Polymer Analogous Reactions$

PJ Roth, Curtin University, Bentley, Perth WA, Australia

P Theato, University of Hamburg, Hamburg, Germany
r 2016 Elsevier Inc. All rights reserved.

1 Historical Background and Definitions 1

2 General Considerations 2
2.1 Classifications 2
2.1.1 Additions 2
2.1.2 Substitutions 3
2.1.3 Eliminations 3
2.1.4 Isomerizations 3
3 Functional Groups Employed in Chemical Modifications 3
3.1 Activated Esters 4
3.2 Anhydrides, Isocyanates and Ketenes 6
3.3 Oxazolones, and Epoxides 7
3.4 Aldehydes and Ketones 7
3.4.1 Polymer side chain modifications involving aldehydes and ketones 8
3.4.2 Polymer end group modifications involving aldehydes and ketones 10
3.4.3 Multicomponent reactions involving aldehydes and ketones 10
3.5 Azides with Alkynes 10
3.5.1 Polymer side chain modifications involving azides and alkynes 11
3.5.2 Polymer end group modifications involving azides and alkynes 12
3.5.3 Metal-free 1,3-dipolar cycloaddition 13
3.6 Dienes and Dienophiles 14
3.6.1 Polymer end group modifications involving Diels−Alder reactions 14
3.6.2 Polymer side chain modifications involving Diels−Alder reactions 15
3.7 Halides 15
3.7.1 Substitution 15
3.7.2 Pd-catalyzed coupling and cross-coupling reactions 16
3.7.3 Atom Transfer Radical Addition 16
3.8 Thiols 16
3.8.1 Reactions of thiols 16
3.8.1.1 Nucleophilic substitutions 16
3.8.1.2 Nucleophilic additions 18
3.8.1.3 Radical additions 18
3.8.1.4 Oxidation and reduction 18
3.8.2 Polymer end group modifications involving thiols 18
3.8.2.1 Thiol end groups 18
3.8.2.2 Thiol-reactive end groups 19
3.8.2.3 Hetero-telechelic polymers involving thiol reactions 20
3.8.3 Polymer main chain modifications involving thiols 20
3.8.3.1 Monomer units containing thiols 20
3.8.3.2 Monomer units containing thiol-reactive sites 20
4 Conclusions and Outlook 20
References 21

1 Historical Background and Definitions

Chemical modifications of polymers have been one of the oldest applications of polymer chemistry. One of the first reactions
dates back to 1781 and describes the isomerization of natural rubber in the presence of acids.1 The first application of synthetic

☆
Change History: July 2015. P. Roth and P. Theato updated their Biography and Sections 3.2, 3.4, 3.5, 3.6, 3.7; extended Sections 3.1, 3.3, 3.8, and the reference
section, and added Section 3.4.3 and Scheme 3B.

Reference Module in Materials Science and Materials Engineering doi:10.1016/B978-0-12-803581-8.01420-X 1

2 Polymer Analogous Reactions

polymers is likely to be the nitration of polystyrene in 1845.2 However, the most important step forward was driven by Staudinger,
who developed the concept of ‘polymer analogous reactions.’ He defined those reactions as the ‘transformation of a polymer into a
derivative of equivalent molecular weight,’ based on his results of hydrogenation of rubber3 and polystyrene4 with hardly any
chain degradation. Until today, Staudinger has given the best definition. Thus, a polymer analogous reaction would be the
transformation of a polymer into a derivative with the same degree of polymerization, as the chemical modification of a polymer
implies changing the chemical nature while keeping the degree of polymerization constant. It is worthwhile to cite Staudinger's
Nobel prize lecture during which he coined the term polymer analogous: “In many instances a polymeric compound can be
transformed into derivatives of a different type without any change in the degree of polymerization of the compound in exactly the
same way as small molecules can be transformed. A polymer compound can hence be transformed into polymer analogous
derivatives,…”5 Polymer analogous reactions have an enormous impact, which can be explained by the variety of reactions that
can be applied. Most older investigations focused on chemical modifications of polymers, i.e. fundamental exploration of the
chemical possibilities utilizing the variety of organic reactions known at that particular time. However, in recent years polymer
chemists addressed more and more the precise attachment of specific functional molecules onto polymer chains. Pioneering work
for the synthesis of functional polymeric materials utilizing polymer analogous reactions had been done by the group of Ring-
sdorf.6 They demonstrated that it is possible to synthesize polymers via polymer analogous reactions that were otherwise very
difficult or impossible to synthesize. Also reactions on telechelic polymers and end group modifications can be regarded as
polymer analogous reactions as they have gained recent interest.
In 1983, Carraher and Moore published a monograph on the modification of polymers,7 but since then the applications of
polymer analogous reactions have increased dramatically. However, no thorough update on new developments in the area of
polymer analogous reactions has been compiled. This can partly be accounted to the fact that the applications of polymer
analogous reactions have become very broad, ranging from materials science to life science. All the same, some specific reviews as
well as some textbooks cover a certain area of polymer analogous reactions as a synthetic strategy to prepare functional poly-
mers.8–16 Besides, there are strong research activities in reactions on cellulose17 as well as other very specialized functionalization
reactions. Those are not covered in this review. This chapter rather tries to a certain extend to cover different polymer analogous
reactions without being exhaustive. It is the intention to provide the reader with a general overview of the synthetic possibilities
that polymer analogous reactions combined with modern polymerization techniques can offer.

2 General Considerations

2.1 Classifications
Due to the enormous range of different organic reactions that can be used for polymer analogous reactions, it actually represents a
very wide domain of polymer chemistry. The following sections are intended to provide a general classification of different
polymer analogous reactions based on mechanistical aspects with a small number of selected examples. A classification according
to functional groups is then given in the next section, which covers modern reactions in greater detail.

2.1.1 Additions
Addition reactions are very useful for the modification of polymers and practically, many are identical to their small molecule
counterparts. In order to give a flavor of the possible addition reactions, only a small fraction of examples shall be given. In
general, a small molecule reacts with a functional group of the polymer in an addition reaction. Various examples have been
investigated in the past.
Technologically most important is the hydrogenation of polymers. Recently, the hydrogenation of polystyrene gained certain
technological interest.18 But also the hydrogenation of polydienes has applications as it has been possible to vary the micro-
structure.19 For example, hydrogenation of 1,4-polybutadiene resulted in blocky structures,20 while the degree of hydrogenation of
poly(1-pentenylene) could be controlled resulting in materials ranging from amorphous to crystalline.21 Similar to hydrogenation,
also halogenation and hydrohalogenation of unsaturated polymers has been conducted. For example, the bromination of
polybutadiene resulted in flame retardant materials.22
Another possibility to introduce halogens to polymers following an addition reaction is based on the radiation-induced
addition of e.g. carbon tetrachloride onto 1,2-polybutadiene by a radical chain mechanism.23,24 In a similar radical chain reaction
also thiols can add to double bonds,25–27 a reaction that found a revival in recent years.15,16 But also the radical-induced addition
of organic phosphites (dimethyl phosphite) onto poly(1-pentenylene) in the presence of dibenzoyl peroxide has been studied.28
Epoxidation of double bonds represents another useful addition reaction for the functionalization of unsaturated polymers, i.e.
epoxidation of polybutadiene. In this context, Zuchowska found that epoxidation of 1,4-polybutadiene proceeds B1.9 times
faster than that of 1,2-polybutadiene.29
But also concerted addition reactions have been studied in respect to polymer functionalization. As one example, the ene
addition of maleic acid onto unsaturated polymers, such as natural rubber, should be mentioned.30
 Polymer Analogous Reactions 3

2.1.2 Substitutions
Substitution reactions are probably the most important class of reactions used within polymer analogous reactions to prepare
functionalized polymers. Practical implication has the chlorination of polyethylene (PE), which proceeds through a free radical
substitution mechanism.31 Noteworthy, the chlorination in the solid state begins predominately in the amorphous areas and on
crystalline surfaces of PE. But also the chlorination of polyvinylchloride (PVC), polypropylene, and fluorinated polymers has been
studied. Furthermore, replacing the chlorine atoms in chlorinated polymers, such as PVC, was investigated.
Esterification and hydrolysis reactions have been the subject of numerous studies. Common is the esterification of poly
(methacrylic acid) utilizing carbodiimides as condensing agents. During the course of the reaction, first a cyclic anhydride is
formed as an intermediate structure, which, in the presence of an alcohol, reacts then to yield the respective ester.32,33 As such, the
intermediate formation of a cyclic anhydride results in a limited conversion of the overall esterification. Esters of cellulose
represent a class of commercially produced polymers, which are prepared by esterification of cellulose.17,34
Alternating copolymers of maleic anhydride have been studied with respect to hydrolysis of the anhydride moiety.35 However,
the most prominent example of a hydrolysis reaction represents hydrolysis of poly(vinyl acetate) yielding poly(vinyl alcohol),
which cannot be synthesized directly because the respective monomer does not exist.
Various examples of reduction and oxidation reactions have been studied as polymer analogous reactions. For example, the
synthesis of poly(N-alkylethyleneimines) is performed best through reduction of the corresponding poly(N-acetylethyleneimines),
which are easily accessible through the ring-opening polymerization (ROP) of oxazolines.36
Oxidations are mostly problematic, because they are accompanied by degradation reactions that often result in chain breaking.
Oxidation of poly(vinyl alcohol) with NaOCl and HCl did result in poly(enol-ketone).7
Amination and quarternization has been intensively investigated. Most prominent are the substitution reactions of chlor-
omethylated polystyrenes.37–39 In general, the modification of polystyrene has been conducted using Friedel–Crafts reactions with
the modified units being randomly distributed on the chains.40–42 Similarly, the sulfonation of polystyrene has been studied in
great detail since the products find application as ion exchangers.19,43
Lithiation of polystyrene by reaction of BuLi with polystyrene had been used for reactive intermediates for example to prepare
spin-labeled polystyrenes44–,47 or to introduce boronic acid groups.48

2.1.3 Eliminations
The synthetic use of eliminations in polymer analogous reactions has been reviewed by Korshak.49 His classification has been
resummarized in a table,50 with examples given in Scheme 1.

