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Continuous flow mechanochemistry: reactive

extrusion as an enabling technology in
Cite this: DOI: 10.1039/d1cs00657f
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organic synthesis
Robert R. A. Bolt, a Jamie A. Leitch, *a Andrew C. Jones, b

William I. Nicholsonb and Duncan L. Browne *a

Rapid and wide-ranging developments have established mechanochemistry as a powerful avenue in

sustainable organic synthesis. This is primarily due to unique opportunities which have been offered in
Received 11th October 2021 solvent-free – or highly solvent-minimised – reaction systems. Nevertheless, despite elegant advances
DOI: 10.1039/d1cs00657f in ball-milling technology, limitations in scale-up still remain. This tutorial review covers the first reports
into the translation from ‘‘batch-mode’’ ball-milling to ‘‘flow-mode’’ reactive extrusion, using twin-screw
rsc.li/chem-soc-rev extrusion.

Key learning points

(1) There can be limitations to the scale of ball milling mechanochemistry.
(2) Reactive extrusion, most commonly twin-screw extrusion (TSE), can provide a scalable continuous solution.
(3) TSE allows for the fine tuning of reactor design and assessment of other continuous variables.
(4) TSE in organic synthesis is still in its infancy.
(5) Further development in TSE will lead to increased adoption of continuous mechanochemistry in industry.

1. Introduction reaction components and prevent precipitation, clogging or

fouling of the flow tubes.7 The dogmatic use of solvent – and
The development of continuous methods for the processing of often undesired toxic solvents such as DCM and DMF – has
chemicals has revolutionised large-scale synthesis, especially in established a status quo where synthetic chemists are comfor-
industrial settings.1 Furthermore, advances in the translation table with the fact that the majority of their molecular input
from ‘‘batch’’ to continuous ‘‘flow’’ mode have expanded to a reaction flask (solvent), eventually leads – directly or
rapidly, offering valuable opportunities for a variety of research indirectly – to atomic waste.8 The growing importance of
areas including the handling and scaling of hazardous sustainability metrics such as atom economy, e-factor, process
reactions,2 development of flow photochemistry manifolds,3 mass intensity, and space time yields in industrial route design
and the safe introduction of gases4 (Scheme 1A); the benefits of and development,9 has allowed researchers to take a detailed
continuous processing have been reviewed extensively in the look at the ‘‘desired output’’/‘‘waste’’ dichotomy, as the use of
literature.5 bulk solvent plays an important role in the latter two of these
Whilst these advances have continued to transform contem- metrics. Accordingly, reducing the quantities of solvents, and
porary synthesis, they suffer from a key aspect of green chem- the opportunity of removing them completely from the reaction
istry in that bulk solvent is still required to enable effective medium – to conduct chemical reactions ‘‘neat’’ or in the solid-
reactivity.6 Furthermore, low reaction concentrations are rou- state – is incredibly pertinent from the perspective of sustain-
tine within flow chemistry to allow effective solubilisation of able chemistry.10
Within this context, the ability to enact material change on
chemicals through application of mechanical force has been
a
Department of Pharmaceutical and Biological Chemistry, UCL, School of
known for millennia through utility of grinding tools such as
Pharmacy, 29-39 Brunswick Square, Bloomsbury, London, WC1N 1AX, UK.
E-mail: [email protected], [email protected]
pestles and mortars.11 More recently, such application of mechan-
b
Cardiff Catalysis Institute, School of Chemistry, Cardiff University, Main Building, ical force on chemicals – known as mechanochemistry – has
Park Place, Cardiff, CF10 3AT, UK become well-established within the areas of crystal engineering

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and formulation science. This has stimulated the adoption of Moreover, these protocols have been demonstrated to offer
mechanochemical equipment such as mixer mills and planetary favourable reactivity design profiles through drastically
mills (Scheme 1B). Using balls (made from a variety of materials) reduced reaction times, the possibilities of carrying out often-
in jars (also made from a variety of materials), agitation of these sensitive reactions under an air atmosphere,14 and improved/
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jars via oscillation/rotation causes the balls to move within the jar complementary selectivity profiles.15 Despite this, the use of
imparting compressing mechanical forces on the contents. These high-speed ball mills to carry out these transformations have an
are primarily impact forces in mixer mills and shearing forces in upper limit in reaction scale from a safety perspective. Whilst
planetary mills. Further to this, the implementation of mechan- larger mills are available for crushing rocks and extracting
ochemical techniques introduces unique reaction parameters minerals, scaling synthetic organic reactions in the fine-
including: cavity volume (VJ), ball diameter (DB, which influences chemicals sector comes with a requirement for controlling
mass), number of balls, volume of reactants (VR), volume ratios exo- and endo-therms. Reactions at these scales may also lead
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and milling frequency. to typical batch scale up issues of localised hot spots, large
Over the last few decades, synthetic chemists have turned to inventory of potential hazard and high demand on temperature
existing mechanochemical equipment and technology to enable control. Indeed, many of the latter batch considerations can be
solvent-free – or highly solvent-minimised – synthesis.12 For these amplified in the absence of a solvent, solvents often act to
reasons, mechanochemical techniques have been coveted for its improve mixing and enable more effective thermal dissipation.
applications in sustainable synthesis and has been highlighted For these reasons, in order to explore the full opportunity of
for its adherence to the 12 principles of green chemistry.13 mechanochemical synthesis, and to increase the potential for

Robert R. A. Bolt received his Jamie A. Leitch Jamie obtained

MChem from Cardiff University, his MChem at the University of
in 2020. He conducted his final Bath in 2014 then pursued a PhD
year research project under the at the same institution in the
guidance of Dr Duncan Browne. group of Prof. Chris Frost. He
He then began his PhD studies at specialised in the remote C–H
UCL (University College London) functionalisation of arenes using
in September 2020 under the ruthenium(II) catalysis. Following
guidance of Dr Duncan Browne. this in 2017, he took up a
His research focuses on exploring position as a Leverhulme Trust
mechanochemistry for organic Postdoctoral Research Fellow
synthesis and drug synthesis. under the supervision of Prof.
Robert R. A. Bolt Jamie A. Leitch Darren Dixon at the University
of Oxford, as part of the
photoredox team working on the reductive generation of a-amino
and a-oxy radicals. Since 2020, Jamie has been a Leverhulme Trust
Postdoctoral Research Fellow at UCL (University College London),
working with Dr Duncan L. Browne on enabling technologies for
synthesis and catalysis.

Andrew C. Jones received his William I. Nicholson obtained his

MChem degree from Cardiff MChem degree from Cardiff
University in 2018. He conducted University in 2017. He conducted
his final year project under the his final year project under the
guidance of Dr Duncan Browne. supervision of Dr Duncan L.
Following this, he started his PhD Browne. Following this, he
studies at Cardiff University under continued studying under the
the guidance of Dr Duncan guidance of Dr Duncan L. Browne
Browne. His research focuses on obtaining his PhD from Cardiff
the use of mechanochemical tech- University in 2022 investigating
niques for synthetic transformations the utilization of mechano-
throughout organic synthesis, chemical techniques for synthetic
Andrew C. Jones focussing on transition metal William I. Nicholson reactions and catalytic trans-
catalysed cross coupling. formations.

