaction pathways of different types of and it is difficult to ascertain if they play a role in the activation
reactions.972 For instance, the mechanistic scheme suggested mechanism.
for alkene bromination involves a noncovalent complex in The first report about the purposeful use of organic XB
which a Br2 molecule approaches the carbon−carbon double donors as catalysts dates back to 2008, when C. Bölm et al.
bond at an angle of 180° (Figure 121). reported the reduction of 2-phenylquinoline by the Hantzsch
ester catalyzed by haloperfluoroalkanes (Figure 123).980 On the

Figure 121. Representation of a schematic model of the mechanism of

bromination of alkenes evidencing the formation of halogen-bonded
adducts of the type X···π.
Figure 123. Reduction of 2-phenylquinoline in the presence of 1-
Similar halogen-bonded adducts also seem to be involved as iodoperfluorooctane.
intermediates in metathesis reactions between organic halides
and organometallic compounds.973 However, in these reactions basis of 19F and 13C NMR analyses, the authors demonstrated
the XB donor does not function as the catalyst since it is that the substrate activation for the reduction occurs through
consumed during the reaction. In the remaining part of this the formation of XB between I or Br atoms of the catalyst and
section, we will examine only reactions where the XB donor the quinoline nitrogen atom of the substrate. Bromo- and
functions as a catalyst and remains intact over the course of the iodoperfluoroalkanes of different lengths were tested in these
reaction. experiments, with yields up to 98%. In particular, it has been
Elemental iodine is known to accelerate a wide variety of evidenced that longer perfluoroalkanes produce higher yields,
organic reactions, and its use in organic synthesis is well while for catalysts of comparable length, higher conversions are
documented.974−976 In several cases it has been claimed that obtained with iodinated catalysts, consistent with the scale of
the catalytic activity of I2 is related to its Lewis acidity, as, for the XB strength. To further corroborate the role of XB in these
example, in reactions with carbonyl groups such as Strecker- reactions, a competing XB acceptor, (2,2,6,6-tetramethyl-1-
type reactions,977 acetal formation and cleavage,978 imine piperidinyl)oxy radical (TEMPO), was added to the reaction
formation, and Michael additions.974,976 However, no detailed mixture, and as expected, a lower catalytic ability was obtained.
mechanistic studies have been reported in this respect, and The same reduction can also be promoted with high
modes of action of I2 as a Lewis acid are not completely efficiency by a bidentate, cationic XB donor based on a
understood. dihydroimidazoline core (Figure 124).981 The reduction with
On the contrary, iodine trichloride (ICl3) was reported in
2010 to catalyze the ring-opening polymerization of L-lactide in
the presence of 11-bromo-1-undecanol (11-BU) as an initiator
(Figure 122).979 Through accurate FTIR and NMR studies, the
authors were able to suggest a plausible polymerization
mechanism occurring through a double activation of both the
monomer L-lactide and the alcohol initiator (11-BU) by ICl3. Figure 124. Hydrogenation of quinoline with the Hantzsch ester in
the presence of a bidentate XB donor catalyst based on a
dihydroimidazoline core (right).

the Hantzsch ester in dichloromethane proceeds with good

yields (higher than 90%) both with quinolines and with imines,
with a low catalyst loading of 2 mol %. NMR studies and
isothermal calorimeric titrations confirmed the involvement of
XB in the activation mechanism.
The fluoronium cation F+, derived from N-fluororopyridi-
nium triflate, has beem used as a catalyst in aziridine synthesis
starting from N-substituted imines and ethyl diazoacetate
Figure 122. Top: polymerization of L-lactide to poly(L-lactide) with (Figure 125).982 Due to its electrophilic character, the F+ cation
ICl3. Bottom: proposed mechanism for the 2-fold activation. can be assumed to form strong XBs with the imine component,
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Figure 125. Aziridine synthesis in the presence of the fluoronium

cation F+.

activating it toward the following nucleophilic attack by ethyl

diazoacetate.
Recently, Huber et al. reported the use of multidentate XB
donors as activators or catalysts in organic synthesis.970,983,984
In 2011 they reported the first use of bisimidazolium-based XB Figure 128. Halogenated and hydrogenated activating reagents.
donors as catalysts in a Ritter-type reaction: the solvolysis of
benzhydryl bromide in acetonitrile to obtain the N-benzhy- bis(imidazolim) cation, suggesting a competition in the
drylacetamide (Figure 126).983 Since the C−Br bond of the reaction mixture between the triflate and the reaction substrate
for the activating agent. By replacing the triflate anion with the
tetrafluoroborate, the yields increased to 97%, demonstrating
the role of the counteranion in the activity of the XB donor
catalyst.
Isothermal calorimetric titrations were also carried out to
Figure 126. Solvolysis of benzhydryl bromide as a model reaction.
obtain further information on the ability of the synthesized
catalysts to function as effective XB donors.985 In these
benzhydryl bromide is relatively weak and taking into account experiments, the catalysts were titrated with tetrabutylammo-
the ability of halide anions to act as XB acceptors, they nium chloride, bromide, and iodide in acetonitrile at room
reasoned that in the presence of a strong XB donor it should be temperature, and the corresponding heats of binding were
relatively easy to activate the substrate toward a nucleophilic detected. This allowed the binding stoichiometries to be
substitution reaction. The mechanism could be either SN2 or obtained and demonstrated that when the two iodoimidazolium
SN1 (Figure 127). In fact, either the XB donor could coordinate synthons are in the meta-positions on the central phenyl ring, a
bidentate halide coordination is obtained.
The effect of the alkyl chains bound to the imidazolium
nitrogens was also investigated. By introducing longer alkyl
chains (i.e., octyl instead of methyl), the solubility of the XB
donor catalysts in apolar solvents increases. This is very
important since, besides broadening the range of applicable
solvents, stronger binding may be expected in these solvents.
More recently, Huber et al. demonstrated that dicationic XB
Figure 127. Possible modes of activation of a halogenated substrate by donors with noncoordinating counteranions can also activate
the bidentate XB donor catalyst (shown in red). neutral carbonyl substrates toward Diels−Alder reactions
(Figure 129).986 Through DFT calculations they proved the
the bromine atom, polarizing the C−Br bond and thus
facilitating the SN2-type attack by the nucleophile, or
alternatively the C−Br bond can break to form a carbocation
intermediate, which undergoes an SN1-type nucleophilic attack.
The solvolysis of benzhydryl bromide as reported in Figure
126 does not occur either without any catalyst or in the
presence of the classical XB donors, e.g., 1,4-diiodotetrafluor- Figure 129. Left: Diels−Alder benchmark reaction. Right: dicationic
obenzene and 1,3,5-triiodotrifluorobenzene. On the contrary, XB donor activating agent BArF = B[3,5-(CF3)2C6H3]4−.
the use of the bisiodinated calalysts in Figure 128 as activating
agents afforded yields of up to 80%. Upon addition of 1 equiv pivotal role of XB in the activation of the carbonyl group
of the strong acid HOTf, the yields dropped down to 25%, toward the Diels−Alder reaction, while by a series of
allowing any possible role of acid impurities in the catalysis to experiments they were able to rule out the involvement of
be ruled out. According to the XB theory, by replacing iodine traces of acid, while demonstrating the role of the different
atoms with bromine, weaker XB donors are obtained; therefore, structural features of the halogen bond donor.
the corresponding bisbrominated activating agents afford lower As a closely related work, Takeda et al. reported in 2014 that
conversions (54%). The replacement of the halogen atoms with 2-haloimidazolium salts efficiently catalyze the aza-Diels−Alder
hydrogens, instead, leads to a conversion of only 7%, reaction of aldimines with the Danishefsky diene (Figure 130).
demonstrating that in this reaction XB outperforms the HB. Comparative experiments demonstrated that no reaction
Single-crystal X-ray analysis of one of the bisiodinated occurs in the absence of catalysts, and also the classical XB
catalysts in Figure 128 revealed an O···I short contact between donors, e.g., perfluoroalkyl iodides and iodoperfluorobenzenes,
an oxygen atom of the triflate anion and an iodine atom of the were inactive. On the contrary, in the presence of catalyst A
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solvolysis product were obtained when using the tetrahydro-

genated catalyst.
This behavior perfectly agrees with the XB theory and once
again confirms the role of XB in the reaction activation process.
Partly iodinated catalysts were also active in the solvolysis
reaction, although they also afforded sizable amounts of
benzhydrol and dibenzhydryl ether as byproducts.
Bi- and tridentate XB donors containing 5-iodo-1,2,3-
triazolium moieties were also tested in Huber’s group as
activators in the solvolysis of benzhydryl bromide (Figure
132)547 The iodinated bidentate compounds 1,3-IBn/OTf and

Figure 130. Top: Aza-Diels−Alder reaction of an aldimine with the

Danishefsky diene. Bottom: structure of the used XB donor activating
agents.

