Activated Ester Containing Polymers: Opportunities and Challenges

Activated Ester Containing Polymers: Opportunities and Challenges...

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Activated Ester Containing Polymers: Opportunities and Challenges for the Design of Functional Macromolecules Anindita Das and Patrick Theato* Institute for Technical and Macromolecular Chemistry, University of Hamburg, D-20146 Hamburg, Germany 5. Orthogonal and Sequence-Controlled Postmodiﬁcation 6. Functional Materials by Postpolymerization Modiﬁcation 6.1. Cross-Linked Particles 6.2. Hydrogels 6.3. Bioconjugated Polymers 6.3.1. Lipopolymers 6.3.2. Glycopolymers 6.3.3. DNA-Polymer Conjugates 6.3.4. Peptide/Protein Polymer Conjugates 6.4. Metal Polymer Complexes 6.5. Functionalized Surfaces 7. Concluding Remarks Author Information Corresponding Author Notes Biographies Acknowledgments References

CONTENTS 1. Introduction 2. Methods of Preparation of Polymers with Pendent Activated Ester Moiety in the Side Chain 2.1. Free Radical Polymerization for Homopolymers and Statistical Polymers 2.1.1. N-Hydroxysuccinimide (NHS) Ester Monomers 2.1.2. Pentaﬂuorophenyl (PFP) Ester Monomers 2.1.3. Other Activated Ester Monomers 2.2. Controlled Radical Polymerization for Homopolymers and Statistical Polymers 2.2.1. Polymerization of NHS Ester Monomers 2.2.2. Polymerization of PFP Ester Monomers 2.2.3. Polymerization of Other Activated Ester Monomers 2.2.4. Amphiphilic and Stimuli-Responsive Statistical Copolymers 2.3. Block Copolymers 2.3.1. Block Copolymerization of Activated Ester Monomers 2.3.2. Amphiphilic and Stimuli-Responsive Block Copolymers 3. Other Macromolecular Designs 3.1. Star Polymers 3.2. Chain-End-Functionalized Polymers 4. Other Methods of Polymerization of Activated Ester Monomers 4.1. Alkyne Metathesis of Acetylenes 4.2. Ring-Opening Metathesis Polymerization (ROMP) of Norbornenes 4.3. Ring-Opening Polymerization (ROP) of Cyclic Carbonates 4.4. Electrochemical Polymerization of Activated Ester Containing Pyrroles and Thiophenes 4.5. Plasma Polymerization © 2015 American Chemical Society

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1. INTRODUCTION Rapidly growing demand of functional polymers in various interdisciplinary areas of research has accentuated the need for modern synthetic tools to develop advanced polymers featuring a variety of functional groups. Lutz, Sumerlin, and Matyjaszewski stated recently in their editorial to the special issue on precisely controlled polymer architectures “Indeed, controlled polymerization techniques, new routes for post-polymerization functionalization, and the ability to control macromolecular self-assembly have provided access to complex polymer structures that were previously considered inaccessible”,1 thereby highlighting the modern developments in synthesis of functional polymers. While controlled polymerization techniques have found wide acceptance as valuable and sophisticated synthetic tools, the aspect of postpolymerization modiﬁcation has not been recognized as equally important. Postpolymerization modiﬁcation (PPM), also referred to as postpolymerization functionalization or simpliﬁed postmodiﬁcation or postfunctionalization, is as old as the discipline of polymer synthesis. However, postpolymerization modiﬁcation, also known as “polymer analogous reactions”, was ﬁrst deﬁned by Hermann Staudinger, a pioneer in modern polymer chemistry who consequently was awarded the ﬁrst Nobel Prize for

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structures. This marked the need for extremely eﬃcient chemical reactions under mild conditions for PPM. Recent development in chemoselective coupling reactions such as thiol−ene, thiol−yne, Michael addition, nucleophilic activated esters/amine exchange, thiol−disulﬁde exchange, azide−alkyne cycloaddition, Diels−Alder cycloaddition, and many others have laid the foundation for modern polymer analogous reactions.11−13 In modern days, many of those eﬃcient reactions have been summarized under the umbrella of “click” reactions.11,14,15 In combination with controlled polymerization methods16−20 that show improved functional group tolerance in contrast to conventional polymerization techniques, PPM has led to access to numerous deﬁned functional materials. Among the various examples of chemical reactions under the deﬁnition of PPM, activated ester−amine chemistry is a classical one (Scheme 2).21,22 Although activated ester

polymer chemistry. To date, PPM happens to be the most versatile and successful tool for engineering functional polymers. As illustrated in Scheme 1, the PPM technique allows polymerization of monomers with functional moieties that Scheme 1. Schematic Representation for the Synthesis of Functional Polymer by PPM and Direct Polymerization

Scheme 2. PPM Using Activated Ester Amine Chemistry

remain proactive (often also called reactive groups) under the polymerization condition but can be quantitatively and selectively transformed into other functional groups in subsequent steps. Advantages of such approaches over direct polymerization of the respective functional monomers are manifold. Direct polymerization often suﬀers from a limited functional group tolerance under the polymerization condition. This can be due to participation of the functional group attached to the monomer in side reactions that often leads to uncontrolled polymerization or suppressing the polymerization process by poisoning the initiator/catalyst or the monomer. Even incompatibility of the functional groups toward the solvent or the reaction conditions can lead to retarded chain growth. Last but not least, the functional group may simply react with the polymerizable group itself, as, for example, seen in amino-containing acrylates.2 Here comes the utility of PPM into the game, where a chemical modiﬁcation is conducted after the polymerization step, under very mild conditions. Otherwise, this approach is highly attractive for analyzing structure−property relationship behavior as one can think of making a library of functional polymers with identical degree of polymerization and chainlength distributions from a single reactive precursor polymer. Therefore, PPM facilitates diversiﬁcation in a single polymeric backbone, essential for engineering functional materials which are otherwise not possible by direct polymerization. Ever since its discovery, polymer chemists have tried diﬀerent chemical reactions for PPMs to fabricate functional materials. These includes hydrogenation of rubber3 and polystyrene,4 modiﬁcation of polybutadiene backbone via thiol−ene addition,5 chlorination of polystyrene−divinylbenzene used in solid-phase peptide synthesis,6 modiﬁcation of polymers with pendent epoxide functionalities,7,8 and many more. 9,10 However, many of those earlier examples of PPMs suﬀered from nonquantitative installation of functional groups due to poor reaction eﬃciency and required harsh reaction conditions that often lead to potential defects within the polymer

chemistry in polymer synthesis was introduced way before the advent of click chemistry, it was overshadowed by the growing popularity of the 1,3-dipolar cycloaddition reaction, namely, copper(I)-catalyzed alkyne−azide cycloaddition (CuAAC).14,23,24 Without undermining the triumph achieved in PPM utilizing click reactions, it is still believed that activated ester amine exchange has some advantages over other reactions. Primarily, activated esters are useful derivatives for covalent attachment of functional amines based on a stable amide bond formation that is the basis of most biological systems. It is presumed that judicial application of this chemistry can potentially mimic the synthesis of many biostructures and help to comprehend their functions. It comes as no surprise that activated ester chemistry has drawn tremendous interest in synthetic peptide chemistry.25−29 Even from the synthetic standpoint, activated ester amine chemistry is advantageous owing to the abundant availability of most amines from natural or commercial sources when compared with other abiotic synthons (e.g., azides and alkynes) commonly employed in alkyne−azide click reactions. Additionally, the auxiliary use of toxic metal catalysts in 1,3-dipolar cycloaddition reactions during PPM limits the practical application of those polymers in biomedical research. On the down side, activated ester amine chemistry is a substitution reaction, which requires the removal of the released alcohol afterward. However, the removal of small molecular compounds from polymers is a routine procedure that is conducted anyways and allows recycling of the activating alcohol. The objective of this review is to provide the readers with an extensive overview of the advancement made in the area of polymeric activated ester chemistry in designing precisely deﬁned functionally diverse polymer structures, starting from utilizing classical polymerization techniques to state-of-the-art controlled polymerization methods and to highlight their potential applications in various interdisciplinary research areas. This review is divided into two parts. The ﬁrst part will 1435

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Table 1. Structures of Various Activated Ester-Containing Monomers

emphasize the development of activated ester chemistry in constructing diﬀerent reactive polymer structures where detailed information will be provided on various activated ester monomers being used under diﬀerent polymerization techniques, and their advantages and drawbacks will be discussed explicitly. In the second part, focus will be on the versatility and ﬁdelity of this chemistry in fabricating numerous functional materials and their possible opportunities in diﬀerent areas of application ranging from biomedical sciences to materials chemistry. Considering the vast literature available

in this area, only selected examples will be presented in each subsection to make the review comprehensible while citing many similar studies in the corresponding references.

2. METHODS OF PREPARATION OF POLYMERS WITH PENDENT ACTIVATED ESTER MOIETY IN THE SIDE CHAIN Ringsdorf21 and Ferruti22 introduced the concept of activated ester chemistry for preparing reactive polymers. Soon after, polymer chemists started developing numerous activated ester1436

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aminolysis of polyNHSA with allylamine, which could not be prepared by direct polymerization of the corresponding monomer. However, the major drawback of polyNHSA or polyNHSMA is their poor solubility in most organic solvents (except DMF and DMSO) that accounts for their limited use as homopolymers. Thus, NHSA and NHSMA are most often copolymerized with other monomers (Scheme 3b) to enhance the solubility of the resulting copolymers in a wide range of solvents. This extends their scope for aminolysis with diﬀerent amines of varying polarity. To gain insight into the distribution proﬁle of the activated ester group along the polymer backbone during copolymerization, it is important to have an idea of the reaction kinetics and/ or the reactivity ratio between the reactive and the nonreactive monomer during copolymerization. The reaction kinetics for the copolymerization of NHSMA31 with other commonly used (meth)acrylate monomers such as butyl acrylate (BA) and methyl methacrylate (MMA) during free radical copolymerization have been studied by automatic continuous online monitoring of the polymerization technique (ACOMP).32 The results revealed a similar reactivity ratio (r) between the MMA/NHSMA pair in contrast with the BA/NHSMA pair, providing useful information on copolymerizations of NHSMA. Copolymerization of NHSA with hydrophilic monomers can lead to water-soluble reactive polymers that can be functionalized, for example, with various biomolecules. Therefore, the kinetic behavior of NHSA with aqueous soluble N-acryloylmorpholine (NAM) during radical-initiated copolymerization has been investigated in 1,4-dioxane at 60 °C in the presence of AIBN.33 The reactivity ratios of two monomers were determined to be rNHSA = 0.63 ± 0.03 and rNAM = 0.75 ± 0.01, illustrating an almost perfectly random copolymerization behavior of the binary comonomer mixture, leading to the synthesis of macromolecules with homogeneous composition. The average copolymer composition and sequence of monomeric distribution within the linear chain was also determined by 1H NMR and 13C NMR spectroscopies. Similarly, kinetic studies for copolymerization of NHSA and N-vinylpyrrolidone (NVP) were investigated in DMF using 4,4′-azobis(4-cyanopentanoic acid) as an initiator.34 The reactivity ratios of the two monomers were determined to be rNHSA = 0.27 ± 0.04 and rNVP = 0.01 ± 0.01, which seemed to have a strong impact on the overall rate of copolymerization. Unlike the previous example, it indicates a strong alternating tendency during copolymerization.35 During copolymerization of N-isopropylacrylamide (NIPAM) with NHSA in THF/toluene mixture and AIBN as initiator, the molecular weight of the copolymer, poly(NIPAMco-NHSA), was found to depend heavily on the solvent composition and showed a rise in molecular weight with increasing ratio of toluene to THF. Even by adjusting the comonomer feed ratio, it was possible to control the activated ester content per polymer chain, determined from the UV absorption band (259 nm) of the N-hydroxysuccinimide anion generated during aminolysis of the copolymer with isopropylamine.36 Even photopolymerization of NIPAM with NHSA was conducted in the presence of the photoinitiator 2,2-dimethoxy2-phenyl-acetophenone using a UV source, resulting in random copolymers poly(NIPAM-co-NHSA) with molecular weights varying between 10 and 20 kD.37 The reactive prepolymer was conjugated with diﬀerent proteins (α-lactalbumin, albumin, and IgG) via their amine binding sites. The surface-initiated polymerization of N-methacryloyl-β-alanine N′-oxysuccinimide

based monomers that could be easily polymerized under mild conditions to generate reactive precursor polymers. Table 1 provides a glimpse of various types of monomers featuring diﬀerent activated ester moieties that have been used as a reactive entity for postpolymerization modiﬁcation. This section has been categorized into diﬀerent subsections to allow the readers to have clear insight into how this area of reactive polymer synthesis utilizing diﬀerent activated ester monomers has advanced from an era of conventional free radical polymerization to modern controlled chain polymerization and in present day created a facile route for highly functional block copolymers. Particular emphasis is given to the synthesis of reactive homopolymers and statistical copolymers utilizing both free and controlled chain polymerization methods followed by synthesis of reactive functional block copolymers. Focus will be on the synthetic aspects, the reaction kinetics, and the advantages and drawbacks of using one reactive monomer over the other. In addition, utilizing this chemistry, synthesis of numerous amphiphilic and stimuli-responsive polymers will be discussed in detail in separate subsections. Reactive polymers based on azlactone have been excluded in this review as their chemistry of PPM is the addition reaction of nucleophiles with no release of a leaving group unlike in the case of conventional activated ester amine substitution reactions. 2.1. Free Radical Polymerization for Homopolymers and Statistical Polymers

Following are lists of diﬀerent activated ester monomers that have been used for the synthesis of homopolymers and statistical copolymers by free radical polymerization. 2.1.1. N-Hydroxysuccinimide (NHS) Ester Monomers. Among several activated ester monomers, N-hydroxysuccinimide (NHS) ester-containing monomers are the oldest and most popular ones and have attracted a lot of attention in making diﬀerent functional polymers. The earliest examples of free radical polymerization of N-hydroxysuccinimide acrylate (NHSA) and N-hydroxysuccinimide methacrylate (NHSMA) (also sometimes named as N-acryloxysuccinimide, NAS, or Nmethacryloxysuccinimide, NMAS) were described by Ringsdorf and Ferruti with azobis(isobutyronitrile) (AIBN) (Scheme 3a).21,22 NHS-ester-based reactive polymers are quite (yet not fully) resistant to hydrolysis30 and subjected to nucleophilic aminolysis with primary and secondary amines under mild reaction conditions to generate functionalized polyacrylamide derivatives. Under identical reaction conditions, polyNHSA was found to be more reactive than polyNHSMA.21 Ferruti et al.22 illustrated the synthesis of linear poly(N-allylacrylamide) by Scheme 3. Free Radical (a) Homopolymerization and (b) Copolymerization of NHSA/NHSMA

