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Standing on the shoulders of Hermann Staudinger: Post-polymerization modification from past to present†
Kemal Arda Günay,
Ecole Polytechnique Fédérale de Lausanne (EPFL), Institut des Matériaux and Institut des Sciences et Ingénierie Chimiques, Laboratoire des Polymères, Bâtiment MXD, Station 12, CH-1015 Lausanne, Switzerland
Ecole Polytechnique Fédérale de Lausanne (EPFL), Institut des Matériaux and Institut des Sciences et Ingénierie Chimiques, Laboratoire des Polymères, Bâtiment MXD, Station 12, CH-1015 Lausanne, Switzerland
Ecole Polytechnique Fédérale de Lausanne (EPFL), Institut des Matériaux and Institut des Sciences et Ingénierie Chimiques, Laboratoire des Polymères, Bâtiment MXD, Station 12, CH-1015 Lausanne, Switzerland
This Highlight is based in on a chapter entitled “History of post-polymerization modification” published in the book “Functional Polymers by Post-Polymerization Modification—Concepts, Guidelines, and Applications” (P. Théato, H.-A. Klok, eds.), Wiley-VCH, in press.
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The history of post-polymerization modification also known as polymer analogous modification or reaction is arguably as long as the history of polymer science. As early as 1840, Hancock and Ludersdorf independently reported the transformation of natural rubber into a tough and elastic material upon treatment with sulfur.1 In 1847, Schönbein exposed cellulose to nitric acid and obtained nitrocellulose,2 which was later employed as an explosive. In 1865, Schützenberger prepared cellulose acetate by heating cellulose in a sealed tube with acetic anhydride. The resulting material has found widespread use as photographic film, artificial silk, and membrane material, amongst others.3 Although the post-polymerization modification of these natural polymers was widely used in the late 19th and early 20th century, the nature of these materials and their modification reactions were only poorly understood. This comes as no surprise as it was at the same time that Hermann Staudinger, one of the pioneers of modern polymer science, was struggling to gain acceptance for the notion of the existence of macromolecules.4 Staudinger also developed the concept of post-polymerization modification, which he termed as “polymer analogous reactions.” Detailed studies of the hydrogenation of rubber5 and polystyrene6 led to the definition of a polymer analogous reaction as “transformation of a polymer into a derivative of equivalent molecular weight.”7 He also referred to it during his Nobel prize lecture: “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, ….”4 Clearly, his early conception laid the foundation to use these reactions as an attractive approach to fabricate functional materials.
The general acceptance of the concept of macromolecules as proposed by Staudinger also marked the beginning of an increased use of post-polymerization modification reactions to engineer synthetic polymers. Serniuk et al. reported the functionalization of butadiene polymers with aliphatic thiols via thiol-ene addition in 1948.8 Chlorinated polystyrene-divinylbenzene beads were first used in the 1950s as ion exchange resins9 and later by Merrifield to develop solid phase peptide synthesis.10 The modification of halogenated or lithiated poly(meth)acrylates was first investigated in the early 1960s11, 12 and followed by Iwakura's studies on the post-polymerization modification of polymers bearing pendant epoxide groups.13–15 Although many of the early developments in polymer science can be attributed to the utilization of post-polymerization modifications, the variety of chemical reactions allowing quantitative post-polymerization modification was relatively limited (Fig. 1). This, however, rapidly changed with the emergence of living/controlled radical polymerization techniques such as ATRP, RAFT, NMP, and SET-LRP (only the abbreviations will be included in text, as there will be a list of abbreviations in the Highlight article). since the early 1990s.16–20 The improved functional group tolerance of these methods when compared with conventional polymerization techniques allowed the preparation of well-defined polymers bearing a wide variety of functional groups that can be quantitatively and selectively modified using relatively mild conditions without any side reactions. The emergence of living/controlled radical polymerization techniques coincides with the discovery/revival of several chemoselective coupling reactions such as CuAAC, thiol-ene addition, and many others, which are now commonly referred to as “click” reactions. Together these two developments provide the basis for the explosive growth in use and versatility of post-polymerization reactions since the 1990s.
This Highlight article aims to give an account of the evolution of post-polymerization modification from the early days into the modern synthetic toolbox, which it represents for nowadays polymer chemists. Emphasis is placed on the side chain post-polymerization modification of reactive polymer precursors. Polymer end-group modification, in contrast, which is also frequently employed and for which a range of dedicated strategies is available21–29 is not explicitly discussed. This article consists of two parts. The first part will provide a short discussion of post-polymerization modification from a mechanistic perspective. In the second part, the evolution of eight main classes of post-polymerization modification reactions will be outlined (Scheme 1). For the selection of these reactions, strategies that involve the use of, for example, poorly controlled nucleophilic substitution reactions and the modification of relatively inert groups, such as alcohols and carboxylic acids were not considered. Instead, emphasis was placed on readily available reactive groups that do not require an additional deprotection step before post-polymerization modification.