(Figure 130), a 57% conversion was obtained, and the

introduction of CF3 electron-withdrawing substituents on the
molecular scaffold (catalyst C) increased the yields to 80%. No
reaction occurred in the absence of iodine (catalyst D) or with
the neutral XB donor E. All these experiments clearly Figure 132. Bi- and tridentate polycationic XB donors based on the 5-
iodo-1,2,3-triazolium synthon.
demonstrated that the stronger the XB donor, the higher the
yield of this kind of reaction and once again suggested the
important role of XB in the activation mechanism. 1,3-IOct/OTf gave, respectively, 78% and 62% conversions after
To widen the library of multidentate XB donors to be used in 96 h of reaction, while the nonhalogenated compounds 1,3-
organocatalysis, further compounds were developed and tested HBn/OTf and 1,3-HOct/OTf afforded only 7% and 11%
in Huber’s group. First, the azobis(halopyridinium) compounds conversions, respectively, in the same reaction time, confirming
reported in Figure 131 were synthesized and tested in the the role of XB in the activation mechanism. The tridentate XB
solvolysis reaction of benzhydryl bromide.984 donor 1,3,5-IBn/OTf turned out to work far better with yields
higher than 95% after only 48 h, suggesting a tridentate binding
mechanism.
Besides these multidentate cationic XB donor catalysts, the
same group also reported the use of polyfluorinated neutral
activating agents.987 Neutral XB donor catalysts can offer some
advantages compared to the cationic ones. The latter, in fact,
being soluble only in polar solvents, can be applied only to
certain organic reactions. Moreover, complications may arise
from the presence of anions that can compete with the
substrate for the XB donor site.
Figure 131. Synthesis of 4,4′-azobis(halopyridinium)-based XB In 2013 Huber et al. reported the first example of carbon−
donors and reference compounds. carbon bond formation catalyzed by the XB. In particular, they
tested the XB donors F, G, and H (Figure 133) in the reaction
Iodinated and brominated catalysts, in the presence of of 1-chloroisochroman with silyl ketene acetals.
pyridine to quench traces of acid, were active in the solvolysis After 12 h at −78 °C, conversions of 37% and 91% were
reaction, affording high yields, whereas the analogous non- obtained in the presence of a 10 mol % concentration of the
halogenated compound, in the same conditions, gave only
negligible yields. However, unexpectedly, in the absence of
pyridine, the tetrahydrogenated catalyst was active in the
solvolysis reaction, affording a 69% yield. Single-crystal X-ray
analysis of this catalyst, obtained directly from the reaction
mixture, helped in understanding this behavior. In fact, in the
structure there were Br42− anions interacting through XB with
the cations. This suggested the formation of Br2, during the
reaction, by oxidation of HBr. Since Br2 can act as an XB donor,
it can activate the substrate toward the solvolysis reaction,
explaining the unexpected yield obtained with the tetrahydro-
genated catalyst in the absence of pyridine. Addition of
cyclohexene quenches the activity of elemental bromine,
allowing evaluation of the activation potential of the
halopyridinium. Therefore, in the presence of pyridine and Figure 133. Top: structures of neutral polyfluorinated XB donors.
cyclohexene, the tetraiodinated and brominated catalysts gave Bottom: selected test reaction of 1-chloroisochromane (left) to the
yields of 93% and 76%, respectively, while only traces of the corresponding ester.

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iodinated XB donors F and H, respectively, while the analogous electronics, photonics, and sensing.990−992 The emissive
noniodinated species did not afford any reaction. The addition properties of organic chromophores are greatly affected by
of strong XB acceptors (20 mol % tetrabutylammonium their packing in the solid state.993 On one hand, it is of interest
chloride) makes the XB donors F and H totally inactive, to dynamically tune the packing, and consequently the optical
proving the role of XB in the activation process. Moreover, the properties, via external stimuli.994,995 On the other hand, there
meta-substituted compound G and the monodentate variant is a need to predictively design solid-state materials with desired
(1,3,5-triiodo-2,4,6-trifluorobenzene) were not active in this optical properties,996 and XB-based crystal engineering has
type of reaction, confirming the importance of the number and emerged as a promising tool for this. In this section we will
relative orientation of the iodine substituents. discuss the role of halogenation in the emissive properties of
Another important aspect in organocatalysis concerns organic chromophores and present the recent progress in
catalyst recycling. Legros et al.988 synthesized a f luorous halogen-bonded fluorescent and phosphorescent crystals as well
organocatalyst by reacting diazabicyclooctane (DABCO) with as amorphous materials.
2 equiv of perfluorooctyl iodide, obtaining the trimeric halogen- The bare size of halogen atoms plays an important role in the
bonded complex I in Figure 134. The perfluorinated chains photoluminescence of halogenated chromophores. For in-
stance, it has been reported that in halogenated monohydroxyl
corroles the singlet-to-triplet intersystem crossing rate increases
by a factor of 60 when using iodinated corroles as compared to
their fluorinated counterparts.997 This is explained through
intramolecular spin−orbit perturbations, also known as the
heavy-atom effect.998,999 The heavy-atom effect renders
Figure 134. halogenated chromophores of potential interest as photo-
sensitizers in photodynamic therapy1000 and as phosphor-
deeply affect the solubility of the catalyst, which can be easily escence emitters, but for obtaining fluorescence emission with a
precipitated from the reaction mixture and recovered by high quantum yield, its role is typically detrimental. This is
filtration. This fluorous catalyst promoted the Morita−Baylis− exemplified by comparing chromophores 10a and 10b shown
Hillman reaction between aromatic aldehydes and Michael in Figure 136A: The iodinated one, 10a, showed a low
acceptors with yields as high as 92% (Figure 134). The
recovered catalyst can be reused for up to five iterative cycles,
albeit with a little decrease of the activity.
Finally, Charette et al.989 reported on halogenated rhodium
carboxylate catalysts that are active in the enantioselective
cyclopropanation of alkenes with α-nitrodiazoacetophenones
(Figure 135).

Figure 136. A selection of (A) fluorophores studied in refs 486, 1001,

and 1002 and (B) halogen/hydrogen bond donors cocrystallized with
12 in ref 1002.

fluorescence quantum yield of 0.14 in toluene, while for the

noniodinated 10b, a quantum yield of 0.90 was reported.486
Furthermore, for 10a XB drives the self-assembly in the solid
state into infinite chains that exhibit no fluorescence. 10b, in
Figure 135. Cyclopropanation reaction with different Rh-based
turn, exhibits bright fluorescence due to J-type aggregation
halogenated catalysts.
driven by aryl−fluoroaryl interactions.486 As a counterexample,
halogenation has a positive impact on the solid-state emission
The tetrachlorinated catalysts showed enantioselectivities
of compounds 11.1001 Microcrystals of 11c exhibit an
higher than those of the analogous hydrogenated compounds
exceptionally high solid-state fluorescence quantum yield of
(80−93% ee vs 2−43% ee). Single-crystal X-ray analysis of the
0.95, while crystals of 11d outperform the other compounds in
halogenated catalysts revealed an all-up conformation stabilized
the efficiency of electrochemiluminescence. Clearly, more
by Cl···O XBs between the chlorine atoms and oxygen atoms of
investigations are needed to comprehensively understand the
the phthaloyl group. 1H−13C heteronuclear NOESY (nuclear
effects of halogenationand XBon the photoluminescence
Overhauser effect spectroscopy) experiments suggested that
of organic molecules and molecular crystals.
this all-up conformation is also kept in solution and is
The first demonstration of the XB-based cocrystallization
responsible for the high enentioselectivities observed.
strategy to tune the fluorescence of solid-state materials was
6.2. Optical and Optoelectronic Systems reported by Jones and co-workers in 2011.1002 They employed
6.2.1. Light-Emitting Materials. Organic solid-state the stilbene derivative 12 (Figure 136A), cocrystallized with
luminescent materials have in recent decades received a lot of several nonfluorescent halogen and hydrogen bond donors
attention due to their potential applications in organic (Figure 136B) capable of interacting noncovalently with the
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cyano groups of 12. Each of the cocrystals showed distinct

crystal packing compared to the pure 12 (Figure 137, top).

Figure 138. (A) Scanning electron micrograph of the 12:A

Figure 137. Top: crystal structures of pure 12 and related cocrystals nanococrystals. (B) Fluorescence spectra of the nanococrystals at
12:A, 12:B, 12:C, 12:D, and 12:E, which each shows a distinct different temperatures. The inset shows the fluorescenece intensity
packing. Bottom: photographs of samples of pure 12 and of the related ratios at I465nm/I532nm and the dependence of the color coordinates on
cocrystals. (i, ii) Powder samples under daylight and UV illumination, the temperature. Reprinted with permission from ref 1003. Copyright
respectively. (iii, iv) Single-crystal samples under UV illumination and 2013 Wiley-VCH.
daylight as observed through a fluorescence microscope (50×). (v)
Two-photon luminescence under 800 nm laser excitation. Reprinted
with permission from ref 1002. Copyright 2011 Wiley-VCH. reversibly tuned with the temperature (Figure 138B), whereas
heating above 200 °C resulted in an irreversible structural
change from 12:A nanococrystals into nanocrystals of pure 12.
This, in turn, strongly affected their optical properties as shown These two studies convincingly demonstrate that the XB-based
by the photographs of Figure 137, bottom, allowing the tuning cocrystallization strategy is a promising route toward tuning the
of the emission color from blue to green to yellow as emissive properties of organic crystalline materials.
determined by the stacking arrangement of the chromo- Due to the heavy-atom effect, the large size of XB donor
phores.1002 The cocrystals also served as efficient two-photon atoms renders XB-based solid-state materials particularly
emitters when pumped with an 800 nm near-infrared light promising for the design of phosphorescent materials, as was
source. In a follow-up study, the same authors developed an first shown by the group of Jinsang Kim in 2011.1004
ultrasound-assisted method to fabricate halogen-bonded nano- Conventionally, materials exhibiting high-quantum-efficiency
cocrystals.1003 Their sonocrystallization procedure yielded phosphorescence are based on organometallics;1005,1006 purely
monodisperse spherical 1:1 cocrystals of 12 and A with an organic, metal-free materials with efficient phosphorescence
average size of 60−70 nm (Figure 138A). Without the emission are rare.1007,1008 XB, however, may change the picture,
ultrasound treatment, no cocrystals were formed. The nano- as was demonstrated using the materials shown in Figure 139A.
sized cocrystals may differ from their macroscopic counterparts The aromatic carbonyl group was used as a triplet generator. In
in terms of their optical properties, as was also observed in this solution, the compounds exhibited weak fluorescence, and the
work. For example, the fluorescence lifetimes were prolonged triplet emission was inactive. In the crystal form (Figure 139B),
by the nanoconfinement, and the emission spectrum exhibited Br···OC XB brings the aromatic carbonyls and the bromine
distinct features as compared to that of the macrodimensional atoms into close proximity, triggering the heavy-atom effect and
crystals. The emission from the nanococrystals could also be giving rise to green phosphorescence with an emission
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beneficial in terms of material cost, tunability, and device

