50th Anniversary Perspective: Polymer Functionalization

Perspective pubs.acs.org/Macromolecules

50th Anniversary Perspective: Polymer Functionalization Eva Blasco,‡,§ Michael B. Sims,∥ Anja S. Goldmann,†,‡,§ Brent S. Sumerlin,*,∥ and Christopher Barner-Kowollik*,†,‡,§ †

School of Chemistry, Physics and Mechanical Engineering, Queensland University of Technology (QUT), 2 George St., Brisbane, QLD 4000, Australia ‡ Macromolecular Architectures, Institut für Technische Chemie und Polymerchemie, Karlsruhe Institute of Technology (KIT), Engesserstr. 18, 76128 Karlsruhe, Germany § Institut für Biologische Grenzflächen, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany ∥ George & Josephine Butler Polymer Research Laboratory, Center for Macromolecular Science & Engineering, Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States

ABSTRACT: The translation of small molecule chemistries into efficient methodologies for polymer functionalization spans several decades, enabling critical advances in soft matter materials synthesis with tailored and adaptive property profiles. The present Perspective exploresbased on selected examples50 years of innovation in polymer functionalization chemistries. These span a diverse set of chemistries based on activated esters, thiol−ene/yne processes, nucleophilic systems based on isocyanates, reactions driven by the formation of imines and oximes, ring-opening processes, cycloadditions, andin a recent renaissancemulticomponent reactions. In addition, a wide variety of chain types and architectures have been modified based on the above chemistries, often with exquisite chemical control, highlighted by key examples. We conclude our journey through polymer functionalization with thein our viewmost critically required advances that have the potential to move from “science fiction” to “science fact”.

1. INTRODUCTION At its heart, polymer chemistry is principally concerned with the production of interesting and useful materials, commonly through the polymerization of functional monomers. While polymerization chemistry has advanced remarkably in recent decades, postpolymerization modification has similarly evolved, allowing polymer chemists to leverage the might of synthetic organic chemistry for the generation of increasingly complex and functional macromolecules. Functionalization of a reactive polymeric precursor can often prove advantageous over direct polymerization of functional monomers, such as in the synthesis of a library of functional polymers from a single parent precursor, ensuring that all polymers in the series will share identical degrees of polymerization, tacticities, and molecular weight distributions as those of the reactive precursor. Postpolymerization modification further offers a route to the synthesis of polymers with pendent groups that would otherwise undergo side reactions under polymerization conditions or that would prove challenging © XXXX American Chemical Society

for processing or characterization. In view of these benefits and others that are discussed herein, we believe postpolymerization modification has matured to the extent that it and direct polymerization should be considered equally viable techniques for the preparation of functional polymers. Many seminal reports that have led to the current state of the art were published in Macromolecules, so it seems fitting that we would review this subject 50 years after the journal’s genesis. For much of its history, postpolymerization modification has been perceived as a “necessary evil”, that is, a process only to be considered when one is unable to synthesize a polymer by direct polymerization. This assertion has not always been unwarranted, as many modifications of the past would be considered rudimentary and unviable by modern standards. Nevertheless, the Received: March 2, 2017 Revised: May 23, 2017

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DOI: 10.1021/acs.macromol.7b00465 Macromolecules XXXX, XXX, XXX−XXX

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chemistry,2 featuring unique stability toward extreme chemical environments (e.g., strongly acidic, basic, oxidizing, and reducing conditions), compatibility with diverse functionalities, and accessibility from two of the most common functional groups in chemistry: amines and carboxylic acids. It therefore comes as little surprise that amides evolved as Nature’s connector of choice for the intricate molecular machinery of proteins. Chemists have long drawn inspiration from the elegance of biochemical processes, and the application of amides for the functionalization of synthetic macromolecules is no exception. However, the structural simplicity of the amide bond sometimes belies the synthetic complexity required to forge it. Amidation via direct condensation of amines and carboxylic acids typically requires the use of heat and a means of forcing the reaction equilibrium toward products, yet these conditions, while applicable to robust substrates like poly(2-oxazoline)s,3 are impractical for most common polymers. A number of approaches have therefore been developed to enable efficient amidation under mild conditions,4 and among these, activated esters (AEs, Scheme 1) have

development of both reversible-deactivation radical polymerization (RDRP) techniques and the advent of click chemistry fostered a renewal of interest in facile modifications that enable the synthesis of new functional polymers. As will become apparent from the examples discussed herein, the judicious combination of efficient chemical transformations with functional macromolecular scaffolds can afford a plethora of materials with compelling properties, multitudinous functionalities, and elaborate architectures. Furthermore, functional groups can be precisely installed at various locations on the polymer chain, some functionalization reactions can “self-report” when they are complete, and macromolecules can be coupled within seconds. Such a list of possibilities reads almost like a work of science fiction, but as will be shown herein, they have become well within reach of modern polymer science. The present toolbox of techniques for functionalizing both natural and synthetic polymers is vaster than ever, but this should not engender a sense of complacency. To the contrary, polymer chemists should remain vigilant in the search for new, even more precise routes to macromolecular modification, whether this entails retrofitting old chemistry for present demands or adapting novel reactions from the small molecule literature. This is certainly no small task, especially considering the astonishing rate at which new chemical transformations are currently being developed. Fortunately, the stringent demands for a useful postpolymerization modification can considerably narrow the scope of investigation. In particular, our vision of the ideal polymer functionalization reaction is one that parallels the highly stringent criteria of the click chemistry philosophy: rapid, innocuous, high yielding, orthogonal, amenable to large-scale purification, and efficient under equimolar conditions.1 In addition to these, several other themes have recently emerged that merit consideration, such as the ability to perform transformations under catalytic conditions, when possible, and the potential to perform multiple functionalizations from a single reactive moiety. These criteria should not be considered exclusive, as we do not intend to strictly regiment the definition of a “useful” modification. Yet, a reaction that exemplifies many of these features should arouse interest, as it may very well prove to be a worthwhile addition to the synthetic toolbox. The history and scope of polymer functionalization are immense, and it would be nearly impossible to fully discuss its intricacies in a single entry. Our objective is therefore not to provide a comprehensive enumeration of postpolymerization modification examples, but to broadly assess what we believe to be many of the most impactful chemical transformations investigated over the past 50 years within polymer science. Of course, these reactions include the venerable click chemistries such as copper-catalyzed azide−alkyne cycloadditions (CuAAC) and thiol−ene additions, but we also aim to emphasize those reactions that do not strictly satisfy the click criteria yet are still highly useful to the resourceful polymer chemist, such as amidations of activated esters and multicomponent reactions. We particularly strive to highlight both the specific synthetic utilities and drawbacks of each reaction in the context of polymer science. In doing so, we hope the reader will gain a strategic sense of postpolymerization modification in terms of both functional group compatibility and the appropriate pairing of modification and polymerization chemistries.

Scheme 1. Overview of Amidation Reactions Involving (A) N-Hydroxysuccinimide Esters and (B) Amidation of Pentafluorophenyl Esters

emerged as some of the most adaptable reagents for polymer functionalization. AEs have gained traction within the polymer community for a few reasons: (i) (meth)acrylic AEs offer a facile route to functional poly(meth)acrylamides, (ii) many AE moieties are stable toward radical polymerization, and (iii) the use of AEs can circumvent the relatively limited functional diversity of (meth)acrylate/(meth)acrylamide monomers (due to the reactivity of α,β-unsaturated carbonyls with many nucleophilic functional groups). Functionalization of polymeric AEs was arguably the first modification chemistry that exhibited the modern features that have come to be associated with click chemistry (e.g., modularity, efficiency, compatibility with mild conditions, and innocuousness of byproducts). Whereas many now-ubiquitous modifications such as CuAAC and thiol−ene addition (vide inf ra) were not developed until the codification of the click chemistry paradigm in the early 2000s,5,6 AE chemistry dates back to as early as 19597 and has fundamentally changed very little in the ensuing years. Since that time,

2. CURRENT STATUS: SELECTED EXAMPLES 2.1. Functionalization of Polymeric Activated Esters. The amide bond is one of the most versatile linkages in organic B


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Figure 1. Preparation of poly(allyl acrylamide) by both direct polymerization (right) and postpolymerization modification (left). Reactivity of allyl groups toward free radicals renders the direct polymerization route unviable due to the presence of cross-linking and chain transfer reactions. Postpolymerization modification affords a straightforward route to linear poly(allyl acrylamide) through the functionalization of poly(NHS acrylamide).

appropriate acrylamide monomers. These confluent factors enabled Whitesides to determine the optimal sialic acid content for inhibition as well as probe the effect of side-chain sterics on inhibition by synthesizing a number of iteratively functionalized polymers. The advent of RDRP16 marked a revolutionary moment in the history of polymeric AEs by enabling the preparation of reactive homo- and copolymers with predetermined molecular weights, narrow molecular weight distributions, defined end groups, and high compositional homogeneity. The synthetic opportunities were manifold. Providing one of the first examples of the power of AE chemistry when combined with RDRP, Hawker and his team explored steric effects in the functionalization of linear polystyrene with dendrons, a study made feasible by the ability to prepare well-defined copolymers of styrene and succinimidyl 4-vinylbenzoate by nitroxide-mediated polymerization (NMP).17 The reactive polymers bearing pendent NHS esters were functionalized with Fréchet-type polyether dendrons ranging in size from G2 to G5 (G = dendron generation). Interestingly, the functionalization efficiency was independent of dendron size for polymers containing up to 20% NHS ester-containing structural units, despite the vastly different sizes of the dendrons that were appended. The authors were also able to determine that functionalization with G5 dendrons was greatest for polymers containing 20% NHS ester-bearing structural units, but, somewhat counterintuitively, lower overall functionalization was observed for polymers with a higher concentration of AEs than this. These findings led them to conclude that there is a subtle interplay between the sterics of the dendron and the quantity of reactive sites along the polymer backbone, and it was the ability to precisely target specific incorporations of NHS ester units via RDRP that facilitated this finding. The next advance came from the group of Müller, who employed atom-transfer radical polymerization (ATRP) to prepare well-defined polyNHSMA as a precursor to model therapeutics based on poly(N-2-hydroxypropyl methacrylamide) (polyHPMA).18 This synthetic approach to polyHPMA was especially intriguing in view of the infamous propensity of monomeric HPMA toward autopolymerization, which necessitates careful thermal control during synthesis and storage. PolyNHSMA homopolymers were first functionalized with a naphthylamide model compound then fully converted to polyHPMA copolymers by treatment with excess of 1-amino-2propanol. Modification reactions were monitored by Fourier transform infrared spectroscopy (FT-IR) and found to proceed smoothly with minimal AE hydrolysis or side reactions. Despite this and other successes achieved through ATRP of NHS(M)A, reversible addition−fragmentation chain transfer (RAFT) polymerization of NHS(M)A has been markedly less successful, as homopolymerization of NHS(M)A commonly leads to unacceptably broad molecular weight distributions.8,9,19 Random and block copolymerizations have been explored to