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industrial adoption, translation from ‘‘batch-mode’’ ball milling

to ‘‘flow-mode’’ reactive extrusion is paramount (Scheme 1C).
Extrusion equipment has been routinely employed for decades
in both the food (notably for the preparation of dried pasta and
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breads) and the polymer industries. Furthermore, the manipula-

tion of solids and/or liquid chemicals via reactive extrusion has
already been widely studied in crystallization (especially co-
crystallisation), final-form preparation, MOF and supramolecular
porous cage synthesis, and also in the preparation of deep eutectic
solvents.16 To this end, in 2019 – alongside flow chemistry – reactive
extrusion was highlighted by IUPAC as one of the 10 most
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important chemical innovations that could change our world.17

Crossing the interface of organic chemistry and engineering
science, a significant barrier to adoption for organic synthesis
applications has been witnessed. To this end, this review will aim
to break down these barriers, covering the first forays into the
design and development of reactive extrusion methodology within
the context of molecular organic synthesis. Following this, based on
our findings and our own studies, we have formulated a ‘‘how-to’’
protocol for designing extrusion reactions.

2. Reactive extrusion
The most common type of reactive extrusion uses a twin-screw
extruder. This screw-based system can be divided into four
distinct areas to consider; input, feed, reaction centre, and
output (Scheme 2A). Each area offers its own distinct variables
and parameters that must be considered. Herein we present the
pioneering work in this field and bring together observations
and possible learnings that appear to be collectively demon-
strated in the context of extrusion. It should be noted that
screw-based ‘‘batch’’ mixers have been used previously in the
synthesis of OLED materials,18 however the continuous extru-
der will be the focus of this tutorial review.

Duncan L. Browne received his

PhD in organic synthesis from
the University of Sheffield under
the mentorship of Prof. Joseph
P. A. Harrity (Syngenta, CASE).
This was followed with a one year
Doctoral Prize Fellowship from
the EPSRC before moving in
2010 to the University of Cam-
bridge for postdoctoral studies
with Professor Steven V. Ley FRS
CBE. In September 2014, Duncan Scheme 1 Reactive extrusion in the context of batch and continuous
established his independent research solution-phase chemistry and solid-state ball milling.
Duncan L. Browne
group at Cardiff University focussing
on the use of enabling technologies for synthesis and catalysis. In 2017 he
was recognised by both Green Chemistry and Reaction Chemistry and 2.1. Input
Engineering as an ‘Emerging Investigator’ and was a recipient of a Prior to addition to the extruder, compounds can be slurried
Thieme Chemistry Journal Award. In 2019, Duncan was appointed as together, mixed with a pestle and mortar, and even mixed in a
Associate Professor of Organic Synthesis and Drug Discovery at UCL ball mill to evenly distribute material. Furthermore, solution-
(University College London). phase continuous flow systems can be linked to allow addition

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Scheme 2 Scaling up mechanochemistry using reactive extrusion (A). Twin-screw extruder parameters and (B) photographic details. Filtr. = filtration,
LLE = liquid–liquid extraction, crystal. = crystallisation/recrystallization.

of reagents through liquid feeders (Scheme 2B). Addition of paste formation, gumming, or blockages, in turn nullifying
solvents as liquid-assisted grinding (LAG) agents can assist in reactivity (the latter can also be achieved by feeding material
screw flow, in turn stopping blockages. Furthermore, solid too quickly into the reaction centre). The screws themselves can
additives known as glidants (similar to grinding auxiliaries in be configured with ‘‘conveying’’, ‘‘reverse’’ and ‘‘kneading’’
smaller scale batch mechanochemistry) can be added to facil- elements. These elements can be configured in a ‘‘plug-and-
itate flow and/or serve as a reaction surface. play’’ system and are simply slid along the screw rod to
configure. Moreover, kneading elements can be positioned at
2.2. Feed 30, 60 (in either a forward or reverse orientation), and 90
Following this, materials can be added to twin-screw extruders degrees, and it is widely understood that these elements impart
via feeders located either before or during the screw set-up. the greatest mechanical forces onto materials. After they have
These are normally either solid (where you can also add been configured, in certain extruders these screws can then be
slurries) or liquid feeders (where compounds are added via rotated either in a ‘‘co-rotating’’ or a ‘‘counter-rotating’’ fashion
syringe or HPLC pump). The additions can be both manual or which will also exert different mechanical forces. Importantly,
automated (via a syringe pump for example), and the latter different sections along the length of the extruder can be heated
affords the user control over the feed rate (FR) which has a to different temperatures. Whilst predominately a single tem-
direct influence on the residence time (TR) in the screw. perature can be utilised, this facet enables fine-tuning of reaction
optimization, especially in cascade reactions (vide infra).
2.3. Reaction centre
The reaction centre of the twin-screw extruder offers a plethora 2.4. Output
of variables to consider. The screws are rotated by a motor The mixture that is ejected from the screw is often a powder/
which can be used to modulate screw speed (which will affect paste and can be further manipulated via quenching, further
TR) and the torque of the screw (which will also be dependent reactivity, or undergo purification. At this point, analysis of the
on the nature of the reactants). Users should avoid allowing the crude reaction mixture, including both standard solution phase
screws to be ‘‘torqued out’’ which shuts down rotation due to methods such as NMR spectroscopy, but also powder X-ray

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diffraction (PXRD), can take place. In this review, how the comparisons to solution phase and ‘‘batch-mode’’ ball milling
reaction mixture is purified will be highlighted, whether it will also be given where available.
is filtration (filtr.), liquid–liquid extraction (LLE), column
chromatography, or through a recrystallisation/crystallisation
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protocol (crystal.) 3. Reactive extrusion in synthesis

Other variations on the extruder including home-made
devices have been employed and further details will be given 3.1. Crawford & James – 2017
where appropriate. Despite the utility of extrusion equipment in other fields of
The key papers to date will now be discussed in a case-study chemistry, remarkably it wasn’t until 2017 when the first
style format and details of sustainability/reactor metrics such studies in molecular organic synthesis were reported. The
as space time yield will be given where available. Furthermore, Knoevenagel reaction between vanillin and barbituric acid
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Scheme 3 Twin-screw extrusion as an enabling technology in solid state organic synthesis.20,21