stability, rendering the material concept of potential interest in
display and lighting applications as well as in sensing. In a
follow-up study,1009 the authors showed that the quantum
efficiency of phosphorescence is highly dependent on the
composition of the mixed crystal, and that both too high and
too low emitter concentrations severely diminish the emission
efficiency. The optimum concentration range was found to be
1−10 wt %. The reduced quantum efficiency at the low-
concentration regime was attributed to poor inclusion of the
13b “impurities” in the crystal of 13a. It was also shown that
mismatch between the alkyl chain lengths between the emitter
and the host reduced the phosphorescence quantum yield. This
study further elucidated the findings of ref 1004, yet the
quantum yield of 55% remained unbeatable.
The above studies revealed that bright, color-tunable room-
temperature phosphorescence is achievable in organic crystals
Figure 139. (A) Chemical structures of the hosts a and aldehydes b due to the XB-directed heavy-atom effect. However, in terms of
used in ref 1004. (B) Schematic depiction of the crystal packing of practical applications, the crystal-engineering-based approach
13b, highlighting the carbonyl oxygen−bromine XB. It is believed that may not be the best, since the stringent requirement of high-
this contact is responsible for the phosphorescence observed from
quality crystals to activate the triplet emission complicates the
crystals of 13b (C). Reprinted with permission from ref 1004.
Copyright 2011 Nature Publishing Group. sample preparation procedure. In this respect, amorphous film-
forming materials would be more attractive, but they may suffer
from pronounced vibrational dissipation and suppression of
quantum yield of 2.9% (for the crystal of 13b). By diluting the phosphorescence as compared to crystalline materials. Kim et
chromophore in a nonemissive but structurally similar host al. also tackeled this issue, showing that efficient phosphor-
compound to prevent self-quenching (1 wt % 13b in 13a), an escence emission is indeed possible in glassy polymer
emission quantum yield as high as 55% was reported.1004 matrixes.1010 When embedded into atactic poly(methyl
Interestingly, when bromine was replaced with iodine, no methacrylate) (PMMA), the organic phosphor 13b exhibited
phosphorescence was detected, which was attributed to inferior green phosphorescence with a quantum yield of 0.7% at room
size matching between the iodine atom and the aldehyde group. temperature. Even if weak, the activation of phosphorescence
By varying the electron density and conjugation length of the was itself an indication of restricted vibrational decay due to the
chromophore (Figure 139A), the emission color could be rigidity of the polymer matrix. Importantly, the phosphor-
tuned from blue all the way to orange/red (Figure 139C). escence quantum yield could be enhanced by an order of
Compared to organometallics, the all-organic design may be magnitude by using isotactic PMMA, due to reduced β-

Figure 140. (A) Top: the new organic phosphor G1 appears particularly promising in enhancing phosphorescence in an amorphous PVA matrix.
Bottom: the green phosphorescence of G1 embedded in PVA is explained by synergistic effects brought about by simultaneous use of halogen and
hydrogen bonds. (B) The phosphorescence emission of 1 wt % G1 in PVA depends linearly on the humidity, while the fluorescence emission is
insensitive to the humidity, which allows (C) fluorescent watermarks to be reversibly written onto the amorphous polymer film. Reprinted with
permission from ref 1011. Copyright 2014 Wiley-VCH.

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relaxations compared to those of atactic PMMA, which further

suppressed the vibrational dissipation. The optimum emitter
concentration was again around 1 wt %, suggesting that at very
low concentrations the number density of the emitters is too
low for the emission-enhancing chromophore−chromophore
XB to occur. As a proof-of-principle application, the authors
demonstrated the use of their amorphous phosphor as a
temperature sensor in a microfluidic device.1010 To further
optimize the room-temperature emission in amorphous films, a
design strategy combining halogen and hydrogen bonding was
devised (Figure 140A).1011 The role of the former was again to
promote the intersystem crossing, while the latter served to
supramolecularly cross-link the matrix polymer poly(vinyl
alcohol) (PVA) and therefore further suppress the nonradiative
decay processes from the triplet to the ground state. For this, a
new organic phosphor (G1) (Figure 140A) was designed. In a
material containing 1 wt % G1 in PVA, a phosphorescence
quantum yield of up to 24% was observed, which is a significant
improvement compared to that of the previously reported
13b−isotactic PMMA. The system is also strongly water-
sensitive as the water molecules interfere with the HB between
G1 and the polymer matrix. As the bonds break, the
phosphorescence emission is quenched, whereas the fluores-
cence emission remains intact (Figure 140B), which allows for
humidity-triggered phosphorescence-to-fluorescence switching.
This switching was used for reversible direct writing of
fluorescent watermarks and moisture sensing (Figure 140C).
Parallel to the work of Kim et al., the XB-based design of
organic phosphors has been intensively studied by the group of
Prof. Wei Jun Jin, as has been recently reviewed in a book
chapter.1012 Their main target has been to harness halogen···π
interactions, the type of XB that was quantified already in the
1940s and 1950s,51,58,59 to engineer phosphorescent crystals.
Two types of fluorophores were employed: (i) fluorene and its
heterocyclic analogues1013−1015 and (ii) polycyclic aromatic
hydrocarbons,649,1016−1018 typically cocrystallized with 1,4-
diiodotetrafluorobenzene (DITFB). Cocrystals of DITFB and
carbazole constitute a beautiful example of C−I···π XB-driven
crystal engineering (Figure 141, left), where DITFB acts as
both the cement to link the carbazole molecules via XB and
also as a heavy-atom perturber to enhance the phosphorescence
emission.1013 The crystals assemble into a 2:1 DITFB/
carbazole stoichiometry, forming infinite chains constructed
by the C−I···π XBs and further stabilized by π−π stacking
interactions between the DITFB molecules. The parallel chains
are linked together by C−H···I HBs (Figure 141, left); hence,
in these systems the iodine atom simultaneously acts as an XB
donor and an HB acceptor. The resulting cocrystals exhibited Figure 141. Top: infinite-chain structure of the carbazole/1,4-
strong phosphorescence in the solid state as well as in the form diiodotetrafluorobenzene cocrystals (left), driven by C−I···π XBs
of microparticles suspended in water. The authors verified via and further stabilized by π−π stacking (right). The adjacent chains are
powder X-ray diffraction experiments that the microparticles linked together by C−H···I HBs (bottom). Reprinted with permission
have the same structural characteristics as the cocrystals. The from ref 1013. Copyright 2012 Royal Society of Chemistry. Bottom:
phosphorescence quantum yield of the microparticle suspen- phosphorescence excitation and emission from naphthalene/1,4-
sion was determined to be 0.33.1013 Also fluorene, dibenzofur- diiodotetrafluorobenzene (top) and phenanthrene/1,4-diiodotetra-
an, and dibenzothiophene yielded C−I···π XB-driven phos- fluorobenzene (bottom) cocrystals. The insets display the phosphor-
escence color of the cocrystals under UV excitation through a mask.
phorescent cocrystals when complexed with DITFB,1014 and Reprinted with permission from ref 649. Copyright 2012 Royal Society
especially the latter may turn out interesting in combining of Chemistry.
luminescence and electron transport in halogen-bonded
crystals. In carbazole-containing crystals, the emission can be
further tuned by N-methyl and N-ethyl substitutions.1015 emission from the ethyl-substituted carbazole is very weak and
Compared to the unsubstituted carbazole,1013 methyl sub- blue-shifted compared to its unsubstituted counterpart, and the
stitution leads to red-shifted phosphorescence and a 1:1 donor-to-acceptor stoichiometry is 1:2. This highlights that
stoichiometry between the donor and acceptor, while the substitution-induced changes in the crystal packing have a
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pronounced effect on the luminescence of materials (see also influenced by the position of the nitrogen atom in the pyridine
ref 1002). The luminescence and packing of cocrystals ring due to steric hindrance, which in turn affected their
assembled between polycyclic aromatic hydrocarbons and emission properties. In another study, the authors showed that
diiodotetrafluorobenzenes depend delicately on the number the luminescence properties of cocrystals of diiodotetrafluor-
of aromatic rings of the bond acceptor. In pyrene-containing obenzene and diphenylacetylene can be controlled with the
cocrystals, the C−I···π XB did not take place,1016 while it did stoichiometry of the crystal. Both 1:1 and 1:2 cocrystals were
occur in the smaller naphthalene- and phenanthrene-containing driven by halogen···π interactions, the former into a chevron-
cocrystals, both exhibiting a 1:2 stoichiometry between the like arrangement and the latter into 2D C−I···π networks.
emitter and the diiodotetrafluorobenzene.649 These two Interestingly, the 1:1 stoichiometry leads to luminescence
cocrystals emit strong green and orange phosphorescence dominated by fluorescence, while the 1:2 cocrystal is a pure
(Figure 141, right), respectively, exhibiting monoexponential triplet emitter with a phosphorescence quantum yield of 6% at
phosphorescence decays with lifetimes of 0.067 and 1.449 ms. room temperature (Figure 142, bottom), pointing toward a
In the phenanthrene cocrystal, phosphorescence was also new strategy for controlling the emissive properties of all-
obtained using 1,4-dibromotetrafluorobenzene as an XB organic crystalline solids.1021
donor,1017 while this was unsuccessful in the case of Overall, halogenated/halogen-bonded chromophores serve
carbazole-based organic phosphors.1013 as a promising class of light-emitting solid-state materials
Finally, Ventura et al. have studied the luminescence diplaying unique properties brought about by XB (as
properties of several 1,8-napthalimide derivatives (Figure 142, convincingly illustrated by the examples of this section), in
addition to being useful analytical tools. Some recent examples
of the latter comprise the work of the Würthner group on the
role of halogen−arene interactions in the self-assembly of
squaraine dyes,1022 the work of Beer et al. on porphyrin- and
haloimidazolium-based receptors for anion recognition and
sensing,1023,1024 and the study of Xie et al. on the XB between
molecular iodine and the photoinduced electron-transfer
molecule ciprofloxacin under weakly alkaline conditions and
its role in the charge-separation process.1025
6.2.2. Light-Responsive and Nonlinear Optical Materi-
als. Since the first reports published in 2012,489,859 XB has also
appeared as a promising tool in the design of light-responsive,
azobenzene-containing materials. Even if still in its infancy, this
line of research is highly promising, comprising amorphous
polymers,855,859,860 liquid crystals,489,851 and even crystals that
deform under light irradiation.1026,1027 The photoisomerization
of azobenzene derivatives1028 (Figure 143A) can give rise to a
cascade of motions beyond the size scale of an individual
molecule. In a polymeric or liquid-crystalline environment, the
molecular alignment of the azobenzenes can be controlled with
polarized light. This phenomenon is particularly useful in the
context of liquid crystals, the alignment of which can be