however, the scope of AE chemistry has expanded from simple oligopeptide synthesis to include precise functionalization of synthetic macromolecules. Similarly, an incredible number of AE moieties have been exploited for polymer modification. Two particular AEsN-hydroxysuccinimide esters and pentafluorophenyl estershave been especially popular among polymer chemists and will be the foci of the upcoming section. For a more comprehensive survey of polymeric activated esters (polyAEs), the reader is directed to excellent landmark reviews by Théato in 20088 and 2016.9 Modification of N-Hydroxysuccinimide Esters. N-Hydroxysuccinimide (NHS) esters were initially developed in 1964 and were distinguished from other AEs in use at the time by the innocuous and water-soluble nature of the NHS byproducts.10 In 1972, Ringsdorf11 and Feré12 and their teams independently reported the first direct polymerizations of N-hydroxysuccinimide (meth)acrylate (NHS(M)A) and further modified the resultant NHS ester-bearing polymers with aliphatic amines such as cyclohexylamine, n-butylamine, piperidine, and allylamine. While it was noted that polyNHSMA unfortunately featured poor solubility (being only soluble in DMSO and DMF), nearly quantitative modifications were still accessible. The preparation of poly(N-allyl acrylamide)12 was especially important because it established what would later become one of the central utilities of postpolymerization modification (PPM): the ability to access polymers formally derived from monomers that cannot be directly polymerized without significant side reactions (Figure 1). Ringsdorf astutely noted that polyAEs were highly applicable to the preparation of pharmacologically active polymers11 in large part due to the ease of functionalizing them with biomolecules, foreshadowing a major research direction for the field in the ensuing decades. Examples of such work include functionalization of poly(NHSA-co-N-vinylpyrrolidone) with oligonucleotides13 and of NHS-polynorbornene with sugars.14 An exemplary study was conducted by the team of Whitesides, who elegantly exploited the reactivity of polyNHSA to prepare copolymers bearing sialic acid moieties that inhibited the interactions between influenza virus X-31 and erythrocytes, an important process in influenza infection.15 Far from being an inconvenient necessity, postpolymerization modification proved to be a critical technique for the synthesis and evaluation of a library of polymeric inhibitors for several reasons. First, preparing every inhibitor from a single polyNHSA feedstock ensured that all polymers in the library featured identical degrees of polymerization, molecular weight distributions, and tacticities (i.e., that of the parent polyNHSA). Additionally, PPM circumvented the common issue of compositional drift in free radical copolymerizations and likely ensured a more uniform distribution of sialic acid moieties along the backbone. Finally, PPM of polyNHSA enabled the rapid synthesis of a diverse library of functional polymers as there was no need to separately prepare C


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Figure 2. Overview of potential reactions of NHS (meth)acrylates. Reaction with amines largely produces the desired acyl substitution product (middle pathway), but side reactions involving succinimide ring-opening (top pathway) and imidation of adjacent structural units (bottom pathway) also appreciably occur. Such side reactions are more prevalent for the more sterically hindered poly(NHS methacrylates). Partially reproduced with permission from ref 22. Copyright 2006 Elsevier.

remediate of this drawback,19 and NHS-functional RAFT chain transfer agents (CTAs) have been exploited to achieve precise end-group modification. The R- and, to a lesser extent, Z-groups of many RAFT chain transfer agents (CTAs) contain carboxylic acid functional groups that are viable sites for the installation of an NHS moiety. When such a CTA is used for polymerization, the NHS ester functionality is conferred to the appropriate chain end(s). The first reported synthesis of an NHS ester-functional CTA came from D’Agosto, Charreye, and co-workers, who prepared an NHS ester-containing dithiobenzoate.20 Although no polymeric substrates were modified (the small molecule CTA was instead modified with various biologically relevant amines prior to polymerization), it was observed that the thiocarbonylthio moiety was retained without aminolysis during the reaction, an important outcome if subsequent chain extension or modification of CTA moieties is desired. Sumerlin and his team employed this strategy to prepare thermoresponsive polymer−protein conjugates by grafting NHS ester-terminated poly(N-isopropylacrylamide) (PNIPAM-NHS) to the amine residues of lysozyme (LYS). The effect of PNIPAM molecular weight, equivalents of PNIPAM-NHS, and solution pH on the extent of conjugation were studied.21 For lower molecular weight polymers (∼5000 g/mol), conjugation efficiencies could be improved by increasing the [PNIPAM]/[LYS] stoichiometric ratio, although the use of higher ratios led to the grafting of multiple chains. When polymers of 10 000 g/mol and higher were grafted, the amount of conjugation was independent of reaction stoichiometry, suggesting that the extent functionalization becomes limited by the size of the conjugated polymer when multiple reactive sites are present on a protein. Finally, selective modification of the LYS N-terminus could be achieved by maintaining a solution pH that protonated lysine residues (pKa = 10.5) while leaving the N-terminus (pKa = 7.6−8.0) intact. This result points to the surprising hydrolytic stability of NHS esters: the reactive moiety could be retained even under basic conditions as long as the solution was maintained below pH 9.0.

NHS esters have had a long and productive partnership with polymer chemistry, but they are not foolproof coupling agents. The fidelity of polyNHSMA modification was called into question when it was observed that amidation of polyNHSMA was plagued to a significant extent with two side reactions: (1) ringopening of NHS moieties and (2) formation of backbone glutarimides by attack of initially formed methacrylamides on adjacent NHS esters (Figure 2).22 These reaction pathways, while less thermodynamically favorable than the desired acyl substitution reaction, are believed to be promoted by steric congestion at the poly(methacrylate) backbone. Careful studies by Putnam and Wong revealed that these deleterious side reactions could be mitigated by increasing the reaction time, temperature, and equivalents of amine conjugate;23 nevertheless, the realization of these inefficiencies was a strong motivation for the adaptation of pentafluorophenyl esters for polymer modification. Modification of Pentafluorophenyl Esters. Pentafluorophenyl (PFP) esters were first introduced in 1973 as peptide synthesis agents that were more reactive than NHS esters with lower steric bulk than pentachlorophenyl esters.24 Somewhat surprisingly, PFP esters were not exploited for synthetic polymer functionalization until the seminal report by the group of Théato in 2005 on the preparation and modification of poly(PFP (meth)acrylate) (polyPFP(M)A),25 perhaps due to the widespread adoption of NHS esters at the time by the polymer community. Yet, polymeric PFP esters afford several advantages over their NHS ester counterparts. Unlike polyNHS(M)A, which is only soluble in dimethyl sulfoxide or N,N-dimethylformamide, polyPFP(M)A is fully soluble in most common polymerization and modification solvents. In addition, polyPFP(M)A can be partially modified with aromatic amines and alkoxides, although functionalization efficiencies are typically lower than those achieved with aliphatic amines. PolyPFP(M)A modification progress can be conveniently monitored by 19F NMR spectroscopy via loss of the characteristic pentafluorophenyl signals (Figure 3). Finally, PFP esters have been shown by De Geest et al. D


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with glucosamine and galactosamine.28 Quantitative PFP ester conversion was observed within an hour, although slow addition of reagents was necessary to maintain good polymer solubility. Styrenic polymers are also amenable to facile amine modification via PFP esters through the functionalization of poly(pentafluorophenyl 4-vinylbenzoate) (polyPFP4VB). These substrates were found to be more reactive than comparable (meth)acrylates to the extent that they could be quantitatively modified with even aromatic amines.31 Nilles and Théato cleverly exploited this disparate reactivity to achieve orthogonal functionalization of poly(PFPMA-co-PFP4VB), a copolymer containing only PFP moieties.32 The benzoate repeat units of both statistical and block copolymers were first selectively modified with aromatic amines, then modification of methacrylate units with isopropylamines afforded the fully functionalized copolymers (Figure 4). The adaptability of PFP ester chemistry is such that it has increasingly been used to prepare and modify polymers with a high degree of structural and functional complexity. Roth and co-workers used polyPFPA as a scaffold to synthesize polysulfobetaine copolymers randomly interspersed with hydrophobic repeat units,33 structures that would be exceedingly challenging to prepare by direct polymerization due to the large difference in comonomer polarities. In contrast, synthesis of these polymers by PPM was a straightforward, homogeneous, one-pot process, as hydrophobic content could be modified simply by changing the reaction stoichiometry. This allowed the upper critical solution temperature of the sulfobetaine copolymers to be tuned between 6 and 82 °C depending on the extent of hydrophobic modification. Hedrick and his team expanded the scope of PFP ester modification to polyurethanes through the synthesis of a PFP-ester containing diol that could be polymerized with diisocyanates.34 This protecting-group free approach enabled efficient access to a variety of functional PUs from a single pair of monomers, a highly useful approach given the commercial relevance of these materials. PFP Transesterifications. There have been efforts recently to expand the scope of polymeric PFP ester modification to include transesterification reactions along with the more common amidations. Functionalization reactions involving alcohols are surprisingly uncommon, likely a result of the sluggish nucleophilicity of the hydroxyl group. Nevertheless, the importance of alcohol functionalization is underscored by the fact that they are among the most ubiquitous functional groups in organic chemistry and are compatible with a wealth of other functionalities. Das and Théato developed a general approach to the preparation of functional polyacrylates from poly(PFPA)35 that employed a simple N,N-dimethylaminopyridine catalyst under mild conditions. Quantitative to near-quantitative conversion of PFP esters was observed for alcohols containing aliphatic, benzylic,