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has become an archetypal study for ball-milling reactions. elected to explore this methodology further in a continuous
Crawford, James, and co-workers reported a translation of a setting. All screw speeds (30–250 rpm) at room temperature
Knoevenagel reaction for scale up via twin-screw extrusion.19 resulted in no conversion. An elevated temperature of 40 1C at
Initial investigations using a screw system made-up of convey- 55 rpm resulted in a visual and physical change, producing a
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ing and kneading sections (standard screw) showed that – after golden yellow liquid and a conversion of o5%. After further
pre-mixing the starting materials and feeding them into the increase of temperature, the addition of reverse segments to the
extruder – the reaction could successfully be achieved at 160 1C screw configuration after kneading segments – a technique to
with a screw speed of 55 rpm. increase residence time and kneading duration – was found to
Interestingly, no reaction was found to occur at low tem- be key, obtaining up to a 98% conversion at 120 1C and 200 rpm
perature o40 1C. This is in part attributed to the melting point (Scheme 3C). In addition, complete conversion was only
of the staring materials. Differential scanning calorimetry achieved when the reagents were premixed in a planetary mill
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(DSC) and contact angle experiments uncovered that the wet- (170 rpm, 5 minutes). This new reverse screw configuration
ting of barbituric acid by the aldehyde (vanillin) is necessary for resulted in an extended residence time (12 minutes) leading
effective reactivity. Therefore, increased temperatures of that to a throughput rate of 0.070 kg h1 with a STY of 3.5 
above vanillin’s melting point (483 1C), allowing for lubrica- 104 kg m3 day1. However, due to the formation of unidenti-
tion of the reaction mixture, was shown to be optimal and this fied by-products, purification via flash column chromatography
system was applied to a small range of vanillin derivatives was required.
exhibiting a range of melting points (40–166 1C). Notably, the Kaupp and co-workers have previously shown the aldol
only by-product in the reaction mixture was water, which was reaction of ninhydrin and dimedone to provide quantitative
removed as steam within the screw barrel. product without the need for further purification.22 This reac-
The authors calculated space time yields (STY, kg m3 day1) tion was then investigated by James, Crawford and co-workers
for each extrusion reaction (equation located at Scheme 3, top by TSE (Scheme 3D). It was found once again, that Na2CO3
left), a metric which can be utilized in examining reactor efficiency (10 mol%) was required. Complete conversion to product could
and process intensification of a reaction. Larger STY values denote be achieved at 100 1C, however a low feed rate (0.8 g min1) was
improved efficiency; and favorable STY metrics can drive indus- required to overcome an undesired increase in torque. Both
trial route design. From a throughput rate of 0.52 kg h1 (from a ball milling and TSE methodologies have been shown to be
feed rate of 0.60 kg h1), the phenol example shown (Scheme 3A, superior to the analogous solution reaction which proceeds to
top) was found to have an impressive space time yield of 2.6  only 78% yield overnight at reflux, highlighting that TSE
105 kg m3 day1. For comparison, a representative solution provides an excellent opportunity for continuous synthesis.
phase reaction, processing 1 g of a 500 g mol1 material in Finally, the synthesis of C–N bonds through condensation to
20 mL (0.25 M) solvent in a 50 mL flask with a 12 hour reaction form an imine has previously been demonstrated mechano-
time would give a STY of 40 kg m3 day1 (480 kg m3 day1 if full chemically in batch mode. For TSE application, screw speeds
conversion observed in 1 hour). between 55 and 250 rpm were performed at room temperature,
Following this successful translation from ‘‘batch-mode’’ with all speeds above 55 rpm resulting in decreased conversion
ball-milling to ‘‘flow-mode’’ extrusion, the reaction of vanillin (o28%) due to decreasing residence times. Alteration of barrel
and malononitrile (mp = 32 1C) was explored. Subjecting this temperature resulted in complete conversion at 80 1C. Having
reaction to the above optimized conditions (55 rpm, 160 1C) previously been added manually the reagents were now intro-
resulted in no product formation, attributed to unproductive duced automatically at set rates. Below 0.45 g min1 gave
polymerization of malononitrile. To circumvent this issue, the no conversion with subsequent rates of 0.73 g min1 and
authors introduced Na2CO3 (10 mol%) as a catalyst which 0.79 g min1 giving conversions of 70% and 90% respectively.
permitted the use of a lower temperature of 120 1C, which in Complete conversion was achieved using a temperature of
turn enabled complete conversion to the condensation adduct. 120 1C (Scheme 3E). No purification was required, resulting in
It must be noted the output of this reaction was not separated analytically pure product produced at a throughput rate of
from the carbonate catalyst. Furthermore, the reaction of liquid 0.030 kg h1 and an STY of 1.5  104 kg m3 day1. This report
inputs was also shown to be compatible with this process with constituted an important step in showcasing what can be
the reaction of vanillin with ethyl cyanoacetate. In this case the achieved using extrusion equipment in molecular organic
vanillin and sodium carbonate were introduced via the solid synthesis.
feeder and the cyanoacetate was injected into the liquid feeder
via syringe pump (Scheme 3B). Reaction at 160 1C at a screw-
speed of 55 rpm gave complete conversion to product allowing 3.2. Isoni – 2017
for a space time yield of 5.6  104 kg m3 day1. Whilst continuous reduction processes utilizing HPLC pumps
Even with preliminary optimization studies into the ball- and pre-packed columns (packed with Celite, NaBH4 and LiCl)
milling enabled cascade condensation/Michael addition have been established by Seeberger and co-workers, this system
between vanillin and dimedone, conversions of only 7.5% were was limited to gram-scale, and also required organic solvents
obtained. Despite this, as TSE can introduce the ability to fine- and regular regeneration of packed columns.23 To this end,
tune temperature control and screw configuration, the authors Isoni and co-workers proposed and developed a ‘‘greener’’

