TRANSISTION METAL USE AS A CATALYST IN

C-C COUPLING REACTIONS

Project report submitted in partial fulfilment of the requirement for the

degree

of

Integrated Msc
Chemistry by

PRADEEP KUMAR GOLLAPALLI

(20CY1005)

guided by
Dr. Tanmoy Kumar Saha

Department of Chemistry

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 National Institute of Technology, Durgapur

CERTIFICATE

It is certified that the work contained in the project report titled

Transition metal use as a catalyst in C-C coupling reaction by
Pradeep Kumar Gollapalli, has been carried out under our
supervision and that this work has not been submitted elsewhere for a
degree.

Dr Tanmoy Kumar Saha Head of the Department

(Project guide)

STUDENT DECLARATION

I declare that this written submission represents my ideas in my own words and
where others’ ideas or words have been included, I have adequately cited and
referenced the original sources. I also declare that I have adhered to all principles
of academic honesty and integrity and have not misrepresented or fabricated or
falsified any idea/fact/source in my submission.

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I understand that any violation of the above will be cause for disciplinary action by
the institute and can also evoke penal action from the sources which have thus not
been properly cited or from whom proper permission has not been taken when
needed

ACKNOWLEDGEMENT

I am highly grateful to Dr Tanmoy Kumar Saha for allowing me to work under her guidance in
her laboratory. I also express my heartfelt gratitude to Dr Tanmoy Kumar Saha for guiding me
throughout the project at each and every step.

I would also like to express my sincere gratitude to my lab seniors for being the prime support
pillar throughout the project and guiding me from time to time.

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Introduction
Transition metal-catalyzed cross-coupling reactions of organic electrophiles and
organometallic reagents have emerged as a tremendously powerful synthetic tool, and the
development has reached a level of sophistication that allows for a wide range of coupling
partners to be combined efficiently.In the past 3 decades, this paradigm for carbon-carbon
bond construction has allowed chemists to assemble complex molecular frameworks of
diversified interests encompassing total synthesis of natural products, medicinal chemistry,
and industrial process development as well as chemical biology, materials, and
nanotechnology. The emergence of cross-coupling as a popular method in synthesis arises
from both the diversity of organometallic reagents utilized in these reactions and the broad
range of functional groups which can be incorporated into these reagents.Since initial
submission of this review, the importance of this general class of reactions was recognized by
the awarding of the Nobel prize in chemistry to Richard Heck, Ei-ichi Negishi, and Akira
Suzuki “for palladium-catalyzed cross-couplings in organic synthesis”. This review details
transition metal-catalyzed crosscoupling of C(sp3 ) organometallics with various organic
electrophiles (Figure 1a). Historically, the use of C(sp3 )- organometallics in cross-coupling
reactions has suffered from several serious problems, making its development much slower
than related C(sp2 )- couplings. The issues include but are not limited to the following: (1) the
spontaneous decomposition of alkyl organometallics via β- elimination or by proto-
demetalation; (2) the necessity to preform the organometallic reagents without purification as
they are not air-stable, making the use of superstoichiometric (3-4 equiv) amounts required to
achieve satisfactory conversions; and (3) often slow transmetalation (vide infra), thereby
requiring various additives.Additionally, evaluation of the general proposed mechanism
reveals several features which can lead to undesired side products, especially when
considering the emerging area of C(sp3 )-C(sp3 ) cross-couplings between alkyl halides or
pseudohalides and alkyl organometallics (Figure 1b, c)In general, metal-catalyzed cross-
coupling reactions proceed through three critical organometallic processes: (1) oxidative
addition of an electrophilic carbon-heteroatom bond into the low valent transition metal, (2)
transmetalation or displacement of a heteroatom leaving group by the nucleophilic partner,
and, finally, (3) reductive elimination to form a new CC bond. The use of C(sp3 )-
electrophiles generally results in slower oxidative addition, which is proposed to be either a
nucleophilic

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substitution (SN2) with a Pd-complex or radical in nature with Ni or Comparatively, oxidative
addition of sp or sp2 analogues is faster and generally proceeds in a concerted manner. Slow
oxidative addition with alkyl electrophiles leads to the formation of homocoupling products,
or β-hydride elimination generating various possible side products. Finally, sluggish reductive
elimination also can lead to competing β-hydride elimination. These issues have made it
necessary to identify sometimes complex combination of ligands, metals, and conditions to
effectively promote cross-coupling reactions of C(sp3 )-organometallics especially with
C(sp3
)-electrophiles.

