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Biphasic Chemistry and The Solvent Case


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Eco-compatibility of Organic Synthesis Set
coordinated by
Max Malacria

Volume 3

Biphasic Chemistry and
The Solvent Case

Edited by

Jean-Philippe Goddard
Max Malacria
Cyril Ollivier


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First published 2020 in Great Britain and the United States by ISTE Ltd and John Wiley & Sons, Inc.

Apart from any fair dealing for the purposes of research or private study, or criticism or review, as
permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced,
stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers,

or in the case of reprographic reproduction in accordance with the terms and licenses issued by the
CLA. Enquiries concerning reproduction outside these terms should be sent to the publishers at the
undermentioned address:
ISTE Ltd
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London SW19 4EU
UK

John Wiley & Sons, Inc.
111 River Street
Hoboken, NJ 07030
USA

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© ISTE Ltd 2020
The rights of Jean-Philippe Goddard, Max Malacria and Cyril Ollivier to be identified as the authors of
this work have been asserted by them in accordance with the Copyright, Designs and Patents Act 1988.
Library of Congress Control Number: 2019951189
British Library Cataloguing-in-Publication Data
A CIP record for this book is available from the British Library
ISBN 978-1-78630-509-1


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Contents


Chapter 1. Solid-phase Supported Chemistry . . . . . . . . . . .
Géraldine GOUHIER
1.1. Introduction . . . . . . . . . . . . . . . . . . .
1.2. Principle of solid-phase chemistry . . . . . .
1.3. Advantages . . . . . . . . . . . . . . . . . . .
1.4. Safety and environment . . . . . . . . . . . .
1.5. Disadvantages and limitations . . . . . . . .
1.6. Evolution . . . . . . . . . . . . . . . . . . . . .
1.7. Supports: linear skeletons . . . . . . . . . . .
1.8. Three-dimensional resins . . . . . . . . . . .
1.8.1. Macroporous resins . . . . . . . . . . . .
1.8.2. Gel resins . . . . . . . . . . . . . . . . . .
1.9. Characteristics of gel supports . . . . . . . .
1.9.1. Functionalization rate . . . . . . . . . . .
1.9.2. Swelling properties . . . . . . . . . . . .
1.9.3. Size of the beads . . . . . . . . . . . . . .
1.9.4. Influence of cross-linking on swelling .
1.9.5. Diffusion effect. . . . . . . . . . . . . . .
1.9.6. Influence of cross-linking on diffusion .
1.9.7. Influence of steric bulk . . . . . . . . . .
1.9.8. Influence of agitation . . . . . . . . . . .
1.9.9. Proximity and pseudodilution effects . .
1.9.10. Proximity effect. . . . . . . . . . . . . .
1.9.11. Pseudodilution effect . . . . . . . . . .
1.9.12. Availability and costs . . . . . . . . . .
1.10. Functionalization of the solid support . . .

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vi

Biphasic Chemistry and The Solvent Case


1.10.1. Spacer arms. . . . . . . . . . . . . . . . . . .
1.10.2. Linkers . . . . . . . . . . . . . . . . . . . . .
1.10.3. Influence of functionalization . . . . . . . .
1.11. Analytical methods and reaction monitoring .
1.11.1. Centesimal analyses . . . . . . . . . . . . . .
1.11.2. Colorimetric dosages . . . . . . . . . . . . .
1.11.3. Indirect analyses . . . . . . . . . . . . . . . .
1.11.4. Infrared spectroscopy . . . . . . . . . . . . .
1.11.5. Nuclear magnetic resonance spectrometry
1.11.6. Mass spectrometry . . . . . . . . . . . . . .
1.12. Solid-phase syntheses . . . . . . . . . . . . . . .
1.12.1. Supported reagents . . . . . . . . . . . . . .
1.12.2. Supported chiral catalysts . . . . . . . . . .
1.12.3. Scavengers . . . . . . . . . . . . . . . . . . .
1.13. Innovative applications and processes . . . . .
1.13.1. Examples . . . . . . . . . . . . . . . . . . . .
1.13.2. Parallel syntheses on a solid support . . . .
1.14. Activation on solid phase . . . . . . . . . . . . .
1.14.1. Microwave reactions . . . . . . . . . . . . .
1.14.2. Reactions under high pressure . . . . . . . .
1.14.3. Reactions under ultrasound . . . . . . . . .
1.14.4. Supported electrochemical reactions . . . .
1.14.5. Reactions in ionic liquid . . . . . . . . . . .
1.15. Industrial applications and prospects . . . . . .
1.16. Conclusion. . . . . . . . . . . . . . . . . . . . . .
1.17. References . . . . . . . . . . . . . . . . . . . . . .