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alternative for aldehyde reduction, capable of multikilogram 3.3. Crawford & James – Nov 2017
continuous scale operation.24 The ability to carry out multi-step reactions in continuous
Initial optimization was conducted using water insoluble extrusion has already been exemplified by Crawford, James
aldehydes (such as 4-chlorobenzaldehyde) and an improvised and co-workers, and in a subsequent report, the authors
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high-shear reactor (550 W, 14 000 rpm, food blender) on gram- expanded this concept to demonstrate how multiple subse-
scale (Scheme 4A). It was found that the reaction could be quential reactions can be telescoped together with one device
performed in the absence of organic solvents and in less than through the addition of successive reagents further along the
one minute with variable conversion (25–95%), and upon extrusion barrel (Scheme 5A).27 This was elegantly showcased
addition of aqueous 1 M NaOH conversion increased further using the Knoevenagel condensation of vanillin and malononi-
(498%). Using the model reaction conditions from above trile followed by the subsequent Michael addition upon the
(summarized in Scheme 4B), the reaction was then performed
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introduction of dimedone.
on pilot kilogram scale (Scheme 4C) passing the slurried Using the previously optimized Knoevenagel condensation
mixture under a nitrogen atmosphere through a modified conditions (for details, see Section 3.1)19 and sub-stoichiometric
twin-screw extruder, producing 1.41 kg of the benzyl alcohol quantities of Na2CO3, 120 1C and a screw speed of 55 rpm
product in just 17 minutes (4.53 kg h1) with high purity (89%), afforded complete conversion. When exploring the Michael
where simple vacuum filtration and washing with water was all addition step, alteration of the reaction temperature was impor-
that was required to obtain the reduced alcohol. Inspection of tant and was studied at intervals between 25 and 160 1C.
the equipment at the end of the continuous run highlighted Notably, for a telescoped process in a single extruder, because
fouling of the NaBH4 slurry inlet nozzle which led to a decrease the screw speed is set for the process as a whole rather than
in conversion over the duration of the run. Moreover, it was individual sections of the screw/barrel, temperature control
noted that a temperature increase of 15 1C (23 to 38 1C) in less becomes the key variable. Interestingly, below 140 1C the reac-
than 5 minutes of operation was observed and thus further tion was shown to be ineffective, however above this the product
reactor design and engineering would be required to more formed with maximum conversion at 160 1C owing to the
reliably control this scale up process. The authors did however formation of a melt. However, some notable issues that arose
detail several key potential benefits over batch alternatives, were (1) the formation of ‘‘bridges’’ at the feeders due to
which include: (a) 22 times greater volume efficiency; (b) 11 temperatures being greater than that of the melting point of
times volume efficiency (including work-up); (c) more than 33 the input feeds and (2) abnormally long (40 minutes) residence
times more energy efficiency (MJ per ton product); (d) no time due to uncontrollable fluctuation in reaction rheology.
organic solvent used (THF in batch) however more NaOH use These were resolved by the temperatures at the feeder locations
(potential to recycle this in TSE); (e) OPEX (Operating expenses) being lowered below that of the reagents melting points and the
were more than 16 times greater for batch. use of lower feed rates. This led to uncovering a ‘‘one-screw’’

Scheme 4 Twin-screw extrusion in the aqueous reduction of aldehydes, home-made high shear blender used instead of a ball mill for assessment of
reaction in batch mode.25,26 * Space-time yield metric calculated using parameters given by Isoni and co-workers.

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Scheme 5 Telescoped cascade processes through reactive extrusion.

cascade reaction affording the addition adduct in 100% conver- sectors due to the numerous documented positive impacts that
sion. This system also serves to showcase one of the unique the inclusion of fluorine atoms can have on many functional
practicible points of extrusion technology, in that fine-tuning of molecules, such as improving the efficacy of pharmaceutical
the temperature of each individual section is possible. and agrochemical compounds.28 These structures are generally
Following this, a multi-component equivalent analogous accessed via either electrophilic or nucleophilic fluorination
method was sought, by mixing all three reaction components methodologies using reagents such as Selectfluor or NFSI (as
together with the base catalyst, using a screw speed of 55 rpm and substitutes to F2) or various fluoride sources. Many fluorinated
a temperature of 160 1C, the same adduct was produced in compounds can be attained through building blocks such as
excellent conversion (Scheme 5B). These multi-component reac- fluorinated 1,3-dicarbonyls but production of these compounds
tion (MCR) conditions also resulted in a slightly greater through- can suffer with selectivity issues due to potential mono and
put rate of 0.16 kg h1 and a STY of 8.0  104 kg m3 day1. di-fluorination at the acidic 2-position, which remains a sub-
Further to these findings, Crawford, James and co-workers stantial challenge necessitating careful control of reaction
also demonstrated the Petasis reaction by twin-screw extrusion, conditions and system design. Browne and co-workers have
which notably had not been mechanochemically performed in developed a range of highly selective protocols for the synthesis
batch before. Initial use of the standard screw configuration of both fluorinated building blocks under ball milling condi-
resulted in low conversions to product (o20%). Substitution to tions including, heterocycles and 1,3-dicarbonyls.29 In 2016,
a reverse screw configuration amplified the duration of both while investigating the fluorination of 1,3-diketones they found
kneading segments, leading to increased reaction efficiency. excellent reaction selectivity for producing either the mono or
Optimisation of the screw temperature and speed resulted in difluorinated products using additive control in solvent-free/
the crucial conditions of 50 1C and 150 rpm to ensure complete minimised mechanochemistry. Here addition of MeCN (Z =
conversion (Scheme 5C). These conditions produce a residence 0.13 mL g1 of total mass of reagents) as a liquid additive
time of just 7 minutes, equivalent to a throughput rate of selectively produces the mono-fluorinated species whereas use
0.18 kg h1 and a STY of 9.2  104 kg m3 day1. The boron- of Na2CO3 (1.0 equiv.) afforded selective formation of the di-
based by-product was then readily removed via a liquid–liquid fluorinated species.
extraction using ethyl acetate and water to generate the pure Successful translation to twin-screw extrusion from the
product. mixer mill using the same additive-dependent switch was
achieved maintaining the excellent selectivity observed previously
3.4. James & Browne – 2018 (Scheme 11).30 Key to the adaption of this reaction was the
Fluorinated compounds – and methods for their efficient synth- increased reaction temperature (60–70 1C) along with the intro-
esis – have become ever more important for many chemical duction of NaCl as a glidant (grinding agent) (Scheme 6).

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Scheme 6 Twin-screw extrusion enabled fluorination of 1,3-dicarbonyls. * recrystallisation only used on di-fluorinated species.

Using a screw configuration including conveying, kneading, shows the potential for the use of this solvent free continuous
and reverse sections, continuous extrusion was demonstrated method for the construction of fluorinated building blocks.
to produce difluorinated products, after filtration and recrys-
tallisation from cyclohexane, in 70% isolated yield (values given 3.5. Métro – 2018
in Scheme 6 are NMR yields) at a rate of 3.94 kg h1. This is a The importance of the development of efficient, atom econom-
stark increase when compared to 0.14 kg h1 that could ical, and sustainable methods for the forging of peptide bonds
theoretically be achieved under the optimized ball-milling in industrial settings cannot be overstated. Two of the major
conditions. Similarly, the mono-fluorinated diketone was research avenues that have been employed to provide solutions
formed in an excellent yield up to 90%, corresponding to a to the above are (a) methods negating the need for stoichio-
high throughput rate of 5.14 kg h1, isolated as a mixture of metric activating reagents, which in turn produce large quan-
isomers through simple filtration. This work demonstrates the tities of atomic waste, (b) the development of solvent-free
potentially facile nature of process intensification which can be amide coupling reaction methodology, through mechanochem-
achieved through the application of the extruder technology to ical techniques such as ball-milling. To this end, in 2009,
previously established ball milling procedures. Furthermore, it Lamaty and co-workers described the solvent-free synthesis of

Scheme 7 Bulk solvent and CRM-free peptide coupling enabled by recirculating screw extrusion. aSolution values calculated using NEt3 as base and
DMF as solvent.