Figure 3. 19F NMR spectra of PFPA monomer (top) and polyPFPA (bottom). Reproduced with permission from ref 25. Copyright 2006 Elsevier.

to be superior coupling agents for the graf ting-to synthesis of polymer−protein conjugates.26 Conversely to the case with NHS ester-containing monomers, polymerization of PFP esters is typically not possible with ATRP9 due to hypothesized interactions between Cu(I) and PFP moieties. However, the combination of RAFT polymerization with PFP ester chemistry has been quite productive. Both dithiobenzoate27 and trithiocarbonate28 CTAs have been used to polymerize PFP(M)A, and PFP ester-bearing CTAs have been employed to prepare α-, ω-, and α,ω-functional telechelic polymers.29 Klok and his group showed that linear polyPFPA can be functionalized with a diverse range of amines, including oligoand polyethylene glycols, amino acids, sulfonates, and quaternary ammonium salts, work that again demonstrated the ability to rapidly generate a library of functional polymers with identical degrees of polymerization and molecular weight distributions via AE chemistry.30 At the same time, Boyer and Davis reported the one-pot synthesis of narrow MWD glycopolymers by quantitative postpolymerization modification of polyPFPA

Figure 4. Orthogonal modification of an all-PFP ester polymer with two different amines. More reactive PFP4VB units are selectively functionalized with aromatic amines (e.g., aniline), and the remaining PFPMA units are functionalized by treatment with aliphatic amines (e.g., isopropylamine). Reproduced with permission from ref 32. Copyright 2010 Wiley Periodicals, Inc. E


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Figure 5. Modification of polymers containing 4-dimethylsulfonium phenoxy triflate esters. Heating above 90 °C induced irreversible demethylation to yield unreactive 4-methylthiophenoxy esters.37

allylic, propargylic, acrylic, amino, and carboxylic functionalities, among others. Notably, this modification did not require harsh conditions and was highly efficient: DMF/N,N-dimethylaminopyridine was found to be the ideal solvent/catalyst system, and no more than 1.5 equiv of the alcohol was required to achieve maximum conjugation. Wagener and Sumerlin later reported the modular modification of segmented hyperbranched polymers containing poly(tetrafluorophenyl acrylate) (TFPA) linear segments with amine-bearing sulfonic and phosphonic acids as well as aminobisphosphonate alcohols.36 Interestingly, the transesterification proceeded to an appreciable, although not quantitative, extent without any additional catalyst. Other Activated Esters. The polymeric AE landscape continues to be dominated by NHS and PFP esters, but other AEs have recently emerged that feature more specialized reactivity. Kakuchi and Théato reported a temperature-responsive AE based on 4-dimethylsulfonium phenol that could be “turned off” by the application of heat (Figure 5).37 The key insight into this discovery was the observation that 4-dimethylsulfonium phenol triflate (pKa ≈ 7.5) underwent spontaneous demethylation at 90 °C to yield 4-methylthiophenol (pKa ≈ 10.0); the increase in pKa (and electron density of the phenyl ring) consequently resulted in decreased reactivity of the corresponding ester. Acrylate monomers containing this thermoresponsive moiety were found to be compatible with RAFT polymerization, and the modification of the resultant polymers with primary and secondary amines such as N,N-dimethylaminoethylamine, pyrrolidine, and isopropylamine proceeded to high conversions. When the polymer was heated to 120 °C, quantitative demethylation occurred, and the polymer was rendered unreactive toward amidation. The intrigue of this chemistry lies with the possibility for spatiotemporal control over modification, as heat can be applied at discrete locations and times much in the same manner as light. In an effort to improve the long-standing issue of hydrolytic sensitivity of NHS and PFP esters, Klok38 and, later, Nuhn, De Geest, and co-workers39 employed squaric esters (Scheme 2) for the conjugation of proteins to ATRP and RAFT polymers, respectively. In the former report, the ATRP of polyethylene glycol methacrylate (PEGMA) was initiated with an alkyl halidecontaining squaric ester to yield telechelic amine-reactive polyPEGMA.38 Bovine serum albumin (BSA) was then quantitatively

Scheme 2. Functionalization of Squaric Esters with Amines Yielding Squaramides

coupled to these polymers in pH 9.1 borate buffer, confirming the significant hydrolytic stability of ethyl squarate moieties. Later, De Geest and co-workers corroborated these findings by showing that poly(N,N-dimethylacrylamide) (PDMA) RAFT polymers bearing ethyl squarate end groups (PDMA-SQA) were more competent protein conjugation partners than similar NHS ester-terminated polymers (PDMA-NHS). The conjugation of lyzsozyme to PDMA-SQA in pH 11 borate buffer reached ∼90% conjugation, but a similar conjugation of Lys PDMA-NHS afforded ∼80% protein modification. This difference was further exaggerated when both polymers were incubated in demineralized water for 24 h prior to conjugation: PDMA-SQA retained its previous conjugation efficiency, whereas the extent of conjugation to PDMA-NHS dramatically dropped to ∼55%. To our knowledge, there have been few, if any, experimental studies into the origin of the unusual hydrolytic stability of squaric esters. Nevertheless, squarates and squaramides have been computationally determined to be weakly aromatic,40 a property that would likely reduce their hydrolytic susceptibility. In short, squarates are robust and competent agents for polymer−amine modification and should certainly be considered if functionalization under basic conditions is desired. 2.2. Thiol−X Modification. Thiol chemistry is an extraordinarily popular route to polymer modification due to the broad scope of commercially available functional thiols and large number of efficient transformations they can participate in (a class of reactions broadly termed “thiol−X” chemistries41). Sulfur-based modifications are perhaps the oldest transformations in polymer chemistry, dating back to Charles Goodyear’s invention of vulcanized rubber in 1844.42 Despite a history nearly as long as polymer science itself, however, thiol chemistry remained underutilized for postpolymerization modification until the turn of the millennium. The combination of exploding interest in highly efficient, modular transformations driven by the development of click chemistry1,5,43−45 with the pioneering work F


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Scheme 3. Overview of Selected Reactions That Have Been Used To Modify Polymers with Mercaptans: (A) Free-RadicalMediated Addition of Thiols to Nonconjugated Olefins (Thiol−Ene”); (B) Base-Catalyzed Addition of Thiols to Conjugated Olefins (“Thiol−Michael”); (C) Pyridyl Disulfide Exchange Resulting in Unsymmetrical Disulfide Formation; (D) Ring-Opening of Thiolactones Followed by Addition of Liberated Thiols to Olefins

by Bowman and the late Hoyle on thiol−ene polymerization,46,47 much of which was published by Macromolecules, led to the recognition that both radical and nucleophilic thiol reactions were promising routes to polymer side-chain and end-group functionalization. Indeed, a number of comprehensive reviews evaluating the utility of thiol reactions have been published,47−52 including one specifically on the interface of RAFT polymerization and thiol−ene modification.53 Numerous addition reactions are classified as “thiol−X” reactions, but we will predominantly discuss four transformations: radical addition of thiols to terminal alkenes and alkynes (“thiol−ene/yne”), Michael addition of thiols to electron-deficient olefins (“thiol− Michael”), thiol−disulfide exchange, and the more recently developed double modification of thiolactones (Scheme 3). Free Radical Thiol−Ene Reaction. The radical mechanism of thiol addition to olefins has been known since the 1930s,54 and the ensuing decades saw extensive development of this reaction as a powerful tool for small molecule and polymer synthesis.55 Initial applications of thiol−ene chemistry were largely focused on the modification of residual olefins in natural rubbers56,57 and polybutadiene (PB).58,59 Justynska and Schlaad provided an estimable demonstration of this chemistry in 2004, functionalizing the pendent double bonds of

poly(butadiene)-b-poly(ethylene oxide) that was prepared by living anionic polymerization with amine-, ester-, and carboxylic acid-containing mercaptans via a radical-mediated addition reaction.60 Like Ferruti (vide supra) and many others before them, they highlighted the potential of postpolymerization modification for the synthesis of polymers with mutually incompatible functionality and polymerization chemistry (i.e., polymers derived from anionic polymerization that bear protic functional groups). The utility of thiol−ene chemistry as a functionalization tool was later expanded to substrates prepared from the full suite of controlled polymerization techniques, including cationic,61 ring-opening,62 ring-opening metathesis,63 and even organometallic ring-opening64 polymerizations. Unfortunately, it has proven challenging to apply radical thiol−ene modification to polymers derived from RDRP due to the reactivity of both olefins and thiols under polymerization conditions. One route around this synthetic roadblock is ensuring the polymerizable and modifiable olefins have highly differentiated reactivities, thereby enabling direct polymerization of alkene-functional monomers. Hawker and his team demonstrated this approach by copolymerizing styrene and a homoallyl ether-functional styrenic monomer by both ATRP and RAFT polymerization and then modifying the resultant polymers with a G


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Figure 6. Preparation of PNIPAM with tunable lower critical solution temperatures (LCSTs) by thiol−ene/yne end-group modification. The observed LCSTs could be tuned within a 35 °C window depending on the end-group identity and extent of functionalization. Adapted with permission from ref 72.