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amines as well as with alcohols. In general, PFP-ester polymers were found to be slightly more reactive than the NHS-ester polymers, while their acrylate backbones show extremely high reactivity compared to their own methacrylate analogue. Although the reactivity of polyPFPA toward primary and secondary amines was investigated to be satisfactory, low conversion was observed for aromatic amines and alcohols (Scheme 5). The physical properties (such as glass transition temperature) of MMA are often improved by randomly copolymerizing it with PFPMA via free radical polymerization.44,45 However, the refractive index and the light transmittance properties of these copolymers remained close to that of PMMA. Nilles and Theato46 demonstrated free radical polymerization of diﬀerent activated ester monomers based on 4-vinyl benzoic acid and compared their reactivity toward series of functional amines. Most interestingly, among all tested activated ester polymers of 4-vinyl benzoate, pentaﬂuorophenyl 4-vinyl benzoate (PFP4VB) (Table 1) exhibited the highest reactivity. Its reactivity was even much higher compared to its own polymethacrylate or polyacrylate analogues as demonstrated by its quantitative reaction with even less nucleophilic aromatic or secondary amines such as aniline and morpholine or N-propylpiperazine, respectively. Conversions with aliphatic amines proceeded within less than 5 min at 0 °C and practically immediately at room temperature. The same group later described free radical polymerization of novel PFP-functionalized 1,1-disubstituted-2-vinylcyclopropane (PFP2VCP) with AIBN to produce polyPFP2VCP (Scheme 6), which could also be easily modiﬁed with amines.47 Noteworthy, many of the resulting polymers featured an upper critical solution temperature (UCST) in ethanol/water mixtures, with the npropylamide derivative showing additionally a large UCST hysteresis and gelation behavior. 2.1.3. Other Activated Ester Monomers. Compared to the vast literature available on NHSA/NHSMA or PFPA/ PFPMA polymers, examples of polymers featuring other activated ester groups are very limited. Although some of them have few advantages they could not show up to the standard of the two earlier mentioned classes of activated ester polymers. Ringsdorf and co-workers48 reported free radical polymerization of acrylates and methacrylates of trichlorophenol (TCP) or N-hydroxy benzotriazol (NHB) derivatives. On one hand, the toxicity of trichlorophenol limited the use of TCP-based polymers, while on the other hand, the hydrolytic susceptibility of NHB-based polyesters raised the question of their long lasting stability. Rejmanova and Kopecek 49 copolymerized a new class of methacrylate monomer, p-nitro phenyl methacrylate (PNPMA) (Table 1), with N-(2hydroxypropyl)-methacrylamide (HPMA) under free radical

ester (MAC2AE) using a self-assembled monolayer of an azo initiator was achieved on silicon oxide substrates with very high grafting density.38 Aminolysis of NHS-ester groups within the brush with various n-alkylamines were studied by infrared and surface plasmon spectroscopy. Using inverse microemulsion/ free radical polymerization,39 reactive microparticles of copolymer, poly(NHSA-co-NVP), were prepared in one pot that could be coupled with amine-functionalized dye to generate ﬂuorescent particles. Although NHS-ester-based polymers are the most commonly used reactive polymers, they have some limitations. There is proof of unexpected side reactions taking place during the aminolysis step such as ring opening of the succinimide functionality and formation of N-substituted glutarimides by attack of amides on neighboring activated esters (Scheme 4).40 Scheme 4. Side Reactions during Aminolysis of polyNHSA/ polyNHSMA

Even methods to combat those side reactions have been achieved by carrying out the substitution at high temperature and using an excess of amine or proton scavengers such as triethyl amine or 4-dimethylaminopyridine.41 2.1.2. Pentaﬂuorophenyl (PFP) Ester Monomers. After NHS-ester monomers, pentaﬂuorophenyl (PFP) ester-based acrylates (PFPA), methacrylate (PFPMA), and vinylbenzoates (PFP4VP) stand as the second most explicitly explored activated ester monomers that can be subjected to free radical polymerization.42 The ﬁrst paper on the synthesis of PFPA and its polymerization in bulk was reported by Blazejewski and coworkers.43 However, the insolubility of the polymeric material did not allow further characterization by size exclusion chromatography or other analytical techniques available. Eberhardt and Theato42 illustrated homopolymerization of PFPA and PFPMA using AIBN as a thermal initiator. Unlike polyNHSA/polyNHSMA, whose solubility is limited to DMSO and DMF, polyPFPA and polyPFPMA were found to be soluble in a wide range of organic solvents and thus considered superior for PPMs from a solubility aspect. A comparative study between the reactivities of polymethacrylates and polyacrylates of both PFP-ester and NHS-ester as well as between these two diﬀerent classes of activated ester polymers were conducted by treating all four of them with primary, secondary, and aromatic

Scheme 5. Comparative Study of the Reactivity of polyPFPA with Various Nucleophiles

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Scheme 6. Synthesis of polyPFP2VCP and Its PPM with Primary Amines

polymerization.50−53 However, incorporation of PNPMA within the copolymer resulted in a low polymerization yield as also observed by Okawara et al. for poly(styrene-coPNPA).54 For a series of copolymers of p-nitrophenyl acrylate (PNPA) with styrene, methyl acrylate, and N,N-dimethylacrylamide (DMA), the rate of aminolysis was studied in dioxane and chlorobenzene.55 The reactivity of the pendent PNP-ester was found to be dependent on the nature of the polymer backbone, highest for poly(DMA) due to the activating eﬀect of the dimethylamide groups. Photosensitive polymers containing pendent chalcone moieties were prepared by free radical homopolymerization and copolymerization of PNPMA with vinyl-chalcone monomers that acted as a photosensitizer. Photochemical cross-linking by UV irradiation was found to be faster for the copolymer when compared to chalcone homopolymer.56,57 Agosto and Pichot58 introduced a new class of bifunctional activated ester monomer, named di-NHSA, obtained as a byproduct during NHSA synthesis. Under free radical polymerization, homopolymerization reached only 5% conversion, probably due to cross-propagation to minimize steric hindrance from homopropagation. However, high molecular weight poly(NAM-co-di-NHSA) could be obtained with 92% conversion using NAM as a comonomer (Scheme 7). This new

As alternative activated esters that can be used in aqueous conditions, sulfonated NHS-esters were proposed.60−63 4Sulfotetraﬂuorophenyl (STP) esters were also proposed as an alternative activated ester to be used under aqueous conditions but have not found broad application.64,65 Metz and Theato66 reported free radical polymerization of acetone oxime acrylate (AOA) to develop a new class of activated ester polymer that exhibits solubility in various organic solvents (Table 1). The same group later introduced salicylic-acid-derivatized acrylates (SAA)67 as novel reactive monomers for free radical polymerization. The resulting polymers could be subjected to facile postfunctionalization with both primary and secondary amines (Scheme 8). Although

Scheme 7. Free Radical Copolymerization of di-NHSA

kinetic studies revealed a lower reactivity toward amines when compared with polyPFP(M)A, salicylate ester polymers showed a far less in vitro cytotoxicity as expected from the released salicylic acid derivates in contrast with toxic pentaﬂuorophenols during aminolysis of polyPFP(M)A. Consequently, such reactive precursor polymers look very promising for in vivo synthesis of biologically relevant functional polyacrylamides.

Scheme 8. Synthesis of Polymers from Salicylic-AcidDerivatized Acrylates (SAA) and Their PPM with Primary and Secondary Amines

2.2. Controlled Radical Polymerization for Homopolymers and Statistical Polymers

The advent of modern polymerization techniques such as atom transfer radical polymerization (ATRP), reversible addition− fragmentation chain transfer (RAFT), and nitroxide-mediated polymerization (NMP) has embarked on a new era of advance polymer synthesis. Combining PPMs with controlled polymerization techniques has created new possibilities to realize highly functionalized and complex polymeric scaﬀolds that were never achieved before by free radical pathways. This section will highlight synthesis of a variety of reactive polymers using stateof-the-art polymerization techniques and their contribution in tailoring amphiphilic and stimuli-responsive polymers utilizing activated ester amine chemistry, while complex poly(meth)acrylamides designed for targeting speciﬁc applications will be discussed in the respective subsections (see section 6). 2.2.1. Polymerization of NHS Ester Monomers. Müller and Brocchini68 described ATRP polymerization of NHSMA with controlled molecular weight and narrow molecular weight distribution using 2-bromo-2-methyl(2-hydroxyethyl)propanoate, CuBr, and 2,2′-bipyridine as initiator, catalyst,

reactive polymer displayed two reactive sites per incorporated di-NHSA monomer and is therefore capable of exhibiting a multivalent eﬀect upon PPM, compared to copolymers with a single activated ester as side groups. An interesting class of activated ester polymers that can potentially replace polyNHS(M)A is thiazolidine-2-thione (TT)-based polymers. Ulrich and co-workers59 copolymerized TT-based methacrylate monomer (MAPTT) (Table 1) with HPMA to prepare water-soluble reactive polymers with controlled molecular weight and narrow dispersity. Unlike NHS- or PFP-ester polymers, these reactive polymers displayed rapid aminolysis in aqueous medium with a negligible rate of hydrolysis when the solution pH was maintained within 7.4− 8.0. Although TT-based reactive polymers appear promising for aminolysis in aqueous medium, they exhibit poor selectivity between amines and thiols under identical reaction conditions. 1439

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Scheme 9. Graft-Copolymer Synthesis by a “Grafting-from” Approach by Immobilizing a RAFT Agent on an NHSA Copolymer by PPM

and ligand, respectively. Pan et al.69 later improved the initiator eﬃciency using NHSA monomer. Haddleton et al.70 subsequently optimized the polymerization conditions for polyNHSMA with CuBr, N-(n-propyl)-2-pyridylmethanimine, and ethyl-2-bromoisobutyrate in DMSO and successfully achieved conversion up to 70%. While a plethora of welldeﬁned homopolymers and statistical copolymers of NHSA/ NHSMA71 have been achieved by ATRP, their homopolymerization by RAFT often led to polymers with broad molecular weight distributions. However, their copolymerization with other acrylamide monomers by RAFT have been successfully achieved with good control of molecular weight and polydispersity.72−75 Thayumanavan and co-workers74 standardized conditions for copolymerization of NHSMA with NIPAM under most commonly used ATRP, RAFT, and NMP methods to obtain control over the molecular weight distribution. Among all three controlled CRP methods, RAFT was able to aﬀord copolymers with the lowest molecular weight distribution (Mw/Mn = 1.1−1.2). Gilbert and co-workers76 described RAFT copolymerization of NHSA and n-butyl methacrylate (BMA) to produce linear poly(BMA-co-NHSA) chains. The statistical copolymer was later immobilized with primary hydroxyl-functionalized RAFT agents through nucleophilic substitution at the activated ester sites (Scheme 9). Immobilized RAFT agents along the side chains were further used to polymerize BMA to synthesize linear-graft copolymer, poly(BMA-co-NHSA-graf t-BMA). Möller and et al.77 synthesized α,ω-isocyanate-telechelic poly(MMA-co-NHSA) and poly(MMA-co-acrylamidohexanoic succinimide) using carboxylic-acid-functionalized RAFT agent followed by two-step PPM of end functional groups to generate isocyanate-immobilized homotelechelic copolymers. Obtained polymers featuring isocyanate groups at the chain ends produced reactive polyurethanes by condensation polymerization with diols. Recent interest is developed in activated ester polymers based on 4-vinyl benzoate for their greater reactivity compared to the (meth)acrylate analogues. For instance, Tew et al.78 reported RAFT polymerization of NHS-ester of 4-vinyl benzoic acid (NHS4VB) (Table 1) with controlled molecular weights (44−61 kDa) and a narrow molecular weight distribution (Mw/ Mn < 1.07). Hawker and co-workers79 described nitroxidemediated copolymerization of NHS4VB and NHSA with styrene in the presence of 2,2,6,6-tetramethylpiperidinoxy (TEMPO) as a stable radical. Quantitative amidation with amine-based polyether dendrons resulted in dendritic-linear graft copolymer. Using surface-initiated atom transfer radical polymerization (SI-ATRP), polymer brushes with high grafting density were

prepared from NHSMA80 and NHS4VB.81 The feasibility and versatility of these reactive polymer thin ﬁlms toward nucleophilic substitution with a variety of n-alkylamines were investigated. Even reactive polyNHS4VP brushes were eﬀectively used as macroinitiators for block copolymerization of styrene.82 2.2.2. Polymerization of PFP Ester Monomers. As mentioned earlier, PFPA/PFPMA has emerged as an attractive alternate to NHSA/NHSMA polymers for their better hydrolytic stability, higher reactivity, and good solubility in a wide range of organic solvents. However, homopolymerization of PFP(M)A via ATRP does not proceed eﬃciently, owing to the interference of copper(I) catalyst with the monomer, which may potentially lead to hydrolysis of the ester and protonation of the metal ion and the ligand.83 As a result, only lower molecular weights have been reported.84 Recent careful investigation also led to some success in the polymerization.85 On the contrary, RAFT polymerization of these activated ester monomers has been very successful. For example, homopolymerization of PFP(M)A by RAFT can be controlled. Theato et al.86 described polymerization of PFPA with a precisely controlled molecular weight and narrow molecular weight distributions (Mw/Mn ≤ 1.2) using cumyl dithiobenzoate or 4cyano-4-((thiobenzoyl)sulfanyl)-pentanoic acid. Under similar conditions, linear diblock copolymers consisting of a reactive PFP-ester block were achieved. Employing this monomer, Klok and co-workers87 created diverse libraries of functional watersoluble polymers, demonstrating the potential of PFP-ester monomers for designing functional polyacrylamides. Barz and Zentel88 described the synthesis of water-soluble HPMA-based homopolymers89 and copolymers,90 one of the most investigated polymers in biomedical research, by PPM of PFPMA with 2-hydroxypropyl amine. Interestingly, the aminolysis step does not contribute to additional cytotoxicity87 after intensive dialysis when compared with direct polymerization of HPMA.91,92 This makes the PPM approach eﬀective for structure−property relationship studies of those biologically active polymers under physiological conditions. Frey et al.93 reported the synthesis of linear-hyperbranched graft-copolymers of polyHPMA via “grafting-to” approach by sequential modiﬁcation of polyPFPMA backbone with a dendritic amine followed by 2-hydroxypropylamine. In a slightly diﬀerent strategy, they synthesized polyHPMA with pendent β-cyclodextrin via triple PPM of polyPFPMA obtained by RAFT. The water-soluble copolymer was used to fabricate reversible linear-graf t-(linear-hyperbranched) supramolecular graft terpolymers by complexation with monoadamantylfunctionalized linear polyglycerols.94 1440