While various organic reactions can be utilized in post-polymerization modification, this section will provide a general classification based on mechanistic aspects. These can be divided into additions, substitutions, eliminations, and isomerizations.
Addition reactions that are used in post-polymerization modifications are often identical to their small molecule counterparts. As such, a functional group on the polymer will react with, in most cases, a small molecule in an addition reaction. This class encompasses the hydrogenation of unsaturated polymers. Examples are the hydrogenation of polystyrene30 and polydienes31 such as 1,4-polybutadiene32 or poly(1-pentenylene).33 Similarly, the halogenation and hydrohalogenation of unsaturated polymers, in particular the bromination of polybutadiene, has been used for the preparation of flame retardant materials.34 The addition of small molecules to a polymer via a radical chain reaction has been employed for the addition of CCl4,35, 36 thiols,37–39 or phosphites40 onto unsaturated polymers. Another example is the functionalization of butadiene polymers with aliphatic thiols via thiol-ene addition as reported by Serniuk et al.8 But also the epoxidation of unsaturated bonds, e.g. epoxidation of polybutadienes,41 and concerted addition reactions, for example, -ene addition of maleic acid onto unsaturated polymers,42 belong to the class of addition reactions on polymers. A final example of the utilization of addition reactions is the post-polymerization modification of polymers bearing pendant epoxide groups.13–15
By far, substitution reactions are the most important class of reactions that are utilized in post-polymerization modifications. This comprises the chlorination of polyethylene via a free radical substitution.43 But also esterification, amidation, and hydrolysis reactions of poly(acrylic acid) and poly(methacrylic acid) derivates find frequent application in post-polymerization modification.44–46 Esterification plays an important role in the modification of cellulose,47 while the hydrolysis of poly(vinyl acetate) represents the only suitable synthesis of poly(vinyl alcohol). In contrast, oxidations and reductions find only limited use in post-polymerization modification, with examples being the reduction of poly(N-acetylethyleneimines) yielding poly(N-alkylethyleneimines)48 or the oxidation of poly(vinyl alcohol) with NaOCl yielding poly(enol-ketone).49 Functionalized polystyrenes have been prepared by various substitution reactions, which include amination and quaternization of chloromethylated polystyrene,50–52 Friedel-Crafts reactions on polystyrene,53–55 sulfonation of polystyrene,56 as well as the lithiation of polystyrene.57–61 Other examples include the chlorination of cross-linked polystyrene-divinylbenzene beads10 as well as the modification of halogenated or lithiated poly(meth)acrylates.11, 12
Post-polymerization modification on the basis of eliminations reactions has also been performed.62, 63 These can be listed as dehydrochlorinations, dehydrogenations, and dehydrations resulting in unsaturated—ideally conjugated—polymers. Examples encompass dehydrochlorination of poly(vinyl chloride) or dehydration of poly(vinyl alcohol) both yielding polyacetylene. But also cyclodehydration reactions find common use in the synthesis of polybenzoxazoles and polyimides.
According to IUPAC, a configurational change is usually not referred to as a chemical modification, but it is worthwhile to be considered in this context. Even though, isomerizations result in a change of the chemical structure, the molecular weight of the macromolecules remains constant. In principle, one can distinguish between configurational isomerizations, constitutional transformations, and exchange equilibria. Polydienes undergo a cis–trans isomerization triggered through UV irradiation in the presence of radical transfer agents.64 More commonly polymers with chromophoric groups have been utilized for isomerizations. In particular, polymers containing azobenzene moieties featuring the cis–trans isomerization are readily investigated.65–73 Treating isotactic poly(isopropyl acrylate) with catalytic amounts of sodium isopropylate resulted in atactic poly(isopropyl acrylate).74 Cyclizations as constitutional transformations have also been described, with the prime example of polyacrylonitrile, which undergoes a cyclization when heated in an inert atmosphere to 200 to 300 °C.75
POST-POLYMERIZATION MODIFICATION REACTIONS
This second part will discuss the evolution of eight of the most frequently used classes of reactions for the post-polymerization modification of synthetic and biological polymers.
Post-polymerization Modification via Thiol-ene Addition
The anti-Markovnikov addition of thiols to alkenes is usually mediated by a radical source or by UV irradiation.76 One of the earliest systematic studies regarding the post-polymerization modification of polyBu via radical thiol addition was reported by Serniuk et al. in 1948.8 They proposed that only the vinyl groups generated by 1,2-addition of butadiene units (i.e. pendant vinyl groups) were functionalized, which was later confirmed by Romani et al.77 Since these early studies, thiol-ene post-polymerization modification has developed into a powerful synthetic tool. Table 1 provides an overview of different alkene functional polymers that have been used as substrates for post-polymerization modification.