2.1.4 Isomerizations
In contrast to the previous reaction classes, isomerizations result in a change of the chemical structure, however, the molecular
weight of the macromolecules does not change. Even though, according to IUPAC a configurational change is not usually referred
to as a chemical modification, but it shall still be mentioned in this context. In principle, on can distinguish between config-
urational isomerizations, constitutional transformations, and exchange equilibria.
A typical configurational isomerization is the cis-trans isomerization of polydienes, often triggered through UV irradiation in
the presence of radical transfer agents, such as organosulfides or halogens.9 An isomerization between tactic polymers has for
example been described of isotactic poly(isopropyl acrylate) when treated with catalytic amounts of sodium isopropylate yielding
atactic poly(isopropyl acrylate).51 But also polymers with chromophoric groups that feature a photochromic behavior have found
interest in research. Most commonly, azobenzene containing polymers have been subject of investigation due to the cis-trans
isomerization of azobenzene.52–60
Among constitutional transformations, cyclizations are most common. Polyacrylonitrile undergoes a cyclization when heated
in an inert atmosphere to 200–300 1C.61 Further heating results in pyrolysis yielding graphene-like structures, which essentially
form carbon nanofibers.62,63
When segments between two polymer chains can be interchanged, one speaks of an exchange equilibria. During these exchange
reactions the number of macromolecules and the degree of polymerization remain unchanged. Exchange equilibria have been
known for a while, however, they have found profound interest in recent years due to advances in the area of dynamers, which
have been promoted by Lehn.64–66

3 Functional Groups Employed in Chemical Modifications

While the previous section focused on a general classification according to reaction types, the following part will highlight certain
functional groups that find broad application in polymer analogous reactions.
4 Polymer Analogous Reactions

Scheme 1 Examples of elimination reactions.

3.1 Activated Esters

Activated esters have proven to be very useful reactive derivates for covalently linking amines with carboxylic acids to yield the
respective amides and thus have found application in organic chemistry and especially peptide chemistry.67–71 Pioneering work on
reactive polymers based on activated esters was published independently by Ringsdorf and Ferruti.6,72 Since their first reports,
polymeric activated esters yielded in applications reaching into materials and life science. Scheme 2 summarizes common activated
ester monomers as well chain transfer agents (CTA) and initiators featuring an activated ester. Over the years, numerous reviews
have been published, highlighting different aspects of activated ester chemistry in polymer science.73,74
N-Hydroxy succinimide acrylate (NHSA) (also called N-acryloxysuccinimide) and –methacrylate (NHSMA) have found
extensive use as reactive monomers to prepare reactive polymers. These reactive polymers poly(N-hydroxy succinimide acrylate)
(PNHSA) and poly(N-hydroxy succinimide methacrylate) (PNHSMA) can then be used in a polymer analogous reaction with
amines under very mild reaction conditions, yielding functionalized polyacrylamide or polymethacrylamide derivates.75–78 By
reaction of reactive polymers with various amines, functional polymers are accessible which cannot be prepared by the direct
polymerization of the respective acrylamide monomers. Conversions of polymeric activated esters are usually quantitative for
small amines and proceed without any side reactions under mild conditions, such as stirring at room temperature. In the
classification scheme of Sharpless, the reaction of activated esters with amines represents a prime example for a ‘click’ reaction.
Noteworthy, in contrast to many other reactions including 1,3-dipolar cycloadditions, the reaction of activated esters with amines
proceeds without the need for an auxiliary (metal) catalyst.
Synthesis of polymeric activated esters from the respective activated ester monomers provides several advantages over the
transformation of poly(acrylic acid) or its copolymers in a reaction with dicyclohexylcarbodiimide (DCC) or 1-Ethyl-3-[3-
dimethylaminopropyl]carbodiimide hydrochloride (EDC) and N-hydroxysucciniimide or pentafluorophenol into the respective
 Polymer Analogous Reactions 5

Scheme 2 Chemical structures of activated ester monomers, chain transfer agents and initiators.

polymeric activated esters. First, the reaction of poly(acrylic acid) with carbodiimides usually proceeds via cyclic anhydrides, which
limits the following conversion. Secondly, separation of the formed urea is not always easy. But also, the apparent difference in
solubility between the starting polymer, e.g. poly(acrylic acid), and the product represent a synthetic challenge. But nevertheless,
the concept has been applied to many carboxylic acid containing polymers including poly(p-phenylenevinylene)s PPVs,79 or
amphiphilic block copolymers.80
The high fidelity in functionalization of polymeric activated esters by reaction with functional amines has been employed in
many applications.81 Besides polymerization in solution, various activated ester monomers have also been employed in plasma
polymerization. For example, the groups of Förch and Gleason investigated the plasma polymerization of pentafluorophenyl
methacrylate (PFPMA) resulting in polymeric reactive films.82,83 Such films enable an easy immobilization of various biomole-
cules exhibiting an amine functionality and thereby provide the basis for biological assays and microfluidic biosystems.
Similarly, Langer and coworkers studied the chemical vapor deposition of functionalized [2,2]paracyclophanes resulting in
reactive polymer layers.84,85
Recent advances in the area of polymeric activated esters focus on the precise synthesis of defined polymeric structures utilizing
controlled polymerization techniques.10
Several groups have shown the successful atom transfer radical polymerization (ATRP) of N-hydroxy succinimide methacry-
late.86–88 By dialing in the precise length of the polymer chain, Müller and coworkers had been able to use these reactive precursor
polymers for the synthesis of polymer-drug conjugates derived from copolymers of N-(2-hydroxypropyl)-methacrylamide
(HPMA).86 Also the extension to the synthesis of block copolymers featuring one polymeric activated ester block has been
explored. It has been employed for the preparation of (i) metal-ligand containing polymers and block copolymers,89 (ii) charged
polymers capable to complex plasmid DNA,90 (iii) stable core cross-linked micelles,91 hexa-armed star block copolymers,92 or (iv)
thermo- and/or light-responsive polymers.54,55,93,94 Besides NHSMA and NHSA also the ATRP of endo-N-Hydroxy-5-norborene-
2,3-dicarboxyimidacrylate (NorbNHSA),95 p-nitrophenyl methacrylate96 and 2,3,5,6-tetrafluorophenyl methacrylate (TFPMA)97
has been described.
Complementary to ATRP, a lot of studies have been conducted on reversible addition–fragmentation chain transfer (RAFT)
polymerization of activated ester monomers. Early studies on the polymerization of NHSMA and NHSA under RAFT conditions
showed only a moderate control,98 with slightly better results for copolymerizations with different methacrylamides.99–102
Nevertheless, these reactive copolymers found versatile application in for example shell cross-linked nanoparticles.102 RAFT
polymerization was also shown for p-nitrophenyl methacrylate,103 which could even extended to the synthesis of reactive block
copolymers.104,105 Alternatively, the successful RAFT polymerization of pentafluorophenyl acrylate (PFPA) and PFPMA had been
demonstrated106–108 and found useful applications in areas of gold nanoparticle functionalization108 or defined reactive diblock
copolymers to yield functional HPMA-based self-assembled nanoaggregates for efficient drug delivery.109
6 Polymer Analogous Reactions

Besides the popularity of acrylate and methacrylate monomers, there had also been several reports on activated esters based on
4-vinyl benzoic acid. The group of Tew described the polymerization of N-succinimide activated ester of 4-vinyl benzoic acid
(NHS4VB).110 Similarly, the group of Theato had successful demonstrated that also the RAFT polymerization of penta-
fluorophenyl ester of 4-vinyl benzoic acid (PFP4VB) leads to a very precise control of degree of polymerization.111,112 Further, poly
(PFP4VB) exhibits an excellent solubility in a variety of organic solvents and a remarkably increased reactivity towards amines. The
astonishing difference in reactivity between PFP4VB and PFPMA has been taken advantage of in the synthesis of double reactive
block copolymers that can provide a selective conversion with amines with varying reactivity.113
The N-succinimide activated ester of 4-vinyl benzoic acid could also be employed in the nitroxide mediated copolymeriza-
tion.114 The successful nitroxide mediated polymerization (NMP) of acetonoxime acrylate (AOA) was also demonstrated using n-
tert-butyl-1-diethylphosphono-2,2-dimethylpropylnitroxide (DEPN) as the stable radical.115
In recent years it turned out that particularly for the synthesis of functional polymers it is of great advantage to activate the
moieties that carry the functionality rather than to activate the functional groups at the polymer backbone. This is of particular
importance if an ester linkage is used. Polymer analogous reactions based on poly(meth)acrylic acid chlorides with hydroxyl-
derivatives have the disadvantages that already small traces of hydrolysis reactions may lead to crosslinked and insoluble materials.
To overcome this issue it is of great advantage to activate the moieties to be attached to the polymer backbone. Hence, functional
polymers featuring hydroxyl functions have been reacted with low molecular weight activated acid chloride derivatives.
This approach was successfully used for homopolymers, copolymers as well as block copolymers particularly when complex
mesogenic side groups had to be attached. For example, Adams and Gronski synthesized homopolymers as well as block
copolymers with liquid crystalline side chains by this approach.116 The corresponding polyalcohol was obtained by quantitatively
converting the olefine double bonds of 1,2-polybutadiene via a hydroboration reaction with 9-borabicyclo[3.3.1]nonane and a
subsequent oxidation with H2O2. A further polymer analogous reaction was performed with activated cholesteryl derivatives.
Posers group synthesized block copolymers based on styrene and trimethylsilyl–protected hydroxyethyl methacrylate (HEMA),
followed by a cleavage of the protecting groups and subsequent conversion with cholesteryl derivatives.117 Block copolymers with
azobenzene chromophores on the basis of hydroxyl functionalized segments were investigated by several research groups118–126 to
obtain polymer materials for advanced complex applications.
Recent developments have focused on the synthesis of new activated ester monomers. As a very successful monomer class is
based on vinylcyclopropanes, which undergo a radical ROP leading the activated ester polymers where the reactive sites are
separated by 5 main chain carbon atoms, thereby reducing the sterical hindrance.127–130 Consequently, these polymers show
highly exciting properties, including a UCST behavior in ethanol/water mixtures.