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Scheme 10. Schematic Representation of Sequence-Controlled Installation of PFP4MB to the Polystyrene Chains Prepared by NMP

Scheme 11. Synthesis of polyPFPMA Brushes by SI-RAFT and PPM with Amines

Nilles and Theato reported RAFT polymerization of PFP4VB with extreme precision and further displayed it as potential macrochain transfer agent (CTA) for diblock copolymerization of styrene derivatives.95 Remarkably increased reactivity of PFP4VP has been taken advantage of in creating dual-reactive statistical copolymers poly(PFPMA-coPFP4VP) that oﬀered selective modiﬁcation with amines of varying reactivity.96 In a joint work, the groups of Lutz and Theato97 showed sequence-controlled installation of pentaﬂuorophenyl 4-maleimidobenzoate (PFP4MB) within a polystyrene backbone by kinetically installing it at diﬀerent stages of a nitroxide-mediated polymerization (Scheme 10), followed by postpolymerization functionalization with polar and nonpolar amines. Apart from polymerization in solution, Klok and coworkers98 reported surface-initiated RAFT polymerization (SIRAFT) of PFPMA. The resulting reactive brushes could be postmodiﬁed in quantitative yields with various amines (Scheme 11). That conversion of the PFP-ester groups can be conducted in bulk has been reported by the group of Theato, who synthesized polyPFPMA-containing photocleavable block copolymers for the preparation of functional nanoporous thin ﬁlms.83,99 PPM modiﬁcation of a nanoporous polyPFPMA with amines could be achieved without destroying the nanoporous character of the ﬁlm. Also, photo-cross-linking of reactive ﬁlms obtained from a copolymer of PFPA and an onitrobenzyl-protected amine-based monomer using a photomask created pattern surfaces (Scheme 12).100 2.2.3. Polymerization of Other Activated Ester Monomers. Besides polymerization of NHS- and PFP(meth)acrylates, various other activated ester monomers have been subjected to controlled radical polymerization. Kim and Theato101 showed ATRP polymerization of 2,4,5-trichloro-

Scheme 12. Schematic Representation for the Preparation of Photo-Cross-Linked Films Obtained from polyPFPA Containing o-Nitrobenzyl Protected Aminesa

a

Redrawn after ref 100. Copyright 2013 Royal Society of Chemistry.

phenyl acrylate (TCPA)102 and endo-N-hydroxy-5-norbornene2,3-dicarboxyimide acrylate (NHNorbDA) (Table 1) in bulk and DMSO, respectively, using 2-bromoisobutyric ethyl ester, CuBr, and 2,2′-bipyridine. Both polymers showed improved solubility compared to polyNHSA/polyNHSMA in a wide spectrum of solvents. Even polyNHNorbDA was obtained with quantitative initiator eﬃciency and could be used for a block copolymer synthesis with MMA. Liu and Pan103 described polymerization of PNPMA in bulk by ATRP. Accumulation of Cu2+ ions within the polymer resulted in poor conversion and 1441

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higher than that of polyPFP(M)A, although their aminolysis followed an opposite trend.112 2.2.4. Amphiphilic and Stimuli-Responsive Statistical Copolymers. Well-deﬁned amphiphilic polymers ﬁnd tremendous applications in biology and medical sciences. Examples comprise the use of polymeric materials in drug delivery,113 gene delivery,114 tissue engineering,115 antibiotic agents,116 and so forth. The high ﬁdelity in functionalization of polymeric activated ester with variety of functional amines has been greatly taken advantage of in amphiphilic polymer synthesis. Utilizing polymeric activated esters, amphiphilic statistical copolymers are commonly prepared via two synthetic approaches: (1) Sequential conversion of a reactive precursor homopolymer with diﬀerent functional amines of varying polarity117−121 (often the minor component or the most precious amine (based on availability) is incorporated in the ﬁrst step to ensure quantitative consumption of the amine, followed by aminolysis of the remaining activated ester units with the amine that makes up the majority of the copolymer composition); (2) Copolymerization of an activated ester monomer with another nonreactive polar/apolar monomer, followed by aminolysis with hydrophobic or hydrophilic amines.122−125 Amphiphilic polymers with stimuli-responsive functional groups are subjected to conformational changes upon exposure to external stimuli (pH, temperature, light, etc.) and therefore are highly interesting for various biomedical applications. Widespread synthetic strategy for stimuli-responsive polymersalso called “smart polymers”mostly takes advantage of PPM via aminolysis of an activated ester (meth)acrylate.30 In this regard, polyacrylamides, more precisely polyNIPAM, have attracted great interest as thermoresponsive polymers in aqueous medium owing to its lower critical solution temperature (LCST) in water at 32 °C, being very close to the human body temperature.126 LCST of functional polyNIPAM can be shifted to higher or lower values by copolymerizing NIPAM with an activated ester monomer and subsequent modiﬁcation with functional amines.127−129 A library of structurally isomeric copolymers of poly(N-npropylacrylamide) and polyNIPAM was prepared from a single reactive polyNHSA by aminolysis with varying fractions of 1propyl- and 2-propyl-amines.130 The LCST of all copolymers, featuring identical moleculat weight, degree of polymerization, and polydispersity, was found to be linearly dependent on the feed ratio of the more hydrophobic poly(N-n-propylacrylamide). A series of dye-labeled polar polyNIPAM and nonpolar poly(N-octadecylacrylamide) was generated from a precursor polyNHSA by double PPM. Their phase-selective solubilities were measured in a mixture of polar (90% EtOH−H2O mixture) and nonpolar (hexane) thermomorphic solvents at 25 °C.131 Starting from polyPFPA, temperature-responsive polyNIPAM132 or poly(N-cyclopropylacrylamide)133 copolymers containing 1.0 or 3−5 mol % of pyrene side chains, respectively, were prepared. The LCSTs of the copolymers were governed by the amount of hydrophobic pyrene moiety incorporated. Those copolymers were employed to disperse single-walled carbon nanotubes (SWNT) in water. They triggered temperature-responsive dispersion behavior of SWNT and controlled the extent of exfoliation or bundle formation of the nanotubes. In recent years, polymers that respond to multiple stimuli have attracted more attention. Utilizing activated ester chemistry, numerous multiresponsive polymers have been generated from polyNHSA37,134,135 or polyPFPA136,125 by

broad molecular weight distribution. However, block copolymerization of PNPMA with styrene by ATRP proceeded with controlled molecular weight and low dispersity. Under RAFT conditions, homopolymerization104 and block copolymerization105,106 of PNPA resulted in better yield and control. Gan and co-workers107 described controlled ATRP of 2,3,5,6tetraﬂuorophenyl methacrylate (TFPMA) (Table 1) using CuBr2 deactivator. Although being less reactive than polyPFPA, quantitative reaction with unhindered primary amines was successfully achieved at elevated temperature for the obtained polyTFPMA. Notably, the possibility to characterize polyTFPMA by 1H NMR makes it advantageous over polyPFP(M)A. Metz and Theato66 conducted polymerization of AOA by both RAFT and NMP. Partial modiﬁcation with isopropylamine imparted a reactive copolymer of poly(NIPAM-co-AOA) featuring LCST at 61 °C that disappeared on complete substitution with ammonia. Godula and Bertozzi108 treated polyAOA with hydrazides to obtain poly(acryloyl hydrazide) (PAH) with pendent free amines that was later used to immobilize glycans to form glycopolymers. Kakuchi and Theato109 described RAFT polymerization of a novel monomer, 4-acryloxyphenyldimethylsulfonium triﬂate (APDMST), that oﬀered an external stimuli-triggered reactivity switch for activated ester amine click reaction. The reactive form poly(APDMST), which readily reacts with amines as expected for an activated ester, could be converted to a nonreactive form by thermo-triggered demethylation to yield poly(4-acryloxyphenyl methylsulﬁde) (polyAPMS). The nonreactive polymer could not aﬀord a conversion with amines, hence featuring a “switched oﬀ” reactivity (Scheme 13). Scheme 13. Temperature-Induced Switch in the Reactivity of polyAPDMST

Nuhn and Zentel110 developed a series of novel activated ester polymers with adjustable molecular weights (16−30K) and a narrow molecular weight distribution (PDI = 1.15−1.3) from 1,1,1,3,3,3-hexaﬂuoroisopropyl methacrylate (HFIPMA) (Table 1) via RAFT polymerization, providing a versatile tool for multifunctional water-soluble polymers. These activated ester polymers showed potential for block copolymerization. Formation of a volatile byproduct 1,1,1,3,3,3-hexaﬂuoroisopropanol during aminolysis makes the puriﬁcation step easier but limits a potential recycling. Studer et al.111 described nitroxidemediated homopolymerization and alternating copolymerization of HFIPA with n-butyl vinyl ether (Scheme 14) with sterically hindered alkoxyamine initiator followed by quantitative amidation with primary amines. Percec et al. even showed that polyHFIPA and polyHFIPMA can be subjected to quantitative transesteriﬁcation using DBU as catalyst. The rate of alcoholysis of polyHFIP(M)A was found to be even 1442

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Scheme 14. Nitroxide-Mediated (a) Homopolymerization and PPM (b) Alternate Copolymerization of HFIPA with n-Butyl Vinyl Ether

reacting with functional amines containing stimuli-responsive groups. Temperature-responsive polyNIPAM featuring photoresponsive azobenzene137−139 side groups were prepared by copolymerizing NIPAM with diﬀerent NHS-ester monomers followed by aminolysis with light-responsive (3aminopropyloxy)azobenzene.140 Photoirradiation of azobenzene from a more hydrophobic trans to cis isomer contributed to a change in the phase transition temperature of polyNIPAM. Besides azobenzene, copolymers of NIPAM with other photochromic moieties in the side chains such as fulgimide141 and salicylideneaniline142 groups have been synthesized via a double PPM of polyPFPA. Light-induced changes in the LCST behavior of these polymers could be observed. Besides polyNIPAM displaying photoresponsive groups, polyNIPAM copolymers that exhibit both temperature and pH sensitivity were fabricated from precursor poly(NIPAM-co-NHSA) by installation of pH-sensitive m-aminophenylboronic acid at the NHS-ester site.143 Dual temperature- and pH-responsivefunctionalized polyNIPAM 144,145 and poly(methacrylamide)146−148 microgels have been prepared using PNPA as a reactive copolymer for installation of pH-responsive 4methylpyridine and folic acid as a targeting ligand. Collagenase-sensitive peptide-based polyNIPAM copolymers, poly(NIPAM-co-GAPGL-NH 2 ) and poly(NIPAM-coGAPGLF-NH2), have been constructed by derivatization of poly(NIPAM-co-NHSA) with the corresponding peptides. Both copolymers revealed an increase in LCST when subjected to enzymatic degradation in the presence of collagenase.149 Starting from polyPFPA, a thermo-sensitive polyNIPAM featuring both light-responsive (azobenzene) and redoxresponsive (TEMPO)150 side groups was fabricated by sequential substitution of the PFP-ester with N-(2-aminoethyl)-4-(2-phenyldiazenyl) benzamide (amino-azobenzene) and 4-amino-2,2,6,6-tetramethyl-1-oxyl-piperidine (aminoTEMPO). Remaining PFP-esters were treated with an excess amount of isopropylamine to generate a triple-responsive copolymer (Scheme 15).151 Besides polyNIPAM, poly/oligo(ethylene glycols) (PEG/ OEG) are another class of thermoresponsive polymers that have attracted signiﬁcant attention due to their well-established biocompatibility. Ethylene glycol chains can be easily incorporated within the polymer scaﬀold by PPM. Davis and

Scheme 15. Synthesis of a Triple Responsive NIPAM-Based Copolymer by PPM of polyPFPA

Lowe117 obtained a library of thermoresponsive poly(meth)acrylamides with ethylene glycol side chains of varying lengths by treating polyPFPA or polyPFPMA with diﬀerent PEG-based amines. Similarly, Ghosh et al.122 created a series of amphiphilic random copolymers from a single reactive prepolymer made by RAFT copolymerization of NHSMA with a hydrophobic methacrylate monomer with octyl chains, followed by substitution of pendent NHS-ester groups with diﬀerent hydrophilic OEG-amines. All polymers obtained showed an identical degree of polymerization and equal extent of randomness. The aggregation behavior123 and thermoresponsive phase transition of these polymers could be adjusted by incorporating OEG-amines of diﬀerent chain lengths. Noteworthy, the reactive precursor-based synthetic approach provides the opportunity for structure−property relationship studies that are otherwise diﬃcult to achieve by employing direct polymerization. In an alternate approach, Lowe, Davis, and Boyer152 copolymerized PFPA with oligoethylene glycol acrylates (OEGA) or diethylene glycol acrylate followed by quantitative amidation with hydrophobic amines to tailor the thermoresponsive behavior of the resulting amphiphilic copolymers. Ion-sensitive polymers, those with the ability to undergo conformational changes in solution, have also been designed and constructed utilizing activated ester amine chemistry. Fluorogenic ion sensors were developed from ion-responsive copolymers. They were prepared by statistical copolymerization of NHSA with a polarity-sensitive ﬂuorophore-based monomer followed by substitution of the NHS-ester groups with SO42− 1443