suite of thiols.65 Interestingly, homoallyl groups were found to be stable toward polymerization whereas allyl groups yielded an insoluble gel, emphasizing the importance of a two-methylene spacer in the monomer structure. A more common approach to side-chain thiol−ene modification is installing either the thiol or the ene functionality by a separate postpolymerization modification. The team of Stenzel adopted this strategy, employing two sequential postpolymerization modifications to access carbohydrate-functionalized polymers.66 First, pendent hydroxyl groups of poly(2-hydroxyethyl methacrylate) were converted to alkenes by an acyl substitution reaction with 4-pentenoic anhydride. The newly installed internal olefins were then functionalized by the radical thiol−ene reaction of glucothiose to yield the targeted glycopolymers. McCormick and co-workers later used a similar method to build a library of functional water-soluble block copolymers, employing the highly efficient tin-catalyzed alcohol−isocyanate reaction to install allyl groups via allyl isocyanate on poly(N,N-dimethylacrylamide)-b-poly(2-hydroxyethyl acrylamide) RAFT polymers followed by radical thiol− ene reactions with various thiols.67 Free Radical Thiol−Yne Reaction. The sequential addition of two mercaptans to terminal alkynes, termed the “thiol−yne” reaction, is a relatively recent addition to the thiol−X toolbox, having been reintroduced to the polymer community by Anseth and Bowman in 2009,68 approximately 60 years after its initial discovery.69 A review by Lowe52 charts the history of this chemistry as a tool for both small molecule and macromolecular transformations. Similar to its olefinic counterpart, the thiol−yne reaction has predominantly been used to generate networks70 or other branched architectures like hyperbranched polymers71 with a high degree of fidelity, yet it is distinguished by the ability to append two units of a given functionality to a single alkyne, affording denser functionalization than can be achieved with thiol−ene modification alone. In an initial report on the efficacy of this reaction for polymer modification, Lowe and his group demonstrated that the cloud point of PNIPAM could be tuned between 25 and 34 °C by chain-end modification with hydrophilic or hydrophobic thiols.72 Both thiol−ene and thiol−yne reactions were employed to functionalize PNIPAM bearing either allyl or propargyl chain ends, respectively, and the ability to selectively modify polymers with either one or two thiols afforded a relatively large window of cloud points (Figure 6). Thiol−yne modification has particularly found usage in the synthesis of biologically active polymers, where controlling the degree of functionalization is critical to achieving desired therapeutic outcomes. Stenzel and co-workers reported the preparation of polymers conjugated with platinum drugs by modifying vinyl- and ethynyl-containing side chains with chelating mercaptosuccinic acid groups;73 Ren and Cheng

functionalized alkyne-containing polyesters synthesized through O-carboxyanhydride ring-opening polymerization with primary ammonium moieties to yield cell-penetrating agents;74 and Wooley and her team demonstrated that well-defined poly(phosphoesters) with pendent alkynes could be modified by thiol−yne chemistry to yield functional biodegradable polymers.75 A distinct advantage of radical thiol−ene/yne modifications is the ability to generate reactive thiyl radicals via photoinitation. Like its thermal variant, the photoinitiated thiol−ene reaction rose to prominence through the work of Hoyle and Bowman on photocured thiol−ene networks.46 While the mechanisms of the two reactions are virtually identical, Hawker and co-workers observed that photoinitiation afforded polymer modification that was significantly faster and more efficient in a broader scope of solvents than comparable thermal modifications.65 Light irradiation also offers unique spatiotemporal control that is difficult to achieve under traditional thermal conditions. Patton and his team applied this property to surface-bound polymer functionalization, showing that a variety of patterns with different chemical properties can be crafted from a single polymeric substrate through the combination of photomasking and judicious thiol modification. In an initial report, surface-tethered polymers bearing alkyne units were functionalized in a grid pattern by photoinitiated thiol−yne reactions using a Cu photomask; mask removal, surface washing, and thiol−yne modification of the unmasked substrate yielded a surface that was patterned with two different functional polymers.76 Although this report and others77 showed that thiol−ene/yne modification could be initiated in ambient sunlight, this chemistry unfortunately typically requires relatively harsh UV irradiation to achieve efficient functionalization. The group of Boyer offered an improvement in this regard, performing thiol−ene modification of poly(allyl methacrylamide) and PB under blue LED irradiation by using a Ru(bpy)3 photoredox catalyst and p-toluidine redox mediator.78 In polar aprotic solvents like NMP, DMF, or acetonitrile, the reaction displayed extraordinarily fast kinetics, with complete conversion achieved in 20 min. Additionally, the reaction could be cycled on and off by controlling the light irradiation, demonstrating the expected temporal control from this photoredox system. As there is presently significant interest in photoredox chemistry for controlled polymerization,79−81 we anticipate the development of further advances in visible-lightinitiated thiol−ene/yne chemistry. Nucleophilic Thiol−Ene Reaction. The base-catalyzed nucleophilic addition of thiols to electron-deficient olefins, also known as the thiol−Michael reaction (Scheme 5B), is considered complementary to its radical-mediated counterpart, with both comprising the larger subset of thiol−ene reactions.47,49,82 H


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Figure 7. Preparation and modification of maleimide-terminated polymers from RAFT polymerization. Chain-end maleimides are modifiable by both nucleophilic thiol−ene (top pathway) and Diels−Alder reactions (bottom pathway). Adapted with permission from ref 88.

end groups can be installed to enable facile functionalization with a range of nucleophiles. In fact, this route is preferable for the functionalization of polymers with biomolecules due to the ubiquity of mercaptans and amines in many biologically relevant compounds, including proteins. Sumerlin and co-workers developed one synthetic approach to Michael accepting polymers by reacting thiol-terminated PNIPAM (generated from the aforementioned RAFT CTA aminolysis reaction) with an excess of diethylene glycol bismaleimide to yield a maleimide-terminated polymer.88 This polymer was then further functionalized by either another thiol−Michael addition or a Diels−Alder reaction (Figure 7). The same group later used this approach to prepare a thermoresponsive PNIPAM−BSA conjugate that exhibited activity even at temperatures above the cloud point of the conjugate.89 Maynard and co-workers similarly prepared polymer−protein conjugates with a different Michael acceptor. The reaction of thiol-terminated poly(PEG acrylate) with divinyl sulfone yielded polymers bearing Michael accepting chain ends; then BSA was coupled via the free cysteine residues to yield a conjugate that largely retained the activity of the original protein.90 This general method of reacting a chain-end mercaptan with a difunctional Michael acceptor, while straightforward and modular, comes with some synthetic limitations: the installation of thiol end groups must be straightforward, and the other functionalities present on the polymer must be stable to treatment with an excess of a Michael acceptor that is commonly quite reactive. For situations where these stipulations are not attainable, an alternative approach was developed in the group of Maynard that utilizes an ATRP initiator bearing a maleimide moiety that is protected as a Diels−Alder adduct.91 A major challenge in this work was finding a Diels−Alder adduct that was stable to polymerization temperatures but did not require excessive heat for deprotection: furan−maleimide adducts were partially reversible at 70 °C and led to broad molecular weight distributions due to polymerization through liberated maleimide chain ends, but dimethylfulvene adducts were found to be stable at the polymerization temperature (80 °C) and were successful in generating narrow dispersity maleimide-terminated polystyrene after deprotection at 110 °C. However, it must be noted that this approach, unlike those in the aforementioned examples, requires greater synthetic effort prior to polymerization. Nucleophilic thiol−yne reactions, while less commonly encountered than thiol−Michael functionalizations, are also

Like radical thiol−ene reactions, this chemistry is challenging to apply to side-chain modification due to the difficulty of directly polymerizing monomers containing either thiols or Michael acceptors. One synthetic route around this limitation, however, involves the use of monomers containing protected thiols. To this end, Barner-Kowollik and his team developed an ATRPcompatible methacrylate monomer containing photolabile o-nitrobenzylthioether moieties.83 Complete preservation of protecting groups was observed as well as retention of living behavior throughout the polymerization. Nitrobenzyl photodeprotection often required somewhat long irradiation times (60 h) to reach completion, but it could be conducted in tandem with thiol−Michael functionalization to afford a one-pot process. Analogously, Collard and co-workers demonstrated the synthesis and functionalization of polylactide copolymers that contained backbone α,β-unsaturated esters.84 As with RDRP, the presence of Michael accepting functional groups would have a deleterious effect on the ring-opening polymerization; thus, a novel chloromethyl-substituted lactide monomer was developed thatafter polymerizationafforded the desired unsaturated repeat units through dehydrohalogenation under remarkably mild conditions (40 °C in the presence of N,N-diisopropyl-Nethylamine). With the Michael acceptor-containing polymer in hand, the team performed quantitative base-catalyzed thiol− Michael functionalization reactions with aliphatic, aromatic, and benzylic thiols. Furthermore, they found that drop-casted films of olefinic PLA could be functionalized by exposure to an aqueous thiol solutionin this case, SAMSA fluorescein. The observation of fluorescence from these films suggests that this postpolymerization thiol modification holds promise as a method for functionalizing bulk materials. These examples elegantly demonstrate that thiol−ene sidechain modification is feasible under mild conditions; however, the majority of reports involving thiol−Michael polymer functionalization utilize the reaction for chain-end modification, particularly that of RAFT polymers.53 Seminal work by BrokkenZijp coworkers established a now-ubiquitous two-step reaction sequence for the chain-end functionalization of RAFT polymers, in which aminolysis of RAFT CTA end groups liberated a chainend thiol that was quickly reacted with the Michael acceptor 2-hydroxyethyl acrylate to yield α,ω-dihydroxyl-terminated PMMA.85 In fact, this method proved to be so versatile86 that it has now become a general protocol for the removal of thiocarbonylthio end groups.87 Alternatively, Michael acceptor I