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key peptide bonds, via the ball-milling-enabled coupling of comparisons which employed industrially undesired NEt3 and
a-amino ester salts with urethane-protected a-amino acid DMF reaction conditions. When compared to solution phase
carboxyanhydride (UNCA) using simple NaHCO3 as base.31 reactions using NaHCO3 as base and acetone as solvent, a 2356
Following this, a selection of further ball milling processes fold increase was observed. These STY results – alongside the
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have been described in the literature for the formation of amide sequential coupling reactions, and the application of this
bonds, most often employing amide coupling agents such as methodology to the synthesis of peptide fragments such as
EDC and CDI. Within this context, in 2018, Hernandez and co- aspartame – showcase the potential opportunities for industrial
workers described the papain-catalyzed homo-oligomerization production of peptide sequences using reactive extrusion.
of amino acid residues using twin-screw technology.32 Notwith-
standing this exception, all of the mechanochemical amide 3.6. Kulkarni – 2019
bond formation reactions have been hampered by scale As an alternative to the use of two screws to impart continuous
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through reliance on ‘‘batch-mode’’ ball milling. extrusion, Kulkarni and co-workers designed and built a dis-
In 2018, Métro and co-workers reported an important step tinct jacketed single vertical screw reactor (Scheme 8), particu-
towards the continuous solvent-free synthesis of di- and tri- larly useful for neat solids with solubility issues as well as
peptides via reactive extrusion.33 Furthermore, the authors slurries.34 The unique design, based on a Teflon-screw inside a
targeted a CMR-free (carcinogenic, mutagenic, or reprotoxic) condenser-type glass container, allows for precise temperature
method – requiring the omission of not only toxic coupling control of the extrusion process as well as the ability to monitor
reagents but also ubiquitous solvents such as DMF, DCM, the visual changes over the reaction due to a see-through
and THF. For the extrusion process a co-rotating twin-screw reactor wall, both of which lead to increased safety and
extruder (MC15 microcompounder, Xplore) containing a feed efficiency compared to previous methodology. Furthermore,
recycler – dubbed ‘‘recirculating screw extrusion’’ in this the vertical orientation is preferred to remove the potential
review – was employed (Scheme 7A). Whilst mimicking twin- for unsafe generation of friction. The introduction of the
screw extruders discussed above, here, a recirculating loop can reagents is by the direct addition to the feeder screws or via a
be brought into play, allowing recirculation of the reaction pump for fluid reagents. Reactions can also be performed
mixture which leads to extended reaction/residence times. After under solvent-free or solvent-minimised conditions and this
the desired recirculation time, the feed changer can be system is designed to process solid mixes, pastes and slurries
switched to eject the reaction mixture. The authors optimized alike. The authors applied this novel single-screw extruder to a
on a model system of the peptide coupling of the activated ester portfolio of nine distinct organic transformations, including
Boc–Trp–OSuc and HClH–Gly–OMe, and stemming from pre- catalytic reactions and redox adjustments. Notably this screw
liminary planetary mill results, the authors demonstrated that system (like the RSE above) do not contain kneading screw
the addition of acetone (Z = 0.15 mL g1) as a liquid assisted sections, suggesting mechanical force is elicited through shear-
grinding (LAG) agent was crucial for efficient flow through the ing against the wall of the reactor.
extrusion chamber. Furthermore, using a recirculating time of The synthesis of azo dyes and their associated diazonium
10 minutes, heating the chamber to 40 1C, and a screw speed of intermediates has previously been explored in continuous flow,
150 rpm, 85% yield of Boc–Trp–Gly–OMe (3.72 g) was achieved pestle and mortar grinding as well as solid support reactivity.
with 99% ee at the stereogenic center maintained. As means of However, these techniques generally either require polar
post-extrusion manipulation (which was also used in other solvents (including DMF) or are unsafe for large scale production
examples), the dense paste ejected from the extruder, was dried of dry diazonium salts due to well-established sensitivity towards
overnight under reduced pressure over P2O5, then submitted to friction, heat or shock. To this end, the production of the
liquid–liquid extraction work-up, which – after concentration in popular azo dye, Sudan dye has been achieved under contin-
vacuo – in all cases afforded pure peptide product without the uous solvent-minimised conditions using Kulkarni’s screw
need for further purification. This methodology was expanded design (Scheme 8A). Firstly, the diazo reagents were synthesised
to the coupling of HClH-Phe-OMe with Boc-Trp-OSuc and in a tubular reactor before being fed directly into the single
Boc-Asp(OBzl)-OSuc to form the dipeptide structures in 61% screw extruder (SSE) along with 2-naphthol. It was found that
and 92% yield respectively. the addition of NaOH and water was crucial due to the
By simple submission of the dipeptide products formed formation of a basic media. The reaction was maintained at
above to an atmosphere of dry HCl overnight to remove the 0 1C with a screw speed between 120–150 rpm. Complete
Boc protecting group, the free amine dipeptides could then be conversion was observed after only 20 s as a red slurry, which
resubmitted to the extrusion methodology forming tripeptides required further filtration to afford the desired dye in 95% yield
Boc-Asp(OBzl)-Trp-Gly-OMe and Boc-Asp(OBzl)-Trp-Phe-OMe in on a 25 g scale. Remarkably, the scalability of this process was
excellent yield (486%), and purity (494%). highlighted through the synthesis of nearly 1 kg of the target
When the space-time yield values for the RSE-enabled pep- dye along with the potential to scale-up further to 500 kg should
tide coupling were compared to ‘‘batch-mode’’ planetary ball the equipment run continuously for 7 days.
mill and solution-phase counterparts, remarkable 20–200 fold BINOL and its derivatives provide the backbone to many
increases were observed. Even more notable is that the authors privileged ligand systems. Synthesis is often achieved via oxi-
benchmarked their extrusion work against solution phase dative homocoupling of 2-naphthol in the presence of an

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Scheme 8 Use of single screw extruders in organic synthesis.36,37

oxidant such as FeCl36H2O. Batch reaction has previously been flash column chromatography). It was noted that the poor yield
achieved by grinding using a pestle and mortar followed by is due to the formation of a semisolid/adhesive solid at elevated
heating at 50 1C for 2 hours.35 temperatures, which consequently gives poor mixing/heat
Application to SSE at 50 1C gave no product formation but transfer. The addition of a solvent (H2O : MeOH, 1 : 1) along
raising this temperature to 160 1C at a screw speed between with the use of lower temperatures (90–100 1C) and a lower
830–900 rpm pleasingly afforded the crude product in 50 s screw speed of 250–350 rpm reduced these effects allowing for
leading to 38% of the pure product after purification (silica gel the formation of a more free flowing paste and thus more

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Scheme 9 Use of single screw extruders in organic synthesis (continued).