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Scheme 16. Synthesis of Polyacrylamide-Based Fluorogenic Ion Sensor by PPM of polyNHSA Copolymer

Scheme 17. Synthesis of Sulfobetaine Copolymer from polyPFPA

Scheme 18. Synthesis of PNPMA-Based Block Copolymer (a) by ATRP Using PNPMA as the Second Monomer and (b) by RAFT Using PNPMA as the First Monomer

ion-selective tris(3-amino-propyl) amino ligand153 (Scheme 16). Conformational change of the copolymer upon binding with SO4 2− ions in aqueous solution caused a decrease in the local polarity across the ﬂuorophore that signiﬁcantly enhanced the observable ﬂuorescence signal. Zwitterionic polymers such as polysulfobetaines have received great attention as a very promising class of materials.154−156 They exhibit dual responsiveness toward temperature and salts. Roth et al.157 described a facile synthetic route for hydrophobically modiﬁed sulfobetaine-based zwitterionic copolymers. In a single step, polyPFPA was derivatized with a mixture of 3-((3-aminopropyl) dimethylammonio)propane-1-sulfonate (ADPS) and diﬀerent hydrophobic amines in propylene carbonate solvent (Scheme 17), creating those

polymers. Notably, it is very diﬃcult to prepare those zwitterionic copolymers by direct polymerization techniques.158 2.3. Block Copolymers

2.3.1. Block Copolymerization of Activated Ester Monomers. The ability of block copolymers159−161 to undergo phase separation and nanostructure formation has initiated research on developing new synthetic strategies to design complex block copolymers for targeting various applications in both biomedical162,163 and materials science.164,165 Controlled chain polymerization in combination with PPM166 continues to be the most eﬃcient tool to access well-deﬁned and chemically diverse block copolymers. Along this line, activated ester chemistry has been extensively employed in engineering multifunctional block copolymers. 1444

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Scheme 19. Convergent Approach for Synthesis of Cleavable Block Copolymer from Two Separate Homopolymers with Complementary Reactive Handles at the Chain End

The diversity in block copolymer architectures can be enhanced many fold if one of the blocks features an activated ester group that performs as a functional handle for PPMs. Additionally, this approach allows synthesis of block copolymers with blocks that cannot be generated by direct block copolymerization of certain monomers owing to their incompatibility toward the polymerization conditions or methods. Currently, activated ester monomers can be directly involved in structuring one of the blocks or an additional precursor for postincorporation of target functionalities within the preformed blocks. The choice of monomers and their sequence of addition during the course of block copolymerization are highly crucial. During sequential copolymerization, the activated ester monomer can be either the part of the macroinitiator or macro-CTA that mediates the polymerization of the second monomer or itself polymerized in the second step from a macroinitiator or macro-CTA developed from a nonreactive block. Most activated ester monomers subjected to controlled chain polymerizations can be used in designing functional block copolymers (see also section 2.2).82,107,110,167 However, their sequence of addition sometimes has an inﬂuence on the rate and quality of polymerization that depends on the eﬃciency and living character of the ﬁrst block. For example, Pan et al.103 synthesized well-deﬁned block copolymer polySt-b-polyPNPMA by ATRP in bulk using CuBr/bpy as catalyst and polystyrene as a macroinitiator (Scheme 18a). Poorly controlled homopolymerization of PNPMA under similar ATRP conditions restricted their use as a reactive macroinitiator for polymerization of styrene in the second step. Hydrolysis or aminolysis of the polyNPMA segment with n-butylamine resulted in two new block copolymers, polySt-block-poly(methacrylic acid) and polyStblock-poly(N-butyl methacrylamide), respectively, both diﬃcult to prepare directly from their corresponding monomers. Interestingly, the same group later described controlled homopolymerization of PNPMA under RAFT conditions using cumyl dithiobenzoate as the CTA and AIBN as the initiator with 90% monomer conversion. Also, the living character of the reaction was illustrated by controlled chain

extension of polyPNPMA when used as a macro-CTA for the RAFT polymerization of diethoxypropyl methacrylate (DEPMA)105 (Scheme 18b). The resulting block copolymer polyPNPMA-b-polyDEPMA prepared in 86% yield revealed an orthogonal reactivity of the two diﬀerent blocks, featuring activated esters and protected aldehydes. Similar to PNPMA, homopolymerization of PNPA by ATRP proceeded with low yield and did not show a living character. However, their RAFT polymerization aﬀorded controlled polyPNPA chains with an intact terminal dithioester groups that could reinitiate the polymerization of styrene as the second block.104 Therefore, it is evident that the method of polymerization often determines the sequence of addition of the activated ester monomer during block copolymer synthesis. When it comes to NHS-ester monomers, reports on their use both as ﬁrst or as second block by ATRP polymerization is well known. Haddleton and co-workers70 demonstrated controlled chain extension of MMA from a polyNHSMA macroinitiator. PolyNHSMA was prepared by ATRP using Cu(I)Br and N-(npropyl)-2-pyridylmethanimine catalyst and ethyl-2-bromoisobutyrate as the initiator. Transformation of the reactive block to poly(N-benzyl methacrylamide) by reaction with benzyl amine oﬀered an indirect route for polyacrylamide synthesis which usually does not proceed well by ATRP with Cu(I) catalysts.168 Tew et al. followed an inverse pathway to generate poly(NHSMA-b-MMA) or poly(NHSMA-b-St) by using PMMA or polystyrene macroinitiators for polymerization of NHSMA using a Cu(I)Br/PMDTA catalyst.169,170 The reverse strategy produced better results compared to when polyNHSMA was used as a macroinitiator. This was due to the fact that under identical conditions, polyNHSMA induced less eﬀective initiation for polymerization owing to their signiﬁcant chain termination. Following a similar strategy, Segalman et al.171 prepared poly(NHSMA-b-St) from a polystyrene macroinitiator. The precursor block copolymer was developed into a polymeric ionic liquid by PPM of polyNHSMA block with histamine and subsequent treatment with triﬂuoroacidic acid to synthesize an imidazole pendent block copolymer. In contrast, synthesis of diblock copolymers using polyNHNorbDA (Table 1445

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Scheme 20. Synthesis of Thiol-Functionalized (top) and Fluorophore-Functionalized (bottom) Block Copolymers from Reactive PFPMA

Scheme 21. Synthesis of Functional Block Copolymer Featuring Donor−Chromophore−Acceptor Segments Using PFPA

1) as macroinitiator and MMA as the second block has been successfully achieved with CuBr and 2,2′-bipyridine catalyst using ethyl-2-bromoisobutyrate as the starting initiator.101 Unlike polyNHSMA, the initiation with polyNorbNHSA was quantitative as no homopolymer peak could be detected from GPC after polymerization of MMA. However, Thayumanavan and co-worker172 depicted a novel convergent approach for a cleavable reactive block copolymer, polyNHSMA-b-PMMA, utilizing a pyridyldisulﬁde-functionalized ATRP initiator. In this method, they separately prepared pyridyldisulﬁde chain-endfunctionalized polyNHSMA and PMMA from the corresponding initiator. Selective reduction of the disulﬁde linkage at the chain end of PMMA with dithiothreitol (DTT) generated terminal free thiol. The thiol-terminated PMMA was reacted with the second pyridyldisulﬁde-terminated polyNHSMA homopolymer to synthesize disulﬁde linked redox-sensitive polyNHSMA-b-PMMA. Again, the block copolymer could be cleaved into its constituent homopolymers under mild exposure to DTT (Scheme 19). As homopolymerization of NHS(M)A under RAFT conditions does not go well, they are usually employed in

constructing the second block, during their block copolymerization by RAFT. Usually, the ﬁrst block is constructed from a nonreactive monomer that mediates the polymerization of NHSA/NHSMA to construct the second block.75,72 In this regard, using PFPA/PFPMA is more advantageous, as they can be used in building of either the ﬁrst or the second block. Theato et al.86 used polyPFPMA as a macro-RAFT agent for block copolymerization of MMA, NAM, or N,N-diethylacrylamide. In all these cases, controlled chain extension occurred and the resulting diblock copolymers had a molecular weight distribution Mw/Mn close to 1.3. Comparing the GPC proﬁle of the resulting block copolymers with polyPFPMA, less than 5% fraction of the homopolymer was detected in the diblocks, possibility due to naturally occurring chain termination. This fraction is less when compared with macroinitiation from polyNHSA or polyNHSMA, prepared by ATRP. Thus, synthesis of block copolymers by RAFT using PFP-ester monomers oﬀers better access to reactive copolymers of diverse attributes. Yet, Sohn et al.173 successfully showed the synthesis of diblock copolymer, PMMA-b-polyPFPMA, from a polymeric macro-CTA of PMMA, with both blocks of equal degree of 1446

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ester amine chemistry is highly celebrated in making functionalized stimuli-responsive amphiphilic block copolymers.182,183 Precise functional group incorporation requires installation of the activated ester monomers selectively within the hydrophobic or hydrophilic segment during the course of block copolymer synthesis, which provides a synthetic handle for postintroduction of target functionality. Now, the hydrophilic and hydrophobic blocks either can be generated by polymerizing two nonreactive monomers of varying polarity or can be engendered by treating activated ester-containing blocks with polar or apolar amines. Categorically, functionalized ABCs can be synthesized by two pathways: (1) By homo- or copolymerization of activated ester monomers from either a hydrophilic or a hydrophobic nonreactive macroinitiator or macro-CTA and (2) growing a hydrophobic or hydrophilic chain from an activated ester-containing macroinitiator or macro-CTA. Now, depending on whether the macroinitiator is hydrophilic or hydrophobic, core or shell modiﬁcations are further possible. 2.3.2.1. Block Copolymerization from a Nonreactive Macroinitiator/Chain Transfer Agent. PEO-based functional block copolymers have drawn considerable interest in pharmaceutical applications. They are often prepared by conjugating PEO with reactive polymers that facilitate chemical modiﬁcation of the hydrophobic block.184,185 Brocchini et al.30 prepared a library of pH-responsive cationic block copolymers, all with an identical degree of polymerization from a single precursor block copolymer, made by ATRP polymerization of NHSMA with PEG-macroinitiator. Sequential conjugation with a diﬀerent amount of secondary, tertiary, or quaternary amines introduced a varying density of positive charges within the polymer backbone that determined their ability to bind with plasmid-DNA. From a PEG-macroinitiator, Ghosh and coworkers186 copolymerized MMA and NHSMA to prepare a precursor block copolymer, PEO-b-P(MMA-co-NHSMA). The activated ester groups distributed within the hydrophobic segment were chemically modiﬁed with β-alanine to yield pHsensitive amphiphilic block copolymers. Those polymers selfassembled into micelles in water, featuring a carboxylic-acidfunctionalized hydrophobic core that endowed it with swelling/ deswelling properties upon pH regulation. To this end, Bong et al.187 synthesized PEG−polyacrylamide diblock copolymers comprised of a melamine-rich hydrophobic segment by treating a reactive PEG-b-PNHSA with aminoethylmelamine. Installation of melamine functionality within the block copolymer helped in structure formation in the presence of a complementary hydrogen-bonding small molecule such as 5ﬂuorouracil (5-FU) or cyanuric acid (CA). Under similar conditions, a control polymer bearing acyl-protected melamine failed to complex with 5-FU or CA due to a lack of hydrogen bonding. Prefunctionalization of NHSA with amidine-based amines and subsequent polymerization of the resulting monomer (Namidino)dodecyl acrylamide with PEG initiator lead to CO2responsive block copolymers endowed with gas-sensitive properties, conferred by the amidine functionality.188 Starting from a PEO-based macro-CTA, Theato et al. prepared photocleavable amphiphilic block copolymers comprised of a hydrophobic block of polyPFP(M)A and a hydrophilic block of PEO connected together with a photoresponsive o-nitrobenzyl ester group. Phase separation of the two incompatible blocks followed by selective degradation of the PEO segment resulted in nanoporous thin ﬁlms of polyPFP(M)A that could be

polymerization. From this single reactive lamellar diblock copolymer precursor, two individually functionalized daughter block copolymers featuring a ﬂuorophore and a quantum dot (QD) binding thiol-based ligand were developed (Scheme 20). Blending of those two sibling polymers together employed dual-functionalized lamellar nanostructures, incorporated with both QD and organic ﬂuorophore. Similarly, Zentel and coworkers prepared a series of block copolymers featuring a reactive polyPFPA block for covalent anchoring of inorganic nanoparticles or quantum dots to realize their application as optoelectronic materials.174−178 A donor−chromophore−acceptor-type system was fabricated from a block copolymer synthesized by chain extending a p-type semiconducting block of poly(vinyltriphenylamine) PVTPA with an anchoring block of polyPFPA179,180 (Scheme 21). The polyPFPA block was modiﬁed with amine-functionalized perylene bisimide dye and dopamine that acted as a ligand for ZnO nanoparticle acceptors to create polymeric dye-sensitized organic solar cells.179 Theato et al.95 exploited the potential of PFP4VB as an extremely important activated ester monomer in constructing functional polymers under RAFT conditions, especially for their exceptionally high reactivity toward amines.96 They standardized the conditions for polymerizing PFP4VB by RAFT to obtain polymers with good control over molecular weight and narrow molecular weight distributions and further investigated their behavior in diblock copolymer synthesis. The reactive monomer was tested as either the ﬁrst or the second block. However, when used as a ﬁrst block, the polymerization with nonreactive styrene derivatives such as 4-octylstyrene or 4acetoxystyrene gave better control over the molecular weight distribution compared to when they were polymerized from macro-CTA of styrene or its derivatives. Unlike PFP4VB, other activated ester monomers of vinylbenzoate, namely, poly(2,4,5trichlorophenyl 4-vinylbenzoate), poly(pentachlorophenyl 4vinylbenzoate), poly(benzotriazole 4-vinylbenzoate), poly(Nhydroxy-5-norbonene-2,3-dicarboximide 4-vinylbenzoate), and poly(imino-2-phenylacetonitrile 4-vinylbenzoate), did not produce satisfactory results and could not match up to the standard of their PFP-ester analogue. Considering the importance of sulphonamides as biologically active drugs, polymeric activated esters of sulfonic acid such as poly(pentaﬂuorophenyl 4-vinylbenzenesulfonate) [poly(PFP4VBS)] were successfully prepared by both RAFT and NMP, and their reactivity toward amines was tested.181 Unlike polyPFP4VB, structurally similar polyPFP4VBS revealed a lower reactivity for amines and more susceptibility toward hydrolysis. Further, investigating PFP4VBS monomer for block copolymer synthesis, either as the ﬁrst or as the second block did not work out as eﬀectively as PFP4VB monomer. 2.3.2. Amphiphilic and Stimuli-Responsive Block Copolymers. Amphiphilic block copolymers (ABCs) are widely used in a variety of biomedical and pharmaceutical applications owing to their ability to assemble into discrete core−shell nanostructures in aqueous medium, where the core is comprised of the hydrophobic block, while the shell consists of a hydrophilic segment. Introducing responsive receptors within amphiphilic polymers oﬀers the additional advantage of stimuli-responsive morphology transitions that make such polymers extremely important for triggered drug delivery applications. Targeting speciﬁc functions requires precise positioning of the functional groups within the tailormade polymeric structures that contribute signiﬁcantly to the selfassembly behavior and the properties of the ABCs. Activated 1447

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Scheme 22. AFM Images of (a) Phase-Separated Structures of PEG-b-polyPFPMA and (b) Cysteamine-Functionalized Nanoporous Filmsa

a

Rearranged after ref 83. Copyright 2013 American Chemical Society.