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cleotide.97 Studies of the functionalization kinetics as a function of pH revealed that disulfide modification was fastest at pH 8, possibly due to the deprotonation of thiols under such conditions to form more reactive thiolates. The first reported RDRP of PDS-containing monomers came from the group of Thayumanavan in 2006, who homopolymerized a PDS methacrylate monomer to afford well-defined polymers with reactive pendent disulfides.98 Treatment of the polymer with undecanethiol afforded full conversion of PDS moieties within 3 h, and the reaction progress could be conveniently monitored by observing the appearance of the strongly absorbing 2-pyridinethione byproduct by UV−vis spectroscopy. Soon after, the Centre for Advanced Macromolecular Design (CAMD) team employed PDS modification chemistry to ligate BSA via the cysteine residues to a PDS-containing PEG macroCTA to yield a conjugate that could then be further chain extended with other vinyl monomers.99 Like thiol−Michael functionalization, chain-end disulfide functionalization is most conveniently performed on polymers derived from RAFT polymerization due to the availability of a one-pot process developed by the team of Davis that converts thiocarbonylthio end groups into PDS moieties.100 These reactive chain ends can subsequently be modified with biomolecules such as DNA, peptides, and carbohydrates.101 Davis and his team reported a facile route to the preparation of ternary biomolecule−polymer−protein conjugates that crucially employed a RAFT CTA bearing PDS moieties on both the R- and Z-groups. BSA modified to retain only a single free cysteine residue was first functionalized with this CTA; then a “grafting-from” polymerization yielded a PDS-terminated polymer−protein conjugate. This conjugate was finally functionalized with either thiocholesterol or a thiol-functional rhodamine dye to yield the final complex.102 Key to the success of this strategy was the observation that modification of the RAFT CTA with two BSA proteins was sterically suppressed, ensuring the retention of the second modifiable PDS group. Finally, it has also been demonstrated that PDS modifications are orthogonal to CuAAC chemistry through the preparation and biofunctionalization of α-azido, ω-PDS PNIPAM, further expanding the toolbox of available conjugations.103 Ring-Opening of Thiolactones. Increasing attention has been directed to developing reactive units that can facilitate sequential, even orthogonal functionalizations. This is commonly achieved by one of two methods: employing a moiety that contains multiple sites that can be separately functionalized or by designing a group that releases a second modifiable group after the first functionalization. Thiolactone chemistry, recently reviewed by the group of Du Prez in 2011,104 falls into this latter strategy. Thiolactones are readily ring-opened by a range of nucleophiles, subsequently generating a thiol moiety that allows for further functionalization through the toolbox of thiol−ene chemistries (Scheme 3D).104 In a seminal study, thiolactone-functionalized copolymers were prepared by NMP or RAFT copolymerization of a thiolactone-containing styrenic monomer with either styrene or methyl methacrylate.105 The thiolactone moieties were treated with an excess of different amines (i.e., propylamine, benzylamine, ethanolamine, and Jeffamine M-1000) to yield functionalized polymers that also contained reactive thiol groups derived from the ring-opened thiolactones (Figure 8). These groups were then further modified via thiol−Michael reaction with N-benzylmaleimide. The success of this modular double modification was proven by NMR and SEC measurements. In a second investigation, the same authors reported a one-pot

possible through the use of electron-deficient acetylenes. This reaction has been known since at least 1954,92 yet was revisited by Dove in 2013,93 who adapted it into its current incarnation as a catalytic ligation reaction. These authors particularly examined reactions involving propiolic esters (alkynyl analogues of acrylates), screening a variety of amine and phosphine bases as well as solvent conditions. Interestingly, amidine and guanidine bases (e.g., diazabicycloundecene and triazabicyclodecene (TBD), respectively) as well as dimethylphenylphosphine were highly effective catalysts, facilitating complete conversion of propiolic ester to the β-alkylthio-α,β-unsaturated ester product within 10 min, even under nearly equimolar conditions. Thiol difunctionalization was also observed when at least a 2-fold excess of thiol was employed in the presence of the stronger TBD catalyst, and this reaction was employed to sequentially functionalize the chain-end of PEG-bispropiolate with dodecanethiol and benzyl mercaptan. Thiol difunctionalizations under nucleophilic conditions are also possible with the development of dibromomaleimide (DBM) chemistry (analogous to the relationship between thiol−ene and thiol−yne chemistries). This reaction is mechanistically distinct from thiol−maleimide coupling, proceeding through sequential conjugate addition and HBr elimination reactions that retain the maleimide olefin.94 The first reports of this modification on polymeric substrates came from O’Reilly and co-workers, who also importantly found that the DBM moiety was stable to radical polymerization. In their first report, a DBM-containing RAFT CTA was used to prepare well-defined polyacrylates that were then modified with thiophenol.95 Base catalysis afforded an extremely rapid reaction, with full functionalization achieved in less than an hour. However, only high kp monomers, such as acrylates, were found to be polymerizable with the DBM-CTA due to hypothesized interactions between propagating radicals and DBM moieties. The same group later expanded this chemistry to include sidechain modification by preparing and modifying copolymers of DBM (meth)acrylates and MMA, oligo(ethylene glycol) methacrylate (OEGMA), tBA, and triethylene glycol acrylate.96 Again, it was found that DBM moieties inhibited the polymerization, necessitating relatively low DBM monomer loadings. Nevertheless, the properties of the polymers could be rationally tuned through modification with various thiols. In particular, the cloud point of POEGMA could be tuned within an 11 °C window solely through side-chain modification with one of four different thiols. Another unique aspect of this modification is that the dithiomaleimide products fluoresce at approximately 520 nm compared to the nonfluorescent products of thiol−maleimide chemistry. Indeed, the ability of a reaction to “report” its completion is a powerful property, one that we believe should be considered when developing new postpolymerization modification chemistries. Thiol−Disulfide Exchange Reactions. Disulfide-containing polymers are attractive linkages in the field of polymeric therapeutics due to the ubiquity of disulfide bonds in biological organisms and the facile nature of reductive disulfide cleavage. Functional decoration via disulfides is most commonly achieved through thiol substitution of pyridyl disulfide (PDS) moieties installed either on the side chain or at chain ends (Scheme 5C). This approach was first reported in 1998 by the group of Ruffner, who employed free radical polymerization to prepare statistical copolymers of HPMA and a PDS-containing methacrylamide monomer that were subsequently functionalized with both a cysteine-containing peptide and a fluorescently labeled oligonuJ


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Figure 8. Postpolymerization modifications involving ring-opening reactions of thiolactones.105 For further ring-opening procedures including epoxides,108 aziridines,109 azlactones110 please refer to section 2.5.

modification toolbox,47 is an especially useful technique for the chain-end modification of RAFT polymers due to the aforementioned simplicity of generating thiol chain ends from thiocarbonylthio moieties. In a seminal report, the group of Lowe established that aliphatic and aromatic isocyanates could be rapidly coupled to the chain end of thiol-terminated poly(N,Ndiethylacrylamide) with trimethylamine catalysis.111 Real-time monitoring of reaction progress revealed nearly quantitative conversion of isocyanates within 15 min, highlighting the extreme efficiency of this transformation. Patton and co-workers later demonstrated the orthogonality of this reaction to thiol− yne chemistry by preparing and sequentially modifying surfacetethered poly(propargyl methacrylate-co-2-isocyanatoethyl methacrylate) (Figure 9). The first modification was a DBUcatalyzed addition of benzyl mercaptan to isocyanate groups, which was followed by a photoinitiated thiol−yne functionalization with dodecanethiol.112 Alcohol−Isocyanate Modification. Alcohols have been known to react with isocyanates under basic or tin(II) catalysis since the 1940s,113 but the scope of this reaction in a macromolecular context was historically limited to polyurethane synthesis. Sherman and colleagues in collaboration with the Barner-Kowollik team laid a strong foundation for the modification of both end-group and side-chain hydroxyl groups with isocyanates under dibutyltin dilaurate (DBTDL) catalysis.114 End-group modification was performed on hydroxy-PEG and hydroxyl-terminated RAFT polymers with isocyanates containing a vast array of functionalities such as ethyl iodide, fluorene, naphthalene, anthracene, and viologen groups. The functionalization efficiency was confirmed to be quantitative by both NMR spectroscopy and ESI-MS. In contrast, the efficiency of side-chain functionalization appeared to depend on the bulkiness of the conjugated isocyanate. 1-Naphthyl isocyanate was conjugated with virtually quantitative efficiency, but the reaction of 2-anthracenyl isocyanate proceeded to only 65% completion. Modification of Polymers Containing Latent Isocyanates. The development of methods for the in situ generation and modification of isocyanates arose from the challenge of preparing and storing polymers containing unprotected isocyanate moieties. McCormick and his team found that direct RAFT polymerization of 2-(acryloylxy)ethyl isocyanate could be performed in dioxane at 50 °C with a tertiary amine-containing dithiobenzoate CTA, but only moderate monomer conversions and molecular weights could be achieved while retaining polymerization control.115 It is more synthetically preferable to instead “mask” the isocyanate group until the desired time for

double modification of a thiolactone-containing PNIPAM copolymer.106 In order to demonstrate the versatility of the concept, different functional amines and Michael acceptors were employed, and it was shown that both modification reactions proceeded in a quantitative manner. In addition, it was found that the cloud points of these thermoresponsive polymers were tunable by adjusting the degree of amine functionalization. Thiolactones have additionally been installed at the end groups of polystyrene and poly(butyl methacrylate) through functional ATRP initiators and at the hydroxyl end groups of poly(εcaprolactone) with a thiolactone isocyanate to afford polymers that can undergo chain-end double modification.107 2.3. Isocyanate Modification. The nucleophilic addition of alcohols, amines, and thiols to isocyanates (Scheme 4) features Scheme 4. Overview of Reactions Involving Addition of Nucleophiles to Isocyanatesa

a

Amines are sufficiently reactive to undergo rapid uncatalyzed addition, alcohols require catalysis typically with Sn(II) species, and thiols react under sufficiently basic conditions to generate reactive thiolate species.

many attractive qualities (e.g., fast reaction kinetics, stability of isocyanates toward radicals, and perfect atom economy) that make it eminently qualified for macromolecular functionalization. Unfortunately, the toxicity and functional sensitivity of many isocyanates mitigate the efficacy of these reactions. Furthermore, it is often difficult to maintain the fidelity of isocyanate-containing polymers due to the fact that even adventitious moisture degrades isocyanates. Nevertheless, the almost unparalleled efficiency of this reaction has strongly driven efforts aimed at overcoming these detriments by improving the kinetics of modification and “masking” isocyanates until the moment of modification. Thiol−Isocyanate Modification. The base-catalyzed thiol− isocyanate reaction, a surprisingly recent addition to the polymer K


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Figure 9. Orthogonal modification of surface-tethered poly(methacrylates) bearing both isocyanate and electrophilic functionalities by sequential thiol−isocyanate and thiol−yne reactions. Adapted with permission from ref 111.