3.2 Anhydrides, Isocyanates and Ketenes

Side chain functionalization of polymers utilizing anhydrides has been employed through the alternating copolymerization of
several monomers with maleic anhydride.131–133 The inherent high reactivity of anhydrides makes them ideal for the ring opening
reaction with amines.134 Usually, conversions are performed in buffer (DMSO/0.5 M NaHCO3) for 3 h and reach in almost
quantitative conversions.
Similarly, isocyanates have been used as reactive carbonyl groups for a polymer analogous reaction. Isocyanate containing
polymers have been prepared by copolymerization of vinyl isocyanate, 1-methyl-vinylisocyanate, or m-isproprenyl-a,a0 -dimehtyl
benzyl isocyanate with other vinyl monomers. Conversion of these isocyanate groups can be conducted using amines or alcohols.
While amines react quantitatively with isocyanates under ambient conditions within minutes, the reaction with alcohols requires
either an excess of alcohol or a catalyst.135 Homopolymers of 2-(acryloyloxy)ethylisocyanate, prepared by RAFT polymerization,
were reacted with amines and thiols.136
However, the inherent high reactivity of isocyanate groups demands dry conditions for the polymerization step. To circumvent
these problems, poly(4-vinylbenzoyl azide) has been studied as a new isocyanate generating polymer, see Scheme 3(A). 4-
Vinylbenzoyl azide can be polymerized under free radical polymerization conditions at 35 1C without degradation of the carbonyl

Scheme 3A Poly(4-vinylbenzoyl azide) as a ‘dormant’ precursor for isocyanate group containing polymer.
 Polymer Analogous Reactions 7

azide moiety. Afterwards, heating the polymer solution to higher temperatures in the presence of alcohols results in the in-situ
formation of the isocyanate through rearrangement, which then directly reacts with the respective alcohol.137 Further, reactive
isocyanates have been used to bind to thiol end groups of polymers, which were readily accessible through RAFT
polymerization.138

3.3 Oxazolones, and Epoxides

Vinyl-functionalized oxazolones (also called azlactones), such as 2-vinyl-4,4-dimethyl-5-oxazolone, 2-(40 -vinyl)phenyl-4,
4-divinylbenzaldehyde, or 2-isopropyl-4,4-dimethyl-5-oxazolone can be homopolymerized via radical polymerization
techniques.139–142 Poly(2-vinyl-4,4-dimethyl-5-oxazolone) has been shown to ring-open rapidly and quantitatively – even in
aqueous solutions – with amines to yield amide-functional polyacrylamides.142 For the ring-opening with alcohols, it is necessary
to use a catalyst, such as acids, bases, trialkylphosphines or cyclic amidines (see Scheme 3(B)).143,144
The oxazolone functionality has been receiving growing interest from the polymer chemistry community in recent years. Its
reactivity toward amines is somewhat lower than that of pentafluorophenyl activated esters,145 but as an addition reaction, the
ring-opening with nucleophiles does not produce any side products. Oxazolone side group functionality in homo-and copolymers
has thus been employed, among others, for the functionalization of fibers and fiber-based materials,146 the synthesis of glyco-
polymers,147 of temperature-148 and pH-responsive149 (co)polymers, and the functionalization of magnetic nanoparticles,150
Oxazolone end groups have been introduced into polymers through the use of a functionalised RAFT chain transfer agent.151
Epoxide-functionalized monomers, such as glycidyl methacrylate (GMA), 4-epoxystyrene or glycidyl acrylate, can be homo-
polymerized by radical polymerization techniques.152–158 It further has been demonstrated that the epoxide groups can react with
carboxylic acids, alcohols, thiols, anhydrides, azide, and amines, even though primary amines lead to ring-opening under for-
mation of a secondary amine, which then results in crosslinking or formation of cyclic structures via reaction with another epoxide.

3.4 Aldehydes and Ketones

The idea to functionalize polymers via carbonyl groups as reactive side groups was already born in the 1950s by Schulz and his
group, who synthesized acrolein polymers like poly(1,2-acrolein) via free radical polymerization and converted the aldehyde side
group in various ways.159–163 In the last decade, polymers with protected aldehyde side groups, i.e. with acetal side groups, gained
high attention11 when Maynard and coworkers started to polymerize 3,30 -diethoxypropyl methacrylate. First, they used free radical
polymerization and applied the resulting polymers to pattern proteins on surfaces.164,165 Then they used ATRP to produce well-
defined reactive polymer scaffolds, which could, after acidic deprotection, be reacted with O-(carboxymethyl)hydroxylamine, a
potential linker for drugs and peptides, and aminooxy-functionalized tetra(ethylene glycol) and thus are promising candidates for
the development of polymeric therapeutics.166 The combination of this monomer with methacrylates carrying activated ester side
groups even allowed for the synthesis of polymers with orthogonally reactive side groups.104,105
The reactivity of aldehydes and ketones originates from the positively polarized carbon in the carbonyl group, which can easily
react as an electrophile. Nucleophiles frequently used for the conversion of aldehydes or ketones in polymer side chains are for
example primary and secondary amines, O-hydroxylamines, and hydrazines or hydrazides yielding imines,162,163,167,168 enam-
ines,169 oximes,160,164–166,170,171 and hydrazones,162,170,172 respectively. Also, carbon-based nucleophiles can be reacted with a
carbonyl group, or it could be oxidized or reduced, however, these reactions are less popular for polymer analogous reactions on
aldehydes or ketones, and this section will thus focus more on the reactions with the nitrogen-based nucleophiles. Among these,
the conversion with O-hydroxylamines and hydrazines/hydrazides into oximes and hydrazones are usually the favored ones due to
the hydrolytic stability of the products between pH values of 2–7 and 5–7, respectively, and their selectivity in the presence of
amines.11,172,173 Conversions with amines result in the less stable imines and, hence, are very often followed by a reduction of the
imine to a stable secondary amine linkage with sodium boron hydride (NaBH4) or sodium cyanoborohydride (NaBH3CN). The
latter can be used under milder conditions and at neutral pH values and thus is more selective.174 The combination of these two
steps is referred to as reductive amination. However, it should be mentioned that, in contrast to various amines, O-hydroxylamines
are rarely available commercially. Possible ways to synthesize them from the corresponding bromide or the corresponding
alcohol/amine using N-(tert-butyloxycarbonyl)hydroxylamine (Boc-hydroxylamine) or Boc-aminooxyacetic acid, respectively,
usually involve two steps.104,166,175,176,177 (Scheme 4).

Scheme 3B Ring-opening of a 4,4-dimethyl-5-oxazolone with alcohols and amines (R¼vinyl or backbone).

8 Polymer Analogous Reactions

Scheme 4 Functionalization possibilities utilizing carbonyl groups in reaction with N-nucleophiles.

Instead of the free aldehyde or ketone, which can undergo undesired side reactions during different polymerization pro-
cesses,178 very often acetals or ketals are used in monomer structures. These protected analogs of the aldehyde or ketone then are
hydrolyzed under acidic conditions,179 very often using trifluoroacetic acid (TFA) or hydrochloric acid, after the polymerization in
order to obtain the aldehyde- or ketone-functionalized polymers. Depending on the nature of the protective group employed,
acetals and ketals with different reactivity can be realized. Dialkyl acetals, for example, are less stable than cyclic acetals like 1,3-
dioxolanes under hydrolytic conditions,175,180 and thus the acid lability of the side group employed can be tuned by the choice of
the protective group, or independently functionalizable side groups can be incorporated in a copolymer by using monomers with
differently protected carbonyl groups.
Both types, however, are stable under basic conditions and thus suitable candidates for the combination with monomers with
activated ester groups to copolymers with orthogonally reactive side groups. They can also be copolymerized with azide-functional
monomers to yield polymers with orthogonally reactive handles.

3.4.1 Polymer side chain modifications involving aldehydes and ketones

In the following, a variety of monomers and the synthetic pathways, by which aldehyde or ketone containing polymers can be
obtained from these, will be presented, as well as examples for polymer analogous reactions on them. The homo- and copoly-
merization of vinylbenzaldehydes (VBA) has already been studied intensively during the last century, more precisely free radical
polymerization of free vinylbenzaldehydes as well as several protected derivatives as (4vinylphenyl)diethoxymethane and imines
of vinylbenzaldehyde has been conducted by several authors.181–184 Moreover, various protected derivatives have been poly-
merized by anionic polymerization and afterwards been hydrolyzed to yield the reactive polymer precursor poly(vinylbenzal-
dehyde) (PVBA).185–190 Ritter and coworkers further studied the conversion with N-isopropylhydroxylamine.191 Wooley and her
group developed a straightforward way toward well-defined poly(4-vinylbenzaldehyde) via RAFT polymerization of the unpro-
tected monomer using S-1-dodecyl-S0 -(a,a0 -dimethyl-a00 -acetic acid)trithiocarbonate as CTA and AIBN in 2-butanone.192 The
amphiphilic PEG-b-PVBA, synthesized with the same method only using a monomethoxy-terminated PEG-based macro-CTA,
could be assembled into vesicles in aqueous solution and then in a one-pot reaction be labeled with an amine-functionalized dye
and crosslinked via reductive amination with a diamine and NaCNBH3.193 And also a double-functional monomer, namely 2-
formal-4-vinylphenyl ferrocene carboxylate, could be polymerized successfully with AIBN and the CTA 2-cyanopropyl-2-yl
dithiobenzoate via the RAFT process in THF.194
Further reactive monomers, which can be polymerized in a free radical process as well as via RAFT polymerization, are the
ketone containing monomers N-(1,1-dimethyl-3-oxobutyl)acrylamide,195 phenyl vinyl ketone and different alkyl vinyl
ketones.196–198 Among these, methyl vinyl ketone (MVK) is an interesting monomer not only because of its reactivity toward
different nucleophiles, but also because PMVK can be oxidized with m-chloroperbenzoic acid in a Baeyer-Villiger reaction to yield
poly(vinyl acetate).178 The free radical polymerization of MVK and its conversion with hydroxylamine was already reported in
1938,196 however, it cannot be homopolymerized via ATRP due to complexation of the copper catalyst by the monomer, while
copolymerization with methyl methacrylate is possible via reverse ATRP.178 This example demonstrates why, in many cases,
protected analogs of aldehyde or ketone carrying monomers are used.
A very popular monomer, which has been successfully polymerized via free radical polymerization, ATRP as well as RAFT
polymerization and subsequently deprotected with diluted trifluoroacetic acid, is 3,30 -diethoxypropyl methacrylate.104,105,164–166
As observed by several authors, polymers with aldehyde side groups tend to become insoluble upon deprotection due to inter- and
intramolecular non-covalent interactions or even covalent crosslinking,166,199,200 and thus, their deprotection should be con-
ducted in situ prior to the desired functionalization step. Due to the stability of the acetal under basic conditions, it is an ideal
candidate for the synthesis of copolymers with orthogonally reactive side groups via combination with activated esters, which can
be converted with amines under basic conditions.10 So, the activated ester moieties can be reacted first and then, the acetal groups
 Polymer Analogous Reactions 9