Scheme 23. Synthetic Strategy for PLA-b-poly(NHSA-co-NVP) Starting from a Macroalkoxyamine Initiator

postmodiﬁed with functional amines (Scheme 22).83,99 Bolamphiphilic multiblock copolymers comprised of a hydrophilic polynorbornene shell made from a diblock of PEG- and NHS-ester-based norbornenes and a hydrophobic inner core of ﬂuorescent conjugated polymers were prepared by ROMP.189,190 These amphiphilic polymers produced ﬂuorescent nanoparticles in water that were surface functionalized with folic acids at the NHS-ester sites to target and image tumor cells. Besides PEO, polyHPMA has shown signiﬁcant pharmaceutical importance. Zetterlund and Stenzel191 prepared an ABC comprised of a hydrophobic polyPFPMA block generated from a hydrophilic PHPMA macro-CTA. The resulting polymer was used as an amphiphilic macro-RAFT stabilizer to generated pH-responsive polymeric nanocapsules following an inverse miniemulsion periphery RAFT polymerization technique. When a hydrophobic macroinitiator is used to polymerize activated ester monomers alone or in conjunction with a hydrophilic monomer, amphiphilic block copolymers are obtained that integrate activated ester groups within the polar domain. Polymeric micelles produced from such polymers oﬀer scope for shell modiﬁcation.192 Pichot and co-workers193 used

dithioester-functionalized poly(tert-butylacrylamide) as a macro-CTA to copolymerize NAM and NHSA. The obtained amphiphilic block copolymer, featuring a hydrophobic block of poly(tert-butylacrylamide) and a hydrophilic block of a copolymer of NHSA and NAM. Polymer−oligonucleotide conjugates were obtained by partially reacting an amine-based starter of oligonucleotide (OND) with the activated ester groups of the polymer. Taking advantage of the remaining activated ester groups, the polymer was grafted onto hydroxylated controlled pore glass (CPG) support for OND synthesis. Nitroxide-mediated copolymerization of NHSA and Nvinylpyrrolidone (NVP) by SG1-functionalized poly(D,L-lactide) macro-alkoxyamine (PLA-SG1) resulted in the amphiphilic block copolymer PLA-b-poly(NHSA-co-NVP) (Scheme 23). The block copolymer was used for surface modiﬁcation, diaﬁltration, and nanoprecipitation of PLA.194 Dual pH- and temperature-responsive block copolymer featuring a poly(εcaprolactone) (PCL) hydrophobic block and a hydrophilic poly(triethylene glycol) block copolymerized with an aminoacid-functionalized monomer was produced by combining ROP with ATRP.195 In the ﬁrst step, a bromide-terminated alcohol 1448

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Scheme 24. Synthesis of P2 by ATRP of NHSMA with a Supramolecularly Engineered Hydrophobic Initiator Followed by PPM with Water-Soluble Amine and Its Self-Assembly in Water and Benzenea

a

Reprinted from ref 200. Copyright 2013 American Chemical Society.

was used to catalyze the ROP of ε-caprolactone. In the second step, the obtained macroinitiator (PCL) with the terminal bromide functionality catalyzed the ATRP of a mixture of methoxytri(ethylene glycol) methacrylate and NHSA to prepare an amphiphilic block. pH-responsive amino acids were then installed within the polymeric micelles at the activated ester sites by PPM. Zhang and co-workers196 followed a reverse sequence of RAFT and ROP to obtain a thermoresponsive amphiphilic triblock copolymer, poly(NHSA-b-NIPAM-b-CL). A terminal carboxylic acid group of the diblock copolymer poly(NHSA-b-NIPAM) prepared by RAFT was sequentially modiﬁed for the initiation of ROP of εcaprolactone. The reactive terminal polyNHSA block was modiﬁed with biotin-NH2 to enhance the tumor cell permeability of the resulting polymeric micelles. In a two-step RAFT polymerization process, Uhlmann and co-workers197 prepared two diﬀerent amphiphilic triblock copolymers that comprised of a hydrophobic block of randomly copolymerized tert-butylstyrene and n-hexyl acrylate and a hydrophilic blocks derived from polyDMA. An additional anchor block of polyNHSA was introduced either in the middle between the hydrophobic and hydrophilic segments or at the hydrophilic terminus of the polymer chain by varying the sequence of addition of the monomers. They enabled attachment of these polymers onto textile surfaces to facilitate their cleaning process. Reactive diblock copolymers prepared by ROMP of NHSNorb from a hydrophobic benzylic macroinitiator were modiﬁed into an amphiphilic peptide−polymer conjugate that self-assembled into micelles in water and showed an enzymetriggered reversible morphology transition.198,199 Special types of ABCs with engineered hydrophobic blocks were demonstrated by Ghosh and et al. (Scheme 24).200 Apart from using a linear nonpolar block, a supramolecularly engineered wedge-shaped hydrophobic macroinitiator was used to polymerize NHSMA. After substitution with water-

soluble amines, the resulting polymer (P2) showed interesting self-assembly properties, not in water alone but in nonpolar solvent such as benzene. Similarly, Lowe and Davis201 copolymerized DMA and NHSA from bis-pyrene- or bischolesterol-functionalized CTA to generate hydrophobically modiﬁed end-functionalized amphiphilic polymers that displayed bis-ω-cholesteryl or bis-pyrene as the hydrophobic chain-end segments. These examples illustrate that instead of extended hydrophobic blocks even a small segment can induce self-assembled structures in water if properly designed. The smaller segment can be cholesterol, which has a deﬁnite hydrophobic packing mode, or pyrene for π-stacking or a NDIbased wedge-shaped group for synergistic hydrogen bonding and π-stacking. 2.3.2.2. Block Copolymerization from an Activated Ester Containing Macroinitiator/Chain Transfer Agent. The alternative approach for ABC synthesis starts with an initial controlled chain polymerization of an activated ester monomer to produce a reactive macroinitiator or CTA that upon chain extension with a hydrophobic or hydrophilic monomer leads to a precursor diblock copolymer. When a hydrophilic monomer is used, the method directly leads to ABC where the reactive block also represents the hydrophobic block. For a hydrophobic monomer, the precursor diblock copolymer is postfunctionalized with polar amines to generate ABCs. However, an important parameter that needs to be considered in this method of polymerization is the solubility compatibility of the reactive macroinitiator/CTA and the second monomer during the chain extension step. When used as macroinitiator/CTA, polyNHS(M)A are copolymerized with other monomers to improve their solubility. For example, Tribet and co-workers202 made a hydrophilic macro-CTA containing two randomly distributed monomers, oligo(ethylene oxide) methacrylate (OEGMA) and NHSA, which was then used to polymerize a cholesterol-derivatized acrylate monomer (Scheme 25). Co1449

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Scheme 25. Synthesis of Light-Responsive Amphiphilic Block Copolymer Featuring Cholesterol-Derivatized Polyacrylate as the Hydrophobic Block

Scheme 26. Synthesis of Phosphonic-Acid-Terminated Amphiphilic Block Copolymer

valent attachment of azobenzene functionalities at the NHSester site within the amphiphilic polymer produced lightresponsive rod-like micelles in water with a photoisomerizable corona. Unlike polyNHSMA/polyNHSA, polyNHSNorb can be used as a reactive macroinitiator for ROMP of (PEG-Norb). Following ROMP, Zang et al.203 synthesized PEG-based amphiphilic triblock copolymer brushes by sequential block copolymerization of NHSNorb and PEGNorb. PPM with nucleic acid sequences allowed polycondensation of the polymer chains by DNA hybridization of the terminal brushes. Roth and Lowe204 polymerized DMA from dithioesterterminated polyPFPA to prepare a reactive parent diblock copolymer. PPM with histamine resulted in CO2-responsive amphiphilic copolymers that revealed a reversible assembly− disassembly switching by a change of polarity of the histamine block as a function of CO2 bubbling.205 The synthesis of other CO2-responsive polymers and hydrogels via activated ester amine-based PPM has also be explored.206,207 Reactive polyPFPA generated from terminal phosphoric acid bearing RAFT agent was chain extended with a hydrophilic block, polyOEGA, to synthesize a reactive amphiphilic block

copolymer (Scheme 26) that could adhere to the surface of magnetic iron oxide nanoparticles (IONPs) through its terminal phosphoric acid group.208 Those surface-functionalized nanoparticles featuring a reactive inner core of polyPFPA could be postmodiﬁed with various functional amines to fabricate diﬀerent multifunctional NPs. Zentel and co-workers engineered a library of amphiphilic diblock copolymers featuring poly(HPMA) as the hydrophilic block and poly(laurate methacrylate) as the permanent hydrophobic block from a polyPFPA macro-CTA.90,209−214 Coderivatization of the PFP-ester residues with 2-hydroxypropylamine and/or a dye or radioactive or other bioconjugated amines resulted in highly functionalized amphiphilic polymers of pharmaceutical importance.

3. OTHER MACROMOLECULAR DESIGNS Signiﬁcant advances in controlled radical polymerization (CRP) techniques have simpliﬁed the synthesis of macromolecules with complex architectures and programmed chemical composition. Availability of exceptional variety of functional monomers and initiators or chain transfer agents and their wide 1450

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Scheme 27. Synthesis of Amphiphilic Star Block Copolymers with (a) PNIPAM Arms and (b) Miktoarms Comprised of P(NIPAM-co-HMAA)

Scheme 28. Synthesis of Star Block Copolymer by (a) ATRP from Triphenylene Core and (b) RAFT from Dendrimer Core

central core. Star polymers form compact nanostructures and, therefore, ﬁnd application in drug delivery, catalysis, photonics, etc.217 They can be further classiﬁed depending on the chemical composition of the arm segments: (1) homoarmed stars in which all radiating arms have identical structures and chemical compositions; (2) heteroarmed stars, commonly known as miktoarm star polymers, are comprised of more than one arm segment with diﬀerent structure or chemical compositions. They can be further categorized based on the methods of their preparation as core-ﬁrst or arm-ﬁrst routes, which diﬀer from one another by the sequence of formation of the core and the arms. The core-ﬁrst route is a divergent approach where the core is prepared ﬁrst, followed by propagation of the polymer arms from the core. In the arm-ﬁrst approach, star polymers are usually synthesized via a convergent method by covalent attachment of preformed linear arm precursors to a core or with polymerization of divinyl monomers forming a cross-

tolerance limit to various controlled polymerization techniques have opened doors for new polymeric structures with a vision to mimic the elegance and complexity of Mother Nature. Simple synthetic strategies that enable control over both structure and function of polymers are in high demand. High ﬁdelity of activated ester chemistry makes it a versatile choice for polymer chemists to design novel polymeric architectures. Inevitably, well-deﬁned block copolymers are one of the best designs achieved until today, both in terms of structure and function. This section will showcase the achievements and future scope of PPM via activated ester amine chemistry in combination with CRP in engineering other structurally diﬀerent polymers215 with distinct conﬁguration following a modular approach. 3.1. Star Polymers

Star polymers216 are one of the simplest forms of branched polymers in which all chains of a polymer are connected to a 1451