efficient mixing. This gave an increased yield of 52%, although speeds between 300–450 rpm, delivered the product after a
coupled with an increase in residence time of 300 s residence time of 60 s, with filtration being the only purifica-
(Scheme 8B). tion required to give the aldehyde in 93% yield. This solid-state
The aldol condensation remains an integral reaction in continuous oxidation presents advantages over solvent
organic synthesis and has already been explored on multiple versions.39 Firstly, is the omission of DMSO, which is typically
occasions in extrusion technology (Section 3.1) including the used in solvent protocols due to the established poor solubility
synthesis of chalcones which has been performed using multiple of IBX. Secondly, the reaction proceeds much faster with
techniques. Using SSE, the solvent minimised synthesis was completion after just 60 s compared to 12 hour reaction times
achieved using 4-methyl benzaldehyde and acetophenone along typically seen in solution.
with one equivalent of NaOH at 180–200 rpm (Scheme 8C). Metal-catalysed C–C and C–X coupling has recently been
The crude product was afforded with a residence time of 89 s, well explored under ball-milling conditions.40 Solid-state Sono-
with the desired chalcone obtained in 92% yield after washing gashira coupling has previously been achieved in batch
with water. It was noted the starting materials are liquid and the regimes. Whilst continuous methods utilizing solid supports
product solid, allowing for a crude visualisation of reaction have been demonstrated, solid feeding of materials into a solvent-
progression. The application of this continuous chalcone synth- free continuous reactor would be beneficial. With this in mind,
esis could be extended to reaction with veratraldehyde (88%) and using their SSE technology (Scheme 8F), successful coupling was
furfural (90%) using residence times of 68 s and 62 s respectively. achieved with combined feeding of 2-iodothiophene and DABCO
Related to the aldol condensation is the Knoevenagel con- into one inlet and phenyl acetylene with Pd(OAc)2 into the other.
densation, which has previously been explored in continuous The coupled product was achieved in 85% yield in 65 s residence
extrusion (TSE) by James and co-workers for the reaction of time with a screw speed of 350–450 rpm. A reaction temperature
aldehydes with barbituric acid (Scheme 3). The continuous of 0 1C was found to be optimal, which was suggested to temper
synthesis of a valuable coumarin (previously achieved in batch reaction exothermicity, in turn reducing the formation of side
by mortar and pestle)38 has been demonstrated by Kulkarni products.
using the SSE (Scheme 8D). The reaction of salicylaldehyde, Using SSE, the acylation of phenol (in THF) with benzoyl
acetyl acetone and piperidine gave the desired 3-acetyl chloride (in THF) in the presence of NEt3 proceeded efficiently
coumarin in excellent yield (97% after column) after a resi- to give the desired ester in 90% yield after a residence time of
dence time of 30 s at 95–150 rpm. The reaction of all liquid 25 s at 150–210 rpm (Scheme 9A). NEt3HCl was produced as
starting materials started to solidify after just 6 s indicating the by-product without hindering reactivity. It was found that 2-
rapid initiation of the reaction. furoyl chloride could be used in place of benzoyl chloride giving
The SSE has also been applied to the oxidation of primary the desired heteroaryl ester with a 95% yield after just 15 s
alcohols (Scheme 8E). Upon addition of 4-methoxy benzyl residence time, also with no sign of blockage. This presents a
alcohol and IBX (2 equivalents), the reaction initiated almost beneficial alternative to solution-phase flow regimes for the
instantly. Since the product is a solid, the absence of solvent continuous acylation of alcohols, as precipitation and blockage
results in the reaction producing a thick paste. To overcome problems arising from salt formation are negated.
this, a small quantity of EtOAc (5 mL) was added to form a A similar approach can also be taken for nucleophilic
slurry and prevent any detrimental blockages. Rotational substitution of POCl3 for the synthesis of biologically relevant

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organophosphorus compounds. Cetyl alcohol reacts with POCl3 From a mechanochemical stand-point, James and co-workers
in the presence of NEt3 at 0 1C and 160–180 rpm to produce the have explored a more sustainable method for the synthesis of
phosphonic dichloro-intermediate along with NEt3HCl, before PDIs using solvent-free continuous extrusion technology
quenching the dichloro-intermediate with methanol after exit (Scheme 10).43 Initial optimization began with solvent-free ball
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from the extruder to afford the product with a residence time milling of 1,8-naphthalic anhydride with 4-ethoxyaniline using a
of 18 s and a yield of 85% after column chromatography ‘beat and heat’ method whereby the mixture is milled for
(Scheme 9B). 5 minutes before being heated to specific temperatures for
The final reaction reported using the SSE from Kulkarni and 30 minutes. It was found that when temperatures below
co-workers was the TBS-protection of phenols. 4-Methoxy- 110 1C were used the reaction does not proceed. However, at
phenyl, TBSCl and imidazole were directly added to the SSE 110 1C quantitative conversion to product was observed.
at RT and 30–150 rpm. The silylether was produced after a 15 s Translation to continuous extrusion commenced with the
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residence time with a 94% yield (Scheme 9C). Again, an amine manual introduction of 1,8-naphthalic anhydride and 4-ethoxy-
salt – in this case imidazoleHCl, was produced as a byproduct aniline into the extruder over 8 minutes at 55 rpm.
of the process in this reaction and seemingly did not hinder Aligned to the initial ball-milling studies, it was observed
reactivity or operation of the extruder device. that no reaction occurred with barrel temperatures below
110 1C, whereas at 110 1C quantitative yield was again observed.
This protocol was then extended to the reaction of perylene-
3.7. James – 2020 3,4,9,10-tetracarboxylic dianhydride (PTCDA), providing the
Organic dyes are widely utilised across many aspects of organic imminent precursor to many pigment dyes. When using
and material science, but issues arise upon their synthetic PTCDA, the post extrusion materials were also then stirred in
pathways. Conventional solution syntheses suffer from envir- aqueous K2CO3 and held at 80 1C to hydrolyze any remaining
onmental setbacks due to contamination and the use of toxic starting material (Scheme 10). The use of PTCDA and two
reagents and/or solvents. This is highlighted in the synthesis of equivalents of the desired primary amine into the extruder
perylene-3,4,9,10-tetracarboxylic acid diimines (PDIs) where a afforded pigment black 31 and 32 in excellent yields (93% and
large excess of amine and high boiling solvents (4160 1C) are 96% respectively) on a 5 g scale (Scheme 10A). Subsequent
required, often at high temperatures or in the presence of a further scale up using automated feeders with PTCDA and
promoter (i.e., zinc acetate).41 Indeed, several molecules used in the amine to feed into the TSE at rates of 0.65 g min1 and
materials applications also often suffer from solubility pro- 0.5 mL min1 respectively. Hence, producing pigment black
blems and have been a particular focus for the mechanochem- 31 and 32 on a 20 g scale with a 99% yield and a STY nearly 60
istry community.42 times that performed in solution, showcasing a solvent-free

Scheme 10 Synthesis of naphthalene diimide (NDI) pigments via twin-screw extrusion. a Batch STY calculated assuming reaction space is twice volume
of solvent used.