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40

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45

Chapter 2. Fluorous Tags and Phases for Synthesis and
Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Jean-Marc VINCENT

57

2.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. Structures and properties of fluorous tags and phases .
2.2.1. History of fluorous chemistry . . . . . . . . . . . . .
2.2.2. Fluorous tags. . . . . . . . . . . . . . . . . . . . . . .
2.2.3. Fluorous solvents . . . . . . . . . . . . . . . . . . . .
2.2.4. Solid fluorous phases . . . . . . . . . . . . . . . . . .
2.3. Separation/recycling methodologies using fluorous
tags and phases . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.1. Application for catalysis . . . . . . . . . . . . . . . .
2.3.2. Application for synthesis . . . . . . . . . . . . . . .

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Contents

vii

2.4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

90
90

Chapter 3. Chemistry In and On Water . . . . . . . . . . . . . . . .
Marie-Christine SCHERRMANN

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3.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.1. Presentation and history. . . . . . . . . . . . . . . .
3.1.2. Position in the context of green chemistry . . . . .
3.2. General: origin of reactivity in and on water . . . . . .
3.2.1. Water structure and properties . . . . . . . . . . . .
3.2.2. Chemistry in water: the hydrophobic effect . . . .
3.2.3. Origin of reactivity on water . . . . . . . . . . . . .
3.3. Limitations of the method . . . . . . . . . . . . . . . . .

3.4. Reactivity in and on water . . . . . . . . . . . . . . . . .
3.4.1. Pericyclic reactions . . . . . . . . . . . . . . . . . .
3.4.2. Addition reactions of carbonyl derivatives . . . .
3.4.3. Coupling reactions catalyzed by transition metals
3.4.4. Radical reactions . . . . . . . . . . . . . . . . . . . .
3.4.5. Oxidation and reduction reactions. . . . . . . . . .
3.5. Multistep syntheses . . . . . . . . . . . . . . . . . . . . .
3.6. Industrial applications . . . . . . . . . . . . . . . . . . .
3.7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . .
3.8. References . . . . . . . . . . . . . . . . . . . . . . . . . .

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Chapter 4. Solvent-free Chemistry . . . . . . . . . . . . . . . . . . .
Thomas-Xavier MÉTRO, Xavier BANTREIL, Jean MARTINEZ and
Frédéric LAMATY

169

4.1. Introduction . . . . . . . . . . . . . . . . . . . . .
4.2. General information on solvent-free synthesis:
why use a solvent? . . . . . . . . . . . . . . . . . . . .
4.3. Working without solvents . . . . . . . . . . . . .
4.4. Limitations of the technique . . . . . . . . . . .

4.5. In practice: methods and reactivity . . . . . . .
4.5.1. Methods and equipment. . . . . . . . . . . .
4.5.2. Examples . . . . . . . . . . . . . . . . . . . .
4.5.3. Scaling up: industrial applications . . . . .
4.6. Mortar and pestle . . . . . . . . . . . . . . . . . .
4.6.1. Methods and equipment. . . . . . . . . . . .
4.6.2. Examples . . . . . . . . . . . . . . . . . . . .
4.6.3. Scaling up: industrial applications . . . . .
4.7. Ball-mills . . . . . . . . . . . . . . . . . . . . . . .