Figure 142. Top: chemical structures of the 1,8-napthalimide (17)

derivatives with 4-bromine substitution and 2-, 3-, and 4-methylpyr-
idine substitution at the imidic N-position (18, 19, and 20,
respectively) used in ref 1019. Bottom: by controlling the
stoichiometry of diphenylacetylene/1,4-diiodotetrafluorobenzene coc-
rystals from 1:1 (top) to 1:2 ratios (bottom), the photoluminescence
can be “switched” between fluorescence and phosphorescence.
Reprinted from ref 1021. Copyright 2015 American Chemical Society.

top) in solution and in the crystal/cocrystal state,1019 showing Figure 143. Photoisomerization of azobenzene (A) can give rise to a
once again that XB makes a difference. This class of molecules cascade of molecular motions into a material system it is incorporated
into. The most relevant examples in the context of halogen-bonded
is known for their rich optical properties, highly sensitive to the functional materials are (B) photoinduced phase transitions in liquid-
substituents particularly at the 4-position.1020 In compounds crystalline materials, (C) photoinduced surface patterning of initially
18−20, the 4-substituted bromine plays the role of promoting flat polymer surfaces, and (D) photoinduced bending of azobenzene-
intersystem crossing, whereas the methylpyridine substitution containing cross-linked liquid-crystalline polymers or molecular
acts as an anchoring group able to form XBs with (co)crystals. Reprinted with permission from ref 1040. Copyright
diiodotetrafluorobenzenes. The packing of the cocrystals was 2005 Optical Society of America.

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controlled and modulated by thin layers of azobenzene withdrawing tetrafluorobenzene ring (Figure 144A), allowing
“command surfaces”, or by doping a small amount of the role of chromophore−polymer interaction to be decoupled
azobenzene molecules into the liquid crystal.1029,1030 In the from other effects that potentially influence the SRG formation.
latter case, the photoisomerization process can even give rise to Therefore, this series allowed the study of the role of (i) the XB
isothermal phase transitions and turn an aligned liquid-crystal interaction strength (22 vs 23; 3.5 and 5.1 kcal/mol,
system into isotropic and vice versa (Figure 143B).1031 Two respectively, based on DFT calculations) as well as the nature
other relevant processes triggered by azobenzene photo- of the interaction (22 vs 24; XB vs HB, both of similar
isomerization are photoinduced surface patterning and photo- strength) in the surface patterning process. The surface
induced bending. The former was first observed in 19951032,1033 deformation of spin-coated thin films of the polymer−
when it was reported that, by irradiating an amorphous azobenzene complexes was followed in situ by light-diffraction
azopolymer film with a light interference pattern, the polymer measurements (Figure 144B) and ex situ via atomic force
starts to macroscopically move and forms a replica of the microscopy (AFM) (Figure 144C). A strong dependence on
incident irradiation pattern onto the polymer surface in the the bond donor unit was observed as both the diffraction
form of a surface relief grating (SRG; Figure 143C). The SRGs efficiency and the surface-modulation depth developed in the
are easily fabricated and intriguing both from the fundamental order 23 > 22 > 24, i.e., I > Br > H. This result has two
scientific perspective and in terms of their potential applications important implications. First, in the halogen-bonded complexes
in photonics and nanostructuring.1034,1035 The photoinduced the surface patterning efficiency follows the strength of
bending (Figure 143D) takes place predominantly in cross- noncovalent bonding. Second, XB, presumably because of its
linked liquid-crystalline polymers and elastomers,1036 and more higher directionality, seems to outperform hydrogen-bonded
recently also in azobenzene crystals,1037,1038 triggered by systems with a similar polymer−dye interaction strength in
alignment order changes in the solid state. XB-based supra- terms of SRG formation efficiency. Later on, a follow-up study
molecular materials have something to offer on all these fronts was conducted, reporting on an extensive series of the nine
as will be illustrated through the examples given in this polymer−azobenzene complexes shown in Figure 144A, to
subsection. The discussion follows a recent book chapter build up a “supramolecular hierarchy” among halogen and
written by us,1039 which we refer to for a more comprehensive hydrogen bond donors in the surface patterning process.855
treatment. This paper served to strengthen the conclusions made in ref
The first report on halogen-bonded azobenzene-containing 859. By comparing the complexes comprising 23 and 25
materials was based on a polymeric XB acceptor (P4VP) interacting through XB and structurally similar strong (11.8
complexed with azobenzenes 22−24 (Figure 144A).859 The kcal/mol) HB, respectively, it was shown that the final
diffraction efficiencies of the 23- and 25-based complexes
were approximately equal, but the buildup of the grating was
much faster for the halogen-bonded complex. This is
unambiguous proof of the high potential and special role of
XB in mediating light-induced movements into photo-
responsive polymer systems. Second, the paper introduced an
iodoacetylene-functionalized azobenzene (28 )that came out on
top of the hierarchy. The use of a nonfluorinated dye to
produce an XB-based complex with an efficient optical response
may bring the advantage of reducing chromophore aggregation
and phase separation (i.e., allowing higher chromophore
concentrations to be used in the polymer matrix) as compared
to the use fluorinated azobenzenes, which may be beneficial in
Figure 144. (A) Chemical structures of the azobenzene compounds applications that require high optical anisotropy or a nonlinear
studied in refs 859 and 855. Comparison of (B) the diffraction kinetics optical response. Due to the very different electrostatic
and (C) the AFM surface profile of thin films of complexes between
22−24 and P4VP (10 mol % azobenzenes in a P4VP matrix). The
potential surfaces of 25 and 28 (Figure 144D; the positive
samples were spin-coated on silicon substrates, and their thickness was area is spread out in 24, while it is narrowly focused on the
ca. 90 nm. Reprinted with permission from ref 859. Copyright 2012 extension of the C−I bond in 28 and 23), model cocrystals also
Wily-VCH. (D) Electrostatic potential surfaces of compounds 28 constructed with 30 exhibited very different packing features,
(top) and 25 (bottom), ranging from −0.03 (red) to 0.03 (blue) au. the latter being highly linear and the former adapting a zigzag
(E) Ball-and-stick representation of the crystal packing of 30·(25)2 arrangement with an extremely short O···N distance. The
(top) and 30·(28)2 (bottom). Middle: view along the crystallographic higher directionality of XB gives rise to a more rigid polymer−
b-axis of the cocrystal 30·(25)2, illustrating the tendency of 25 to azobenzene junction, which in turn enhances the light-induced
interact via quadrupolar stacking. Reprinted with permission from ref mass transport.855
855. Copyright 2015 Royal Society of Chemistry.
As already brought up previously, XB offers interesting
prospects in designing new types of supramolecular liquid
choice of materials was based on previous work on phenol− crystals from non-liquid-crystalline building blocks, which in
pyridine hydrogen-bonded polymer−azobenzene complexes turn opens up a new route toward light-functional liquid
that had already proven their potential as efficient SRG- crystals. This was first shown using the complex presented in
forming materials.1041,1042 The rationale for replacing the Figure 145A,489 which exhibited a monotropic nematic LC
relatively strong HBs with weaker XBs is that the electronic and phase upon cooling from the isotropic phase. Note that neither
photochemical properties (absorption spectrum, dipole mo- of the constituents contains any flexible chains that are
ment, isomerization kinetics) of the molecules are mainly conventionally used in designing small-molecule liquid-
determined by the dimethylamino donor and the electron- crystalline complexes, which in combination with the presence
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The second example of halogen-bonded photoresponsive

LCs, published in 2014, demonstrated a photoinduced LC-to-
isotropic phase transition in complexes between azopyridines
and molecular iodine (see Figure 107C for the chemical
structures). The phase transition was detected by irradiating the
I2 complex (n = 12) with UV light under a polarized optical
microscope, at a temperature at which it exhibited a liquid-
crystalline (smectic A) phase. As shown in Figure 146, the

Figure 146. Polarized optical micrographs of an azopyridine−I2

complex (see Figure 107C) at its liquid-crystalline phase before
(left) and after (right) UV irradiation. The decreased contrast
indicates photoinduced phase transition due to trans−cis photo-
isomerization. Upon irradiation with visible light, the colored pattern
can be retained due to reverse cis−trans isomerization. Reprinted with
permission from ref 851. Copyright 2014 Royal Society of Chemistry.

liquid crystallinity quickly disappeared upon irradiation, as

evidenced by reduced contrast in the polarized optical
Figure 145. (A) Chemical structure of the halogen-bonded liquid- microscopy (POM) image that turned from colored to dark.
crystalline complex employed in ref 489. (B) Polarized absorption
spectra of a thin film (250 nm) of the complex shown in (A). Black
The color was recovered after the isotropic sample was
curve: initial spectrum (same for both polarizations). The red and blue irradiated with visible light. This is a clear sign that the phase
curves correspond to the polarized absorption spectra in the directions transition is initiated by reversible trans−cis photoisomerization.
parallel (A∥ < A0) and perpendicular (A⊥ > A0) to the polarization Interestingly, the corresponding bromine-containing complexes
plane, taken after 30 and 120 s of irradiation (488 nm, 100 mW/cm2), that provided more stable mesophases851 were not photo-
respectively. The absorption anisotropy is an unambiguous sign of responsive. Even if further studies are needed to fully
photoinduced reorientation of the azobenzene chromophores. (C) understand the photoresponse of these complexes, this result
Atomic force microscopy view of the spin-coated thin film of the points toward the use of XB in building, e.g., supramolecular
complex shown in (A) after SRG inscription (5 min, 488 nm, 300 photoactuators1047 and functional halogen-bonded liquid
mW/cm2). The surface-modulation depth after the SRG inscription crystals and networks.1048
was 600 nm, 2.4 times the initial film thickness. Reprinted with
permission from ref 489. Copyright 2012 Wiley-VCH.
Despite the fact that the photoisomerization may be
hindered in constrained environments, the photomechanical
effects have in recent years also been studied in the crystalline
state.1037,1038,1049 XB and fluorination have several things to
of the dimethylamino group should promote the surface offer in this context. Bléger et al. have shown that ortho-
patterning efficiency.1043,1044 The high-temperature LC phase, fluorination of azobenzenes significantly increases the thermal
in turn, should promote photoalignment.1045,1046 The photo- half-life of the cis-isomers, up to months or even years.1050,1051
responsive properties of the complex were indeed unique. Barrett, Frišcǐ ć, and co-workers1026 used the long half-lives to
Because of the presence of the azobenzene moiety, initially grow single crystals of the cis-forms of symmetrically
isotropic, polycrystalline spin-coated thin films of the complex substituted 4,4′-haloperfluoroazobenzenes (Figure 147, top)
could be uniaxially aligned by irradiation with polarized light, that were subjected to X-ray crystallographic and photo-
achieving a high order parameter of molecular alignment of mechanical characterization. Compared to trans-crystals, the cis-
0.55 (Figure 145B). Interestingly, the films underwent crystals are of lower density, allowing for the cis−trans
irreversible crystalline-to-amorphous transformation upon isomerization to occur in single crystals, whereas the reverse
irradiation with visible light (488 nm, 100 mW/cm2, 30 s). isomerization was inactive (Figure 147, bottom right). Upon
Furthermore, as illustrated in Figure 145C, within an irradiating the cis-single crystal with 457 nm laser light, the
inscription time of only a few minutes, a grating with crystal bent away from the direction of the incoming light
modulation depth of 600 nm could be inscribed on a film (Figure 147, bottom left). The deformation was irreversible,
with a starting thickness of only 250 nm. This result stands out and was accompanied by a crystal-to-crystal transition from a
as among the most efficient SRG-forming materials reported.489 cis-single crystal to a polycrystalline aggregate of trans-crystals,
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into the geometry of the cocrystal, thanks to the directionality