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linked core. Both methods have been realized in the synthesis of star polymers utilizing activated ester chemistry.218−220 Zhuo and co-workers221 described the synthesis of a thermosensitive seven-arm star block copolymer (PLLA-sbPNIPAM) comprised of a hydrophobic poly(L-lactide) (PLLA) arm and six average hydrophilic polyNIPAM arms following a convergent method in three steps (Scheme 27a). In the ﬁrst step, amino-terminated polyNIPAM (PNIPAM−NH2) was prepared by radical polymerization using 2-amino ethanethiol hydrochloride as a CTA. In the second step, resulting PNIPAM−NH2 was transformed into a PNIPAM macromonomer by reacting the terminal amino group of PNIPAM with NHSA. Radical polymerization of the resulting PNIPAM macromonomer using AET_HCl resulted in PNIPAM brush with average degree of polymerization (DP) = 6. Those brushes were ﬁnally connected to a PLLA block by coupling reaction to produce an amphiphilic seven-arm miktostar polymer. In a similar approach, a four-arm star block copolymer, comprised of a hydrophobic PMMA core and an average of three hydrophilic PNIPAM arms, was synthesized by reducing the DP of PNIPAM to 3 and connecting it to a PMMA core.222 Copolymerization of PNIPAM and N-hydroxymethylacrylamide (HMAA) with diﬀerent feed ratios resulted in series of amphiphilic star polymers, PLLA-sb-P(NIPAM-co-HMAA), whose LCST behavior could be tuned by varying the feed ratio of the two monomers (Scheme 27b).223 Starting from a hexahydroxy triphenylene core, Pan and co-worker224 synthesized six-armed star polymer comprised of a triphenylene core and PLLA-b-poly(St-co-NHSA) arms. Hydroxy-terminated polylactide chains obtained by ROP from the tripheylene core were reacted with 2-bromoisobutyryl chloride to generate bromine-terminated stars that acted as macroinitiators for copolymerization of styrene and NHSA (Scheme 28a). The star polymer was obtained, comprised of PLLA as the inner layer and poly(St-co-NHSA) as the shell. Shell cross-linking utilizing the NHS-ester groups followed by hydrolysis of the PLLA block produced hollow nanospheres. The same group also reported the synthesis of dendrimer-star polymers by RAFT polymerization of styrene from a multifunctional dithiobenzoate-terminated poly(propyleneimine) dendrimer. The dendritic-CTA was prepared by coupling an NHS-ester-functionalized CTA with amine-functionalized dendrimer, DAB-Am-8 (Scheme 28b). This star macro-CTA comprised of polySt arms was then employed for block copolymerization of MMA to generate a dendrimer-star block copolymer, Den(PSt-bPMMA)8.225,226 To this end, Guan et al.227 constructed amphiphilic dendritic nanoparticles featuring a hydrophobic dendritic core and reactive hydrophilic arms of a diblock copolymer, poly(OEGMA-b-NHSA), by combining chain walking polymerization (CWP) of ethylene with ATRP of OEGMA (Scheme 29). The dendritic macroinitiator was prepared by copolymerizing ethylene with a monomer bearing a radical initiating site using chain walking palladium−αdiimine catalyst. ATRP of OEGMA from the core created a discrete core−shell structure. Futher, end capping of hydrophilic poly(OEGMA) arms with polyNHSA enabled bioconjugation of the resulting nanoparticles with protein ovalbumin. Combining the arm-ﬁrst approach with active ester chemistry, David et al.228 synthesized a series of well-deﬁned star polymers via RAFT polymerization of PFPA. Initially prepared linear precursor polyPFPA arms were chain extended with PFPA and bis-acrylamide or bis-acrylate cross-linker to generate a reactive star copolymer (Scheme 30a). PFP-ester

Scheme 29. Synthesis of Star Polymer Combining CWP with ATRP

groups were later exploited to attach multiple amino functionalites to the polymer arms to create functional stars. For example, star glycopolymers could be fabricated using an amino sugar, e.g., glucosamine, illustrating the versatility of this method. During aminolysis, the CTA end group is cleaved as well, generating free thiols within the core. A second modiﬁcation via thiol−ene click allowed incorporation of a ﬂuorescent dye inside the core, eventually creating luminescent star polymers. Following a similar convergent strategy, Hawker et al.229 synthesized core−shell PEGylated star polymers185 from diblock copolymer arms comprised of reactive NHS-ester groups. A PEG-based macro-CTA that formed part of the outer arm was used to copolymerize DMA and NHSA. Further chain extension with divinylbenzene or ethylene glycol diacrylate cross-linkers created the core of the star (Scheme 30b). The reactive inner arms featuring NHS-ester groups allowed covalent attachment of amine-functionalized tris(tert-butyl)protected 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (TB-DOTA) for immobilization of 64Cu nuclei to create radiolabeling polymers used in positron emission tomography (PET). Similarly, RAFT cross-linking polymerization of styrene and divinylbenzene with an azide end-functionalized polyNIPAM macro-CTA resulted in thermoresponsive core crosslinked star polymer.230 Postfunctionalization of the azideterminated surface with biotin was achieved following an azide−alkyne click reaction. 3.2. Chain-End-Functionalized Polymers

Functionalization of macromolecules at the α- or ω-chain ends allows installation of a single functional entity per polymer chain that ﬁnds increasing use in creating biomolecule− polymer conjugates, telechelic polymers, and precursor for diblock copolymer synthesis or in surface modiﬁcation by a grafting-to approach. Terminal derivatization of polymers is a synthetic challenge for free radical polymerization and is most cases achieved by controlled chain polymerization techniques using functional initiator or chain transfer agents.231−233 Use of initiators or CTAs equipped with a reactive group oﬀers possibilities for multiple variations by PPM at the chain terminus of the polymer without changing its degree of polymerization, which is nearly impossible in a direct polymerization with initiator or CTA featuring a particular functional entity. Polymerization with activated ester-based 1452

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Scheme 30. Synthesis of Star Polymer with (a) polyPFPA Arm and (b) PEG-b-P(DMA-co-NHSA) Arm Following “Arm-First” Approach

Table 2. Structures of Various Activated Ester Containing Initiators and CTAs

Scheme 31. Synthesis of (a) Lysozyme-Conjugated Homopolymer and (b) Trypsin-Conjugated Copolymer Using NHSI-1 Initiator

Haddleton and co-workers234 described a generalized method for protein−polymer conjugation from NHS-ester αend-functionalized polyPEGMA obtained by ATRP of PEGMA with NHS-2-bromopropionate (NHSI-1) and NHS-2-bromoisobutyrate (NHSI-2) (Table 2). Polymer conjugation with model protein lysozyme through its amine function (Scheme 31a) was found to be dependent on the reactivity of the initiator used. The less reactive NHSI-2 failed to instigate

initiator or CTA happens to be one of the most versatile approaches for chain-end modiﬁcation that can generate polymers with active sites on α-chain ends. These precursor polymers can potentially react with diﬀerent classes of aminecontaining species (biomolecules, surfaces, polymers, etc.) to generate functionalized bioconjugates, surfaces, block copolymers, or other complex polymeric architectures. 1453

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Scheme 32. Synthesis of Maleimide Chain-End-Functionalized Polymer and PPM by Photoinduced Cycloaddition

Scheme 33. Synthesis of Amphiphilic Block Copolymer Connecting Polypeptide with Polyamide Backbone by ROP Followed by RAFT

poly(butyl acrylate) from NHSI-1 by PPM with an amino maleimide linker (Scheme 32).241 When exposed to a UV-ﬂow reactor, the single maleimide unit at the polymer terminus could eﬃciently take part in alkene−enone [2 + 2] photocycloaddition reaction with functional alkenes, leading to complex polymers with diﬀerent cycloadducts at the chain end. RAFT polymerization with activated ester-functionalized CTAs provide an alternative pathway toward chain-endmodiﬁed polymers. Besides ATRP, bioconjugation via RAFT polymerization has also been successfully achieved using activated ester-based CTAs.242,243 From a single NHS-ester containing RAFT agent, structurally diverse CTAs were generated by conjugation with various biotic and nonbiotic functional amines.244,245 Biotin- and galactose-functionalized CTAs generated from NHSCTA-1 (Table2) were used for polymerization of NAM. The reaction proceeded with high conversion, leading to biomolecule−polyNAM conjugates.244 Additionally, NHSCTA1 was employed in the synthesis of ﬂuorescently tagged thermosensitive block copolymer whose critical micellar concentration (CMC) was determined from Förster resonance energy transfer (FRET) between loaded anthracene and endcapped phenanthrene dye.246 A PEG macro-CTA247,248 was prepared in high yield by coupling of NHSCTA-2 with PEG-amine. It was used for RAFT aqueous dispersion block copolymerization of HPMA.249 From a single macro-CTA, a family of amphiphilic

lysozyme−polymer complexation. Protein conjugation with glycopolymers can be achieved if protected glucose- or galactose-based monomers are used.235 Emissive bioconjugates prepared from ﬂuorescently tagged Rhodamine B or Hostasol containing PEGylated polymers allowed in situ monitoring of products using a ﬂuorescent detector equipped SECHPLC.236,237 In a similar approach, thermosensitive protein conjugates have been prepared by covalent attachment of bovine pancreas trypsin with thermoresponsive copolymer P(MEO2MA-co-OEGMA475) starting from an activate ester containing initiator (Scheme 31b).238 As an alternative to PEGylated proteins, biocompatible zwitterionic methacryloyloxyethyl phosphorylcholine (MPC) polymers were prepared and their conjugates with lysozyme and two therapeutic proteins, granulocyte colony stimulating factor (G-CSF), and erythropoietin (EPO) were studied.239,240 Besides bioconjugation, end group modiﬁcation via an activated ester approach allows incorporation of complex functionalities at the chain end, which are diﬃcult to achieve by direct polymerization. Maleimide-functionalized polymers are generally prepared from furan-protected maleimide initiators or monomers to avoid copolymerization. Deprotection by retro-Diels−Alder reaction after the polymerization step generates free maleimide-containing polymers. However, direct installation of maleimide units can be achieved by PPM. High ﬁdelity and versatility of activated ester chemistry have been illustrated in preparing a maleimide end-functionalized 1454

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Scheme 34. Diﬀerent Strategy for Grafting Polymers to Silica Nanoparticles

Scheme 35. (a) Synthetic Scheme for Heterotelechelic Water-Soluble Polymers Featuring (b) Thyroxin and Biotin and (c) Oregon Green Cadaverine and Texas Red Dye at the α- and ω-Chain End, Respectively

block copolymers was obtained whose morphology (worms, vesicles, or spheres) could be tuned by varying the degree of polymerization of the hydrophobic polyHPMA block. Similarly, polyethylene (PE) containing RAFT agent, made by amidation of NHSCTA-2 with PE-NH2, was used as a macro-CTA for block copolymerization of n-butyl acrylate.250 In a diﬀerent strategy, amine-functionalized RAFT agent was prepared from reactive NHSCTA-3 and used for sequential ring-opening polymerization (ROP) of α-amino acid N-carboxyanhydride (NCA) monomer from the amine terminal and RAFT polymerization of NIPAM from the trithiocarbonate end group to generate an amphiphilic block copolymer connecting

a polypeptide backbone with pendent polyamide chain (Scheme 33).251,252 Polymer chains with an activated ester end group also oﬀer a versatile and eﬃcient approach for surface modiﬁcation.253 NHS-ester-functionalized alkoxyamine initiator, nitroxide SG1 (NHS-SG1) (Table 2), was used in NMP of styrene, n-butyl acrylate, or MMA. Those polymer chains with high chain-end functionality were grafted on amino-coated silica particles (Scheme 34) and revealed a grafting density of 0.1−0.2 chains nm−2. In contrast, following a one-pot grafting strategy, where polymerization and graft on worked simultaneously, much higher grafting density (0.9 chains nm−2) could be obtained using amino-coated silica, NHS-SG1 initiator, and the 1455

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Scheme 36. Synthesis of (a) Telechelic Polymer with Azobenzene Chain End and (b) High Molecular Weight Condensation Polymer

respective monomer in one pot.254 Combining NMP with ROP, polystyrene-block-poly(D,L-lactide) or polystyrene-blockpoly(propylene oxide) was synthesized from NHS-SG1 following a pre- or postfunctionalization approach with ethanolamine that catalyzed the ROP from its hydroxyl end.255 Comparable results obtained following the two diﬀerent pathways illustrated the eﬃciency of the activated ester amine chemistry. Polymer−silica hybrid composites256 were fabricated by end group modiﬁcation of a thermoresponsive statistical copolymer poly(MEO2MA-co-OEGMA) with amino-functionalized silica monoliths. Those composites acted as a potential stationary phase in chromatographic separation of steroid and protein mixtures in aqueous phase under isocratic highperformance liquid chromatographic elution.257 Activated ester-containing CTAs allow a ﬂexible functionalization of the CTA either prior to or after the polymerization.258 Phosphine-based CTAs were synthesized from a PFP-ester-based RAFT agent, PFPCTA-1 (Table 2), by thioesteriﬁcation with P-borane-(diphenylphosphanyl)-methanethiol. The phosphine−thioester CTA was not only found to be suitable for polymerization of styrene but also showed facile polymer chain-end modiﬁcation by Staudinger ligation with a variety of azide-functionalized molecules.259 PFPCTA-2 (Table 2) has been thoroughly investigated by Theato and co-workers in the synthesis of stimuli-responsive PEGMA with reactive chain ends. PPM with diﬀerent amines created a library of α-chain-end-modiﬁed polymers with identical degree of polymerization. The self-assembly behavior and LCST/UCST properties of those polymers could be precisely altered by installation of functional groups at the chain end (Scheme 35a).260,261 Additionally, aminolysis of ωdithioester in the presence of an excess of amine and functional methane thiosulfonate (MTS) allowed one-pot modiﬁcation of both the α- and the ω-chain ends, leading to heterotelechelic polymers. Following this protocol, a biotargeted heterotelechelic polymer, polyDEGMA featuring thyroxin and biotin at the α- and ω-chain ends, respectively, was prepared (Scheme

35b). Orthogonal complexation with site-speciﬁc thyroxin transport protein prealbumin and biotin-speciﬁc streptavidin was studied.262 Using a similar approach, incorporation of a FRET pair, Oregon Green Cadaverine and Texas Red dye at the α- and ω-chain end, respectively, was also achieved (Scheme 35c). Temperature-induced chain collapse or extension was studied from the intensity of FRET emission during phase transition.263 Heterotelechelic PMMA, tagged with ﬂuorescent Texas dye at the α-chain ends, enabled ligand exchange on both gold nanoparticles (AuNP) and CdSe/ZnS quantum dots (QD) through its ω-end-modiﬁed methyl disulﬁde group, leading to polymer/NP or polymer/QD composites. Binding eﬃciency of those composites was determined from energy transfer between the dye and the NP/QD.264 Subsequently, a slightly modiﬁed route conferred dual (thermo and light)-responsive telechelic polyOEGMA with azobenzene functionality at both ends. PPM of the ωdithioester group with an azo initiator (PFP-ACV) containing PFP-ester moieties resulted in incorporation of PFP-ester at both ends of the polymer chain. Subsequent modiﬁcation with amino-functionalized azobenzene employed stimuli-responsive telechelic polymers (Scheme 36a); the LCST of those could be tuned by conformational changes of the two azobenzene groups during photoisomerization.265 Simple replacement of the terminal photoresponsive dye with ethylenediamine produced very high molecular weight polymers by polycondensation reaction between the reactive telechelic PFP-ester polymer and the diamine (Scheme 36b).266 In a completely diﬀerent pathway, heterotelechelic poly(β-amino ester) (PAE) featuring a ﬂuorescent dye and a cell-targeting protein at the two extreme chain terminals was obtained by sequential ring-opening polymerization of ε-caprolactone with a functionalized initiator. Condensation polymerization of the macroinitiator with a diamine, 4,4′-trimethylene dipiperidine, and a diacrylate, hexane-1,6-dioldiacrylate, generated free amine at the ωterminal that was subjected to Michael addition reaction with NHSA to incorporate cell-targeting ligand c(RGDfK).267 1456

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Scheme 37. Synthesis of Poly(t-BuMA-b-DEGMA) from Two Homopolymers Containing Complementary Chemical Handles at the Chain End by Convergent Approach

acid. The reactive monomer was subjected to polymerization using metathesis catalyst tungsten hexachloride (WCl6) in the presence of cocatalyst tetraphenyltin (SnPh4) in dry toluene at 80 °C (Scheme 38a). The broad molecular weight distribution

Apart from chain-end modiﬁcation with diﬀerent abiotic small molecules and biomolecules, the versatility of reactiveCTAs for the synthesis of block copolymers was also demonstrated.268 Stimuli-responsive polyDEGMA was covalently attached on both ends of a diamine-functionalized bocprotected collagen−peptide through its terminal PFP-ester groups. The resulting polyDEGMA-b-collagen-b-polyDEGMA triblock copolymer formed a temperature-dependent triplehelical structure.269,270 Using a convergent strategy, poly(tBuMA-block-DEGMA) was synthesized by click coupling between azide- and alkyne-end-functionalized poly(t-BuMA) and polyDEGMA, respectively.258 The chain-end-functionalized homopolymers were obtained by PPM of PFP-ester of the respective block ends with complementary amines (Scheme 37). An alternative strategy using alkyne- or azide-functionalized CTA obtained from PFPCTA-2 prior to polymerization revealed similar eﬃciency.