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viii

Biphasic Chemistry and The Solvent Case

4.7.1. Methods and equipment . . . . . . .
4.7.2. Examples . . . . . . . . . . . . . . . .
4.7.3. Scaling up: industrial applications .
4.8. Extruders . . . . . . . . . . . . . . . . . .
4.8.1. Methods and equipment . . . . . . .
4.8.2. Examples . . . . . . . . . . . . . . . .
4.9. Microwave irradiation. . . . . . . . . . .
4.9.1. Methods and equipment . . . . . . .
4.9.2. Examples . . . . . . . . . . . . . . . .
4.9.3. Scaling up: industrial applications .
4.10. Photochemistry . . . . . . . . . . . . . .

4.10.1. Methods and equipment . . . . . .
4.10.2. Examples . . . . . . . . . . . . . . .
4.10.3. Scaling up: industrial applications
4.11. Comparison of techniques . . . . . . .
4.12. Conclusion. . . . . . . . . . . . . . . . .
4.13. References . . . . . . . . . . . . . . . . .

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List of Authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

217

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

219


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1
Solid-phase Supported Chemistry

1.1. Introduction
Since Merrifield’s pioneering work in solid-phase peptide
synthesis, which won him the Nobel Prize in 1963, supported organic
synthesis has enjoyed constant popularity and development. The solid
phase was first applied to the oligomeric synthesis of natural products
such as polypeptides, polysaccharides and oligonucleotides. It was the
work of Fréchet and Leznoff in the late 1970s that initiated its use in
the synthesis of small molecules by performing organic reactions in
which a substrate, reagent or catalyst was grafted onto an insoluble

solid polymer. Another application is the purification of reaction
mixtures by trapping agents attached to solid supports: scavengers. A
significant number and diversity of organic reactions have been
successfully transferred to the solid phase and were the beginning of
the development of combinatorial synthesis in the 1990s and then
parallel synthesis.
Solid-phase chemistry limits the use of toxic, flammable solvents,
thus reducing their production and elimination, since it simplifies the
purification steps to simple solid/liquid filtration. The polymer is
recyclable, which reduces waste. Chemical syntheses are less
dangerous and harmful due to the high chemical and physical stability
of the substrates. Microwave, ultrasound and high pressure activations

Chapter written by Géraldine GOUHIER.

Biphasic Chemistry and The Solvent Case,First Edition.
Edited by Jean-Philippe Goddard, Max Malacria and Cyril Ollivier.
© ISTE Ltd 2020. Published by ISTE Ltd and John Wiley & Sons, Inc.


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2

Biphasic Chemistry and The Solvent Case

and the positive influence of green solvents, such as ionic liquids,
have been demonstrated. Finally, the toxicity or volatility of the
grafted compounds is minimal, which helps to prevent accidents,
diseases, explosions and fires. For all these reasons, solid-phase

chemistry has found its place in the concept of green chemistry.
1.2. Principle of solid-phase chemistry
When a reagent is attached to a polymer, the process is usually a
single step. Reagents in solution A and B react with the supported
entity, which may be, for example, a catalyst (Figure 1.1 and
section 1.12). The resulting AB compound is isolated in the filtrate by
simply filtering the regenerated polymer.

Figure 1.1. Use of a supported reagent

When a supported trapping agent (section 1.12.3) is used, excess
reagents or unwanted by-products (denoted C) present in the reaction
medium are fixed to the solid phase and then removed by simple
filtration (Figure 1.2).

Figure 1.2. Using a scavenger


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Solid-phase Supported Chemistry

3

The use of a supported substrate requires prior functionalization
and a succession of filtration (Figure 1.3). The first step involves
grafting of a functionalized spacer arm (called linkers, section 1.10.2)
of variable length onto the polymer, then incorporating a substrate
(denoted A) at its end. As this grafted polymer is generally solid and
insoluble in all solvents, the residual compound A is removed by

simple filtration and washing. In order to obtain quantitative
conversions, reactions can be repeated. This is usually necessary for
processing large quantities. This grafted polymer is then used in
conventional chemical reactions. Thus, a substrate (denoted B) reacts
on the supported active site A to form the compound AB. The reaction
by-products and residual reagent present in the filtrate (liquid phase)
are removed by simple filtration. The polymer (AB) is thus purified
and then the bond between the spacer arm (linker) and the AB
molecule is broken (cleavage) by the action of a reagent C (often an
acid). This cleavage step can, in some cases, also be a chemical
transformation step (e.g. cyclization). The AB molecule is thus
obtained with high purity and the initial polymer is regenerated.