Table 1. Post-polymerization Modification of (co)Polymers via Radical Thiol Addition
A drawback of the thiol-ene addition to poly(1,2-Bu) is that due to the close proximity of the neighboring vinyl groups, the radical formed after the addition of the thiol may attack an adjacent vinyl group, leading to an intramolecular cyclization.79 One possibility to suppress this side reaction is to carry out the post-polymerization modification at low temperature and at relatively high concentrations.83 Gress et al. further illustrated that by increasing the distance between pendant alkene groups, intramolecular cyclization can be suppressed.81 This was demonstrated by the post-polymerization modification of poly2Box, which was quantitatively modified using 1.2 to 1.5 eq. thiol under mild conditions (radicals generated with UV light at room temperature).
Radicals that mediate the thiol-ene addition can be generated either by thermal or photochemical initiation. Campos illustrated that although both initiation pathways lead to the complete conversion of pendant alkenes, milder conditions and shorter reaction times are sufficient when photoinitators are used (Scheme 2).82 Furthermore, they also demonstrated the orthogonality of the radical thiol addition and CuAAC and the compatibility of the alkene group with CRP techniques.
Recently, Ates et al. reported the preparation of an unsaturated polyester (polyGI) via enzymatic ROP of the corresponding cyclic ester monomer containing backbone alkene groups. They demonstrated that these backbone alkene groups are also susceptible to post-polymerization modification via thiol-ene addition, however, near quantitative conversion of these groups is only possible when a high excess of thiol is used, as these backbone alkene groups have decreased reactivity compared with pendant alkenes.90
Post-polymerization Modification of Epoxides, Anhydrides, Oxazolines, Isocyanates
Epoxides, anhydrides, oxazolines, and isocyanates represent a class of reactive groups that have a long history in polymer science. A common feature of these groups is that they are tolerant toward radical based polymerization techniques, which explains why polymers containing these groups were extensively used for the synthesis of functional polymers via post-polymerization modification until already since the 1960s/1970s. Table 2 provides an overview of polymers bearing epoxide, anhydride, oxazoline, and isocyanate groups that have been used for post-polymerization modification.
Table 2. Post-polymerization Modification of (co)Polymers Bearing Epoxide, Anhydride, Oxazoline, and Isocyanate Groups
Although thermosetting epoxy resins were already used in the 1950s for many applications such as tissue embedding for electron microscopy92 or as dental restoratives,93 it was not until the 1960s when Iwakura et al. were the first to systematically study the post-polymerization modification of polymers containing epoxide groups, such as polyGA and polyGMA. They reported that the post-polymerization modification of polyGA or polyGMA with simple secondary amines (1.0–4.0 equiv. of amine) proceeded with low to moderate yields.13–15 Kalal et al. illustrated in 1974 that the post-polymerization modification via epoxide ring opening can be catalyzed by a tertiary amine (TEA) and reported up to 80% conversion of epoxide groups of polyGMA with carboxylic acids in the presence of TEA.94 More recently, Barbey and Klok exploited the catalytic effect of tertiary amine groups on epoxide ring opening by preparing polyGMA-co-polyDMAEMA brushes, which contained pendant tertiary amine groups that were demonstrated to accelerate the rate of post-polymerization modification via epoxide ring opening with amines in aqueous media at room temperature.95 A drawback of epoxide-functionalized polymers is that they are prone to cross-linking upon modification with primary amines due to the reaction between the secondary amines formed after the epoxide ring opening with another unreacted epoxide group.96 While amines are most frequently employed for the post-polymerization modification of polymers bearing epoxide groups, epoxide groups are also reactive toward for example alcohols and carboxylic acids.94, 97
Maleic anhydride (MAn) copolymers have attracted significant attention since the late 1970s and early 1980s with the work carried out by Maeda et al., who prepared the anticancer agent poly(styrene-co-maleic anhydride) conjugated neocarzinostatin (SMANCS).99, 100 Functionalization of Man copolymers with undemanding primary amines was reported to proceed almost quantitatively at ambient temperatures,101, 103, 104 whereas N-substituted maleimide formation was observed at elevated temperatures upon ring closure of the maleamic acid (i.e. amine modified MAn).117, 118
Polymers bearing pendant oxazoline groups can be prepared by the polymerization of VDM, which was first illustrated by Taylor et al. in the early 70′s.119 Similar to MAn copolymers, quantitative modification of polyVDM with amines is possible at room temperature.108, 109 Furthermore, the hydrolytic stability of the oxazoline group allows aqueous post-polymerization modification without side reactions.107 For instance, this selectivity toward amines in aqueous media was utilized for rapid and high-density immobilization of protein A onto polyVDM-functionalized beads at pH 7.5.120