Figure 10. Sequential modification of blocked isocyanate-containing copolymers. Less sterically hindered triazole moieties were modified by treatment with piperidine at room temperature. The more encumbered dimethylpyrazole moieties required heating.116

isocyanate. The strategy was shown to be amenable to in situ chain-end modification by simply adding an alcohol and DBTDL to the polymerization solution, and functionalization of the product polymer with amines was also demonstrated. The stability of chain-end tertiary isocyanates in aqueous solvents was a particularly noteworthy finding of this report, and the same group assessed this property in greater detail in a later study.118 Briefly, chain-end tertiary isocyanates are retained to a high extent during precipitation into 50/50 (v/v) H2O/MeOH solution and even survive polymerization in 10% (v/v) H2O in dioxane at 60 °C. These findings certainly suggest that isocyanate modifications, if judiciously designed, can be exploited in a broader range of systems than previously believed. 2.4. Imine and Oxime Ligation. Unique among nearly every other common macromolecular modification reaction, functionalizations involving the condensation of primary amines with aldehydes or ketones are reversible due to the dynamic nature of the imine equilibrium (Scheme 5). Even oximes, which are sometimes cited as relatively irreversible linkages,119 have been shown to exhibit reversibility under aqueous acidic stimulus.120 A major challenge in adapting imine chemistry for polymer functionalization is selecting amine and carbonyl reaction partners that can forge a robust, hydrolytically stable linkage. Many Schiff base imines, formed from the reaction of carbonyls with aliphatic or aromatic amines, are not adequately stable; hence, oximes and acyl hydrazones are the most commonly utilized imine derivatives for polymer modification. Maynard and co-workers initially reported the modification of methacrylic aldehyde-containing polymers with carboxylic acidand oligoethylene glycol-bearing alkoxyamines.121 Aliphatic aldehydes are commonly incompatible with radical polymerization, so 3,3-diethoxypropyl methacrylate was instead utilized as an acetal-protected aldehydic monomer. After polymerization,

modification, both improving the long-term storage stability of the polymer and expanding the scope of functionalities that could be incorporated into the same polymer. Patton reported an intriguing approach to side-chain nucleophile−isocyanate modification in which monomers containing isocyanates blocked with dimethylpyrazole (Py-NCO), imidazole (Im-NCO), and triazole (Tri-NCO) were polymerized and functionalized with thiols and amines.116 Imidazole- and triazole-blocked isocyanates could be functionalized at room temperature whereas functionalization of the more sterically hindered Py-NCO adducts required heating to 50 °C (Figure 10). As a result of this disparate reactivity, the Tri-NCO moieties of copolymers containing both Tri-NCO and Py-NCO were selectively modified with amines at ambient temperature. The Py-NCO moieties were subsequently orthogonally modified by base-catalyzed thiol addition at 50 °C. Mechanistically, these modifications proceed via either a thermally driven elimination−addition reaction involving explicit isocyanate intermediates (“thermal deblocking”) or an addition−elimination mechanism analogous to acyl substitutions (“chemical deblocking”). In this case, although the exact mechanism was not unambiguously determined, the use of mild temperatures for functionalization reactions suggests a chemical deblocking process. End-group isocyanate modification via direct polymerization of isocyanate-functional RAFT CTAs remains unreported, but Perrier recently established a highly creative method for the in situ generation of chain-end isocyanates through a Curtius rearrangement of an acyl azide-containing CTA.117 This rearrangement, thermally driven at the polymerization temperature, was interestingly observed to occur only after reinitiation of the R-group fragment to produce a propagating chain. Furthermore, rigorous exclusion of moisture was unnecessary due to the unusual hydrolytic stability of the generated tertiary L


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Scheme 5. Overview of Imine Condensation Reactions Involving the Formation of Hydrazones (Top) and Oximes (Bottom)a

a

Oximes are significantly more hydrolytically stable than hydrazones; hence, the reaction equilibrium is strongly product favored.

For instance, epoxy resins are among the most commercially important materials in production, and ring-opening polymerization (ROP) remains one of the most versatile methods for the synthesis of backbone heteroatom-containing polymers.126,127 The majority of ring-opening reactions are thermodynamically driven by the release of ring strain; consequently, the considerable ring strain of three-membered rings renders them highly useful substrates for a number of transformations. In fact, the nucleophilic ring-opening of strained heterocycles was among the first reactions considered to meet the criteria of a “click” reaction.5 The almost unparalleled efficiency of this chemistry is underscored by its ubiquity as a chain-growth polymerization technique: The synthesis of poly(ethylene oxide) (PEO) with a rather modest molecular weight of 10 000 g/mol by anionic ROP requires a selectivity for ring-opening reactions over other competing pathways of greater than 99.5%. It therefore comes as no surprise that these reactions are veritable tools for introducing specific functionalities in a polymer via postpolymerization modification. As will be elaborated upon and as has become apparent in previous sections, both the development of RDRP techniques and the establishment of click chemistry greatly inspired the polymer community to exploit ring-opening reactions for polymer functionalization. Epoxides are certainly the most commonly employed functional group for these modifications, but we will additionally address more recent ringopening modifications involving aziridine- and azlactonefunctionalized polymers (Scheme 6). Epoxide Ring-Opening Reactions. Epoxide-functionalized polymers are surprisingly versatile substrates considering the highly strained nature of the oxirane ring. A large variety of nucleophiles such as alcohols, thiols, azides, amines, and halides have been successfully used to facilitate ring-opening of epoxides.128 In addition to the attachment of the nucleophilic species, epoxide ring-opening also results in the release of a secondary alcohol that can further engage in modification chemistry, conceptually similar to thiolactones. Unfortunately, this can lead to polymer cross-linking through reactions of other oxirane rings with these liberated hydroxyl groups, but the use of protic nucleophiles, including amines, thiols, or azides, in the presence of proton sources has been shown to reduce or even fully suppress these undesirable reactions.128 Pioneering work on the preparation of epoxide-containing polymers was performed by the group of Matyjaszewski, who reported the synthesis of well-defined polymers from glycidyl acrylate via ATRP.129 No functionalization reactions were evaluated in this work, but the same group later reported the synthesis and modification of well-defined epoxide-containing copolymers.108 Statistical copolymers composed of glycidyl methacrylate and methyl methacrylate were prepared by ATRP,

acidic deprotection of pendent acetals and conversion of the liberated aldehydes to oximes both proceeded smoothly in a onepot process. The same group later reported the preparation of alkoxyamine-terminated PNIPAM via an alkoxyamine-containing RAFT CTA that was used to prepare polymer−protein conjugates with ketone-functionalized bovine serum albumin.122 Finally, Sumerlin demonstrated the modular functionalization of polystyrene containing pendent alkoxyamines with cinnamaldehyde, 4-nitrobenzaldehyde, and acetone.123 Notably, this strategy theoretically enables the functionalization of the alkoxyaminecontaining polymer with any aldehyde or ketone, enabling the installation of a highly diverse scope of functionalities. Unlike aliphatic aldehydes, benzaldehydes are stable to free radicals and may be directly polymerized.124 This was cleverly exploited by Foster and Matson for the preparation of H2Sreleasing polymers bearing S-aroylthiooxime (SATO) moieties (Figure 11).125 2-(4-Formylbenzoyloxy)ethyl methacrylate was

Figure 11. Functionalization of aldehyde-containing polymers with S-aroylthiooxime moieties (left) and cysteine-triggered H2S release profiles demonstrating substituent-dependent kinetics (right). Adapted with permission from ref 125.

initially polymerized by RAFT polymerization to yield welldefined reactive scaffolds. After RAFT CTA end-group removal, the aldehyde groups were converted to oximes and hydrazones by treatment with O-benzylhydroxylamine and tert-butylcarbazate, respectively. Additionally, treatment of the aldehydebearing polymers with S-benzoylthiohydroxylamine under trifluoroacetic acid catalysis afforded SATO-functionalized polymers in quantitative yields. Upon treatment with cysteine, the SATO groups degraded to release H2S, and the release profile was found to be tunable by changing the electron-donating or -withdrawing character of the SATO para-substituent. 2.5. Ring-Opening Reactions. Ring-opening reactions, despite the relative recency of their adoption for macromolecular modification, are classical reactions in polymer science. M


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Macromolecules and the epoxide groups in the side chain of the copolymers were subsequently opened with sodium azide in the presence of ammonium chloride in DMF at 50 °C. This ring-opening reaction led to the formation of the corresponding 1-hydroxy-2azido compounds that were then functionalized with PEO methyl either pentynoate by a CuAAC reaction to yield polymeric brushes grafted with hydrophilic PEO side chains (Figure 12). The ATRP of glycidyl methacrylate was initially reported in Macromolecules by Krishnan and Srinivasan130 and has since been exploited numerous times as a scaffold for the preparation of well-defined, biologically applicable aminecontaining polymers. Leroux and co-workers exploited this technique to prepare linear and star-shaped poly(glycidyl methacrylate) (PGMA) from traditional or multifunctional ATRP initiators, respectively.131 The epoxide-containing polymers were functionalized with four different amines (i.e., N-butylmethylamine, propylamine, N-methylpropylamine, and N,N,N′-trimethylethylenediamine) to generate poly(glycerol methacrylate) derivatives that possessed both hydroxyl and amine moieties. Depending on their structure, some aminated polymers were found to exhibit pH-dependent solubility, while others interacted efficiently with cells to deliver an antisense oligonucleotide. In another biological application, the group of Liu reported the synthesis of well-defined polymers with structural units bearing both cationic primary and secondary amine and nonionic hydroxyl units via PPM of PGMA with ethanolamine derivatives and, later, ethylenediamine.132,133 It was found that the polymers possessed very low toxicity while exhibiting excellent transfection efficiency. Furthermore, Ma and co-workers reported the synthesis of poly(glycidyl methacrylate)s and the subsequent modification with different amines such as methylethylamine, 2-amino-1-butanol, and 4-amino-1-butanol. These functional polymers were demonstrated to improve the transfection activity and reduce cell cytotoxicity of polycations with antisense oligonucleotides.134