Figure 1.3. General diagram of solid phase synthesis


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4

Biphasic Chemistry and The Solvent Case

1.3. Advantages
Many advantages have contributed to the use of polymers in
organic synthesis and justify the green chemistry name:
– simplification of product isolation and purification steps. The
resin is separated from the liquid phase by simple filtration, thus
avoiding separation problems (chromatography, distillation,
crystallization, etc.). This saves a lot of time and energy;
– possible use of excess reagents. The yields are then optimized

without increasing the reaction treatment; the excess remains in the
liquid phase and is therefore easily removable and recyclable. In
addition, each step can be repeated for maximum performance;
– polymer regeneration by simple washing and filtration;
particularly useful in the case of expensive chiral substrates or delicate
synthetic substrates;
– remarkable reduction in toxicity and odors due to the nonvolatility of the grafted molecules, particularly desirable in the
chemistry of sulfur, selenium or tin;
– strong stabilization of the supports, allowing reactions to proceed
under a wide range of reaction conditions (temperature, acidobasicity,
etc.) without physicochemical degradation of the polymer. Moreover,
resins rarely require special storage conditions (refrigeration, inert
gas), which also simplify their handling;
– intramolecular cyclization facilitated by pseudodilution (section
1.9.9) due to the heterogeneous medium (solid/liquid) reducing direct
contact between reaction sites;
– automation of multistep reactions possible and use in
combinatorial chemistry and parallel synthesis allowing the rapid
development of libraries of potentially active molecules with several
thousand analogues (section 1.13.2).
1.4. Safety and environment
The use of solid phase in a synthesis strategy reduces the risk of
intoxication and contamination since direct contact with the


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Solid-phase Supported Chemistry

5


compounds by air and skin is avoided. The remarkable stability of
these supports avoids drastic storage conditions that are costly in
terms of energy (low temperature) and the use of inert gas. Finally, the
purification steps are reduced to simple filtration and washing, thus
avoiding long chromatographies that consume flammable toxic
solvents or costly distillations. Safety is therefore improved and
environmental risks and costs are reduced.
1.5. Disadvantages and limitations
This technique, although very practical and effective, has some
limitations:
– two additional steps are required compared to solution synthesis
(grafting and cleavage). These steps must not generate by-products.
However, they can be integrated into the synthesis strategy (traceless
linker, section 1.13.2);
– significant volumes of solvents are required during washing for
the large-scale production of a product. However, they remain lower
than those used for chromatographic column purification;
– the ratio of atoms used to atoms engaged is not optimal. Indeed,
the functionalization of the resins used may be low and, consequently,
a large amount of polymer must be used. The atom economy principle
is far from being respected here. However, the medium is recycled
during the synthesis;
– the adaptation of organic reactions to solid-phase synthesis
generally requires further development because the reactivity of
supported substrates may, in some cases, be different (diffusion and
site accessibility issues, section 1.9.5). In addition, the bonds with the
polymer must be sufficiently stable with respect to all reagents used;
– reaction monitoring and/or solid support analyses (quantification
of loading and determination of the structure of the grafted product)

are more time consuming (section 1.11).


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Biphasic Chemistry and The Solvent Case

1.6. Evolution
Solid-phase chemistry underwent significant development in the
1990s with the advent of automation and combinatorial chemistry.
Fifteen years later, this synthesis strategy refocused on the
development of parallel synthesis in order to produce smaller targeted
libraries. A wide range of supported scavengers, or catalysts, as well
as a wide range of synthesis, extraction and purification automatons
are now commercially available. Finally, the transfer to the solid
phase of new methodologies, reagents and concepts developed in
solution is necessary for the development of pharmaceutical and
agrochemical industries that use these synthetic tools for the
production and screening of innovative chemical libraries.
1.7. Supports: linear skeletons
Linear skeleton polymers are soluble in certain organic solvents,
thus allowing reactions to be carried out in a homogeneous medium
without diffusion problems, with equal accessibility of all supported
reaction sites and kinetics similar to the same reaction under
conventional conditions. In addition, immobilized substrates can be
characterized by standard analytical techniques. Finally, precipitation
by adding a non-solvent to the polymer makes it possible to filter it.
However, it is not always complete and selective, sometimes causing