The isocyanate group is another attractive handle that allows post-polymerization modification with amines, alcohols, and thiols. While the modification of isocyanates with amines or thiols proceeds rapidly and quantitatively and can be further facilitated by the addition of TEA or DBU, quantitative conversion with alcohols is only possible in the presence of a catalyst such as DBTDL (1 in Scheme 3).112, 114 TMI, VI, and MVI are examples of commonly employed monomers for the synthesis of isocyanate containing (co)polymers (Table 2). A special feature of these isocyanate monomers, which they share with MAn, is that their homopolymerization is more demanding compared with their copolymerization. While the homopolymerization of VI by conventional polymerization techniques can be accompanied by a variety of side reactions due to the competing reactivity of the vinyl double bond and isocyanate group,121 TMI homopolymerization does not yield high molecular weight polymer due to the steric hindrance imposed by the α-methyl group to the radical propagation site.122, 123 Beyer et al. synthesized MVI-alt-MAn, in which the isocyanate and anhydride groups were sequentially modified with an alcohol and amine respectively (1 in Scheme 4).112 More recently, Flores et al. reported that a novel isocyanate containing monomer (AOI) can be readily homopolymerized via RAFT polymerization115 unlike VI, TMI, and MI, and Hensarling et al. demonstrated the quantitative modification of polyAOI with thiols within minutes at room temperature.116
Post-polymerization Modification of Active Esters
The synthesis and post-polymerization modification of active ester polymers was pioneered by Batz et al.124 and Ferruti et al. in the 1970s.125 Since then, a broad variety of active ester polymers has been developed utilizing essentially the complete spectrum of available polymerization techniques (Table 3). The reaction of active ester polymers with amines is probably the most frequently used post-polymerization modification strategy. Amines are most often used for the post-polymerization modification of active ester polymers since they can react selectively even in the presence of weaker nucleophiles, such as alcohols.
Table 3. Post-poymerization Modification of (co)Polymers Bearing Active Ester Groups
The most frequently employed active ester polymers are N-hydroxysuccinimide derivatives (NHS), such as polyNAS and polyNMAS. A drawback of these polymers, however, is that their solubility is limited to DMF and DMSO. Furthermore, the post-polymerization modification of these active ester polymers can be accompanied by side reactions, such as succinimide ring opening or the formation of N-substituted glutarimide groups.151 These side reactions can be suppressed by using an excess of amine or proton acceptor, such as TEA or DMAP.152
Polymers bearing pentafluorophenyl (PFP) ester groups are attractive alternatives to NHS ester polymers, as polyPFMA was demonstrated to have higher reactivity, better hydrolytic stability and is soluble in a wide range of solvents as compared with polyNMAS.46, 140, 153 Nevertheless, similar to NHS, PFP ester homopolymers are insoluble in water, and thus cannot be functionalized in aqueous media.
Another class of active ester polymers that is an interesting alternative to polyNAS and polyNMAS are those that contain thiazolidine-2-thione (TT) groups. Šubr et al. reported that polymers bearing thiazolidine-2-thione (TT) groups allow rapid aminolysis in aqueous media while displaying a good hydrolytic stability.147 The difference between the rates of aminolysis and hydrolysis was found to be greatest between pH 7.4 and 8.0. A drawback of TT esters is that they display low selectivity between amines and thiols under identical reaction conditions.
Active ester polymers based on 4-vinyl benzoate (VB) often exhibit higher reactivity compared with their (meth)acrylate analogues. For instance, Desai et al. used polyNSVB to fabricate dendrimer-functionalized polymers with high yields.126 Nilles and Theato illustrated that unlike polyPFMA and polyPFA, polyPFVB can quantitatively react with less nucleophilic aromatic amines.144, 154 In a subsequent study, the same authors prepared statistical and block copolymers from PFVB and PFMA and demonstrated that these polymers could be sequentially modified with an aromatic and aliphatic amine, respectively (2 in Scheme 4).145
An alternative strategy toward orthogonally functionalizable active ester based polymers was developed by Cengiz et al.135 These authors prepared copolymers of NMAS with PEGMA and the carbonate functional monomer SCEMA (3 in Scheme 4). Exposure of this copolymer to allylamine in THF at room temperature lead to complete conversion of the carbonate groups with near quantitative preservation of the active ester moieties, which could be subsequently modified by adding an excess of propargylamine at 50 °C.
Post-polymerization Modification via Thiol-Disulfide Exchange
Thiol-disulfide exchange is ubiquitous in biology where it is involved in a variety of processes such as modulation of enzyme activity,155 viral entry,156 and protein folding.157 Although this reaction has been known since the 1920s from a study of Lecher on alkalisulfides/alkalithiols158 as well as from the work of Hopkins on the biochemistry of glutathione,159 it was not until the late 1990s when Wang et al. first demonstrated that polymers bearing pyridyl disulfide groups can be employed as an appealing platform for post-polymerization modification via thiol-disulfide exchange as it can proceed quantitatively and selectively in mild conditions and in aqueous media below pH 8.160 Table 4 gives an overview of various pyridyl disulfide containing polymers that have been used as a substrate for post-polymerization modification.