More recently, Tozzi and his team validated the versatility of epoxide modification by preparing a library of diversely functional polymers from a single PGMA precursor.135 Secondary amines, thiols, aromatic alcohols, and sodium azide were successfully employed as nucleophiles for ring-opening of the epoxide pendant groups, and even the liberated secondary alcohol was shown to be modifiable via alcohol−isocyanate chemistry. Averik and co-workers reported a new solventassisted method to accelerate the ring-opening reaction of epoxides in PGMA.136 Usually, PGMA modification with amines requires inconveniently long reaction times to drive the reaction to an acceptable degree of functionalization. However, the authors used a fluorinated, mildly acidic solvent, trifluoroethanol, to quantitatively modify PGMA with benzylamine in only 30 min at 60 °C, whereas the use of “classical” reaction conditions employing DMSO as the solvent resulted in only 80% functionalization after 8 h. These conditions were then employed to functionalize poly(OEGMA-co-GMA) with the antibiotic ciprofloxacin to yield polymers with potential antibacterial properties. McLeod and Tsarevsky also reported the efficient alcohol functionalization of a novel styrenic polymer bearing pendent epoxides.137 In this work, an aryl epoxide-containing styrenic monomer, 4-vinylphenyloxirane, was polymerized in a controlled manner by RAFT polymerization. The polymers were subsequently modified with a library of functional alcohols and phenols using Lewis acid catalysts such as CBr4 or BF3 to yield functional homopolymers containing β-hydroxy ether linkages. All of the previous work involved modification of epoxidecontaining vinyl polymers, but the establishment of routes to the modification of substrates such as polyesters, polycarbonates, polyurethanes, etc., is of critical importance due to the commercial significance of these materials. However, reconciling the incompatibility of ROP techniques with many common nucleophilic and electrophilic moieties is a pervasive obstacle to achieving this goal. The team of Hedrick addressed this

Scheme 6. Basic Nucleophilic Ring-Opening Reactions Involving Epoxides (A), Aziridines (B), and Azlactones (C)

Figure 12. Sequential ring-opening and CuAAC modification of poly(glycidyl methacrylate-co-methyl methacrylate).108 N


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Figure 13. Lewis acid-catalyzed ring-opening functionalization of aziridine-containing polymers with aliphatic, fluorous, and polar alcohols. Adapted with permission from ref 109.

well-defined polymers containing a nonsubstituted aziridine due to the presence of side reactions between aziridine groups and the ATRP catalyst or the RAFT CTA. However, better results were obtained by NMP at low to moderate conversions of monomer. In contrast, an N-mesyl-aziride-containing monomer was successfully polymerized via both RAFT and NMP, though ATRP was still not successful for similar reasons. Ring-Opening of Azlactones. Azlactones, also known as oxazolones, are nitrogenous five-membered lactones that can undergo ring-opening reactions in the presence of nucleophiles. While they may appear to be somewhat exotic substrates on first inspection, azlactones may be readily derived from N-acyl-αamino acids, and azlactone-functionalized polymers have been widely investigated in both fundamental and industrial applications. In 2001, Heilmann and co-workers published a comprehensive review describing the chronological development of azlactone-based monomers and polymers,110 and, more recently, Lynn and Buck published a review focusing on the development of azlactone-functionalized polymers over the past 10 years.143 Monomers containing azlactones have been polymerized by various RDRP methods such as NMP,144 ATRP,145 and RAFT,146 and azlactones are commonly partnered with alcohols or amines for nucleophilic ring-opening to yield functionalized polyacrylamides. In an illustrative example, Lynn and co-workers reported the synthesis of a library of amine-functionalized polymers via reaction of poly(2-vinyl-4,4-dimethylazlactone) with different amino nucleophiles possessing both a primary and a tertiary amine.147 The primary amines react rapidly with the azlactone moieties while the tertiary amines do not react, leading to tertiary-amine-containing polymers. The polymers were found to form stable electrostatic complexes with plasmid DNA and, in some of the cases, improve cell transfection of the DNA. When an alcohol is employed for ring-opening, the resultant hydrolytically labile ester linkage can be exploited for additional modifications. Lynn and co-workers have cleverly taken advantage of this property to prepare so-called “charge-shifting” polyelectrolytes from a poly(2-vinyl-4,4-dimethylazlactone) precursor (Figure 14).148,149 The alcohol derivatives selected for the postfunctionalization contained tertiary amines that, upon protonation, yielded cationic polymers. Hydrolysis of the side-chain ester bond then provoked a change (or a “‘shift’”) in the net charge of the polymer due to the cleavage of cationic ammonium functionalities and the formation of negatively charged carboxylates. This feature has been employed to design polyelectrolyte multilayers which allow the promotion and control of DNA. 2.6. Multicomponent Reactions. Inspired by the exceptional success of click chemistry protocols for the functionalization of macromolecules, polymer chemists translated

problem through the ROP of thioether-containing cyclic carbonate monomers that could be functionalized with epoxides under acidic catalysis.138 Both acetic acid and trifluoroacetic acid were found to be effective catalysts, and quantitative yields could be achieved when a large excess of epoxide was used. It should be noted that alkylation of charge-neutral functional groups such as thioethers importantly installs both functionality and charge via the generation of cationic sulfonium moieties, further underlining the utility of PPM for the synthesis of useful materials. Ring-Opening of Aziridines. As nitrogenous derivatives of epoxides, aziridines feature similarly impressive ring strain that predisposes them toward nucleophilic ring opening, but the lesser electronegativity of nitrogen results in attenuated reactivity that introduces additional synthetic considerations.139−141 Generally, aziridines are classified as either activated or nonactivated according to the identity of the N-substituent. Activated aziridines contain N-substituents capable of stabilizing the developing negative charge on the nitrogen during nucleophilic ring opening, and readily undergo even uncatalyzed ring-opening reactions. Nonactivated aziridines are commonly nonsubstituted or N-alkyl substituted and usually require acidic catalysis to facilitate the ring-opening reaction. Aziridines have been rarely explored in polymer science, and only few examples of aziridine-functionalized polymers have been reported, in poignant contrast to the pervasive presence of epoxides. Nevertheless, aziridine-functionalized polymers facilitate the incorporation of highly interesting functionalities, such as β-substituted amines, in the polymer side chain due to the presence of nitrogen in the aziridine ring. The team of Yoon reported the preparation of aziridine-containing copolymers via free radical polymerization of methyl methacrylate together with a methacrylate bearing an N-(1-phenylethyl)aziridine moiety.109 The aziridine units incorporated in the copolymers were subsequently ring-opened with various alcohol derivatives in the presence of the Lewis acid boron trifluoride diethyl etherate (BF3·OEt2) (Figure 13). The functionalization was successfully proven via NMR and FTIR experiments by following the corresponding aziridine signal. Changes in both optical and physical properties were observed in films prepared from the functional polymers before and after the reaction with alcohols, demonstrating the ability to tune various material parameters via postpolymerization modification. Very recently, Tsarevsky reported a detailed study on the polymerization of aziridinecontaining monomers.142 In particular, two styrene-based monomers containing either a nonactivated aziridine moiety or an N-mesyl-substituted activated aziridine moiety were polymerized via RDRP methods. It was found that ATRP and RAFT are not suitable polymerization protocols to prepare O


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Macromolecules

Figure 14. Example of the functionalization of azlactone-containing polymers for the preparation of “charge-shifting” polyelectrolytes. Adapted with permission from refs 148 and 149.

Isocyanide-Based MCRs. As noted above, MCRs were first introduced into polymer chemistry by Meier in 2011. The first publication in this field describes the use of the biorenewable compounds 10-undecenoic acid, 10-undecenal, and heptanal (all derived from the pyrolysis of ricinoleic acid) for the synthesis of polymers via both acyclic diene metathesis (ADMET) polymerization and Passerini step-growth polymerization. The ADMET approach, in which 10-undecenoic acid, 10-undecenal, and a variety of isocyanides were converted to divinyl ADMET monomers via the Passerini reaction, was particularly useful as the isocyanide component facilitated the installation of esters that could be further functionalized after polymerization. Moreover, the accessibility of the monomers from renewable resources is an additional feature that makes the Meier approach highly attractive in terms of sustainability. The Ugi-4CR also belongs to the IMCR class and features just as the Passerini-3CRbenign reaction conditions and a high tolerance toward functional groups. Also as with the Passerini3CR, there are relatively few examples illustrating the use of the Ugi-4CR for polymer-related applications. Nevertheless, in 2015, Tao and co-workers summarized the advances of Ugi reactions in polymer science in terms of monomer synthesis, polycondensation reactions, postpolymerization modification strategies, and applications in polymer science until 2015.168 In 2003, the Ugi-4CR was reported for the first time in the context of polymer chemistry when the group of Wright employed the chemistry to prepare monomers for ring-opening polymerization, although the reaction was not employed for direct polymerization or functionalization.169 Meier and colleagues, in a similar vein to their work on the Passerini reaction, later demonstrated the preparation of a small library of polyamides from α,ω-unsaturated monomers derived from Ugi-4CR of 10-undecanoic acid, 10-undecenal, various primary amines, and different isonitriles.170 The functional α,ω-unsaturated monomers were subsequently used for ADMET polymerization, although it was discovered that the polymerization efficacy was strongly affected by the specific structure of the Ugi-derived linkage, necessitating tailor-made reaction conditions for each specific monomer. A particularly interesting scaffold featured an o-nitrobenzyl-protected amide that could be deprotected via UV irradiation to yield monosubstituted polyamides with different solution and thermal properties compared to their precursors. This photodeprotection strategy could also offer additional opportunities for light-triggered functionalizations. IMCRs advantageously generate significant functional complexity from relatively innocuous starting materials, but subsequent functionalization of Passerini- or Ugi-derived linkages is challenging due to the fact that the generated amide and/or ester groups are commonly resistant to further modification. Nevertheless, Meier and his team again enlarged the toolbox of MCR