of the XB: The all-trans-cocrystal (trans-31)·(trans-bpe) forms
infinite linear halogen-bonded chains, whereas the all-cis-
cocrystal (cis-32)·(cis-bpe) takes a V-shaped zigzag geometry.
Due to the lower packing density, only the crystals containing
the cis-form of 31 or 32 underwent (irreversible) photo-
mechanical deformation. Surprisingly, the crystals remained of
high enough quality even after photoirradiation, which for the
first time enabled in situ monitoring of the photoisomerization
process via X-ray diffraction analysis. Such studies revealed that
the crystal-to-crystal isomerization proceeded via an amorph-
ization phase followed by recrystallization, as illustrated in
Figure 148C.1027
The field of nonlinear optics1054 (NLO) may also benefit
from XB, especially when dealing with second-order NLO
Figure 147. Top: trans- and cis-forms of 4,4′-dibromoperfluoroazo- phenomena occurring only in noncentrosymmetric media.
benzene. Bottom right: in the crystal state, the photoisomerization Typical chromophores for second-order NLO comprise a π-
proceeds only from the cis- to the trans-state, not vice versa. Upon cis- conjugated system that is asymmetrically end-capped with
to-trans isomerization, thin crystals bend irreversibly away from the
electron-donating and -accepting moieties. Due to the electro-
irradiation source. Reprinted from ref 1026. Copyright 2013 American
Chemical Society. negative fluorine atoms, a tetrafluoroiodobenzene unit may
simultaneously act as an XB donor and an intramolecular
electron acceptor, therefore being an ideal building block for
being the first demonstration of permanent photomechanical supramolecular NLO materials. However, before building up
modification of crystal shape in azobenzene crystals.1026 solid-state NLO materials or devices, it is imperative to
The difunctional 4,4′-haloperfluoroazobenzenes have also characterize and understand the NLO response at the
been used as building blocks for halogen-bonded cocrys- molecular level. This can be achieved either using electric-
tals,1052,1053 which may bring additional flexibility to the field-induced second-harmonic generation (EFISH) or hyper-
material design of the photomechanical crystals. Indeed, Barrett Rayleigh scattering (HRS). The first, and thus far the only,
and Frišcǐ ć et al. recently demonstrated the ability of such study on XB-based tuning of molecular-level NLO response
cocrystals to undergo photoinduced deformation,1027 employ- was performed by Cariati et al., who compared the molecular
ing the materials shown in Figure 148A. As Figure 148B hyperpolarizabilities of 33 and 34 (Figure 149A) in chloroform
exemplifies, the geometry of the tectons is beautifully translated and in dimethylformamide (DMF) using EFISH.1055 The

Figure 148. (A) Compounds used in ref 1027. (B) Linear structure of supramolecular chains of (trans-31)·(trans-bpe) and the zigzag structure of
(cis-32)·(cis-bpe) as determined by single-crystal X-ray diffraction analysis. (C) Photoinduced bending of halogen-bonded cocrystals, followed by in
situ X-ray diffraction, reveals that the transition from the unbent cis-single crystal to the bent polycrystalline trans-state proceeds through an
amorphous intermediate phase. Reprinted with permission from ref 1027. Copyright 2014 Royal Society of Chemistry.

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noncentrosymmetric crystals, and an attempt toward this

direction was taken by Cariati and co-workers using the self-
complementary molecules 36 and 37 (Figure 149A).723 The
molecules showed high molecular-level nonlinearities, and
crystallized into head-to-tail halogen-bonded polar chains.
Unfortunately, the chains stacked into a centrosymmetric
arrangement, giving rise to no bulk second-harmonic signal. On
the basis of the knowledge gained on hydrogen-bonded
supramolecular structures,1057,1058 the most promising methods
to order, e.g., 36 and 37, into a noncentrosymmetric alignment
are based on vapor-phase deposition. Due to the self-
complementarity of these molecules, this approach may lead
to spontaneous noncentrosymmetric self-organization of the
bulk structure without applying external fields. This route to
construct halogen-bonded solid-state NLO materials, however,
remains yet to be demonstrated.
Also azobenzene molecules are highly promising as NLO
chromophores,1059 and they possess the additional benefit of
allowing the NLO response at both the molecular1060 and
macroscopic1061 levels to be switched through photoisomeriza-
tion. The photoisomerization process also allows an initially
isotropic azobenzene-containing material system to be optically
poled,1062 and in fact, the only example that XB makes a
difference in solid-state second-order NLO properties employs
this method.860 The materials used in this work are shown in
Figure 144A (compounds 22, 23, and 24), incorporated into a
P4VP matrix in a 1:20 (azobenzene/polymer repeat unit) molar
fraction. The results demonstrated that stronger chromo-
phore−polymer XB resulted in an increased second-harmonic
Figure 149. (A, top) A selection of NLO-phores containing XB donor signal when the bond strength was the only variable (22 vs 23),
groups. (B, bottom) Upon optical poling of azobenzene chromo- and compared to hydrogen-bonded systems, XB seemed to
phores 22, 23, and 24 of Figure 144A in a P4VP matrix (the molar prevail (22/23 vs 24). When the polymer matrix was replaced
ratio between the azobenzenes and the polymer repeat units is 1:20), with polystyrene, which lacks the electron-donating nitrogen
XB clearly boosts the second-order nonlinear optical response of the atom, the NLO response developed in the same order (23 > 22
material system. Reprinted with permission from ref 860. Copyright
2015 Royal Society of Chemistry.
> 24), but the overall magnitude of the response was
significantly lower than in P4VP. This was attributed to weak,
yet non-negligible, halogen···π interactons between the building
former is essentially uncapable of participating in noncovalent blocks. These observations are interesting, but further studies at
interactions, while DMF is a rather strong XB acceptor. In both the molecular (hyper-Rayleigh scattering) and macro-
chloroform the EFISH signal, which actually consists of the scopic (electric-field poling) levels are needed to profoundly
product of molecular dipole moment μ and the hyper- understand them, and to unambiguously judge the applicability
polarizability component along the dipolar axis β, was positive of XB in the design of solid-state polymeric NLO materials.
in sign and of similar magnitude for both compounds, matching Further studies along these lines are presently in progress.
the value reported for the pentafluorinated derivative 35.1056 6.3. Conductive and Magnetic Materials
This shows that the para-substituent of the fluorinated ring,
while extremely pertinent for the ability of the molecule to form XB-based crystal engineering has resulted in several examples of
noncovalent interactions, does not play a major role in the conducting and magnetic materials, based on controlled
molecular-level NLO properties. The situation becomes organization of radical species in the crystalline state. As
markedly different in DMF. For the non-halogen-bonded brought up by Fourmigué,1063 XB can play a dual role in
reference compound 34, μβ decreased somewhat but remained crystals comprising radical species. On one hand, it provides
positive, while for 33 μβ was reversed in sign and increased by a structural control over their solid-state organization, bringing
factor of almost 2.5. The authors attributed the sign inversion predictability in the crystal design and control in the
to a change in direction of μ due to the presence of two conductivity and magnetic-interaction pathways. On the other
competing electron donor sites, the −NMe2 and the solvent hand, XB may play an electronic role and contribute to the
molecule halogen-bonded to the tetrafluoroiodobenzene band dispersion of organic stacks, which may further affect the
moiety. This work shows that XB can be harnessed to tune conductive and magnetic properties of the crystals. Several
the optical nonlinearities of organic compounds at the aspects to be covered here have been reviewed by Four-
molecular level. migué,576,602,1063 while Mercuri et al. have recently highlighted
For building actual NLO devices, the goal with second-order the advancements in tailoring magnetic properties of molecular
NLO materials always lies in the solid state. In other words, it is materials through noncovalent interactions.1064 We direct an
not sufficient to have noncentrosymmetric molecular constit- interested reader toward these works for further details.
uents, but these constituents must adopt an overall non- The design of halogen-bonded conductive materials is largely
centrosymmetric arrangement. This requirement is met in based upon the use of halogenated tetrathiafulvalene (TTF)
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Figure 150. (A) Halogen-bonded radical cation salts formed between partially oxidized halogenated TTF molecules and halide (top) or
cyanometalate (bottom) anions were the first examples of halogen-bond-based molecular conductors.600 (B) Crystal structures of the Ag(CN)2
(top) and Br− (bottom) salts. Reprinted with permission from ref 600. Copyright Elsevier 1995. (C) Chemical structures of the TTF cation and
various anions used in ref 1074. (D) Projection view, along the stacking axis, of the unit cell of the salt (38)4[1,5-Napht(SO3)2], showing the XBs as
dotted lines. Reprinted from ref 1074. Copyright 2011 American Chemical Society.