separation and purification issues.
The most commonly used linear polymers in organic synthesis are
polyethylene glycol (PEG) 1, monomethyl ether polyethylene glycol
(MPEG) 2 and linear polystyrene (PSl) 3 (Figure 1.4).
H

O
PEG

O
x

H

Me

O

O
x

H

MPEG
Figure 1.4. Soluble polymer structures

Ph

x
PSl



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Solid-phase Supported Chemistry

7

The molecular weight of PEGs is generally 20,000, so the number
of grafting sites is very low (around 0.1 meq./g). PEGs precipitate in
diethyl ether or tert-butylmethyl ether, but since these solvents are not
very polar, impurities that are too polar sometimes precipitate with the
polymer. The use of isopropanol helps to overcome this disadvantage.
On the other hand, due to their insolubility at low temperatures in
THF and their chelating potential for metal cations, PEGs are
excluded from organometallic chemistry. In this case, the PSls are
chosen. In addition, the latter can be functionalized at a rate higher
than PEGs (up to 6 or 7 meq./g). However, too much functionalization
can lead to intrapolymeric secondary reactions resulting in undesirable
and irreversible cross-linking that modifies the structure and therefore
the reactivity of the resin (section 1.9.10).
1.8. Three-dimensional resins
Three-dimensional skeleton polymers are in the form of small
beads and are insoluble in almost all solvents. These are cross-linked
polymers generally derived from polystyrene. Their cross-linking rate
is an important characteristic leading to very different physical
properties depending on its degree (section 1.9.4). Two subgroups can
be distinguished, macroporous resins and gel resins.
1.8.1. Macroporous resins
These are characterized by a high rate of cross-linking (≥20%). As

this cross-linking is not homogeneous, polymers have permanent
pores of different sizes. The largest cavities (about 0.1 μm) are
accessible by the molecules in solution without diffusion issues. This
high cross-linking considerably limits the mobility and accessibility of
reaction sites; therefore, high grafting rates can be achieved without
fear of possible interpolymeric interactions between supported sites
(section 1.9.10). The reaction sites are distributed over the surface of
the pores and are therefore accessible. The reactivity of these
polymers does not depend on their swelling in solvents because it is a
surface reactivity inside the pores (>500 m2/g). They are therefore


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Biphasic Chemistry and The Solvent Case

interesting supports for reactions developing very polar, even ionic
intermediates. However, these resins are physically very fragile and
prolonged agitation in a reactor or high temperatures can cause
irreversible damage. Therefore, they are often used for solid–liquid
extraction (SPE: solid-phase extraction) due to the presence of
supported trapping agents (section 1.12.3) or as ion exchange resins.
Some examples of functionalized macroporous polystyrenes (MPs)
are illustrated in Figure 1.5.
2

NEt3,(CO3)1/2
MP-Carbonate


HN NH2
S O

OH
NH2
MP-NH2

S O
O
MP-TsOH

O
MP-TsNHNH2

Figure 1.5. Functionalized macroporous polystyrenes

MP-carbonate resin is chosen to trap amine hydrochlorides,
carboxylic acids or phenols. The MP-NH2 polymer is a trapping agent
for electrophiles such as acids and sulfonyl chlorides or isocyanates.
Para-toluenesulfonic acid grafted onto MP, MP-TsOH, marketed as
Amberlyst A-15, is generally used as a trapping agent for basic species
and particularly amines. The supported hydrazines, MP-TsNHNH2,
trap ketones and aldehydes.
1.8.2. Gel resins
These are weakly cross-linked polymers (0.5–2%). The crosslinking rate is an important characteristic that leads to polymers with
different physical properties depending on their degrees (section 1.9.4).
Styrene and its functionalized derivatives are monovinyl
compounds generally used to form the skeleton of gel resins. Paradivinylbenzene (DVB) is the most common bifunctional monomer
used to create low cross-linking within the matrix. For example,

Merrifield (chloromethylated) resin is obtained either by
copolymerization of styrene, DVB and para-chloromethylstyrene, or


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Solid-phase Supported Chemistry

9

by functionalization of polystyrene by a Friedel–Craft reaction
(Figure 1.6).