multicomponent reactions (MCRs) to the synthesis of elaborately functional polymers with exceptional rapidity after they were rediscovered. MCRs found their way into polymer science less than a decade ago, with initial reports appearing around 2011. The subsequent explosion of interest in MCRs by the polymer community was in no small part due to the high indeed, often perfectatom economy of these reactions. The most evident milestone in the field of MCRs in polymer science was set by Meier and co-workers in 2011, in which the Passerini three-component reaction (3CR) was introduced to polymer science for the first time.150 Their study used the isocyanidebased multicomponent reaction (IMCR)described in 1921 by Passerini151,152and played a key role for the adaptation of polycondensation reactions such as IMCRs or coppercatalyzed MCRs (CuMCRs) into polymer chemistry. The preeminent advantage of MCRs is the ability to introduce a high degree of functional complexity in a single, highly atom economical modification step. MCRs can grouped into three main classes: • Isocyanide-based MCRs (IMCRs) include the Passerini3CR,153 the Ugi four-component reaction (4CR),153 the Groebke−Blackburn−Bienaymé reaction,154 and the van Leusen 3CR.155 • Non-isocyanide-based MCRs include the Biginelli reaction,156 the Hantzsch reaction,157 the Asinger reaction,158 the Kabachnik−Fields reaction,159 the Gewald reaction,160 the Petasis reaction,161 the Povarov reaction,162 and the Doebner reaction.163 • MCRs catalyzed by organometallic species include the Sakurai allylation 3CR,164 the metal-catalyzed 3CR between alkynes, amines, and aldehydes,165 and the Cu(I)-catalyzed 3CRs between alkynes, nucleophiles, and sulfonyl azides (CuMCR).166 The current Perspective will focus onin our opinionthe most important and most interesting of examples of MCRs in polymer chemistry, so only a few earlier and recent key studies using MCRs are selected, rather than providing a comprehensive overview of current research in the field. However, the reader is referred to an excellent book edited by Théato167 and published in 2015 providing a comprehensive overview of multicomponent and sequential reactions in polymer science. Although the use of MCRs in polymer science is constantly growing, this book provides an excellent overview of literature published until the year 2015. The selected multicomponent reactions highlighted in the current section are depicted in Scheme 7. For the class of isocyanide-based MCRs, we will focus on the Passerini and Ugi reactions. The Biginelli and the Kabachnik−Fields reactions, as examples of non-isocyanide-based MCRs, are discussed herein as well as selected examples for Cu-catalyzed MCRs. P


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Macromolecules

Scheme 7. Overview of Selected Examples of Multicomponent Reactions in Polymer Science (Not Complete) Highlighted in the present Perspective: (A) IMCRs: Passerini, Ugi; (B) Non-Isocyanide-Based MCRs: Biginelli, Kabachnik−Fields; (C) MetalCatalyzed MCRs: CuMCR (Adapted with Permission from Ref 167)

functionalization protocols by employing a “convertible” 2-(2,2dimethoxyethyl)phenyl isocyanide as a component that, upon incorporation into an IMCR-derived linkage, could be transformed into a reactive indolyl amide.171 From these indolylcontaining polymers, various postpolymerization reactions were accessible that yielded a wealth of functionalities, including carboxylic acids, esters, thioesters, tertiary amines, and terminal olefins (Figure 15). In fact, one could further envision using other modification reactions, even additional MCRs, on these functional groups, implying an almost limitless functionalization potential for these substrates. The only synthetic consideration emphasized in this work was that mild conditions were necessary for modifications of Passerini-derived polymers to prevent hydrolysis of backbone ester moieties. However, this concern was not an issue for the stable amide-containing Ugi linkages. Later, Meier and co-workers showed that dendronized polymers were accessible by Passerini postpolymerization modification and olefin cross-metathesis,172 and recent publications described applications of the Ugi reaction in different research areas such as the interaction of Ugi-derived glycopolymers with lectins173 or the preparation of protein-reactive polymers.174

A follow-up collaborative work between Meier and Hoogenboom described the postpolymerization side-chain functionalization of polyoxazolines via Passerini-3CR and Ugi-4CR to introduce two or even more functionalizations into these useful materials.175 Polyoxazolines are typically prepared by cationic ring-opening polymerization, conditions that are generally intolerant of the moieties involved in IMCRs. Therefore, oxazolines bearing methyl esters were copolymerized with 2-ethyl-2-oxazoline and hydrolyzed to yield carboxylic acidfunctional polymers. IMCRs were then deployed to functionalize these scaffolds with a number of different substituents, the full elegance of which became apparent when it was shown that the cloud point of the polymers could be tuned between 15 and 78 °C depending only on the identity of the reaction components. Non-Isocyanide-Based MCRs: Biginelli Functionalizations. IMCRs are extraordinarily useful reactions that have found a unique niche in polymer chemistry, but the necessity of isocyanides, many of which feature legendarily noxious odors, can be a significant inconvenience. Enter non-isocyanide-based MCRs, reactions that similarly can be used to produce complex functional polymers but with much more innocuous reagents. One such reaction is the Biginelli reaction, in which aldehyde, Q


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Macromolecules

Figure 15. Isocyanide-based polymers: postfunctionalization strategies from Ugi-4CR and Passerini-3CR-derived polymers. For synthetic details please refer to ref 171. Adapted with permission from Schemes 5 and 6 of ref 171.

β-keto ester, and urea components react to form a cyclic dihydropyrimidinone moiety. These moieties show remarkable similarity to nucleobases such as cytosine and thymine, introducing the possibility of a self-assembly behavior. As with the previously described IMCRs, the Biginelli reaction has found its way to polymer science only very recently, and it is remarkably robust towards many functional groups, such as hydroxyl, carboxyl, olefin, alkyne, and azide groups.167 Furthermore, it is applicable in a broad range of reaction temperatures, different solvents, or the individual catalyst system. In a recent minireview, Tao and co-workers summarized highlights of the Biginelli in polymer science, including postpolymerization modification reactions, preparation of well-defined polymers in a one-pot approach, and different applications of this chemistry.176 An obvious route to the generation of functional polymers is the preparation of monomers via the Biginelli reaction that can be subsequently polymerized.177 Alternatively, a functional monomer can be polymerized; then the resultant polymer can be functionalized via a Biginelli protocol. In a comprehensive report, Tao and Wei demonstrated model functionalizations at both the polymer end groups and side chain with the Biginelli reaction.178 For the former approach, PEG-acetoacetate was coupled with high efficiency to PEG-4-formylbenzoate via the Biginelli reaction, suggesting that MCRs hold potential for block copolymer synthesis or polymer grafting reactions. Next, commercially available acetoacetoxyethyl methacrylate was polymerized in a controlled manner by RAFT polymerization and then functionalized by a Bignelli reaction with benzaldehyde and urea in the presence of acetic acid and MgCl2. As verified by NMR spectroscopy, virtually quantitative side-chain functionalization (>99%) was achieved. Interestingly, this two-step approach could also be translated into a one-pot procedure for simultaneous RAFT polymerization and Biginelli functionalization as both proceed at the same reaction temperature (70 °C). Kinetic studies revealed that, in the first hour, over 90% of the

reactant was converted to the Biginelli monomer, whereas in the same time frame only 20% of the monomer was polymerized. Nevertheless, high monomer conversions could be achieved, and the resultant polymers featured narrow molecule weight distributions (Đ = 1.1). This strategy elegantly shows that multicomponent reactions and RDRP techniques are compatible to design novel functional polymerseven in a one-pot procedure. Kabachnik−Fields Functionalizations. As bioisosteres of amino acids, α-amino phosphonates and polymers that are functionalized with them are useful for the preparation of biologically active materials for such applications as antifouling, among others.179 The Kabachnik−Fields reaction offers a mild route to these moieties through the reaction of aldehyde, amine, and phosphonate components (Scheme 7). Théato and Tao have pioneered the introduction of the Kabachnik−Fields reaction into polymer science for the preparation of α-amino phosphate functional polymers via a metal-free procedure.167,180−182 Inspired by the success of their previous work involving onepot polymerization−Biginelli modification, the team of Tao established a similar protocol for the synthesis of α-amino phosphonate-containing polymers (Figure 16).182 A series of aldehydes were evaluated for efficacy, including p-hydroxybenzaldehyde, p-(dimethylamino)benzaldehyde, trans-cinnamaldehyde, 2-pyridylaldehyde, and hexanal. In each case, modification efficiencies in excess of 85% were observed. Less than a year later, Kakuchi and Théato employed an alternative strategy to conduct a mechanistic investigation of the Kabachnik−Fields reaction and use it to prepare a library of functional polymers.180 Unlike the previously discussed work, the aldehyde component was installed on the polymer through the controlled polymerization of 4-vinylbenzaldehyde. They also screened an impressive range of amine and phosphite components containing aliphatic, aromatic, halogenated, acyl, and even fluorous substituents, observing very high modification efficiencies for all components except aliphatic amines. R


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Macromolecules

Figure 16. Non-isocyanide-based polymers. Left: tricomponent Biginelli reaction via high-throughput polymerization (adapted with permission from Scheme 2 of ref 185). Right: (A) postpolymerization of poly(4-vinylbenzaldehyde) (adapted from Scheme 1 of ref 180); (B) preparation of poly(aminophosphonates) by three different pathways (adapted with permission from Scheme 2 of ref 182).

To prepare the initial reactive polymers, N-Boc-2-aminoethylacrylamide was polymerized by RAFT polymerization to yield molecular weights up to Mn = 39 000 g/mol and narrow dispersities (

50th Anniversary Perspective: Polymer Functionalization

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