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scalable continuous process towards high-value organic dyes. which this can be achieved.45 Among these aims include the
Other PDIs based on aniline-type amines were also synthesised reduction in the use of solvents and providing reactivity with-
but required alteration of the reaction conditions to compen- out the dependence on highly reactive or dangerous reagents.
sate for the reduced nucleophilicity of the amine (Scheme 10B). In 2020, Crawford, Colacino and co-workers’ reported the
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Slower screw-rotational speeds of 15 rpm and increased development of extrusion methodology towards the synthesis
temperatures between 150–200 1C along with a reduced feed of hydantoin-based API’s.46 Previous work from the Colacino
rate (40–60 min) and the addition of K2CO3 afforded pigment group utilizing batch mode ball milling had established the
red 123, 190 and 178 in good yields (60–65%). synthesis of hydrazone containing pharmaceuticals, dantrolene
(muscle relaxant) and nitrofurantoin (antibiotic), from 1-amino-
3.8. El-Remaily – Jan 2020 hydantoin via a base and solvent free protocol.47 Translation of
this method to the continuous production of hydrazones
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Multi-component reactions (MCR) – such as the Ugi reaction –

provide unrivalled modular synthetic strategies towards through twin screw extrusion was initially achieved for model
biologically relevant compounds, due to atom economy, high hydrazide compounds derived from acyl-hydrazine derivatives.
efficiency, low cost, and simple experimental procedure. Using a standard screw configuration, two derivatives were
In 2020, a rapid solvent-free procedure was reported by synthesized with complete conversion in under 2 minutes
El-Remaily and co-workers using a co-rotating extruder. The residence time. Interestingly only the (E)-isomer was observed
reagents were mixed in a glass mortar for an unspecified with phenyl-substituted hydrazide. Further expansion of this
amount of time prior to addition to the LechTech Scientific methodology of this continuous synthesis protocol to the pre-
26 mm twin screw extruder, to ensure liquid reagent retention viously explored dantrolene and nitrofurantoin proved more
(Scheme 11).44 challenging. Their synthesis required the alteration of the screw
For optimization, the model system of benzaldehyde, ani- configuration to allow for increased residence time within the
line, benzoic acid and tert-butyl isocyanide was used. The reactor (ca. 40 minutes), and only the (E)-isomer observed in
highest yields were observed when water was used as a solvent both cases. Notably the construction of these pharmaceuticals
(66%), however, the use of a solvent-less system resulted in a could be carried out in an extruder without the use of concen-
similar yield (63%). Heating of the extrusion system was shown trated mineral acids and bases, which have been previously
to be key, with a reactor temperature of 100 1C accessing required in solution. This consideration is further exemplified
increased yields of 77%. Further to this, screw speeds were by the workup process, where the absence of acids and bases
then lowered to 50 rpm to increase residence time of the obviates the need for additional manual handling steps,
material on the screw, resulting in yields of 93% of the product. although limited information is provided on the exact post-
A nine-compound scope followed optimisation with yields extrusion manipulations. A further study on this system by a
ranging from 69–93% and synthesised in under 20 minutes, consortium of mechanochemistry and extrusion experts truly
demonstrating the reactions versatility to a variety of substitu- highlights the energy consumption and water wastage benefits
ents. Furthermore, the products were obtained in high purity to extrusion methodology when compared to standard solution-
with the only purification requiring adding the extruded mix- phase set-ups for upscaling synthetic protocols (Scheme 12).48
ture to ice water and collecting the precipitate.

3.9. Crawford & Colacino – Aug 2020 4. ‘‘How-to’’ extrusion reaction design
Reducing the overall environmental impact of the synthesis of Whilst every reaction system contains its own subtleties, draw-
active pharmaceuticals is a key aim of the ACS Green chemistry ing knowledge from the case studies above and our own
roundtable, who have set forth a range of key objectives by experience with the development of extrusion protocols allows
us to form a general route for optimization of an extrusion
process (Scheme 13).

(A) Ball-milling optimization

Considering the large quantities of material required for each
extrusion run (410 g of total material), this could prove
incredibly wasteful for studying an extrusion process on high-
value intermediates. Accordingly, a large majority of the pro-
cesses discussed above have been adapted from established
ball-milling protocols. Small-scale optimization can be carried
out using ball-milling apparatus on 50–500 mg scale, with
either mixer mills or planetary mills. Incidentally shear
mechanical forces predominate in the kneading sections of
Scheme 11 Twin-screw extrusion enabled multi-component Ugi the extruder, therefore reactions that perform effectively in the
reaction. planetary mill may be very well-placed for translation into

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Scheme 12 Twin-screw extruder enabled hydrazide and hydrazone formation in the synthesis of API’s.

extrusion protocols. These reactions will allow the user to available for optimization in the extruder will govern how many
optimise the reaction components (reagents, additives, cata- experiments the user is able to conduct to discover an efficient process.
lysts, etc.), as well as reaction time required. Furthermore,
unique ball-milling variables such as milling volumes, ball (D) Investigate extrusion protocols
size/weight, liquid assisted grinding (LAG), grinding auxiliaries, Initial experiments will provide a lot of information about
and oscillating frequency will also be deduced. reaction efficiency which can be judged via standard analytical
techniques, such as thin layer chromatography (TLC), NMR, or
(B) Extract key variables LC-MS, but also by PXRD analysis of the crude extruded material
Information on reaction components and solid and liquid grinding vs. standards of the starting materials and products. Whilst
auxiliaries should be directly applicable to extrusion method devel- there are many problems and causes held within the develop-
opment. Although twin-screw extrusion offers a variety of new ment of an extrusion protocol, we wish to highlight two routine
variables such as screw speed, feed rate, screw temperature, and problems, their common causes, and possible solutions.
screw configuration, which do not have direct comparisons in ball Problem 1; low conversion. This is often due to transferring
milling. Despite this, extracting the ball-milling-specific parameters from ball-milling protocols with reaction times of 41 h to
coupled with reaction time can provide information of the amount extrusion systems with residence times of a few minutes.
of mechanical energy required for a transformation to take place, Whilst residence times can be increased by reducing screw
notably the ‘‘severity’’ of the reaction conditions. For example, if a speed, it is worth noting that this will reduce the mechanical
reaction requires a heavy ball, high oscillating frequencies, and long energy imparted onto the reaction mixture, as screw speed and
reaction times in a ball-mill, it is likely that a high screw speed and specific mechanical energy are proportional as per eqn (1).
residence time will be required in extrusion.
120  p  n  M
SME ðspecific mechanical energyÞ ¼ (1)
(C) Design initial experiments m_
:
Using knowledge from sections (A) and (B), initial experiments where n = screw speed (rpm), M = torque (Nm), m = throughput
1
can be designed. This is when automation capabilities are taken rate (kg h ).
into account, i.e. whether a solid feeder/liquid pump can be Whilst multiple variables will affect the residence time the
used to accurately regulate feed rates of materials. In this case most productive way to increase residence time is reconfigura-
we would recommend starting at an addition rate at around tion of the screws in the extruder. This can be done by
1–2 g min1. If these are not available, one can manually add incorporating reverse elements into the screw configuration,
materials via a spatula or a syringe for initial experiments. Unless either through arrangement of 301 or 601 kneading sections in a
previous investigations demonstrated a need for harsh mechan- reverse orientation, or through inclusion of reverse segments.
ochemical reaction conditions, we would recommend starting Secondly, if low conversion is observed increasing the reaction
with a standard screw configuration (with no reverse sections), a temperature is a good option. Whilst increasing temperature
screw speed of B50 rpm, and a screw temperature of 25 1C. of ball milling apparatus remains non-trivial,42 with extrusion
However, as discussed above, the exact amount of material apparatus it is more straightforward. Through simply