can be deprotected and subsequently reacted with a different type of amines or hydroxylamines, for example, as presented by
Maynard and coworkers (see Scheme 5, right).104,105
Another possible combination of reactive monomers was demonstrated by Weck and coworkers, who synthesized statistical
copolymers from exo-norbornenes with ketones and chloro-substituents in their side groups via ring-opening metathesis poly-
merization (ROMP).199 After nucleophilic substitution of the chloride with sodium azide, these copolymers could be functio-
nalized via copper catalyzed azide-alkyne cycloaddition and conversion of the ketones in a one-pot synthesis, as shown in Scheme
5 (left). Different hydrazides were shown to react quantitatively with the ketones forming hydrazones.199 Comparable experiments
were performed on copolymers with aldehyde side groups, which could be converted with hydrazines, but these polymers were
insoluble in classical organic solvents before and after conversion.
Furthermore, the different stabilities of dialkyl acetals and cyclic acetals as protective groups for aldehydes can be utilized to
introduce multiple functionalities independently. The higher stability of cyclic acetals toward acids180 allows for the deprotection
and functionalization of dialkyl acetals in the presence of cyclic acetals and thus for independent conversion. Appropriate
conditions for the hydrolysis of diethyl acetals, under which cyclic ethylene acetals are stable, were for example found for polymer
coated surfaces prepared from inorganic-organic hybrid materials containing poly(2,2-diethoxyethyl acrylate) or poly(1,3-diox-
olan-2-ylmethyl acrylate) blocks polymerized from functionalized poly(methylsilsesquioxanes) via RAFT.175 After deprotection,
conversion of the aldehyde groups with several amines and hydroxylamines could be used to tune the surface hydrophilicity, and a
thermo-responsive surface was obtained after conversion with amino-terminated poly(diethylene glycol methyl ether methacry-
late) (PDEGMEMA). The same cyclic acetal groups are also used to protect vinylbenzaldehydes during anionic polymerization,
which, however, only resulted in well-defined polymers in the case of 2-(3-vinylphenyl)-1,3-dioxolane and not of the ortho- and
para-analogs.187
In the case, when the 1,3-dioxolanes are not linked to the polymer via the methylene bridge but their ethylene bridge, i.e. on
position 4 or 5 instead of 2, the acidic deprotection results in 1,2-diols. Monomers of this kind, namely (2,2-dimethyl-1,3-
dioxolane)methyl acrylate and (2,2-dimethyl-1,3-dioxolane)methyl acrylamide, could be copolymerized with DEGMEMA via
RAFT polymerization,200 and after cleavage of the dioxolanes, the obtained 1,2-diols could be oxidized with periodic acid (HIO4)
to form aldehyde groups. The efficiency of this polymer analogous multi-step reaction was confirmed via reaction with an

Scheme 5 Orthogonal functionalization of norbornene-based random copolymers and methacrylate-based block copolymers.
10 Polymer Analogous Reactions

amino-functionalized drug, namely desferrioxamine, which was then used to chelate iron ions (Fe3 þ ) after reduction of the imine
linkage with NaCNBH3.200 The different degradation behavior of ester and amide bond polymer side chains was demonstrated
with respect to applications of such polymers as polymeric therapeutics.

3.4.2 Polymer end group modifications involving aldehydes and ketones

Besides the use of functional side groups, polymer analogous reactions can also take place at the end groups of a polymer, which is
very often used for end group modification, for example with a dye, synthesis of linear and non-linear block copolymers, or
bioconjugation. For these purposes, for example, an acetal containing initiator for ATRP was developed by Haddleton and
coworkers. With this functional initiator in hand, PEG methacrylate was polymerized and, after deprotection of the resulting acetal
end group, the polymer could be conjugated to lysozyme via the amino groups of the protein. The obtained imine linkage was
then reduced to a stable secondary amine linkage with NaCNBH3 in phosphate buffer, which also resembles the original amine
group in its basicity and thus is supposed not to disturb the native structure of the protein.201 Anionic polymerization allows to
introduce protected aldehyde groups at the a-end group by using functional initiators like potassium 3,3-diethoxy-1-propanoxide.
The acetal functionalized polymers PEG and PEG-b-poly(lactide) obtained via this method could be converted into aldehyde
functionalized ones via deprotection with diluted hydrochloric acid.202–204 When working at the o-end group, it is also possible to
introduce an unprotected aldehyde group directly after anionic polymerization by the addition of N-formylmorpholine,205 as well
as via lactone termination after ROMP.206 Further, catalytic chain transfer polymerization207,208 and RAFT polymerization209 can
be used to produce polymers with aldehyde end groups. Recently, an aldehyde-containing trithiocarbonate CTA has been syn-
thesized and employed successfully in RAFT polymerization of several vinyl monomers, which could afterward be conjugated to
hydroxylamine-functionalized polymers, obtained from another functional CTA, via a reversible oxime linkage.209 In this context,
it should be mentioned that several methods exist to synthesize well-defined polymers with hydroxylamine end groups, for
example using functional initiators for ATRP or CTAs for RAFT,210–212 and thus, the reaction between aldehydes and hydro-
xylamines, among the other carbonyl reactions discussed above, is a versatile tool for polymer conjugation and the construction of
several other polymeric architectures.

3.4.3 Multicomponent reactions involving aldehydes and ketones

Aldehydes and Ketones were also applied in multicomponent reactions, either the Passerini three-component reaction (Passerini-
3CR) and the Ugi four-component reaction (Ugi-4CR).213–215 In a Passerini-3CR a carboxylic acid, an aldehyde or ketone, and an
isocyanide are reacted leading to an a-acyloxycarboxamide. The Ugi-4CR can be seen as an extended Passerini reaction and
involves an additional primary amine as fourth component and results in a-aminoacylamides.
Because of the efficiency of multicomponent reactions, it comes to no surprise that they have found use in polymer synthesis
recently.216–218 Both Passerini-3CR and Ugi-4CR have been utilized in polymer synthesis in various aspects: (a) monomer
synthesis, (b) step-growth polyaddition, (c) dendrimer synthesis, and (d) polymer modification and conjugation. As such, the
following will shortly highlight some examples in the light of polymer modification and end-group conjugation.
For example, Li and coworkers modified a monofunctional PEG aldehyde with 2-bromo-2-methylpropionic acid, and pro-
pargyl isocyanoacetamide.219 The resulting double alpha-end-functionalized PEG macroinitiator featuring ATRP initiator and an
alkyne moiety allowed for an efficient synthesis of miktoarm star terpolymers.
In a similar way, the Ugi-4CR was utilized in the conjugation of two homopolymers yielding a diblock copolymer with a
defined chemical junction.220 For this, a benzaldehyde terminated PMMA and an aniline terminated PEG 5000 were linked via
addition of an isocyanide and a carboxylic acid. Full conversion of the homopolymers was achieved, when access of the small
molecules was used, making it a very efficient linking strategy.

3.5 Azides with Alkynes

The 1,3-dipolar cycloaddition between azides and alkynes yielding 1,4- and 1,5-substituted 1,2,3-triazoles (see Scheme 6) was
introduced by Huisgen already in 1963,221,222 but its high impact11–14,223–225 on organic chemistry and polymer science was
initiated in 2001, when Meldal and Sharpless both reported on the high efficiency and selectivity of the copper-catalyzed azide-
alkyne cycloaddition (CuAAC).226–228 Using copper(I) as catalyst, the reaction between terminal alkynes, generally poor 1,3-
dipole acceptors, and azides can be accelerated and preferentially results in the 1,4-adduct. Another advantage is that very high
yields can be obtained under mild conditions and in almost all organic solvents as well as under aqueous conditions. In the same
year, Kolb, Finn and Sharpless presented the concept of ‘click chemistry,’227 which envisioned – inspired by nature – “an
expanding set of powerful, selective, and modular” processes for the conjugation of small units via heteroatom links. Among these,
the 1,3-dipolar cycloaddition of azides and alkynes was suggested.
In 2004, Hawker, Sharpless, Fokin and coworkers finally demonstrated the high efficiency of this reaction by using CuAAC for
the convergent synthesis of dendrimers and thus opened the door for its application in polymer science.229
 Polymer Analogous Reactions 11

Scheme 6 1,3-Dipolar cycloaddition between azides and alkynes.

In this section, the use of CuAAC as well as metal-free 1,3-dipolar cycloaddition for the functionalization of polymers via their
side or end groups will be discussed after some general remarks. For more detailed discussion and further references concerning
kinetic and mechanistic studies, a review by Binder et al. is recommended.12
As mentioned before, the 1,3-dipolar cycloaddition between terminal alkynes and azides can be conducted under conditions
leading to high efficiencies and selectivity. Especially valuable is its orthogonality to almost all other reactive groups allowing for the
synthesis of polymers with multiple reactive handles as well as for diverse applications in vitro and in vivo due to its bioortho-
gonality.199,226,228,230 Basically, this azide-alkyne cycloaddition is not affected by other typical reactive groups like amines, alcohols,
aldehydes, ketones, esters and others, as long as these cannot undergo cycloadditions themselves with one of the reactants
(Sharpless et al.231,232 also reported on the cycloaddition of azides to sulfonyl and acyl cyanides, for example) or deactivate the
catalyst via complexation. As a slight exception, thiols should be mentioned, which were found to reduce azides after treatment at
100 1C for several hours or with a catalyst.230,233,234 Also, Glaser coupling between two alkynes might occur as a side reaction.235,236
In general, there are two possible approaches to obtain polymers with the reactive handles required for this functionalization,
i.e. azide or alkyne groups: The functionality can either be introduced after polymerization, which is found very often in the case of
a desired azide end group, which can be created by nucleophilic substitution of a bromide or chloride residue, for example. Or the
reactive group is already incorporated into one component utilized in the synthesis of the polymer, i.e. in the monomers or the
initiator or CTA, and thus available for functionalization directly after the synthesis of the polymer. Here, we will mainly focus on
the latter approach because it allows for immediate polymer analogous reaction.
Furthermore, we have to distinguish between polymers with reactive side groups providing multiple reactive handles for
functionalization and polymers with only one or two reactive end groups allowing for end group functionalization or polymer
and bioconjugation.
In both cases, when the reactive groups are already embedded in the components for the synthesis of the polymer, the
compatibility with the polymerization mechanism needs to be taken into consideration. In the following, some examples will be
given for disadvantageous combinations that should be avoided. Obviously, alkyne groups might interact with the copper catalyst
used in ATRP, hence, monomers like propargyl methacrylate cannot be polymerized in a controlled manner via ATRP.237 The same
holds true for the different ruthenium complexes used as catalysts in ROMP,238 and explains, why instead of the alkyne group the
trimethylsilyl (TMS) protected analog is used very often.239–242 Moreover, the propagating polymer chain in an anionic poly-
merization can be terminated by the acidic terminal proton of the alkyne group.243 Azide groups, on the other hand, can cause
problems in cationic ring-opening polymerization (CROP),11,244 and interfere with electron-deficient vinyl monomers in radical
polymerization or simply decompose, especially at elevated temperatures.245,246
In the following, several examples for the successful synthesis of reactive polymer precursors and their functionalization via
CuAAC will be given, mainly focusing on polymers with functional side groups, but also giving some examples for reactions of the
end groups.