Table 4. Post-polymerization Modification of (co)Polymers via Thiol-Disulfide Exchange
Thiol-disulfide exchange post-polymerization modification is strongly pH dependent. There are opposing claims, however, regarding the optimum pH for quantitative functionalization. While Wang et al. first illustrated that the rate of post-polymerization modification is highest between pH 8 and 10,160 Bulmus et al. later reported higher conversions of pyridyl disulfide groups with terminal cysteine residues at pH 6 compared with pH 10.161
One of the assets of the thiol-disulfide exchange reaction is that it allows to introduce functional groups via a disulfide bond that is reversible and can be cleaved, either via reduction or with an exchange with another thiol. For instance, Zugates et al. first demonstrated the reduction of pyridyl disulfide containing poly(β-amino ester)s modified with glutathione in intracellular media, which led to a 50% decrease in the DNA binding capacity of the polymer.162 Ghosh et al. later illustrated the quantitative release of incorporated thiols from the polymer backbone upon reduction of the newly formed disulfide bonds by DTT.163 Furthermore, they also illustrated the orthogonality of thiol-disulfide exchange and aminolysis of active esters (4 in Scheme 4).
Post-polymerization Modification via Diels-Alder Reactions
The cycloaddition reaction between a diene and a substituted alkene (dienophile), which was discovered in 1928 by Diels and Alder and distinguished with a Nobel Prize in Chemistry in 1950,165 emerged as an attractive tool for post-polymerization modification in the 1990s.166, 167 The Diels-Alder reaction fulfills the “click” criteria,168 as it can proceed with quantitative yields without any side reactions, is tolerant to a wide variety of functional groups and orthogonal with many other chemistries, such as CuAAC.169, 170 Furthermore, many Diels-Alder reactions are reversible and the Diels-Alder adduct can decompose into the starting diene and dienophile at higher temperatures as compared with the temperature required for forward reaction.171 The reversibility of the Diels-Alder reaction has been extensively utilized to prepare thermoresponsive macromolecular architectures such as gels166, 172–175 as well as the synthesis of dendrimers176 and smart copolymers.177
Polymers that can be postmodified using Diels-Alder chemistry can either be prepared via a precursor route based on the deprotection of masked maleimide groups following polymerization of the corresponding monomers175, 178 or by direct polymerization of the monomers containing unmasked dienes, such as furan or anthracene groups (Table 5). In an early example, Laita et al. demonstrated the post-polymerization modification of various furan containing polyurethanes in which the furan group was either incorporated in the backbone or in the side chain of these polymers. While modification of the pendant furans with maleimides proceeded to completion, conversion of backbone furan groups was limited to 30 to 60% at 40 °C using 3.0 eq. of the maleimide.179 Jones et al. later reported higher conversions (60–85%) of the post-polymerization modification of backbone anthracene groups with maleimides in stoichiometric conditions when the reaction temperature was increased to 120 °C.173 Kim et al. prepared copolymers bearing pendant anthracene groups, which were quantitatively modified with relatively bulky maleimide-functionalized chromophores at 120 °C by using stoichiometric amount of maleimide.180
Table 5. Post-polymerization Modification of (co)Polymers via Diels-Alder Reactions
Another interesting class of functional groups for the Diels-Alder post-polymerization modification are pyridinedithioesters. These are attractive since they can act both as a chain transfer agent in RAFT polymerization183 as well as a heterodienophile in [4 + 2] cycloaddition.184, 185 Bousquet et al. exploited this unique feature to quantitatively modify polyttHA at 50 °C by using 4.0 to 5.0 eq. of t-butyl acrylate (polytBA) (Mn = 3500–13,500 g/mol), which was prepared by RAFT polymerization by using benzyl pyridine-2-yl dithioformate as a chain transfer agent.182
Post-polymerization Modification via Michael-Type Addition
Michael-type addition reactions have been frequently employed in polymer science starting from the early 1970s to fabricate a variety of macromolecular architectures including step-growth polymers, dendrimers, and crosslinked networks.186 However, it is only more recently that this reaction has found use to prepare side chain functional polymers as only CRP techniques enable the preparation of polymers bearing Michael acceptors, such as acrylates, maleimides, and vinyl sulfones. Table 6 gives an overview of different polymers that have been used in Michael-type post-polymerization modification. Post-polymerization modification of these polymers with thiols is particularly attractive, as this reaction can proceed quantitatively and selectively in aqueous media at room temperature.187
Table 6. Post-polymerization Modification of (co)Polymers via Michael-Type Addition