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after inclusion of reverse sections, is that the screw speed isn’t

high enough to process the material through the screw, which
can be readily increased by the user to overcome this issue.
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(E) Apply the optimal conditions on higher scale

After optimisation of extruder parameters, running the contin-
uous process for longer periods of time is critical to process
success. This will provide information on reaction and reactor
steady states, including long-term temperature and torque
changes. Running in a continuous fashion will also allow the
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user to exemplify their protocol on industrially-relevant scales.

5. Conclusions & future outlook

Building on pioneering work in crystal engineering and MOF
synthesis (among many other areas), molecular synthetic
organic strategies using reactive extrusion have begun to
emerge in the last few years. Through elegant advances at
the interface of chemical engineering and synthetic organic
chemistry, twin-screw extrusion has placed itself as a unique
technology in the processing of solvent-free and solvent-
minimised reaction systems.
Twin-screw extruders have been shown to enable fine-tuning
of new reaction parameters such as screw speed and feed rates,
but also allowing in the complete modulation of screw config-
urations and modular temperature control of separate sections.
Altogether this has provided a programmable framework for
continuous mechanochemistry. Further to this, this concept
has enabled the showcasing of alternative screw systems such as
single screw extruders, and recirculating screw extruders. Using
extrusion, a variety of transformations have been achieved
including condensations, palladium-catalysed cross couplings,
Michael additions, and oxidative dimerization methods.
This tutorial review has covered the first landmark papers in
this field and hopes to stimulate further research in the area by
spotlighting the opportunities reactive extrusion can offer both
sustainable and continuous chemistry. The future outlook for
Scheme 13 Exemplary ‘‘how-to’’ optimize a twin-screw extrusion
protocol. exploring and implementing reactive extrusion for organic
synthesis is rather exciting. There are a myriad of reactions
that remain to be explored and developed, including several key
increasing the temperature at one or more segments, one can reactions currently applied at high volume with vast amounts of
supplement the mechanical energy imparted on the reagents solvent consumed. Caution of course needs to be applied to
with thermal energy. potential safety hazards for processing materials in this man-
Problem 2; ‘‘over-torquing’’. The other most common ner, avoid anything that could be shock sensitive or rapidly
problem when implementing an extrusion protocol is ‘‘over- release gases, and perform appropriate safety tests prior to
torquing’’. As shown in eqn (1), torque is beneficial to mechan- commencing work. Exploring the use of hybrid continuous
ical energy, however if this becomes too great the screws can no reactors consisting of solid and liquid flow setups to implement
longer turn and the reactor will automatically shut down. multi-step chemical synthesis offers a particularly captivating
Torquing-out is most often caused by an unfavourable reaction prospect. Still, much work needs to be investigated and
morphology. This can be overcome by the addition of liquid recorded on optimising and implementing the use of extruders
grinding agents (such as a co-solvent) or the addition of a and their variety of parameters as well as focus on optimising the
glidant (such as sand or NaCl) to facilitate movement through purification of these processes for maximum purity, and both
the screw. Further to this, it could be that for the reaction minimising the amount of solvent used and number of manual
morphology being studied the reaction feed rate is too high and handling steps required. Furthermore, the translation from ball-
causing the blockage. Secondly, and much more paramount milling to reactive extrusion is often not straightforward, and we

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hope this review may act as a starting point guide for end users J. Org. Chem., 2017, 13, 65–75; (b) D. E. Crawford and
looking to engage in continuous mechanochemistry, and the J. Casaban, Adv. Mater., 2016, 28, 5747–5754.
wealth of opportunities this currently under-utilised technique 17 F. Gomollón-Bel, Chem. Int., 2019, 41, 12–17.
has to offer.49 18 D. E. Crawford, S. L. James and T. McNally, ACS Sustainable
This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

Chem. Eng., 2018, 6, 193–201.

19 D. E. Crawford, C. K. G. Miskimmin, A. B. Albadarin,
Conflicts of interest G. Walker and S. L. James, Green Chem., 2017, 19, 1507–1518.
There are no conflicts to declare. 20 D. Stan, M. Matache, L. Ruta, C. Draghici and C. Dobrota, Rev.
Chim., 2009, 60, 876–879, https://bch.ro/pdfRC/STAN%20
DANA%209.pdf.
Acknowledgements 21 D. E. Crawford, C. K. G. Miskimmin, A. B. Albadarin,
Open Access Article. Published on 04 May 2022. Downloaded on 5/10/2022 11:48:27 AM.

G. Walker and S. L. James, Green Chem., 2017, 19, 1507–1518.

R. R. A. B. thanks UCL for a studentship. J. A. L. thanks the 22 G. Kaupp, M. R. Naimi-Jamal and J. Schmeyers, Chem. – Eur.
Leverhulme trust for a research fellowship (RPG-2019-260). J., 2002, 8, 593–600.
D. L. B. is grateful to the European Union, WEFO, Cardiff 23 K. Gilmore, S. Vukelić, T. McQuade, B. Koksch and
University and Cambridge Reactor Design for a Knowledge P. H. Seeberger, Org. Process Res. Dev., 2014, 18, 1771–1776.
Economy and Skills Scholarship (KESS2) to A. C. J. W. I. N. 24 V. Isoni, K. Mendoza, E. Lim and K. Teoh, Org. Process Res.
thanks Cardiff University for a studentship. The authors thank Dev., 2017, 21, 992–1002.
Margharete Richter (Thermofisher) for valuable discussions. 25 F. Faigl, A. Thurner, B. Molnár, G. Simig and B. Volk, Org.
Process Res. Dev., 2010, 14, 617–622.
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45 D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, A. Porcheddu, F. Delogu, D. E. Crawford, E. Colacino and

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