Figure 1.6. Two ways of synthesizing Merrifield polymer

The control and reproductibility of polymerization reactions
require specific know-how. These reactions allow the preparation of
highly functionalized polymers (rate higher than 50%); however, all
the sites created are not accessible because they are enclosed in the
polymeric mesh. Organic chemists generally directly functionalize the
previously formed polystyrene skeleton.
However, this method has drawbacks. Firstly, because of the
accessibility of the reaction sites being lower than in the homogeneous
phase, due to the size of the matrix, the reactivity is reduced. It is
therefore important to use solvents that allow the resin to swell
optimally (section 1.9.2). Secondly, at the end of the reaction, it is
impossible to purify the polymer. Therefore, the functionalization
reactions of the substrate must be quantitative and chemoselective in
order to avoid the presence of undesirable sites. Finally, this method
allows access to maximum functionalization rates of 30%; however, in

this case, all the sites created are actually active. As this second
approach has been widely used, many reactions meet these criteria and
this method is therefore the most commonly used. Since the early
1980s, Fréchet et al. have been developing various functionalizations
of polystyrene (Figure 1.7).


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Biphasic Chemistry and The Solvent Case

Figure 1.7. Functionalization of polystyrene

1.9. Characteristics of gel supports
1.9.1. Functionalization rate
The functionalization or loading rate is an important parameter. It
determines the number of functionalized benzene rings in relation to
the total number of aromatic rings of the polymer. For example, in the
case of Merrifield resin (Figure 1.6), this parameter is expressed as the
percentage by weight of chlorine (%Cl) or as the number of
milliequivalents of chlorine per gram of resin (nCl). The
correspondence between these different units is shown in Table 1.1.
nCl (mmol/g)

0.8

2.1


4.3

%Cl

2.84%

7.46%

15.27%

Functionalization
rate

9%

32%

56%

Table 1.1. Variation in the functionalization rate of Merrifield polymer

1.9.2. Swelling properties
The resins can, in suitable solvents, swell up to 10 times their dry
volume. This property limits the diffusion issues of the reagents


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Solid-phase Supported Chemistry


11

present in solution and increases the accessibility of the supported
reaction sites. If the reaction solvent does not allow the polymeric
mesh to expand, the mobility of the chains and the accessibility of the
reaction sites are greatly reduced. As a result, the reactivity of the
resin is limited and the conversion rate and reaction rate may be
lower. The swelling of a polymer in a given solvent is very strongly
dependent on its cross-linking, loading and functionalization. The
lower the cross-linking, the better the polymer’s swelling properties.
In general, polar solvents do not promote mesh expansion and the
addition of a suitable co-solvent improves the swelling of the polymer
(Table 1.2).
Solvents

-

Water

MeOH

MeCN

DMSO

THF/Water

Et2O

THF


Vpolymer
(mL.g–1)

1.5

1.5

1.8

1.8

1.8

3.1

3.3

7.7

Table 1.2. Swelling volumes for Merrifield resin 1% DVB

In the absence of a solvent, the volume of the polymer is minimal
because the chains are entangled and the pores are not expanded,
while in the presence of a suitable solvent, the solvation of the chains
causes the mesh to expand and the pores to be reconstituted
(Figure 1.8).