Metal catalyzed C-C coupling reactions are shown in below:

1. Heck Coupling reaction

The Heck reaction also known as the Mizoroki-Heck reaction, is a chemical reaction that
happens when an activated alkene and an unsaturated halide are combined with a base and a
palladium (Pd) species acting as a catalyst to produce a substituted alkene. The Heck
reaction's exceptional trans-selectivity is one of its advantages. The Heck reaction is a Pd-
catalyzed carbon-carbon cross-coupling reaction that occurs in the presence of bases between
activated alkenes and aryl or vinyl halides. The range of donors and acceptors that are
susceptible to the Heck reaction has been expanded as a result of recent advancements in
catalysts and reaction conditions.

Mechanism:

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Previous reports on Heck Coupling reaction

Fig 1. Formation of olefins from heck coupling reaction. Taken from Nature communications
12, 991 (2021)

Fig 2. Formation of olefins from heck coupling reaction. Taken from Dalton trans 38 (2019)
.

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2. Suzuki Coupling Reaction:

Suzuki coupling reaction is an organic coupling reaction wherein the coupling partners
include a boronic acid and an organohalide. Palladium (0) complex is used to catalyze this
reaction. This reaction is named after nobel laureate japanese chemist akira suzuki, who first
published work on this reaction in 1979. This reaction is also called the suzuki-miyaura
reaction or the suzuki coupling. In the suzuki couplings general scheme, the coupling of the
organoboron specimen with the halide over palladium(0) catalyst and a base leads to the
formation of a carbon-carbon single bond this reaction is commonly used in the synthesis of
substituted biphenyls, poly-olefins, and styrenes. Boronic acids are commonly available. They
are also less toxic and environment-friendly when compared to organostannane and
organozinc compounds. The reaction conditions of the suzuki coupling reaction are relatively
mild. Due to these reasons, the suzuki coupling method is preferred over other similar
coupling reactions. Furthermore, the reagents used in this reaction can be easily prepared and
are relatively cheap.

Mechanism:

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Examples:

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 Applications:

1) The Suzuki reaction involves the formation of C single bond C bonds by the cross
coupling of vinyl boronic acid, borate ester or borane with an aryl or vinyl halide or
triflate. The reaction is tolerant to a wide variety of functional groups such as carboxylic
acids, esters, alcohols, aldehydes, and ketones, and this is one of the reasons for its
popularity in natural product synthesis.

2) The Suzuki coupling is probably one of the most extended palladium-catalyzed C-C
coupling reaction involving aryl groups.

Some examples of aryl–aryl coupling including a polyfluorinated ArF groups have been
reported, and this has been used to synthesize complex molecules useful as materials.

Thus, a combinatorial Suzuki coupling has been reported that involves polyfluorinated aryl bromides
and boronic acids to synthesize molecules with liquid crystalline properties.

The introduction of fluorine-containing groups is interesting in the design of electronic organic

conducting molecules such as derivatives of octafluoroanthracenes and hexabenzocoronenes and this
has been achieved using the Suzuki cross-coupling reaction.

Selective monoarylation of mono or difluoro dibromo benzenes is possible, and only one of the bromo
atoms is substituted in the Pd-catalyzed reaction with boronic acids.

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3. Hiyama Coupling Reaction:

A palladium-catalyzed domino Heck cyclization/Hiyama coupling reaction by the trapping

of the σ-alkylpalladium intermediate with arylsilanes is described. All arylsilanes and a wide
variety of aryl-tethered alkenes are compatible with the reaction conditions. The classic
domino Heck cyclization/Suzuki coupling reaction is being replaced by this method, which
exhibits good yields and great functional group tolerance.The Hiyama coupling is
conceptionally similar to the Suzuki coupling but uses an organo-silicon substrate instead of
the organoboron compound used in the Suzuki reaction.

Example:

Mechanism:

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Reaction with Organosilicon Reagents (Hiyama Coupling)

The Hiyama cross-coupling reaction1 represents one of the most used methodologies for
creating new carbon-carbon bonds. This reaction has been mainly used for the formation of
Csp2- Csp2 bonds, for instance to prepare biaryls, and the accepted mechanism involves in
most of the cases an activating reagent such as fluoride for the formation of a pentacoordinate
silicon intermediate able to perform the transmetallation step. Previously, an oxidative addition
takes place on the palladium(0) catalyst, and finally a reductive elimination gives the coupling
product regenerating the active catalytic species.

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