Rieger et al. first demonstrated the synthesis of acrylate bearing polyesters via ROP.188 Quantitative functionalization of these polymers without any backbone degradation was achieved in the presence of a large excess of thiol and pyridine (10.0–25.0 eq.) at room temperature. Weck et al. showed that unmasked maleimide groups are compatible with ROMP conditions. Quantitative modification of maleimide bearing poly(norbornene) based terpolymers was achieved at 25 °C when 2.0 eq. of the thiol were used. Furthermore, these authors also demonstrated that Michael-type addition, CuAAC, and hydrazone formation are orthogonal chemistries that allow both sequential as well as one-pot modification with different functionalities (5 in Scheme 4).191 Polyesters bearing α,β unsaturated ketone groups have recently been prepared by copolymerization of glycidyl phenyl ether and bicyclic bis(δ-butryolactone) monomers by Ohsawa et al. These polyesters contain pendant isopropenyl groups that were shown to react quantitatively with thiols in stoichiometric conditions when AlCl3 was used as a catalyst at room temperature.190 Wang et al. prepared vinyl sulfone functionalized poly(ester carbonate)s by ring-opening copolymerization of a vinyl sulfone carbonate monomer with ε-caprolactone, L-lactone, or trimethylene carbonate. Post-polymerization modification was reported to proceed quantitatively even with bulky thiols (2.0 eq. of the thiol used) at room temperature.192
Post-polymerization Modification via Azide Alkyne Cycloaddition Reactions
The discovery that the Huisgen 1,3-dipolar cycloaddition (CuAAC) reaction between azides and alkynes can be carried out at mild conditions and in regioselective fashion when Cu(I) salts are used as catalyst can be considered as the origin of what is now commonly referred to as “click chemistry.” As already predicted by Rostovtsev et al.193 and Tornøe et al.194 in 2002, the scope of the CuAAC reaction turned out to be enormous. CuAAC often proceeds with quantitative yields both in aqueous and organic media under mild conditions and is orthogonal with almost any type of functionalization strategy. Table 7 gives an overview of azide and alkyne functionalized polymers that have been postmodified using CuAAC.
Table 7. Post-polymerization Modification of (co)Polymers via Azide/Alkyne Cycloaddition Reactions
In 2004, Binder and Kluger reported that the ROMP of oxynorbonenes bearing unmasked alkyne groups proceeds with poor control owing to the competing reactivity of the alkyne group with the ROMP catalyst. This problem was circumvented by preparing alkyne bearing polymers via a precursor route that involves side chain modification of a precursor poly(norbornene) via alkylation with propargyl bromide. These authors also prepared azide bearing poly(oxynorbonene)s via another precursor route based on the modification of pendant alkyl bromide chains with sodium azide.218 In 2005, Parrish et al. first demonstrated the compatibility of the alkyne groups with ROP by copolymerizing αPδVL with ε-caprolactone. Quantitative modification of the alkyne groups was achieved with an azide-functionalized PEG (Mn = 1100 g/mol) in stoichiometric conditions at 80 °C when CuSO4·5H2O/Naasc was used as a catalyst.203 Sumerlin et al. illustrated that while an azide containing monomer (AzPMA) can be successfully polymerized with ATRP, polymerization of propargyl methacrylate proceeded with poor control presumably owing to the side reactions involving the pendant acetylene group. Modification of polyAzPMA proceeded quantitatively with a library of alkynes (1.1 eq. of the alkynes used) at room temperature in the presence of CuBr.195 Riva et al. reported the compatibility of the azide groups with ROP by preparing copolymers of an azide functionalized caprolactone (αN3εCL) with ε-caprolactone, which reacts quantitatively with propargyl benzoate (1.2 eq.) at 35 °C when CuI was used.196 The possibility to synthesize azide/alkyne functionalized polymers via direct polymerization of the corresponding monomers, as demonstrated in these last three examples, marked the onset of an explosive growth of the use of CuAAC post-polymerization modification strategy (Table 7).
A drawback of the CuAAC post-polymerization modification reaction is that removal of the copper catalyst can be demanding as it can form complexes with the triazole ring, which hampers the solubility of the functionalized polymer.197 Furthermore, toxicity of the copper catalyst to cells limits the applicability of CuAAC reaction in biological media.219, 220 An attractive, copper-free functionalization strategy is the strain-promoted azide alkyne cycloaddition (SPAAC) reaction.221 Xu et al. recently demonstrated that the functionalization of pendant azide groups of polyAzDXO via SPAAC reaches quantitative conversion at shorter reaction times compared to CuAAC and at lower equivalents of the cyclooctyne/alkyne used (Scheme 5).202
Post-polymerization Modification of Ketones and Aldehydes
Ketones and aldehydes can selectively react with primary amines, alkoxyamines, and hydrazines to form imines, oximes, and hydrazones, respectively. While imines are usually prone to hydrolysis, oximes and hydrazones are hydrolytically stable between slightly acidic to neutral pH.222, 223 Nevertheless, imines can be further converted to stable secondary amines via reductive amination under the presence of a reducing agent, such as borohydride derivatives.224, 225 Table 8 gives an overview of aldehyde and ketone functional polymers that have been modified via post-polymerization modification.