Scheme 38. (a) Synthetic Scheme for polyPFPEB and PPM with Amines, (b) Structures of Ortho-, Meta-, and ParaSubstituted polyPFPEB, (c) Structures of polyPFPEB with Varying Spacer between the PFP-Ester and the Polymer Backbone

4. OTHER METHODS OF POLYMERIZATION OF ACTIVATED ESTER MONOMERS Besides polymerization of acrylate-, methacrylate-, and styrenebased activated ester monomers in solution phase, on surface, or from surfaces by free and controlled radical polymerizations, various other types of activated ester monomers are known that can be polymerized in solution and/or on surfaces by other advanced polymerization techniques. 4.1. Alkyne Metathesis of Acetylenes

Ever since the invention of conjugated polyacetylenes (PAs),271 winning the Nobel prize, conducting polymers272,273 have received immense attention from various interdisciplinary sciences. It is due to their rich electronic and optical properties that ﬁnd potential applications in conducting materials, organic photovoltaics, sensors, and biomedical sciences. Despite being known for their metallic conductivity in the doped form, diﬃculty with processing due to insolubility and instability to air are the major downside of polyacetylenes that often put into question their practical applicability. This demanded the need for functionalized polyacetylenes274 that could be produced by formally replacing the hydrogen atoms in each repeat unit either by one or by two substituents to yield monosubstituted or disubstituted PAs, respectively. Functional tolerance of several novel metathesis catalysts based on Mo-, W-, Ta-, or Rhbased insertion catalysts enabled easy design and synthesis of functional PAs. Activated ester chemistry has been employed to create widely functional mono- as well as disubstituted polyacetylenes. Theato et al.275 synthesized an activated estercontaining acetylene monomer, pentaﬂuorophenyl 2-ethynylbenzoate (PFPEB), in few steps starting from 4-bromobenzoic

(Mw/Mn < 2.1) obtained for the homopolymer polyPFPEB could be improved by copolymerization with phenylacetylene or methyl 4-ethynylbenzoate. Functional polyacetylenes were obtained by PPM of polyPFPEB with various amines. Signiﬁcant reactivity was exempliﬁed from quantitative reaction of polyPFPEB with aromatic amines. The same group later prepared three constitutional isomers of PFPEB by changing the activated ester site at the ortho, meta, and para positions of the phenyl ring (Scheme 38b).276 The polymerization conditions, conﬁguration of the monosubstituted polyacetylenes, as well as their reactivity toward diﬀerent amines were found to be dependent on the position of the activated ester moiety in the phenyl ring. Although rhodium-based catalyst failed to initiate polymerization of ortho-substituted monomer, polymerization with tungsten catalyst was successful for all isomers. Interestingly, rhodium catalyst-mediated PAs featured 1457

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Scheme 39. Synthesis of polyNHSNorb by ROMP and Their PPM with Amine Containing Sugar Moieties

a cis−transoid conﬁguration, while polymers synthesized using tungsten catalysts revealed a trans−transoid structure. In addition, the reactivity of these polymers toward functional amines could be tailored by varying the location of the PFPester within the monomers. A reduced reactivity of the orthosubstituted polyPFPEB compared to its meta and para analogues was observed. The group of Sun and Tang277 prepared series of monosubstituted polyacetylenes with pendent PFP-ester groups by varying the number of methylene spacers between the PA backbone and the PFP-ester moiety (Scheme 38c). Derivatization of the precursor polyphenyl acetylenes (PPAs) with either or both chiral and achiral alkyl amines resulted in multiple functionalized PPAs with diﬀerent properties. For more rigid polymers, directed helicity could be induced within the polymer backbone from the pendent asymmetric carbon centers, while polymers with more ﬂexible spacers failed to generate helical bias from the chiral centers. Modifying reactive PPAs with amine-functionalized PEGs led to water-soluble polyacetylenes with tunable LCST behavior governed by the length of the hydrophobic alkyl spacer and/or the incorporated amount of the alkyl amine. Following a similar synthetic strategy to that of Theato et al., this group prepared PFP-esterbased disubstituted PPAs from PFPPEB (Table 2) using WCl6−SnPh4 catalyst.278 PPM of the precursor polymer with chiral amine featuring a polar hydroxyl or carboxylic group oﬀered a very convenient strategy for designing functional disubstituted polyacetylenes. This is hard to achieve by direct polymerization of monomers containing polar functional groups as they are inclined to poison the catalyst.

Figure 1. Structure of two random copolymers (left) featuring complementary H-bonding groups introduced by PPM and their mode of self-assembly (right).

Vogel and Theato286 described ROMP of bicycle[2.2.1]hept5-ene-exo-2-carboxylic acid pentaﬂuorophenyl ester (PFPNorb) (Table 1) using Grubbs ﬁrst-generation catalyst, producing polymers with molecular weights up to 75,400 g/ mol. Molecular weights of the polymers could be controlled by varying the monomer/initiator ratio, thereby illustrating the controlled nature of the polymerization. PFP-ester containing polynorbornenes could be successfully postmodiﬁed with functional amines without aﬀecting the polymer backbone. Both NHSNorb287,288 and PFPNorb289 have been employed in constructing reactive diblock copolymers. Kane and coworkers287 described the synthesis of reactive block copolymer with NHSNorb monomers. Grafting with amine-functionalized hexaethylene glycol generated amphiphilic block copolymers. Orthogonally clickable statistical terpolymers and diblock copolymers featuring PFP-ester and protected alkyne side groups were obtained using PFPNorb as one of the monomers.289

4.2. Ring-Opening Metathesis Polymerization (ROMP) of Norbornenes

Ring-opening methathesis polymerization (ROMP) of activated ester containing norbornenes has been another successful method for creating functional polymers. Following this approach, Kiessling and co-workers 279,280 polymerized bicyclo[2.2.1]hept-5-ene-exo-2-carboxylic acid N-hydroxysuccinimide ester (NHSNorb) (Table 1) using ﬁrst-generation Grubbs catalyst. The degrees of polymerization (DP) could be reached between 21 and 150. The obtained reactive polynorbornenes were modiﬁed with diﬀerent amine-based sugar moieties to develop cellular binding assay for Lselectin280,281 (Scheme 39). On modiﬁcation with guanidinium-substituted amines, cell-penetrating polymers were produced, whose cell permeability could be monitored by ﬂuorescence microscopy, when tagged with a ﬂuorophore.282−284 Polynorbornene bearing complementary diamidopyridine and uracil recognition elements were prepared following the precursor polymer approach.285 The random copolymer self-assembled into spherical polymersomes by H bonding between the complementary functional groups and slowly fused together to form larger structures (Figure 1).

4.3. Ring-Opening Polymerization (ROP) of Cyclic Carbonates

Aliphatic polycarbonates are among the most extensively investigated classes of polymers in biomedical sciences for their biodegradability, biocompatibility, and nontoxicity. However, their hydrophilicity, biodegradability, and mechanical properties can be improved many fold by incorporating pendent hydrophilic functional moieties within the polymer chain. Zhuo and co-workers290 copolymerized a novel sixmembered cyclic carbonate monomer 5-methyl-5-(succinimideN-oxycarbonyl)-1,3-dioxan-2-one (MSTC) (Table 2) containing an NHS-ester group with caprolactone (CL) in bulk at 140 °C by organocatalytic ring opening. Aminolysis of poly(MSTCco-CL) with ethylenediamine produced poly(MATC-co-CL) (Scheme 40). The obtained poly(carbonate-ester) with pendent free amine groups showed enhanced hydrophilicity and hydrolytic degradability. In order to expand their scope and versatility, a highly eﬃcient one-pot synthetic route to PFPester-containing cyclic carbonate monomer MTC-OPhF5 was 1458

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Scheme 40. Synthesis and Amidation of poly(MSTC-co-CL)

CsF291 or tetra-n-butylammonium ﬂuoride (TBAF).293 Hydrophobically modiﬁed polyethylenimines (PEIs) were prepared by covalent attachment of low molecular weight PEI to functionalized polycarbonates (MTC) generated from a single reactive poly(MTC-OPhF5) by nucleophilic substitution with diﬀerent hydrophobic amines. The polymer obtained showed improved gene transfection eﬃciency as probed by their DNA binding studies.294 Hydrophilic polycarbonates prepared by the acid-catalyzed ring-opening polymerization of MTC-OC6F5 and consequent reaction with various amino alcohols were developed as a better alternative for PEG for their added advantage of being hydrolytically and enzymatically degradable.295 To expand the future possibilities of this monomer, Hedrich et al.167 synthesized diblock copolymers either using poly(ethylene glycol) monomethyl ether as a macroinitiator or by sequential addition of two MTC monomers, MTC-OC6F5 and MTC-OEthyl, in one pot. Polycarbonate copolymers bearing pendent hydroxyl groups with disulﬁde linkage were used for ROP of lactide or trimethylene carbonate. The two graft polymers polycarbonate-graf t-polylactide and polycarbonategraf t-poly(trimethylenecarbonate) obtained following a graft-

developed by Sanders and Hedrick.291 MCT-OPhF5 synthesis was carried out by reacting two equivalents of commercially available bis(pentaﬂuorophenyl)carbonate (PFPC) with 2,2bis(hydroxymethyl)-propionic acid (bis-MPA) resulting in concomitant transformation of acid into PFP-ester and ring closure of the 1,3-diol to cyclic carbonate, unlike its NHS-ester analogue made earlier in multiple steps (Scheme 41). Taking Scheme 41. Synthesis of MTC-OPhF5 and Its Derivatives by Aminolysis

advantage of the activated PFP-ester moiety, a library of functional monomers was generated by aminolysis with various amines, which on organocatalytic ROP resulted in highly functionalized polycarbonates.292 Transesteriﬁcation with primary alcohols proceeded in near quantitative yields using

Scheme 42. Synthetic Scheme for Cleavable Brush Copolymer from Polycarbonate Backbone Following Grafting-from Approach

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ing-from approach carried redox-responsive detachable brushes.296 The polycarbonate backbone was generated from a single reactive MTC-OPhF5 monomer in few steps. The precursor MTC-OPhF5 was modiﬁed with 2-(tritylthio)ethanol and benzyl alcohol to generate two daughter monomers; those were later copolymerized to produce the polymer backbone (Scheme 42). Deprotection of the thiol group within the copolymer and its further treatment with 2-(2-pyridyldithio)ethanol produced the pendent OH group attached with a dithiol linkage that further mediated the ROP. This method demonstrates the versatility of the approach for generating functionalized tailormade cleavable graft copolymers.

polymer deposition. Solvent permeability could be enhanced by increasing the amount of unsubstituted pyrroles within copolymer ﬁlms.309 This improved the hydrophilicity and thus its reactivity toward water-soluble amines.310 Besides pyrrole, electrochemical polymerization of activated ester-based thiophenes has also been reported.311,312 Similar to pyrroles, reactive polythiophene ﬁlms of varying compositions were obtained by copolymerization of either pentaﬂuorophenyl thiophene-3-acetate (PFPT1) or N-hydroxy succinimidyl thiophene-3-acetate (NHST1) with 3-methylthiophene in diﬀerent ratios (Scheme 44).313 The conducting properties of