3.5.1 Polymer side chain modifications involving azides and alkynes

2-(Pent-4-ynyl)-2-oxazoline could be polymerized and copolymerized with 2-alkyl-2-oxazolines via CROP initiated by methyl
triflate. The obtained polymers exhibited narrow molecular weight distributions, were water-soluble and could be converted
quantitatively with methyl azidoacetate or (trimethylsilyl)methyl azide in water using a slight excess of the respective azide (1.1–
1.6 equivalents per alkyne) and copper(II) sulfate with sodium ascorbate to generate the copper(I) catalyst in situ.244 These results
are of particular interest, because the same group also presented the synthesis of other poly(2-oxazolines) with further functional
groups like aldehyde or amine groups previously,247,248 so that the combination of the respective monomers is very likely to yield
polymers with multiple orthogonally reactive groups.
12 Polymer Analogous Reactions

ROP could also be used for the synthesis of well-defined polyesters with alkyne side groups, namely poly(a-propargyl-δ-
valerolactone) and its copolymers with e-caprolactone (e-CL).249 Ethanol was used as initiator and the polymerization was
mediated by Sn(OTf)2. These polymers could be functionalized with azide-terminated poly(ethylene glycol) (PEG) 1100
monomethyl ether and an azide-functionalized pentapeptide (GRGDS) successfully and were found to be biocompatible. For
these conjugation experiments, copper(II) sulfate and sodium ascorbate were used in a mixture of water and acetone at 80 1C,
however, the use of milder, non-aqueous reaction conditions, i.e. copper(I) iodine in catalytic amount with triethylamine in THF
at 35 1C, might be recommended for polyesters, especially if the less stable poly(lactide) (PLA) is involved.250
Elaborate studies on the preparation of different poly(oxynorbornenes) via ROMP were undertaken by Binder et al., among
other things, investigating the polymerization of a 7-oxynorbornene bearing an alkyne group, namely exo-N-prop-2-ynyl-7-
oxabicyclo[2.2.1]-hept-5-ene-2,3-dicarboximide.238 Due to undesired interaction of the alkyne moiety with the catalyst, this
polymerization resulted in polymers with polydispersity indices (PDI) higher than 1.5. However, alternative methods for the
synthesis of well-defined poly(oxynorbornenes) with either alkyne or azide side groups were demonstrated via post-
polymerization modification. These reactive polymers could then be functionalized in various experiments using CuAAC with
bromotris(triphenylphosphine)copper(I) as catalyst and N,N-diisopropylethylamine (DIPEA) in deoxygenated DMF (50 1C,
48 h).
Different authors tried to polymerize methacrylate or styrene based monomers with an alkyne side group. For example,
propargyl methacrylate could be polymerized via RAFT polymerization using S-1-dodecyl-S0 -(a,a0 -dimethyl-a00 -acetic acid) tri-
thiocarbonate and 2,20 -azobisisobutyronitril (AIBN) in toluene (80 1C, 3 h) resulting in poly(propargyl methacrylate) with a
molecular weight, Mn, of 25 000 g mol1 and a PDI of 1.64.251 This polymer could successfully be used in combination with poly
(2-azidoethyl methacrylate) for the build-up of multilayers on multiwalled nanotubes (MWNT) via layer-by-layer click chemistry.
However, several groups showed that terminal alkyne groups interfere with radical polymerizations; for instance, cross-linking was
observed during NMP of p-ethynyl-styrene,239 and the attempt to polymerize propargyl methacrylate via RAFT polymerization
resulted in a product insoluble in organic solvents like THF and N,N-dimethyl acetamide.242 The amount of cross-linking probably
depends on the particular polymerization conditions, i.e. temperature and time, and, depending on the desired application of the
reactive polymer, the resulting product might be satisfactory. However, for well controlled radical polymerizations the use of a
protective group is recommended. In both cases discussed above, the TMS-protected analog allowed for the synthesis of
well-defined polymers with pendant alkyne groups after deprotection of the polymer with tetra-n-butylammonium fluoride
(TBAF).239–242 Subsequently, azide-terminated poly(vinyl acetate) could be grafted to the poly(propargyl methacrylate) in a
CuAAC using copper(I) iodine and DBU in THF,242 or an azide-functionalized fluorescent dye as well as carbohydrates could be
conjugated using bromotris(triphenylphosphine)copper in combination with DIPEA,241 to give only a few examples.
An early example of polymer analogous reactions on azide containing macromolecules was the labeling of methionine analogs
as azidoalanine and others on the E. coli cell surface with acetylene functionalized PEG via CuAAC using pure CuBr.252 However,
also classical synthetic polymers with azide side groups were produced and functionalized successfully. For example, poly(3-
azidopropyl methacrylate) was synthesized via ATRP with copper(I) bromide and 2,20 -bipyridine,237 and afterwards converted
with propargyl alcohol and other model alkynes. Here, only 1.1-fold excess of the respective alkyne over the azide side groups was
needed for almost full conversion (495%) under mild conditions (2 h stirring in oxygen-free DMSO or DMF) with copper(I)
bromide (0.5 equivalent) as catalyst.
Besides controlled radical polymerization (CRP), also (C)ROP allows for the synthesis of azide carrying polymers like poly(2-
(4-azidophenyl)oxazoline)253 or poly(a-azido-e-CL-co-e-CL).250 The latter is usually synthesized via nucleophilic substitution of
the halide substituent in poly(a-chloro-e-CL-co-e-CL) with sodium azide, but the copolymerization of a-azido-e-CL with e-CL was
also suggested.250 Independent of the synthesis of this copolymer, it could be functionalized via CuAAC by means of a catalytic
amount of copper(I) iodine and triethylamine in THF with propargyl benzoate, 3-dimethylamino-1-propyne, N,N,N-triethyl-
propargyl ammonium bromide, and PEG with a N,N-diethylpropargyl ammonium bromide end group. Under the same condi-
tions, the less stable copolymer poly(a-azido-e-CL-co-DL-LA) was functionalized without indication for degradation.
The orthogonality of the CuAAC to polymer analogous reactions via carbonyl groups was demonstrated in a very effective one-
pot functionalization reaction of a poly(norbornene) with azide and ketone containing side groups. This copolymer was reacted
with phenylacetylene and benzhydrazide at the same time, using copper(II) sulfate and sodium ascorbate as catalyst (2 h at
25 1C).199 The azide side groups were converted into triazoles and the ketone side groups into hydrazones, both quantitatively.
As a general remark, it should be mentioned, that the very high efficiency of polymer analogous reactions via azide-alkyne
cycloaddition at several sites along the polymer backbone is often attributed to the formation of the triazole moiety, which is said
to have a catalytic effect on subsequent cycloaddition reactions in the vicinity and thus turns this polymer modification method
into an autocatalytic process.254

3.5.2 Polymer end group modifications involving azides and alkynes

The development of CRP techniques also paved the way to a variety of synthetic possibilities to create functional polymer end
groups. An azide or alkyne end group can either be obtained via post-polymerization modification or be incorporated already in
the initiators used in ATRP, the unimer for NMP or the CTA for RAFT polymerizations, respectively. One of the most popular
 Polymer Analogous Reactions 13

approaches is probably the introduction of an azide at the o-end group of a polymer synthesized via ATRP.255–257 For this
purpose, the halide resulting from ATRP is simply exchanged in a nucleophilic substitution with sodium azide.256,257 Using this
reactive handle, numerous polymers with functionalized end groups were produced and block copolymers could be obtained via
conversion with acetylene terminated polymers.258–261 Another group presented an azide carrying initiator for ATRP, which could
be used subsequently for the controlled polymerization of methyl methacrylate in combination with N-alkyl-2-pyr-
idylmethanimine and copper(I) bromide, and then for the functionalization of the obtained polymer via CuAAC at the terminal
azide in a one pot synthesis using the same copper catalyst.262 Also an azide-xanthate for macromolecular design via the
interchange of xanthates (MADIX) polymerization was developed and employed for the synthesis of poly(vinyl acetate) azide.242
Furthermore, alkyne-functionalized initiators for ATRP258,263 were synthesized, and different CTAs with either azide or alkyne
groups were designed for RAFT polymerization,264–268 one of them even yielding heterotelechelic polymers with an azide a-end
group and a dithiopyridine o-end group.266 Such a heterotelechelic poly(N-isopropyl acrylamide) (PNIPAAm) could successfully
be reacted with an alkyne-modified biotin using copper(II) sulfate with sodium ascorbate leaving the o-end group unmodified
under these particular conditions and thus ready for conjugation to different thiol-exhibiting biomolecules, as for example the
protein bovine serum albumin (BSA). In general, the combination of controlled polymerization with this type of “click chemistry”
at the polymer end groups allows for the synthesis of a variety of linear polymer architectures like heterotelechelic poly-
mers263,266,269–274 and macromonomers,275,276 block copolymers,258–261,263,265,267,277,278 as well as biohybrids.279–285 Beyond
linear architectures, also cyclic polymers, graft and star copolymers, polymeric networks, polymer decorated surfaces and nano-
particles, dendritic architectures286,287 etc. can be constructed utilizing the described reactive handles in side groups as well as end
groups.12,13,288–292