Table 8. Post-polymerization Modification of (co)Polymers Bearing Ketone and Aldehyde Groups
Although the preparation of polymers bearing pendant ketone groups was already reported by Overberger and Schiller231 and Tsurata et al.232 in the 1960s, these polymers have only recently found use as a platform for post-polymerization modification. Rabuka et al. prepared copolymers containing VMK and IMK both via FRP as well as via RAFT polymerization and demonstrated that the resulting polymers can be quantitatively modified with aminoxy-functionalized sugars at 95 °C when 2.8 eq. of the sugar used (Table 8).226, 233 Yang and Weck reported the synthesis of aldehyde and ketone functionalized polynorbornenes via Ru-catalyzed ROMP of the corresponding aldehyde and ketone substituted norbornene monomer.191, 227 Post-polymerization modification of the ketone substituted polymer with a library of hydrazines proceeded quantitatively at 25 °C. Barrett and Yousaf prepared a library of poly(ketoester)s, which contain ketone groups as part of the backbone of the polymer. Modification of these backbone ketone groups proceeded quantitatively with a library of oximes (1.5 eq. used) at room temperature (Scheme 6).230
First examples of the polymerization of monomers containing aldehyde groups were reported as early as in 1950s by Wiley and Hobson234 as well as by Schulz et al.235 The research activities of the latter authors concentrated on poly(acrolein), which was obtained via redox polymerization, and also included first studies on the post-polymerization modification of these polymers. Polymerization of unprotected aldehyde monomers by conventional polymerization techniques, however, can be accompanied by a variety of side reactions, due to the competing reactivity between the vinyl double bond and the aldehyde group.236 To overcome these problems, precursor routes based on deprotection of masked aldehyde functionalities, such as acetal or dioxolane groups following polymerization of the corresponding monomers by oxidation were employed to prepare well-defined aldehyde bearing polymers starting from 1980s.139, 237–240 In 2007, Sun et al. for the first time reported the direct RAFT polymerization of an unprotected aldehyde containing monomer (VBA).241 Fulton demonstrated that polyVBA prepared via RAFT polymerization can be quantitatively modified using an excess of various acylhydrazides. Fulton furthermore demonstrated the dynamic nature of the reaction between an aldehyde and n-acylhydrazone, and therefore, probed the potential of polyVBA as a platform for the construction of combinatorial libraries.228 Xiao et al. reported the preparation of polyFVFC-co-polyEGMA, which can be quantitatively modified with 1.2 eq. of O-benzylhydroxylamine at 25 °C.229
Post-polymerization Modifications via Other Highly Efficient Reactions
The previous sections have attempted to summarize the emergence and historical development of eight of the most prominent reactions that are used for post-polymerization modification. In addition to these more established post-polymerization modification reactions, there are also other reactions that have received less attention or which have been developed more recently. This final section provides an overview of several of these reactions (Table 9) and discusses their potential for post-polymerization modification.
Table 9. Post-polymerization Modification of (co)Polymers via Pd-Catalyzed Coupling, Atom Transfer Radical Addition, p-Fluoro Thiol, Acetal and Thiol-ene Reactions
The discovery of the catalytic effect of organopalladium compounds for the formation of stable C-C bonds with high yields and at milder conditions compared with many other coupling strategies, which was rewarded with Nobel Prize in Chemistry in 2010, has enormously expanded the scope of organic synthesis as well as polymer science. Although palladium catalyzed coupling reactions tolerate a wide variety of functional groups including halides, alkenes, alkynes as well as organoboron and organotin compounds,251–254 the post-polymerization modification of polymers bearing pendant phenyl halide groups with alkynes (Sonogashira coupling) has been investigated most extensively (Table 9). Stephens and Tour reported that the conversion of brominated poly(p-phenylene) with various alkynes proceeds with moderate to high yields at elevated temperatures when phenylphosphine-based palladium catalysts were used.242 Sessions et al. later demonstrated near-quantitative functionalization of low molecular weight polyBrS at room temperature when the reaction was mediated by [PdCl2(PhCN)2]. However, crosslinking of high molecular weight polyBrS was observed upon modification with 1-hexyne.243 Kub et al. extended the Pd-catalyzed post-polymerization modification to the functionalization of various hyperbranched polyI(PV-PE) copolymers.244
Another attractive reaction for the post-polymerization modification of polymers is atom-transfer radical addition (ATRA), which takes place between alkyl halides and alkenes in the presence of a transition metal catalyst and can be considered as a predecessor of ATRP.255 Lenoir et al. prepared poly(αClεCL-co-εCL) and investigated the modification of this polymer with various alkenes (Table 9).245, 246 They demonstrated that although ATRA post-polymerization modification is tolerant to many functional groups, such as alcohols, esters, epoxides, and carboxylic acids, the extent of modification can be limited by the competing reduction of C-Cl bonds to C-H bonds.247