derivatives as XB donors. TTF has been at the very heart of appeared as powerful XB acceptors, giving rise to high
organic electronics research as a π electron donor1065 since the conductivities of up to 8 S/cm−1 in crystals of (38)4·[1,5-
discovery of the formation of highly conducting charge-transfer Napht(SO 3 ) 2 ] (1,5-Napht(SO 3 ) 2 = 1,5-naphthalenebis-
complexes with the electron acceptor tetracyano-p-quinodi- (sulfonate), Figure 150D).
methane (TCNQ).1066 It can be reversibly oxidized into Chiral iodinated TTF salts have also been actively studied,
cationic TTF+ and TTF2+ states,1067 and it is the mixed valence with the aim of devising multifunctional materials in which the
state that is required for obtaining high conductivities.602 Partial chirality may modulate structural features, gives rise to
oxidation may also enhance the ability of the TTF derivatives to magnetochiral anisotropy, and ultimately leads to supra-
act as both HB and XB donors.576,1065 Imakubo and Kato were molecular systems combining conductivity and magnet-
the first to report on halogen-bonded radical cocrystals, ism.1076,1077 In the case of halogen-bonded TTF salts, chirality
obtained by electrocrystallization of iodinated TTF derivatives can be induced either by using chiral counteranions such as
in the presence of bromide and cyanometalate counterions enantiopure camphorsulfonate1078 or by using TTF derivatives
acting as XB acceptors (Figure 150A).600 The crystal packing of that are both halogenated and chiral.1079 These studies indicate
the resultant structures was driven by I···Br− and I···N XBs, that using chiral counterions favors the presence of multiple
respectively, yet being rather different for the two as dictated by crystallographically independent molecules with different
the shape of the anion (Figure 150B). This pioneering study degrees of charge transfer, whereas in the only example
has prompted several follow-up studies using different employing a chiral halogenated TTF derivative,1079 the
couterions as bond acceptors, to yield a family of highly conductivity was limited by steric constraints imposed by the
conducting, halogen-bonded salts.574,665,670,672,1068−1073 The bulky chiral substituents.
strength of XB in TTF-based salts is evident from the Another approach to utilize XB in the context of conductive
contraction of van der Waals radii215 upon complexation. For materials, also demonstrated by Kato and co-workers, uses
example, Fourmigué et al. investigated a series of cation radical halogen-bonded supramolecular networks between anions and
salts of the donor molecule 3,4-diiodo-3′,3′-(ethylenedithio)- iodinated “innocent” molecules for the creation of multi-
tetrathiafulvalene (EDT-TTFI2, 38) with ClO4− and various component molecular conductors.575,1080,1081 A particularly
organic sulfonates (Figure 150C), identifying I···O distances as elegant example is given in ref 1080 in which a halogen-bonded
short as 77% of the sums of the van der Waals radii of iodine supramolecular network is used as an insulating network
and oxygen.1074,1075 In their studies, organic sulfonates sheathing conducting TTF-based 1D nanowires. An example of
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a structure consisting of TSF stacks isolated by a network of solid state.610 The self-assembly of (2-phenyl)-4,4,5,5-tetrame-
HFTIEB and Cl− (see Figure 151A for the chemical structures) thylimidazolin-1-oxyl-3-oxide and 1,4-diiodotetrafluorobenzene
(PTIO and DITFB, respectively, in Figure 152A) yielded

Figure 152. (A) Self-assembly of DITFB with (2-phenyl)-4,4,5,5-

tetramethylimidazolin-1-oxyl-3-oxide (PTIO) gives rise to trimeric
complexes (top right), while complexes between DITFB and
Figure 151. (A) Chemical structures of a cation radical (TSF) and the ATEMPO assemble into linear chains (bottom right). Reprinted
XB donor (HFTIEB) used to construct sheathed molecular nanowires. with permission from ref 610. Copyright 2006 Elsevier. (B) The
(B) and (C) display the crystal structure and the CPK model of TSF assembly between TMIO and 1,2-DITFB results in a cyclic tetrameric
stacks isolated by a network of HFTIEB and Cl− ions. Reprinted from complex. Reprinted with permission from ref 1084. Copyright 2011
ref 1080. Copyright 2008 American Chemical Society. Royal Society of Chemistry.

is given in Figure 151B,C. Astonishingly, an insulating layer trimers interacting through I···N XB, whereas the difunctional
with a thickness of only 1 nm produces an anisotropy in molecule (4-amino-2,2,6,6-tetramethylpiperidin-1-yl)oxy
resistivity of 8 orders of magnidude along and perpendicular to (ATEMPO) (Figure 152A) afforded 1D chains driven by
the wire axis. This is the highest anisotropy value reported for a both I···O and I···N interactions. Halogen-bonded trimers and
single chemical substance at room temperature. tetramers bearing mononitroxyl radicals as simple or bifurcated
In the search for halogen-bonded magnetic materials, neutral XB acceptors have been reported by Micallef and co-workers
nitroxide free radicals have appeared as promising ever since (see Figure 152B as an example).1084,1085
the first demonstration of a neutral nitroxide ferromagnet.1082 Minguez Espallargas et al.,1086 in turn, have applied XB to
In the solution state, Lucarini et al. have performed electron organize nitronyl nitroxide radicals603 as one-dimensional
paramagnetic resonance (EPR) spectroscopy of the radical XB magnetic chains. By changing the XB donor, they controlled
acceptor (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) in both the separation of the radical chains, aiming at enhanced
perfluorocarbon solution. They showed that, upon addition of magnetic isolation between the chains by increasing the length
iodoperfluorocarbon, nitrogen hyperfine splitting of the of the XB donors, and the intrachain packing of the radicals.
nitroxide group increased significantly, which the authors Indeed, crystals employing 4,4′-diiodooctafluorobiphenyl do-
attributed to redistribution of the spin density when nitroxide nors exhibited much stronger antiferromagnetic interactions
free radicals are involved in XB formation.668 Cavallotti et al. than crystals employing the shorter 1,4-diiodotetrafluoroben-
combined 19F NMR measurements and theoretical calculations zene units (Figure 153A). In this work, XB played a structural
to study the TEMPO−iodoperfluorocarbon complexes, and role: The lack of magnetic exchange through XBs was
their observations also indicated spin transfer between the confirmed via EPR spectroscopy.1086 As a final example, the
TEMPO and the iodoperfluorocarbon molecules.669 Cimino et group of Wei Jun Jin recently reported on XB-induced
al. have in turn carried out theoretical studies on the magnetic modulation of the magnetic properties of [4-(benzoyloxy)-
properties of TEMPO-based supramolecular complexes.1083 2,2,6,6-tetramethylpiperidin-1-yl]oxy (BTEMPO) free radicals
In the solid state, Schöllhorn and co-workers cocrystallized by cocrystallization with 1,4- and 1,2-diiodotetrafluorobenzene
TEMPO radicals with diiodotetrafluorobenzenes, providing the (DITFB).1087 Cocrystals with 1,4-DITFB tend to form infinite
first examples of halogen-bonded nitroxide complexes in the 1D chains (Figure 153B, top right), whereas 1,2-DITFB favors
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packing, varying the electron density of the anilato ring, and

affecting the magnetic behavior of the complexes.1093
6.4. Miscellanea
In this review we have aimed at bringing out the many faces of
XB by comprehensively treating the different fields of research
where it is playing a role, yet some important developments in
organic electronics,488,820,1094 nanoparticle assemblies,1095−1098
polymer−carbon nanotube composites,1099,1100 and on-surface
crystallization1101,1102 do not fall into the categories defined
earlier and warrant a separate discussion.
In section 4 (Soft Materials), we already mentioned that
fluorinated ionic liquids and liquid crystals provide a promising
route to improve the performance of fully organic electronic
devices. It has been shown that, compared to a conventional
ionic liquid electrolyte (1-butyl-3-methylimidazolium iodide)
used in dye-sensitized solar cells, the use of a fluorinated ionic
liquid may improve the efficiency of the device by improving
charge transport within the electrolyte material, and the charge-
transfer dynamics at the organic−inorganic sensitizer/electro-
lyte−TiO2 interface.820 This behavior was tentatively attributed
to the low affinity of perfluorocarbons for organic and aqueous
phases, which may drive the long alkyl chains of the sensitizer
(Z907 was used) into densely packed layers to minimize
interactions with the fluorinated electrolyte, and also lead to
higher I3− diffusion coefficient in the bulk of the electrolyte.
Depending on the length of the alkyl substituents, the
imidazolium iodide-based ionic liquids may even exhibit
liquid-crystalline properties, showing smectic A phases over
wide temperature ranges819 and promoting anisotropic charge
transport in I−/I3− redox couple electrolytes.1103 Abate et al.488
Figure 153. (A) One-dimensional halogen-bonded supramolecular have shown that, for a fluorinated ionic liquid crystal, the phase
chains in complexes between (3-phenyl-2,2,5,5-tetramethylimidazolin- segregation may be further assisted by the fluorophobic effect,
1-yl)oxy and 1,4-diiodotetrafluorobenzene (top) and 4,4′-diiodoocta- and as a result, after the addition of I2 to generate the I−/I3−
fluorobiphenyl (bottom). In both cases the radicals form magnetic redox couple,771 the mesophase is not destabilized, but the
chains isolated by the XB donors, and within the chains, the radicals crystal-to-LC phase transition temperature is reduced by 20 K.
pack into dimeric units. Reprinted with permission from ref 1086. Their material also had the tendency to supercool, allowing
Copyright Royal Society of Chemistry 2012. (B) Halogen-bonded retention of the long-range smectic order in the solid film at
cocrystals 40 and 41 containing the BTEMPO radical 39 exhibit
enhanced antiferromagnetic coupling as compared to the pure single room temperature, which may be of importance in, e.g., solar
crystal of 39. Reprinted from ref 1087. Copyright 2013 American cells, supercapacitors, and lithium batteries.488 Neither of these
Chemical Society. works utilizes XB per se, but they do demonstrate the power of
fluorinated salts in organic electronic applications. Noteworthy
the formation of cyclic tetramers (Figure 153B, bottom right). is also the fact that halide anions are very efficient XB acceptors,
All crystals were antiferromagnetic, but compared to single and therefore, halogen-bonded ionic liquids and liquid crystals,
crystals of pure BTEMPO, both halogen-bonded cocrystals and their use in organic electronics, will be reported in the
exhibited higher antiferromagnetic coupling, the strongest foreseeable future.
being the tetrameric complex of 1,2-DITFB. According to the On top of the two examples described in the previous
authors, in these cocrystals the role of XB is not limited to paragraph, XB has also been shown to give a contribution in
structural control, but it also allows transmission of spin solar cell technology, as reported in 2014 by the Snaith
polarization from the donor to the acceptor connected by the group.1094 Presently, perovskite-based materials are among the
XB.1087 most studied in solar-cell research, combining high energy
Nitroxide free radicals are not the only building blocks used conversion efficiency and low cost in a unique manner.1104,1105
to construct halogen-bonded molecular magnets. Brammer and The state-of-the-art perovskite-based materials employ lead
co-workers have extensively studied the ability of halometalates halide compounds, having a chemical formula of CH3NH3PbX3
to act as XB acceptors,455,554,1088 and they have also prepared (X = I−, Br−, Cl−). The surface of the perovskite crystals
halogen-bonded ferromagnetic chains based on Co(II) contains an excess of halide anions (which are efficient XB-
coordination polymers, with the aim of investigating the role accepting moieties), which can be passivated with XB donors
of XB on interchain magnetic interactions.1089 Molecular spin- (Figure 154, top). As shown in Figure 154, bottom, this
crossover complexes1090 involving XB have also recently been passivation has significant concequences on the performance of
reported.1091,1092 Finally, Mercuri et al. have performed a the solar cell. Whereas the untreated device delivers a power
comprehensive characterization of a family of chiral, halogen- conversion efficiency of 13% and a fill factor of 0.57, the surface
bonded tris(haloanilato)metalate(III)-based complexes, also passivation via XBs leads to a significant improvement of these
pinpointing the dual role of XB, directing the molecular values to 15.7% and 0.67, respectively. The authors explain the
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Figure 154. Top: schematic representation of the XB between the