3.5.3 Metal-free 1,3-dipolar cycloaddition

Despite the broad applicability of CuAAC as a powerful tool for the design of diverse polymer architectures, the necessity of the
metal catalyst for high efficiencies limits its usage for the synthesis of biomedical and pharmaceutical products as well as in vivo
applications due to the toxicity of copper.293 Hence, great efforts have been undertaken to develop other copper-free “click”
methods,293,294 among these, approaches employing alkyne species with increased reactivity, which will be discussed briefly in the
following. One alternative to CuAAC is the so called strain-promoted azide-alkyne coupling (SPAAC). Therefore cyclooctynes are
used as alkyne component (see Scheme 7), which are activated by the ring strain (‘first generation cyclooctynes’).295 Their reactivity
is further increased, if electron-withdrawing substituents are introduced in aposition to the triple bond. Second and third gen-
eration cyclooctynes exhibit one or two fluoro substituents in a-position, respectively,296,297 which results in an acceleration of the
reaction with azides. Another possibility to activate cyclooctynes is via increased ring strain as, for example, in 4-dibenzocy-
clooctynol,298 and also benzynes like o(trimethylsilyl)phenyl triflate are used as alkynes and result in benzotriazoles upon
conversion with azides.299 Since no metal catalyst is required and since it also represents a bioorthogonal reaction,230,300,301 which
can be performed under physiological conditions, SPAAC is already frequently applied in organic chemistry and biology, even in
living cells and living animals.295,296,300–318 Unfortunately, the yields are still relatively low in comparison to CuAAC, the reaction
is not regioselective and the synthesis of these alkynes is usually complex.
In the broadest sense, also cycloaddition-retro-Diels–Alder (cr-DA) reactions can be listed here. They involve the formation of
1,2,3-triazoles from azides and trifluoromethyl-substituted oxanorbornadienes, which are activated by electron-withdrawing
groups next to the alkyne, under release of furan.319,320
Recently, the strain-promoted azide-alkyne coupling also found its first applications in polymer chemistry. Using small
crosslinkers with two cyclooctyne moieties, poly(tert-butyl acrylate) 4-arm stars with azide end groups could be crosslinked via
SPAAC forming networks, which result in hydrogels after hydrolysis of the tert-butyl esters.321 A comparable crosslinker with two
dibenzocyclooctyne groups was used to stabilize a surface coating based on a copolymer of 2-azidoethyl methacrylate and methyl
methacrylate on an alkyne functionalized glass substrate. The obtained ‘clickable coating’ was functionalized with coumarin

Scheme 7 Chemical structures of selected cyclooctynes and o-(trimethylsilyl)phenyl triflate used for a metal-free 1,3-dipolar cycloaddition.
14 Polymer Analogous Reactions

derivatives exhibiting reactive handles like dibenzocyclooctyne or trifluoromethyl oxanorbornadiene in a comparative study. The
octyne showed highest reactivity, while the oxanorbornadiene reached a similar level of functionalization only after longer
time.322 The good reactivity of dibenzocyclooctynes could even be exceeded by a recently developed aza-dibenzocyclooctyne,
which further allows for straightforward conjugation via the nitrogen atom.323 Thus, it could be bond to PEG, which was then used
for effective PEGylation of the azide functionalized enzyme CalB via SPAAC.
Summarizing, the efficiency and biocompatibility of copper-free alternatives for the 1,3-dipolar cycloaddition of azides and
alkynes has been demonstrated, first examples of use in polymer chemistry have already been successful and further application for
polymer analogous reactions can be expected. A small drawback, however, is the usually complex synthesis of the described alkyne
analogs, and the applicability of these reactions in materials science would probably increase tremendously, if the synthetic effort
was reduced or if universally applicable cyclooctynes, for example, became commercially available.

3.6 Dienes and Dienophiles

Dienes and dienophiles undergo [2 þ 4] cycloadditions, also termed Diels–Alder reactions. Molecules containing 1,3 conjugated
double bonds, including such with hetero-atoms can be suited as dienes. As dienophiles, alkenes, alkynes, as well as double bonds
between one or two hetero-atoms can be considered. The reaction yields cyclohexene derivatives.
An important characteristic of the Diels–Alder reaction is that it is thermally reversible through a retro Diels–Alder reaction. The
reaction temperature and processing temperature of products thus need to be considered to avoid decomposition. On the other
hand, an intentional retro Diels–Alder reaction may be a convenient method for cleaving a linkage. One of the most studied
systems is the combination of furan and maleimide, due to reagent availability and their highly efficient Diels–Alder and retro
Diels–Alder reactions.314–317 Furan has thus been used as a thermally-removable protecting group for maleimides (see Sec-
tion 3.8.2.2 for modification of unprotected maleimides with thiols).218 The reversible linkage of the furan–maleimide pair is also
receiving growing interest in the field of self-healing polymers.219
Not all dienes react readily with all dienophiles. The reactivity depends on the amount of overlapping of the orbitals of the
involved atoms and their energetic difference. The reaction takes place between the highest occupied molecular orbital (HOMO)
of one molecule, and the lowest unoccupied molecular orbital (LUMO) of another molecule. The HOMO of electron-rich dienes
may react with the LUMO of electron deficient dienophiles in a normal Diels–Alder reaction. The LUMO of electron poor dienes
may react with the HOMO of dienophiles with a high electron density in an inverse Diels–Alder reaction (reaction with inverse
electron demand). Electron density thus needs to be considered when choosing two reaction partners.
For many combinations of dienes with dienophiles, the reactions are regioselective, very robust, and require only very mild
reaction conditions.
Especially in the last few years there has been a strongly growing interest in these reactions in the polymer arena and the
interested reader is referred to a number of recent reviews on the applications of Diels–Alder reactions in polymer science,220 in the
synthesis of dendritic polymers221 or in polymer modification through strategies involving a combination of click chemistries.222

3.6.1 Polymer end group modifications involving Diels–Alder reactions

A molecule easy to integrate into an initiator, stable during a radical polymerization and reactive towards electron poor
dienophiles is anthracene. ATRP of styrene and divinylbenzene from an anthracene modified initiator resulted in crosslinked
cores exhibiting the anthracene moieties. These were then clicked with maleimide terminated polymers to yield multiarm
stars.323
The [4 þ 2] cycloaddition is orthogonal to the [3 þ 2] dipolar cycloaddition of azides and alkynes and both have been
combined to form ABC triblock structures: An anthracene modified ATRP initiator was used to polymerize styrene; substitution of
the terminal bromide with azide afforded a hetero-telechelic polymer with two different ‘clickable’ groups. Two different polymers
carrying maleimide and alkyne end groups, respectively, were added in a one-pot reaction to give the triblock.324
Maleimides are highly reactive dienophiles and find application in designing polymer architectures. Maleimides have been
incorporated into initiators for ATRP or attached to PEG chains. In order to prevent side reactions during polymerization,
maleimides are protected with furan in a Diels–Alder reaction. Retro Diels–Alder deprotection and reaction of the (unprotected)
maleimide functionalized polymers with dienes can be carried out in a single step, where furan is released and the maleimide
adduct with e.g. anthracene is formed (Scheme 8(A)). Employing a trianthracene core, 3-armed stars were accessible.325,326 In a
similar synthetic strategy, diblock copolymers were prepared from an anthracene terminated polycarbonate and a furan-protected
mateimide-terminaed poly(ethylene glycol) block.328
A very convenient method for end group modification of RAFT polymers is to make use of the terminal thiocarbonyl group as a
dienophile. With especially designed CTA carrying electron withdrawing groups, the thiocarbonyl group reacts readily with dienes
such as cyclopentadiene or open chain alkadienes. Benzyl(diethoxyphosphoryl) dithioformate and benzylpyridin-2-
yldithioformate have been used as CTAs to polymerize various polymers, which could be clicked to a variety of dienes and
multi-diene compounds yielding diblock copolymers316 and stars (Scheme 8(B)).329
 Polymer Analogous Reactions 15

Scheme 8 (A) 2 þ 4 Cycloaddition of PMMA with a protected maleimide end group with anthracene functional cores, e.g., polystyrene derived
from an anthracenyl initiator and crosslinked with divinylbenzene,323 or a tri-functional core (m¼3).326 (B) Example of end group conjugation of
two different polymers with a dithioester as dienophile and cyclopentadiene as diene.327

3.6.2 Polymer side chain modifications involving Diels–Alder reactions

Furan undergoes a variety of Diels–Alder additions as a diene330 and has been used as a reactive site in polymer side groups. (p-
Vinylphenyl)furfuryl ether was copolymerized with styrene, yielding a polymer with pendant furan groups. It could be crosslinked
with a bismaleimide and decomposed again through a retro Diels–Alder reaction at elevated temperature.331 A similar Diels–Alder
chemistry was used on copolymers of N-dimethylacrylamide and furfuryl methacrylate to generate thermosensitive hydrogels
through gelation with a bismaleimide.332
Trans,trans-hexa-2,4-dienylacrylate was successfully copolymerized with styrene via RAFT. The pendant diene groups were used
to graft pyridin-2-yldithioformate terminated polymers onto the copolymer, resulting in a comb polymer.333
A similar approach to comb polymers was accomplished by copolymerization of p-chloromethylstyrene with styrene. Post-
polymerization, the chlorides were substituted with 9-anthracenemethyl alcohol which then served as dienes in the reaction with
maleimide-terminated polymers prepared as described above.325 The same combination of anthracene and maleimide was used to
graft maleimide-terminated polymers onto polymers of anthracene-functional oxanorbornene and of hetero-telechelic anthracene-
polystyrene-oxanorbornene prepared by ROMP.334 An anthracene-functional polyurethane was prepared by condensation of an
anthracene-functional diol with a diisocyanate and then post-modified with maleimide-terminated polymers.335
The Diels–Alder reaction between a pendant norbornene group (as dienophile) in a polystryrene copolymer and a bis(1,2,4,5-
tetrazine)-functional crosslinker (as diene which eliminates dinitrogen) was exploited to study the intra-chain crosslinking of a
single polymer chain.336