Figure 1.8. Evolution of polymeric meshes in a solvent. For a color version of
this figure, see www.iste.co.uk/malacria/biphasic.zip


The chains then become mobile, varying the volume and site of the
pores. Consequently, when the diffusion issues of non-grafted


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Biphasic Chemistry and The Solvent Case

reagents are overcome by a good swelling of the resin, the reactivity
of polymer gels tends to approach the homogeneous phase conditions.
1.9.3. Size of the beads
During their formation by suspension polymerization, polymers
form beads of sizes ranging from 50 µm to 1 mm in diameter. To
ensure a homogeneous reactivity of the resins, the beads are sieved
and grouped according to their size. The analysis of these
homogeneous batches makes it possible to determine the number of
active sites carried by a single bead (Table 1.3).
Size of the
beads(µm)
35–75
(200–400 mesh)
75–150
(100–200 mesh)
75–150
(100–200 mesh)
150–300
(50–100 mesh)

150–300
(50–100 mesh)

Functionalization rate
(meq./g)

Beads (mg)

Loading a bead
(nmol)

1.0

8,000–
16,000

0.06–0.12

1.0

1,000–2,000

0.5–1.0

2.0

1,000–2,000

1.0–2.0


2.0

125–250

8–16

4.0

125–250

16–32

Table 1.3. Influence of bead size

The number of meshes corresponds to the mesh size of the sieve.
As the size of the beads decreases, the finer the sieve is and the higher
the number of meshes. On the one hand, the size of the beads
increases as loading increases. On the other hand, for the same
loading, the more the size of the beads decreases, the more the number
of active sites per bead decreases.
1.9.4. Influence of cross-linking on swelling
The swelling (measured in mL/g) of Merrifield resin, cross-linked
at 1% or 2% DVB, was compared in four solvents (Table 1.4).


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Solid-phase Supported Chemistry

Solvent


MeOH

Ether

DCM

THF

V1% DVB (mL/g)

1.8

3.3

7.4

7.7

V2% DVB (mL/g)

1.6

2.5

5.2

5.9

13


Table 1.4. Influence of cross-linking on swelling

The lower the percentage of DVB, the better the swelling
properties of the polymer. Pore size is therefore inversely proportional
to the rate of cross-linking.
1.9.5. Diffusion effect
Reactions on solid supports are often compared to those performed
in solution. However, this analogy is not always obvious to establish
because a heterogeneous system brings additional parameters that do
not have an equivalence in the homogeneous phase. First of all, the
kinetics of reactions are difficult to set in equation. Indeed, electronic
or steric interactions between the polystyrene backbone and the
substrate in solution can significantly affect the concentration of the
reagent in solution in the vicinity of the supported active site. In
addition, depending on the nature of the solvent that regulates the
swelling of the polymer, the cross-linking of the solid support and
the mode of agitation of the reaction medium, diffusion issues of the
substrate through the mesh can greatly alter the contact between the
two reagents and thus affect the reaction kinetics.
1.9.6. Influence of cross-linking on diffusion
Diffusion is dependent on the cross-linking of the threedimensional skeleton. Two supported triphenyl phosphines with 0.5%
and 2% cross-linking were tested in a Wittig reaction to convert
aldehydes to olefins (Heitz and Michels 1972). It appears that the
more cross-linked the polymer (2%), the more restricted the mobility
of the sites and the more limited the interactions between sites; the
reaction, in this case, is more difficult.


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Biphasic Chemistry and The Solvent Case

1.9.7. Influence of steric bulk
For the same polymer, diffusion is affected by the size of the
substrate in solution and by the reaction solvent used. For example,
the hydrogenation of alkenes in ethanol catalyzed by a supported
Wilkinson catalyst analogue showed that the hydrogenation rate of a
cyclic alkene decreased if the size of the ring increased, while this
effect is not linear in solution (Grubbs and Kroll 1971). The reaction
rate with the supported catalyst can be seven times slower for a cyclic
alkene than for a linear disubstituted alkene with the same carbon
number. In addition, a series of reactions was carried out in a
benzene/ethanol mixture, allowing the mesh to expand. In this
condition, the lower the proportion of ethanol (a solvent not very
favorable to swelling), the faster the hydrogenation.
1.9.8. Influence of agitation
Different agitation techniques were tested in order to obtain, first, a
correct diffusion of the substrates in solution and, second, a good
homogeneity of reaction on the different polymer beads by an infrared
spectroscopy study (section 1.11.4) conducted on each polymer bead
and by fluorescence spectroscopy of the filtrate during a condensation
reaction (Li and Yan 1997). Thus, it has been demonstrated that orbital
or rotational agitation (180°) homogenizes the reactivity of the reaction
sites but is not sufficient for good diffusion. Vigorous agitation is
therefore necessary (magnetic, 360°, nitrogen bubbling) both for the
homogeneity of the reaction and for obtaining good yields.
1.9.9. Proximity and pseudodilution effects