passivating iodopentafluorobenzene (IPFB) unit and a generic halide
anion at the perovskite surface. Bottom: performance of the perovskite
solar cells with (red) and without (black) surface passivation, using Figure 155. (A) Schematics of the formation of assemblies of
spiro-OMeTAD as the hole transporter. Reprinted from ref 1094. functionalized gold nanoparticles (AuNPs) in the presence of bipyridyl
Copyright 2014 American Chemical Society. cross-linkers (BPEB, TPEB, TPM) via XB. (B) Stepwise generation of
assemblies consisting of functionalized gold nanoparticles and different
XB-accepting cross-linkers on organic monolayers (M1 and M2).
Reprinted from ref 1096. Copyright 2011 American Chemical Society.
improvement as follows: Without passivation, the halide anions
act as hole traps, leading to accumulation of charges at the particle-functionalized surfaces were also shown to exhibit
perovskite−hole-transport-layer heterojunction. XB-induced surface-enhanced Raman scattering.1096
passivation prevents this undesired charge accumulation, and It has also been recently shown that iodoperfluorobenzene
therefore improves the device performance. compounds can directly bind to gold nanoparticle surfaces.
In a completely different context, Milko van der Boom and Blakey et al. used a combination of UV−vis difference
co-workers have utilized XB as a supramolecular tool to spectroscopy, surface-enhanced Raman scattering, and synchro-
assemble nanoparticles. They functionalized gold nanoparticles tron X-ray photoelectron spectroscopy to show that the binding
with XB-donating stilbene derivatives (Figure 155A), which occurs through iodine atoms, for a range of both fluorinated
upon mixing with bifunctional XB acceptors formed either and nonfluorinated iodo compounds.1097 An interesting
chainlike structures or large, dense assemblies, depending on utilization of the gold−iodine interaction has been performed
the concentration of the bipyridyl cross-linker (BPEB, TPEB, by Kiguchi et al., who formed single-molecule junctions of gold
TPM; Figure 155B, bottom).1095 The XB-driven aggregation of electrodes bound with 1,4-diiodobenzene and studied their
the gold nanoparticles led to a red shift of the plasmon conductance by the scanning tunneling microscopy break
resonance from ca. 520 to ca. 600 nm, accompanied by a color junction technique (Figure 156).1098 They showed that the
change from red to blue, as observed by the naked eye. To iodine site can be utilized as an anchoring group to build single-
unambiguously associate the observed behavior with XB,1098 a molecule junctions, whereas the junctions were not formed
control experiment was performed where the XB donors on the using dibrominated or dichlorinated benzenes, which was
gold surface were replaced with their perfluorinated counter- attributed to gold−iodine XB. The authors used the distances
parts (lacking the XB-donating site). In this case, no needed to break the single-molecule junctions as an indication
aggregation or color change occurred even within several of the binding strength between the electrodes and the bringing
weeks, whereas the XB-driven aggregates formed already within molecules, and concluded that the Au···I bond is stronger than
a few hours. As a continuation, they prepared surface-confined the Au···NH2 bond, but significantly weaker than the Au···SH
structures, attaching the nanoparticles onto silicon and glass bond. An interesting follow-up for this study could be to use
substrates functionalized with pyridine groups (Figure 155B). 1,4-diiodotetrafluorobenzene or 1,4-bis(iodoethynyl)benzene
Multilayer structures, with controlled morphology obtained by to increase the strength of XB, therefore modifying the
varying the structure of the cross-linker and by the number of properties of the single-molecule junctions.
deposition steps, were prepared by successive depositions of In the context of carbon-based nanomaterials, XB has been
nanoparticles and pyridine-containing cross-linkers. The nano- reported to enhance the thermal and mechanical properties of
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of information at the crossover between the historical

perspective and the theoretical understanding developed in
the past 15 years.
As acknowledged by the IUPAC definition,9 the core feature
of the XB is the electrophilic behavior of halogen atoms.
Hydrogen is the electrophilic atom most frequently involved in
attractive interactions with donors of electron density, and HB
is by far the most studied and used noncovalent interaction.
Similarities between XB and HB are numerous and have been
Figure 156. Left: schematics of a diiodobenzene-bridged single- the subjects of specific studies.859 Analogies in the behavior of
molecule junction. Right: the authors used 2D conductance histograms hydrogen and halogens have been recognized from the very
to determine the conductance of the molecular junction and to early times to the point that some old versions of the periodic
conclude that sufficiently strong XB is required for the junction to table put hydrogen in the same group as halogens, and not on
form. Reprinted from ref 1098. Copyright 2013 American Chemical top of the alkali metals. This was the case for J. Newlands’ table
Society. published in 1863 when he described his law of octaves,1106,1107
or for J. W. Retgers’ table (Figure 157).1108 Interestingly, the
polymer−carbon nanotube (CNT) composites.1099,1100 Salava-
gione et al. have studied dispersions of multiwalled, alkyl-
modified CNTs in a poly(vinyl chloride) (PVC) matrix. The
PVC matrix acts as an efficient “solubilizing agent” for the
nanotubes, leading to composites with excellent mechanical and
thermal properties, which depend on the tacticity of the
polymer host. The high performance was in part attributed to
CCl···OC XB, which improved the dispersion of CNTs in
the matrix.
As the final example, we bring up the work of Facchetti and
van der Boom et al. on on-surface crystallization of halogen-
bonded materials via physical vapor deposition (PVD),
controlled by surface functionalization and the compound to
be deposited.1101,1102 In 2008, the authors proposed stilbazole
derivatives to be ideal candidates for PVD experiments, due to
their high thermal stability and high volatility. Using molecules
containing both XB donor and acceptor functionalities, they
constructed highly crystalline unimolecular halogen-bonded
networks on the surface with a structure identical to that of
solution-grown crystals.1101 More recently, they reported on
the on-surface, solvent-free crystal-to-cocrystal conversion
process, driven by XB. They exposed a surface-confined Figure 157. Periodic table published by J. W. Retgers in 1895 in his
polycrystalline film of a molecule containing XB-accepting paper in Z. Phys. Chem.,1108 a journal established in 1887 by W.
groups, prepared by physical vapor deposition, into vapors of a Ostwald, J. H. van ’t Hoff, and S. A. Arrhenius as the first journal
tailored to scientific papers on physical chemistry.
complementary molecule bearing XB donor moieties. The
subsequent transformation into a halogen-bonded cocrystal was
accompanied by significant changes in the surface morphology, analogy between the two interactions was somehow implied
crystallinity, and optical properties of the deposited materials. and envisaged also by F. Guthrie in 1863, when he assigned the
Such a stepwise vapor-deposition-based approach using XBs formula NH3·I2 to the halogen-bonded adduct between
might develop as a facile and intriguing approach toward the ammonia and iodine and commented on the analogy between
formation of multicomponent organic thin films for functional this adduct and the one formed by ammonia with hydrogen
organic devices.1102 iodide.13
While the analogies between XB and HB were valuable in the
7. CONCLUSIONS recent past to understand the features of the XB, the differences
It has been more than 200 years since the first halogen-bonded between the two interactions may help in the future to identify
complex, I2···NH3, was prepared in a chemical laboratory,12 and the most beneficial applications of the former interaction,
it has been nearly 150 years since it was assigned the correct namely, those where the specific properties of the XB represent
composition.13 A fairly extensive review giving a brief history of an added value. For instance, directionality, tunability, hydro-
the interaction and a snapshot of where we are now, and, phobicity, and variable size of the donor atom are four unique
perhaps, where we are going, seemed therefore particularly features of the XB, which offer new opportunities if compared
timely. to the well-established use of the HB.1109 This was, for example,
During the years, experimental observations and theoretical the case for directionality when allowing some XBs to
modeling have consistently contributed to the development of outperform stronger HBs in writing surface-relief gratings on
the present understanding of the nature of the XB and the thin films of supramolecular polymers,489,855,859 or for donor
potential of its current exploitations. The most important of atom size when altering by the heavy-atom effect the light-
these contributions have been described in previous sections of emitting properties of halogenated dyes by promoting singlet-
this review, and it is now possible to pinpoint briefly two pieces to-triplet intersystem crossing.997 Many other examples of
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specific advantages brought up by the use of XB have been are at a very initial stage, and will probably grow in the near
demonstrated in quite different fields spanning from material future. With new applications of XB being pursued and
sciences (e.g., liquid crystals844,854,1110 and gels83) to separation identified, the quest for a deeper and more subtle under-
and sensing (e.g., anion recognition550,657,719 and trans- standing of the interaction will increase and will prompt further
port213,214). studies on the fundamental aspects. The scope of this review is
Applications in the field of small-molecule−protein inter- to be a tool for those interested in either fundamental or
action and, more in general, in biology and pharmacology are applicative studies on XB.
becoming more and more numerous, but it can be expected
they will increase exponentially. In fact, in a biological scenario, AUTHOR INFORMATION
directionality can offer the possibility to boost specificity and Corresponding Authors
selectivity in binding and recognition processes, tunability can *E-mail: [email protected].
allow for optimizing the interaction strength by single-atom *E-mail: [email protected].
mutation, and hydrophobicity already belongs to the well-
established advantages of introducing halogen atoms. Notes
One of the advantages that the XB has in the fields of biology The authors declare no competing financial interest.
and nanomedicine over classical electrostatic, steric, and HB Biographies
interactions is that halogen atoms in biological molecules are
uncommon, and therefore, site-specific incorporation of
halogenated amino acids or nucleotides into proteins or DNA
can confer a very high degree of control and specificity. A
marvelous example of this is the thyroid hormones, i.e.,
thyroxine (T4), which is the relatively inactive prohormone, and
the active hormone, triiodothyronine (T3) (Figure 158).