3.7 Halides
3.7.1 Substitution
General substitution reactions have been the focus of various studies, in particular the nucleophilic substitution on poly(p-
vinylbenzyl chloride) (chloromethylated polystyrene), which can be obtained by either chloromethylation of polystyrene or direct
16 Polymer Analogous Reactions

polymerization of vinylbenzyl chloride.337 As such, substitution reactions have also been used for the preparation of polymer
carriers or polymer supports, such as nano- or microparticles, which often consist of crosslinked styrene-based copolymers
featuring chemical groups, i.e. benzyl chloride, that allow further functionalization.338 In principle, one differentiates three classes
of such crosslinked materials: polymer reagents, polymer catalysts, and polymer substrates. For example, Grubbs described the
synthesis of a polymer-supported rhodium catalyst.339 Another example represents the quarterinization of crosslinked poly(p-
vinylbenzyl chloride) with trimethylamine or N-chloromethylphthalimide followed by saponification, which results in cationic
ion exchange resins.340,341 More examples are summarized in the literature.342
A further class of monomers and derived polymers carrying reactive halides are pentafluorobenzyl-functional systems which
undergo selective nucleophilic aromatic substitution of the para-fluoro group with thiolates (see Section 3.8.3.2),343–346 alco-
holates,347 and amines.348,349

3.7.2 Pd-catalyzed coupling and cross-coupling reactions

Substitutions of alkyl or aryl halides can also be conducted utilizing the broad variety of Pd-mediated reactions, such as the Heck,
Sonogashira, Suzuki or Stille couplings. In these reactions, different functional substrates can be conjugated to halide-functional
polymers including alkene, alkyne, boronic acid or ester, or organotin species. The coupling can usually be conducted under mild
conditions.350 Most commonly used is poly(p-bromosytrene), which is readily available through radical or anionic poly-
merization.351 Due to steric hindrance of catalyzed reactions on polymer chains, various optimizations have been described in the
literature. For example, use of [PdCl2(PhCN)2] as the catalyst and tri-tert-butylphosphine as ligands resulted in conversions up to
99% at room temperature, however, long reaction times of up to 96 h were necessary.352
Pd-catalyzed coupling reactions have also been used for the preparation of Lewis acid organoboron-functional polymers, which
are exciting candidates in materials science due to their coordination behavior.353

3.7.3 Atom Transfer Radical Addition

Alkyl halides as side chain functional groups have been employed in the polymer analogous reaction utilizing atom transfer
radical addition (ATRA).354 This transition metal catalyzed reaction has been investigated for the functionalization of polyesters
containing a-chloro-e-caprolatone repeating units. The group of Jérôme demonstrated that it is possible to modify polyesters with
very different functional groups, such as alcohols, esters, epoxides, and poly(ethylene glycol) if the respective vinyl component is
available.355–357 ATRA has further been used to graft polymers onto C60. As an example, defined C60 end functionalized four-
armed polymers have been synthesized.358
The related technique ATRP produces polymers terminated with halides, typically bromides or chlorides which are susceptible
to substitution with a variety of nucleophiles including azides (see Section 3.5.2),255–257 thiols,359 thiodimethylformamide360 and
methanethiosulfonates (see Section 3.8.2.2).361

3.8 Thiols
Thiols (or mercaptans, sulfhydryls, or hydrosulfides) are highly versatile functional groups that undergo a variety of different
reactions (Scheme 9).15,362–371 Many of these reactions proceed rapidly to high yields under mild conditions and require only
simple purification. Showing high selectivity, many thiol-based reactions are orthogonal and can be elegantly combined with a
range of other highly efficient modification reactions.15,16,372 Consequently, thiol chemistries, including many reactions that
satisfy the rules for being click chemistry, find many applications in polymer analogous modifications. As many bio-molecules
contain thiols (or reducible disulfides), thiol click chemistry has developed into a very important tool in the preparation of
polymer-bio hybrid materials.373,374
Section 3.8.1 discusses various (click) reactions that thiols undergo, while the following sections provide an overview of
polymer analogous reactions involving thiols, divided into polymer end group (Section 3.8.2), and polymer main chain (Sec-
tion 3.8.3) modifications. Both sections include the modification of thiol-functional polymers and the modification of suitably
reactive polymers with thiols.
For additional information on this very broad subject, the interested reader is directed to literature reviews cited in this
section.15,16,372,375–379 In addition to undergoing organic reactions, thiols coordinate very efficiently to metals enabling surface
modifications through self-assembly. Not falling into the category of polymer analogous reactions, however, this chemistry will
not be covered here.

3.8.1 Reactions of thiols

3.8.1.1 Nucleophilic substitutions
Being more acidic than the homologous alcohols, thiols are deprotonated by comparably weak bases. The resulting thiolates are
very strong nucleophiles,362 their nucleophilicity depending on their substituents, increasing in the order alkylopropionate
oglycolateoaryl.15,362,365 As very soft nucleophiles, thiolates readily substitute soft leaving groups on carbon or sulfur atoms.
 Polymer Analogous Reactions 17

Scheme 9 Overview of reactions of thiols with various substrates as detailed in the text, with cat.: catalyst; rad.: radical; ox.: oxidation; red.:
reduction.
18 Polymer Analogous Reactions

Halidoalkanes, such as the highly reactive a-bromo carbonyl or pentafluorophenyl compounds, require a base catalyst,380 whereas
the ring opening of epoxides with thiols may also be catalyzed with Lewis acids.381 These reactions yield thioethers.
A special class of substrates to undergo nucleophilic attack by thiols or thiolates comprises such with electrophilic sulfur atoms,
such as pyridyl disulfides, methane thiosulfonates, or thiosulfates (Bunte salts). These reactions produce unsymmetrical disulfides
in very rapid and selective reactions, which may be cleaved at demand by reduction. Upon reaction with a thiol, Ellman's reagent
(5,50 -dithiobis-(2-nitrobenzoic acid))382 releases 2-nitro-5-thiobenzoate, the absorbance of which can be used for quantitative
analysis.

3.8.1.2 Nucleophilic additions

As strong nucleophiles, thiols add readily to activated (electron poor) enes, such as maleimides, acrylates,383,384 or vinylsulfones in
thia-Michael reactions forming thioethers, and to isocyanates forming thioureas.385–387 Non-aromatic isocyanates have been
shown to react at a slower rate than phenyl isocyanate.15 For the addition to activated enes, reaction rates are greatly increased with
increasing nucleophilicity of the catalyst, such as hexylamine or triisopropyl phospine. An increasing electron deficiency of the
double bond increases the thiol addition rate.15 Thiol-ene and thiol-isocyanate reactions may be performed in water and thus offer
the possibility for bio-conjugation.

3.8.1.3 Radical additions

Thiyl radicals are generally electrophilic, with electrophilicity depending on the substituent, increasing in the order aryloglyco-
lateopropionateoalkyl15,362,365 They thus react with electron rich enes,362,364,388–392 and with alkynes.16,362,363,365,367,368 As
compared to enes with electron withdrawing groups (such as maleimides) which can be used for nucleophilic addition, non-
activated alkenes, e.g. allyl ethers, can readily be employed in radical addition reactions. Allyl methacrylate can thus selectively
be reacted at the methacrylate group in a nucleophilic thiol-ene reaction using base catalysis, leaving the allyl group intact.393
In cyclic enes ring strain further increases the reaction rates.394 While addition of thiols to enes produces thioethers, alkynes
can add two equivalents of thiols to yield 1,2-dithioglycols, where the second addition (thiol þ vinylthioether) is typically
about three times faster than the initial thiol–yne reaction, leading favorably to bis-adducts.395 Exceptions to this are found
for the addition of thiols to diphenylacetylenes,396 and, unless a large excess of thiols is used, phenylacetylenes.397 Both thiol-
ene and thiol–yne reactions have a high tolerance toward functional groups and are efficient and robust methods with
single radicals being capable of mediating 100–10 000 addition reactions.15,398 Radicals may either be provided by
thermal decomposition of initiators or by photo-cleavable initiators. UV light initiation can eliminate the need for high
temperatures, and more complete reactions with a higher degree of control can be obtained under photochemical
conditions.16,362–367,369–371

3.8.1.4 Oxidation and reduction

The half-reaction RS–SR þ 2e-2RS has a standard reduction potential of  0.25 V. A variety of mild, easy to handle, and
cheap oxidizing agents, such as oxygen, iodine, hydrogen peroxide, or Fe(III) salts may thus be applied to form symmetrical
disulfides from thiols. On the other hand, the absence of oxidizing agents – especially oxygen – may be a necessary precaution to
eliminate oxidation pathways where unintended. Disulfides, both symmetrical and unsymmetrical, can be very selectively
converted into thiols by reducing agents such as the water-soluble reagents dithiothreitol (DTT), tris(carboxyethyl)phosphine
(TCEP), or sodium dithionite (Na2S2O4), as well as organically soluble reducing agents such as trialkylphosphines, or propane-
1,3-dithiols.