The nature of microenvironmental effects is difficult to assess
because it depends on many factors. Depending on the characteristics
of the polymer backbone (cross-linking rate and grafting rate), the
distribution, mobility and nature of the substrates, but also on the
solvent used (by playing on the swelling properties), it is possible to
observe either a proximity effect of the grafted substrates or a
pseudodilution effect (Figure 1.9) (Scott et al. 1977; Crowley and
Rapoport 2007; Shi et al. 2007).


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Proximity effect

15

Pseudodilution effect

Figure 1.9. Microenvironmental effects

1.9.10. Proximity effect
Supported substrates have reduced mobility involving forced
proximity that can lead to electronic interactions and influence
reaction kinetics. As a result, high loading polymers will be highly
subject to this type of interaction. Intrapolymeric reactions are often
side reactions that need to be avoided but could be promoted by the
forced proximity of the supported reaction sites. A common example
of this type of reaction involves benzyl chlorines in Merrifield resin

(Figure 1.10). In contact with a reducing agent, such as zinc, or in the
presence of a Lewis acid, such as aluminum trichloride,
intrapolymeric reactions are observed, favored by proximity effects.
An additional cross-linking is then created, modifying the structure of
the resin and thus its reactivity (Figure 1.10).

Figure 1.10. Proximity effect: cross-linking

1.9.11. Pseudodilution effect
The pseudodilution effect is the opposite of the proximity effect
(Scott et al. 1977; Crowley and Rapoport 2007; Shi et al. 2007). It


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Biphasic Chemistry and The Solvent Case

depends on the distance of the reaction sites from each other. The
more a polymer is cross-linked, the more restricted the mobility of
sites is and the more difficult the interactions between supported sites
are. Similarly, the lower the loading, the further away the sites are
from each other and therefore intrapolymeric reactions are limited.
This effect can be illustrated by the formation of supported titanocene
complexes (Figure 1.11).

Figure 1.11. Proximity and pseudodilution effects

In the presence of a 2% cross-linked polymer, the cyclopentadienyl

titanium trichloride complex leads to titanocene with bispolymeric
ligands. On the other hand, with the highly cross-linked resin, the
complex obtained has only one polymeric ligand.
1.9.12. Availability and costs
A very wide choice of variously functionalized resins is
commercially available and generally classified according to their
specific uses. However, for regular and consistent use, it is preferable
to functionalize your own supports from more affordable basic
supports (Rink (amino), Merrifield (chlorinated), Wang (alcohol),
etc.).
Finally, most syntheses allow the solid phase to be recycled, either
directly after filtration and washing or after a simple acidobasic
treatment. Saving time, energy and solvents with this synthesis
strategy is also a financial parameter to be taken into account.


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1.10. Functionalization of the solid support
Before grafting the desired substrate onto a solid support, it is often
advisable to introduce a spacer arm and/or linker (Figure 1.12).

Figure 1.12. General diagram of a supported substrate

Indeed, if the active site is grafted directly onto the polymer
skeleton, its accessibility, and therefore its reactivity, can be reduced

by the sterically hindered matrix.
1.10.1. Spacer arms
The introduction of a spacer arm moves the supported reaction site
away from the polymeric mesh. It is usually a functionalized linear
chain that must be compatible with solvents, allowing the polymer
mesh to expand, and chemically inert to the desired reactions
(Figure 1.13).

Figure 1.13. Influence of a spacer arm

The spacer arm can also
physicochemical properties of the
structures swell only in aprotic
limiting factor for the chemistry

be introduced to modify the
resin. Polymers with polystyrene
solvents, which is sometimes a
considered. The introduction of