The development of the CuAAC reaction has stimulated the search for alternative “click reactions.” Examples of “click” reactions that have recently emerged and which have found use for post-polymerization modification include pentafluorophenyl click,256 acetal click, and thiol-ene addition reactions (Table 9).257 A common feature of these reactions is that they proceed very rapidly and quantitatively at mild conditions. Becer et al. extensively studied the modification of polyPFS copolymers via pentafluorophenyl click reactions. Quantitative substitution of the p-fluoro position can be rapidly achieved both with amines and thiols, but milder conditions are sufficient when thiols were used (2 in Scheme 3).248, 249 Furthermore, quantitative modification with less nucleophilic aromatic thiols was also achieved at longer reaction times.250 Recently, Obermeier and Frey prepared a polyether derivative bearing pendant vinyl ether groups (polyEVGE), which was not only susceptible to modification via radical-thiol addition but could also be functionalized with alcohols to form side-chain acetal groups (3 in Scheme 3).86 These authors reported quantitative conversion of vinyl ether groups within 10 min under the presence of p-toluene sulfonic acid (PTSA) catalyst with an excess of benzyl alcohol at room temperature. Although the reaction between alkynes and thiols under the presence of a radical source is already known since then 1930s,258 it was only recently revived as a “click” reaction and started to find widespread use for the fabrication of macromolecular architectures.257, 259–261 Hensarling et al. illustrated that the post-polymerization modification of polyPgMA brushes with a library of thiols proceeded quantitatively within minutes under the presence of UV irradiation and photoinitiator at ambient conditions.262 Cai et al. showed that quantitative functionalization of polyPgMA brushes can both be achieved via thiol-ene and CuAAC reaction, whereas milder conditions are sufficient when thiol-ene modification was employed (4 in Scheme 3).217
Many of the early developments in polymer science can be attributed to the use of post-polymerization modification reactions. The (re)discovery of many highly efficient and orthogonal chemistries combined with the development of various functional group tolerant living/controlled polymerization techniques has enormously expanded the scope of post-polymerization modification and resulted in an enormous increase in the use of this approach to synthesize functional polymers. Looking at the developments in this field from an historical perspective, the aim of this contribution was to highlight significant advances and breakthroughs and to provide the reader with a flavor of what has been accomplished and all the possibilities that are yet to be explored.
Kemal Arda Günay was born in Ankara (Turkey) in 1989. He obtained his bachelor degree from Sabanci University (Istanbul) and master degree from Ecole Polytechnique Fédérale de Lausanne (Switzerland) in materials science and engineering. He currently works as a Ph.D. student under the supervision of Prof. Harm-Anton Klok at Ecole Polytechnique Fédérale de Lausanne.
Patrick Théato is Associate Professor for polymer chemistry at the University of Hamburg. He studied chemistry in University of Mainz (Germany) and Amherst (USA), and received his Ph.D. in 2001 from the University of Mainz with Prof. R. Zentel. After postdoctoral research with Prof. D.Y. Yoon (Seoul National University, Korea) and Prof. C.W. Frank (Stanford University, USA), he joined the University of Mainz as a young faculty member and completed his Habilitation in 2007. From 2009 to 2012, he held a joint appointment with the School of Chemical and Biological Engineering at Seoul National University within the world class university program. In 2011 he accepted a prize senior lectureship at the University of Sheffield, UK. Shortly after, he moved to University of Hamburg, Germany. He serves as an Editorial Advisory Board Member of “Macromolecules.” His current research interests include the defined synthesis of reactive polymers, block copolymers, design of multistimuli-responsive polymers, versatile functionalization of interfaces, hybrid polymers, polymers for electronics and templating of polymers.
Harm-Anton Klok is Full Professor at the Institutes of Materials and Chemical Sciences and Engineering at the Ecole Polytechnique Fédérale de Lausanne (EPFL) (Switzerland). He received his Ph.D. in 1997 from the University of Ulm (Germany) after working with Prof. M. Möller. After postdoctoral research with Prof. D. N. Reinhoudt (University of Twente) and Prof. S. I. Stupp (University of Illinois at Urbana-Champaign, USA), he joined the Max Planck Institute for Polymer Research in Mainz (Germany) in early 1999 as a project leader in the group of Prof. K. Müllen. In November 2002, he was appointed to the faculty of EPFL. Harm-Anton Klok is recipient of the 2007 Arthur K. Doolittle Award of the American Chemical Society (ACS) and is Associate Editor of the ACS journal “Biomacromolecules.”