3.8.2 Polymer end group modifications involving thiols

3.8.2.1 Thiol end groups
A major part of thiol-involved polymer analogous reactions falls into this category, because thiol end groups are easily accessible
through the modification of the dithioester, trithiocarbonate, dithiocarbamate, or xanthogenate moieties retained as end groups in
RAFT polymerization.377,399,400 Thiols may be released from these groups by cleavage of the ester/carbonate employing nucleo-
philes or reducing agents such as amines and hydrides. When an isolation of the terminal thiols is compromised by side reactions
of the terminal thiol, such as oxidative interchain coupling (oxidation), or intrachain addition (backbiting), modification of the
released thiol in situ in a one-step reaction is favorable.401–403,410,397,405
A very common technique for RAFT end group modification is the reaction of terminal thiols with functional maleimides or
acrylates as thia-Michael acceptors. Among others, hydroxyl406 and pyrene407,408 end groups have thus been introduced into
polymers. Reacting thiol-terminated polymers with a triacrylate core produced three-armed stars.409
Aminolysis of terminal RAFT dithioesters on polystyrene, poly[(meth)acrylates] and poly[(meth)acrylamides] in the presence
of functional methane thiosulfonate reagents affords terminal functionalized disulfides in (near) quantitative yields. Using this
approach, a butynyl end group as ‘adapter’ to succeed with alkyne–azide clicking (CuAAC) was installed into various polymers.
The disulfide bond enabled cleaving the polymers from a surface after being grafted to it by CuAAC.401 Functional methane
 Polymer Analogous Reactions 19

thiosulfonate (MTS) reagents could also be employed to introduce fluorinated block,410 bio-target,411 or fluorescent dye412 end
groups into stimulus responsive polymers.
The nucleophilic substitution of activated bromides by thiols can also be applied during the aminolysis of RAFT polymers to
give thioether-bound functional end groups.404
The efficiency of thiol-isocyanate click chemistry was demonstrated on (isolated) thiol terminated poly(N,N-diethylacryla-
mide) with a variety of isocyanates, including ones carrying further functional groups, such as double bonds, halogens, or
aromatics.413 The cleavage of RAFT end groups to thiols and subsequent nucleophilic ring-opening reaction of oxiranes was shown
to proceed quantitatively in one-pot on poly(N,N-diethylacrylamide) through hydride cleavage of the RAFT end group whereas the
modification of a poly(styrene)-SH species with oxiranes required the isolation of the intermediate thiol resulting in lower
yields.414
ATRP from a difunctional disulfide initiator was used to prepare polystyrene with a disulfide bridge in the middle. This bond
could be cleaved with DTT, and the resulting mono-thiol terminated polymers could be oxidized to the original disulfide using
FeCl3 again. ATRP from a different difunctional initiator afforded polystyrene with a and o bromo end groups which were
converted into thiols with thiodimethylformamide. The resulting telechelic dithiol could be oxidized to a high molecular weight
disulfide.373 A similar approach to reducible polymers was achieved using a difunctional RAFT agent with subsequent conversion
of the dithioester end groups to thiols, allowing reversible oxidation/reduction.415

3.8.2.2 Thiol-reactive end groups

A large variety of thiol-reactive groups has been introduced as polymer end groups, both before polymerization by initiator
functionalization and by post-polymerization reactions.
Some ‘adapters’ have been presented that can be used on thiol-terminated polymers (e.g. prepared by RAFT) to introduce a
thiol-reactive site at the end group. Usage of an excess of bis(maleinimido)diethylene glycol on thiol-terminated poly(N-iso-
propylacrylamide) (PNIPAM) thus produced maleinimide-terminated PNIPAM. This polymer was susceptible to nucleophilic
thiol-ene modification with various thiols, including low molecular weight thiols as well as thiol-terminated polystyrene.416
Similarly, divinyl sulfone can be used to convert thiol end groups into Michael acceptor functionalities. Bovine serum albumine
was thus coupled to poly[poly(ethylene glycol) methylether acrylate] via its free cysteine group.403
Aminolysis of trithiocarbonates of various RAFT-made polymers in the presence of dipyridyl disulfide produces pyridyl
disulfide terminated polymers. These groups with electrophilic sulfur atoms could be used for coupling of thiol-functional
biomolecules.402
Another example is the base-catalyzed thiol-ene addition of a thiol released in situ from RAFT-made PNIPAM to allyl
methacrylate, generating a polymer with a terminal allyl group. This groups could then be reacted in a radical-mediated thiol-ene
reaction to further modify the end groups. Using propargyl acrylate in a similar approach, PNIPAM with a terminal acetylene unit
was prepared and used for the addition of two equivalents of thiols in a radical thiol–yne reaction.393
RAFT end groups can be replaced with the residues of diazo initiators. This approach has been employed to introduce furan-
protected maleimides. After thermal deprotection, the maleimide end groups were used for protein conjugation.417
Both CTA for RAFT polymerization and initiators for ATRP carrying pyridyl disulfide groups have been synthesized. Con-
jugating these compounds to BSA allowed to graft polymers from this protein by ATRP418 and RAFT, without loss of its bioac-
tivity.419 Polymers derived from pyridyl disulfide modified CTA were also conjugated to BSA in a polymer analogous reaction.420
ATRP is an advantageous method as is produces polymers terminated with halides. The terminal bromide of a poly(methyl
acrylate) sample has been substituted by thioglycerol in a nucleophilic substitution reaction. The two terminal hydroxyl groups
were then acylated with 2-bromopropionyl bromide to equip the end group with two new initiators for ARTP, thus constituting an
effective synthetic pathway for bromo-terminated macromolecular dendrimers.372
Substitution of the terminal bromide on ATRP-made poly(tert-butyl acrylate) with sodium methanethiosulfonate produced a S-
polymer methanethiosulfonate which was susbceptible to nucleophilic attack of thiols at the electrophilic sulfur producing
asymmetrical polymer-SSR modified polymers.361
ATRP can also used in combination with an olefin-modified initiator. After polymerization, the double bond was radically
reacted with mercapto acetic acid. The authors additionally performed azide-alkyne clicking at the other end group of the polymer
and showed that both reaction types are compatible and may be performed in either sequence.421
A furan-protected maleimide with an alcohol group was used as initiator for polymerization of lactic acid, which could be
followed by deprotection of the maleimide via retro-Diels–Alder chemistry and conjugation with thiols to the ene end group.422
Further methods to create thiol reactive end groups on polymers have involved reacting hydroxyl end groups originating from
the CTA mercaptoethanol in a free radical polymerization with divinylsulfone.423 The hydroxyl end group of poly(ethylene glycol)
or pluronic can been modified to bear thiol-reactive groups, such as pyridyl disulfides, or methoxycarbonyl disulfides. Examples
are discussed in literature reviews.417
Limitations to the use of radical thiol-ene coupling to produce stars or diblock copolymers have been reported. In the attempts
to click ene-terminated polymers to thiol terminated polymers or to small cores containing multiple thiols, only very low yields of
the desired diblock copolymers and stars were found, which was attributed to bimolecular termination processes.424
20 Polymer Analogous Reactions

3.8.2.3 Hetero-telechelic polymers involving thiol reactions

Due to the high selectivity of many thiol-based reactions, they are well compatible with other (click) chemistries. Several com-
binations of two orthogonal reactions have thus been applied to produce hetero-telechelic polymers. For example, thiol reactive
end groups, such as methane thiosulfonates, pyridyl disulfides, and maleimides have successfully been combined with activated
ester and azide groups at the opposite chain end, to produce polymers carrying two different biological411,425 or fluorescent
dye412,426 end groups.

3.8.3 Polymer main chain modifications involving thiols

3.8.3.1 Monomer units containing thiols
Polymers with pendant thiol groups, including partially esterified poly(acrylic acid), but also modified chitosan, cellulose, or
alginate find applications as mucoadhesive polymers as they bind to cysteine-rich subdomains of mucus glycoproteins through
disulfide exchange or oxidation.427 Postmodification of an activated ester precursor with cysteamine produced a block carrying
pendant thiol groups used to anchor to a semiconductor nanoparticles.428 Care needs to be taken to avoid oxidation and
crosslinking of thiol-functional polymers.

3.8.3.2 Monomer units containing thiol-reactive sites

A readily polymerizable monomer containing a thiol-reactive site is pentafluorostryrene, which can undergo substitution of the
para-fluoride with thiols under base catalysis after polymerization.343,344
After (co-)polymerization by NMP, glycopolymers were prepared from poly(pentafluorostyrene) employing a thiol-
functionalized glucose with acetate-protected alcohol groups.345,429
Thiol-reactive pentafluorobenzyl-functional (meth)acryalte monomers were prepared through Passerini multicomponent
reactions and successfully homo- and copolymerized through RAFT. The resulting (co)polymers reacted quantitatively with thiols
under very mild conditions. Compared to poly(pentafluorostyrene), pentafluorobenzyl-functional (meth)acrylate polymers had
better solubility in organic solvents including alcohols and allowed for copolymerization with the the larger (meth)acrylic family
of monomers.346
Poly(butadiene) with its pendant vinyl groups is a suitable candidate for side group thiol-ene modification and was shown to
react readily with thiolated bio-molecules such as amino acids, sugars, or cholesterol with sunlight as initiator in these radical
reactions. Due to the closeness of the vinyl groups, cyclization of neighboring side groups occurs as side reaction.430
Several monomers bearing (unprotected) thiol-reactive groups have been polymerized directly through controlled radical
polymerization techniques,431 including 2-(acryloyloxy)ethylisocyanate,136 vinyloxyethyl methacrylate,432 propargyl methacry-
late,433 and several other olefinic side chain (meth)acrylates and styrenes.347,421,434 Carefully controlled polymerization condi-
tions are necessary in order to suppress side reaction of the pendent unsaturation with the growing chain end resulting in
crosslinking reactions.421,432,347,434,435 6-allyl-e-caprolactone has been polymerized and copolymerized with e-caprolactone by
ROP catalyzed by stannous octoate. Modification with a variety of thiols and compatibility with azide-alkyne click chemisty was
demonstrated in many cases.421
Residual vinyl groups in crosslinked poly(divinylbenzene) microspheres are accessible through radical thiol-ene chemistry
producing functionalized microparticles.436 Copolymerization of styrenic derivatives carrying alkenes with maleic anhydride gave
polymers with two orthogonally reactive groups which could be addressed with amines (maleic anhydride) and thiols
(alkenes).437
Another especially designed monomer for thiol conjugation is pyridyl disulfide ethyl methacrylate, which was successfully
polymerized by ATRP438 and RAFT.439 In a diblock copolymer with N-hydroxysuccinimidyl methacrylate, both blocks could
independently be addressed with thiols and amines, respectively, in a one-pot reaction. A styrenic derivative carrying two pyridyl
disulfide groups offered the possibility to easily attach thiolated PEG side chains to a water soluble copolymer, without endan-
gering the integrity of acetal bridges within the polymer. Upon pH responsive cleavage of the acetal groups, the bio-inspired
polymeric carriers became membrane-disruptive and were studied for a direct cellular uptake.440

4 Conclusions and Outlook

Polymer analogous reactions represent a synthetically very appealing approach for the synthesis of functional polymers. Different
synthetic concepts of organic reactions are merging in polymer science leading toward the synthesis of architecturally well-defined
multifunctional polymers. The different classes of reactions provide the synthetic polymer chemist with tools of unprecedented
precision, thereby opening the doors for materials synthesis in an interdisciplinary world. Even though, the idea of polymer
analogous reactions as well as the chemistries employed is a rather old topic, it appears that this research topic of polymer
chemistry gains a dramatic new momentum and we can look forward to future developments in high precision polymer synthesis.
 Polymer Analogous Reactions 21

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