Gabriella Cavallo obtained her Ph.D. in chemistry in 2006 at the

University of Salerno (Italy). After two years of activity in Pirelli
Laboratories, a research unit of Pirelli Tyres, she joined the NFMLab
at the Politecnico di Milano in 2008 as a postdoctoral researcher. Then
she became an ssistant professor in 2012 at the same university. In
Figure 158. Molecular structures of thyroid hormones and the binding 2011 she was a visiting researcher at the VTT-Technical Research
activities of the RNA aptamer complexes described in ref 1111. Centre of Finland. Her research interests are in the synthesis of
halofluorinated compounds for recognition processes and molecular
Thyroid hormones basically regulate the development, growth, materials. In 2011 she was a cofounder of FLUORIT, a Politecnico di
and metabolism of every single cell in our body. Structural Milano spin-off company for fluorine technologies.
studies have demonstrated that XB plays an important role in
the binding1112 of thyroid hormones to the body’s hormone
receptor and affects their activity.1111 The fact that Nature has
used iodinated hormones and XBs might find a possible
explanation in the fine-tuning needed by the complex
regulatory system of the thyroid gland. In fact, by single-atom
mutations, i.e., removal of one iodine atom from the hormone
structure, our body discriminates what is inactive and needs to
be transported in the target organs, T4, from what is the active
hormone, T3, and what needs to be recycled, T2, to recover the
iodine needed to again convert T3 into T4.
The properties of a nanostructured system partly result from
the chemical and physical characteristics of the single
constituent molecules and partly depend on the structural
organization of the molecules in the given structure.
Intermolecular interactions play a major role in determining Pierangelo Metrangolo is a full professor at the Politecnico di Milano
the structure of any aggregate, and different structures may (since 2011) and a part-time research professor of molecular
result in different properties, like in the case of polymorphs. recognition at the VTT-Technical Research Centre of Finland (since
When a new interaction becomes available, new structures, 2010). In 2015 he was appointed as a visiting professor at the Centre
namely, new functions, become available. This was the case for of Excellence in Molecular Engineering of Biosynthetic Hybrid
the XB that only recently has become a routine tool for Materials of Aalto University, Finland. He was a European Union
controlling aggregation and assembly phenomena. Applications Fellow at the University of Toulouse (France, 2001) and a visiting

2570 DOI: 10.1021/acs.chemrev.5b00484

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Chemical Reviews Review

professor at the University of York (U.K., 2005) and the University of

Jyväskylä (Finland, 2006). His awards include the 2005 “G. Ciamician”
medal of the Division of Organic Chemistry of the Italian Chemical
Society and the 2005 Journals Grant Award of the Royal Society of
Chemistry (RSC). He was a cofounder of the NFMLab at the
Politecnico of Milano in 2003 and of the spin-off company FLUORIT
in 2011. He is on the editorial boards of CrystEngComm (RSC) and
Crystal Growth and Design (American Chemical Society), and is a
coeditor of Acta Crystallographica Section B (International Union of
Crystallography). In 2013 he was awarded a European Research
Council Consolidator grant (ERC-StG2012) entitled “FOLDHALO
Folding with Halogen Bonding”. In 2015 he was elected a titular
member of the Physical and Biophysical Chemistry Division of
IUPAC. The focus of his research is on supramolecular chemistry and
nanomedicine with a particular interest in the design of functional and Arri Priimagi earned his PhD degree in 2009 from the Department of
biomimetic materials. Applied Physics, Helsinki University of Technology (nowadays known
as Aalto University), Finland. After a two-year postdoc at Chemical
Resources Laboratory, Tokyo Institute of Technology, and a 10-month
International Fellowship at Politecnico di Milano, he was in 2014
appointed to the position of a tenure-track assistant professor at the
Department of Chemistry and Bioengineering at Tampere University
of Technology, Finland. In 2014 he received an Academy of Finland
research Fellowship, and in 2015 was awarded an European Research
Council Starting Grant entitled “Tunable Photonic Structures via
Photomechanical Actuation”. His research interests lie in functional
soft matter, with a particular emphasis in photonic and light-responsive
materials.
Roberto Milani obtained a joint Ph.D. degree in materials science and
engineering at the University of Padova and in structure and dynamics
of reactive systems at the University of Lille I (France) in 2008. He
was an invited postdoc at the University of Lille I in 2009. He was a
senior postdoc at the Center for Nanoscience and Technology of the
Italian Institute of Technology (2010−2011), and was appointed as a
research scientist at the VTT-Technical Research Centre of Finland in
2012. In 2014 he received an Academy of Finland Research
Fellowship. His research interests include supramolecular chemistry,
biomimetic and hybrid materials, and surface functionalization.

Giancarlo Terraneo became an assistant professor at the Politecnico di

Milano in 2008. He was a VLAG Fellow at the University of
Wageningen (The Netherlands, 2003) and a visiting scientist at the
University of Zurich (Switzerland, 2004) and the University of York
(U.K., 2008). He received a silver medal at “Premio Primo Levi
2007Società Chimica Italiana” and has served since 2013 on the
Doctoral Program Board of the Ph.D. in industrial chemistry and
chemical engineering at the Politecnico di Milano. In 2011 he was a
Tullio Pilati retired as a senior researcher of the National Research cofounder of FLUORIT, a Politecnico di Milano spin-off company for
Council in 2011. Since then, he has been a research associate at the fluorine technologies. In 2015 he was promoted to associate professor
NFMLab of the Politecnico di Milano. His research interests are in the
at the same university. His research interests are on self-assembly and
field of crystallography of perfluorocarbon−hydrocarbon hybrid
materials, bioactive compounds, and minerals. He is also developing crystal engineering with a focus on structural studies via X-ray
software packages for analysis of lattice dynamics and crystal geometry. crystallography.

2571 DOI: 10.1021/acs.chemrev.5b00484

Chem. Rev. 2016, 116, 2478−2601
Chemical Reviews Review

DIOFS 4,4′-diiodooctafluorostilbene
DIPFO 1,8-diiodoperfluorooctane
1,4-DITFB 1,4-diiodotetrafluorobenzene
ETS extended transition state
HB hydrogen bond
HMTA hexamethylenetetramine
HMET 1,6-bis(trimethylammonium)hexane diiodide
HOMO highest occupied molecular orbital
HTIPEB 2,2′,4,4′,6,6′-hexafluoro-3,3′,5,5′-tetrakis[[4-
(iodoethynyl)phenyl]ethynyl]biphenyl
IIF 5-iodoisophthalic acid
K.2.2.2 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-
hexacosane
LAG liquid-assisted grinding
Giuseppe Resnati became a full professor at the Politecnico di Milano LC liquid crystal
in 2001. He was a NATO fellow at the University of Clemson (United LUMO lowest unoccupied molecular orbital
States, 1990) and a visiting professor at the Université Paris Sud XI MO molecular orbital
(France, 1993), Nagoya University (Japan, 2001), and Université de MOF metal−organic framework
Strasbourg (France, 2012). He was awarded the 2008 Research Prize NSAIDs nonsteroidal anti-inflammatory drugs
of the Division of Organic Chemistry of the Italian Chemical Society NIS N-iodosuccinimide
and the European Lectureship in Chemical Science by the Royal NOCV natural orbitals for chemical valence
Society of Chemistry in 2010. He is on the editorial boards of the P4VP poly(4-vinylpyridine)
Journal of Fluorine Chemistry (Elsevier) and Crystal Growth and Design PEG polyethylene glycol
(American Chemical Society). He is a member of Academia Europaea. RT reverse transcriptase
He was a cofounder of the NFMLab at the Politecnico of Milano in T3 3,5,3′-triiodothyronine
2003 and of FLUORIT in 2011. His interests are in fluorine chemistry, T4 thyroxine, 3,5,3′,5′-tetraiodothyronine
spanning the synthesis of fluoroorganic compounds and their use in TBTP tetrabromoterephthalic acid
material chemistry, and in self-assembly processes, where he focuses TEMPO (2,2,6,6-tetramethyl-1-piperidinyl)oxy radical
on halogen-driven recognition phenomena (halogen bonding). THR thyroid hormone receptor
TITFPP tetrakis(4-iodotetrafluorophenyl)pentaerythritol
TPC tetrakis(4-pyridyl)cyclobutane
ACKNOWLEDGMENTS TPP tetrakis(4-pyridyl)pentaerythritol
We are grateful to all colleagues, graduate and Ph.D. students, TTF tetrathiafulvalene
and postdoctoral associates who worked with us on the XB. TTR transthyretin
Some of them are mentioned in the references. Their XB halogen bond
dedication and enthusiasm have been fundamental. P.M.
gratefully acknowledges the financial contribution from the
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