4.4. Electrochemical Polymerization of Activated Ester Containing Pyrroles and Thiophenes

Scheme 44. Electrocopolymerization of NHST1 or PFPT1 with 3-Methylthiophene

Electrochemical polymerization297 of pyrroles298 and thiophenes299 happens to be a standard protocol for making smooth and robust conducting polymer ﬁlms that ﬁnd widespread use in bioelectrocatalysis, sensors, or even diagnostics by acting as templates for biomolecular immobilization. Activated ester-containing pyrroles and thiophenes oﬀer additional possibilities for surface modiﬁcation in tailormade electropolymers, whose properties can be manipulated by incorporating diﬀerent functional motifs during aminolysis of the activated ester groups. Cooper and co-workers300 illustrated the electrochemical polymerization of PFP-ester-containing βsubstituted pyrroles (PFPPy-1) (Table 1) into reactive polypyrrole ﬁlms. Multiple functional polypyrroles were obtained on treatment with a variety of diﬀerent nucleophiles, including amine-based sugar moieties. Even electropolymerization of various activated ester-containing N-substituted pyrroles are well known. They have been modiﬁed with amino acid, dopamine, and chiral sugar derivatives to generate highly functionalized conducting ﬁlms.301 Cystine-based polypyrroles act as a novel surface for binding redox-active cofactors such as iron−sulfur clusters to create ferredoxin electrodes.302,303 Immobilization of diiron complex into the electropolymer is achieved by a postpolymerization technique. As the diiron unit is sensitive to oxidative degradation during electrochemical polymerization of pyrrole, it can be immobilized into the electropolymer only by PPM.304 Chemical modiﬁcation of a reactive ﬁlm derived from Nderivatized pyrrole305 (PFPPy-2) with a solution-phase model nucleophile, ferrocene ethylamine (Scheme 43), was analyzed

these reactive ﬁlms were similar to that of unsubstituted polythiophene and also unaﬀected by surface modiﬁcation with diﬀerent amines. Systematic variations in the monomer structures by incorporating a diﬀerent number of methylene spacers between the activated ester and the thiophene center seemed to have no eﬀect on both electrochemical polymerization or postfunctionalization of the surface.314 Conducting polymer ﬁlms obtained by copolymerizing a binary mixture of activated ester-based pyrrole and thiophene revealed lower incorporation of thiophene monomers within the polymer chain compared to the respective pyrroles as described by Ryder et al.315 Polythiophene has been successfully used as an electrically conducting material for covalent immobilization of biochemically interesting molecules.316 A simple and straightforward two-step procedure for amperometric polythiophenebased enzyme electrodes was presented by Schuhmann et al.317 This was achieved by electrochemical deposition of polythiophenes comprising NHS-ester groups on an electrode surface and subsequent covalent binding of enzyme glucose oxidase onto the electroactive surface via its amine functionality. Following a similar strategy, oligonucleotides were immobilized on conducting polythiophene surfaces that acted as electrochemical biosensors for detecting the sequence of short DNA oligomers.318−320 Besides bioconjugation, electrooxidation polymerization of terthiophenes has been advantageously used for reduction of HAuCl4 to gold nanoparticles (AuNPs). Polyamidoamine (PAMAM) dendrimer-encapsulated AuNPs decorated with a polythiophene outer shell were synthesized from a PAMAM-terthiophene precursor that worked as a reducing agent for simultaneous formation of AuNPs and electro-oxidative polymerization of terthiophene (Scheme 45).321 Besides electrochemical polymerization, electrografting of acrylates and methacrylates featuring activated ester moieties was developed as another powerful technique for surface modiﬁcation of conducting substrates.322−324 Jerome et al.325 showed electrografting of NHSA onto a conducting substrate by voltammetry in the presence of a conducting salt, tetraethylammonium perchlorate. Surface modiﬁcation with electroactive ferrocene or bioactive proteins or enzymes by

Scheme 43. Modiﬁcation of polyPFPPy-2 Film with Ferrocene Ethylamine

by in situ neutron reﬂectivity.306,307 The rate of modiﬁcation was not uniform throughout the entire ﬁlm thickness and proceeded faster at the polymer−solution interface and much slower in the dense inner part of the ﬁlm. It was due to limited diﬀusion of the amines into the inner parts of the ﬁlm.308 Other parameters that inﬂuence the chemical reactivity of the conducting ﬁlms include identity of solvents, its adsorbed amount within the ﬁlms due to swelling, and the rate of 1460

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Scheme 45. Formation of Polyterthiophene Dendrimer-Coated AuNP by Simultaneous Electropolymerization and Reduction

SWNTs aggregates could be derivatized with glucose oxidase to investigate electrocatalytic oxidation of glucose within those SWNTs assemblies. Following scanning electrochemical microscopy (SECM),331 patterned microelectrografting of reactive spots of NHSA on an electrode surface was achieved. Subsequent derivatization of the electrografted reactive polymer coating with a ﬂuorescent probe highlighted those micropatterened surfaces, a technique that is being used in biomolecular electronic devices or in multisensory arrays.

nucleophilic substitution provided an easy method to fabricate electrochemical sensors or biosensors. Duwez et al.326 electrografted polyNHSA brushes from silicon surface of an atom force microscopy (AFM) tip. They further described singlemolecule delivery and immobilization of polyNHSA electrografted from a gold-coated AFM tip on amine-functionalized surfaces (Scheme 46).327,328 This was achieved by simply Scheme 46. (a) Schematic Representation for the Transfer of Polymer Chain Grafted to an AFM Tip to a Reactive Surface; (b) Chemical Bonding of a polyNHSA graft to an Amine-Functionalized Surfacea

a

4.5. Plasma Polymerization

Plasma polymerization,332 also named glow discharge polymerization, is an eﬃcient technique to fabricate polymer ﬁlms from acrylate and methacrylate monomers. This method of polymerization leads to extremely branched and cross-linked insoluble polymer ﬁlms that can strongly adhere to a variety of solid substrates such as metals or glass or even other polymer supports. These excellent properties of this technique contribute to their growing application in the ﬁeld of protective coatings, adhesion promoters, selective membranes, biomedical materials, diagnostic biosensors, etc. Plasma polymerization of activated ester monomers is a widely established strategy for immobilization of biomolecules on reactive surfaces that forms the basis for biological assays333 and microﬂuidic biosystems.334 Förch et al. demonstrated pulsed plasma polymerization of PFPMA.335,336 The reactive ﬁlms obtained revealed very high retention of activated ester groups that provided a reactive site for conjugation of various amines. As a proof of demonstration, surface reactivity toward diaminohexane and protein immunoglobin was studied in aqueous buﬀer solution using FTIR spectroscopy, X-ray photoelectron spectroscopy, and real-time surface plasmon resonance spectroscopy. Following same technique, Gleason and co-workers337 achieved cross-linked polyPFPMA ﬁlms by copolymerizing PFPMA with ethylene glycol diacrylate. Surface modiﬁcation with ﬂuorescently labeled amines could even produce patterned ﬁlms through microcontact printing. The versatility of plasma polymerization method was further illustrated by achieving layer-by-layer polymer deposition. PFPMA was vapor deposited on silicon wafers in the presence of a divinyl cross-linker. The reactive ﬁlms were quantitatively reacted with amine-functionalized biotin that conferred layer-by-layer self-assembly via biotin− streptavidin interactions.338,339 Langer and co-workers340 reported chemical vapor deposition of PFP-ester-functionalized [2.2]paracyclophanes (Scheme 47). The reactive poly[pxylylene carboxylic acid pentaﬂuorophenol ester-co-p-xylylene] template was patterned by microcontact printing with biotinNH2 and used as template for speciﬁc protein and cell binding.334 Following this technique, surfaces with high amine density can be developed by grafting poly(L-lysine) dendrigrafts

Reprinted from ref 327. Copyright 2006 Nature Publishing Group.

pulling away the AFM tip from the surface that broke the weaker chemical bond between the polymer and the AFM tip. In an alternative approach, an amino thiol-functionalized AFM tip was covalently connected with polyNHSA chains electrografted onto gold substrates.329 Amidation resulted in a strong bonding between the polymer chain and the AFM tip. Also, single-wall carbon nanotubes (SWCTs) untangled in room-temperature ionic liquids (RTILs) provided large surface area for electrografting of NHSA.330 Reactive polymer-coated 1461

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Scheme 47. Chemical Vapor Deposition of PFP-Ester-Functionalized [2.2]Paracyclophanes

Scheme 48. Schematic Representation of the Orthogonal and Reversible Functionalization of a Random Copolymer Featuring NHS-Ester and Pyridyl-Disulﬁde Groups

onto plasma-activated polymers.341 Chemical modiﬁcation of the dendrigraft was achieved by partially treating the amine residues on its surfaces with NHSA or other NHS derivatives.

a bifunctional polymer precursor with two orthogonal reactive handles by copolymerizing NHSMA and pyridine disulﬁdefunctionalized methacrylate monomer by ATRP. The copolymer oﬀers two functionalities, complementary to amine and thiol (Scheme 48).343 Quantitative modiﬁcations in either one pot or by sequential addition resulted in the same complex functional polymer with interesting properties. Using polyNHSNorb, Kiessling and co-workers344 polymerized maleimide-substituted norbornene to obtain a diblock copolymer featuring two orthogonally reactive pendent functionalities, NHS-ester and maleimide. Dual-reactive precursor polymer was subjected to reversible Diels−Alder reaction with a furan-based resin. This provided a means for solid-phase polymer synthesis by derivatization of the immobilized polymer with various amine functionalities of interest. To this end, Sanyal et al.345 described copolymerization of NHS4VB with a furan-protected maleimide-based styrene monomer to generate orthogonally functionalizable random copolymers, reactive toward thiols and amines. Studer et al.111 described a nitroxide-mediated alternating copolymerization of HFIPMA with 7-octenylvinylether. Sequential chemical modiﬁcation of the resulting copolymer was achieved by thiol−ene and amidation reactions. Novel pentaﬂuorophenyl-based (meth)acrylate monomers obtained by Passerini multicomponent reactions revealed selective para-ﬂuoro substitution with thiols. Copolymerizing those monomers with PFPA produced orthogonally reactive precursor copolymers where the reactivity of the two functional groups was speciﬁc to thiols and amines.346 A statistical terpolymer, with three orthogonally functionalizable groups comprising of PFP-ester, maleimide, and silyl-protected alkyne was successfully prepared by ROMP. A three-step PPM with benzyl mercaptan, hexylamines, and piperonyl azide, respectively, led to multifunctional polymer (Scheme 49).289

5. ORTHOGONAL AND SEQUENCE-CONTROLLED POSTMODIFICATION Rapidly growing demand of polymeric materials in various interdisciplinary applications has created the need to construct multifunctional macromolecules with precisely controlled architectures following simple but eﬃcient chemical transformations. Polymers bearing “clickable” moieties generate scope for multiple functionalizations from presynthesized macromolecular scaﬀolds by PPM. Near quantitative yields, mild reaction conditions, and tolerance toward a wide range of functional groups have led to the utmost use of click reactions as synthetic tools for PPM that includes azide−alkyne cycloaddition, Diels−Alder, thiol−ene and −yne, thiol− maleimide, and activated ester amine reactions.11,14 Most of these reactions under the broad umbrella of click chemistry are orthogonal in nature and perform with tremendous ﬁdelity and selectivity in the presence of other reactive groups that form the basis of most biochemical pathways.342 Combined click reactions can facilitate synthesis of even more complex macromolecules. Inspired by Mother Nature, several research groups have developed orthogonally functionalizable polymers featuring two or more chemoselective handles that can react speciﬁcally with functionally diverse complementary reactive tools either simultaneous in one pot or in stepwise/sequential fashion. By combining activated ester amine chemistry with other click reactions, extremely versatile and eﬃcient multifunctional polymers have been prepared.105 Thayumanavan et al. designed 1462

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Scheme 49. Sequential Modiﬁcation of a Statistical Copolymer into Multifunctional Polymer by Triple Click Reaction

Scheme 50. Cascade Strategy for Multifunctionalization of NHS-Ester-Containing Copolymer

Precise positioning of functional groups within a polymer chain during PPM is another challenging task. The group of Theato developed a new synthetic strategy for difunctional polymers with precise functional group display from a single PFP2VCP monomer (Table 1).47 PolyPFP2VCP featured two sequentially accessible reactive side groups, such as ketone and PFP-ester, for stepwise multifunctionalization with amines and other ketone reactive moieties such as alkoxyamines or hydrazides.352 In contrast with orthogonally functionalizable copolymers obtained from acrylate/methacrylate monomers, where the two chemoselective groups are either randomly distribution within the polymer chain or in two speciﬁc blocks, ROP of disubstituted vinylcyclopropane confers allocation of two functional groups per repeat unit at a precise position with respect to each other along the entire polymer chain. This was also realized by stepwise PPM of poly(pentaﬂuorophenyl 4vinylbenzenesulfonate) by aminolysis followed by a Mitsunobu reaction with alcohols.353 Nitroxide-mediated sequence-controlled copolymerization of styrene and its derivatives with pentaﬂuorophenyl 4-maleimidobenzoate (PFP4MB) allowed precise positioning of single reactive groups along a polymer chain.97,354,355 Those polymers were used for speciﬁc allocation of functional moieties by PPM.356 Incorporation of an

Even incorporating two diﬀerent activated ester monomers within a polymer chain with disparate reactivities allows for selective aminolysis by sequential addition of amines. Exploring the reactivity diﬀerence of PFP4VB and PFPMA, Theato et al. sequentially modiﬁed individual repeat units of statistical and block copolymers of PFP4VP and PFPMA with aromatic and aliphatic amines selectively.96,347 As an alternative, the diﬀerence in reactivity of azlactone and PFP-ester toward various amines was explored in selective amidation of a copolymer featuring these two activated esters. Sequential aminolysis led to amphiphilic block copolymer.348 Similarly, selective reactivity of PFPA ester and methyl salicylate acrylate (MSA) ester toward isopropylamine/cyclopropylamine and N,N-diethylethylenediamine, respectively, was utilized in generating dual temperature- and pH-responsive block copolymers.349 For a copolymer featuring NHS-carbonate and NHS-ester, stepwise conjugation with two diﬀerent amines was achieved utilizing greater reactivity of NHS-carbonate for carbamate formation.350 Following a one-pot cascade strategy, Hawker et al.351 prepared complex macromolecular architectures from a single reactive NHS-ester-functionalized copolymer by simultaneously utilizing amidation and CuAAC reactions with an amine and azide moiety in the same reaction medium (Scheme 50). 1463

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Scheme 51. Intramolecular Chain Folding by Two Orthogonal Click Reactions

additional monomer such as N-propargyl maleimide along with PFP4MB within the polymer backbone enabled chain folding by sequential conjugation of the two orthogonally reactive alkyne and activated ester groups with one equivalent of a bifunctional linker featuring both an azide and an amine functionality (Scheme 51).357,358

Graft copolymers comprised of acrylic acid and 2methacryloylethyl acrylate (MEA) backbone with polyNIPAM or polyNIPAM-co-PEG grafts were synthesized by partial esteriﬁcation of polyNHSA with 2-hydroxyethyl methacrylate (HEMA) and subsequent amidation with polyNIPAM-NH2 and PEG-NH2.368−370 Free radical polymerization of MEA within thermally-induced micellar assemblies produced dual pH- and temperature-responsive cross-linked particles. Morphology of those could be tailored by the presence or absence of grafted PEG chains.368 Starting from reactive poly(PFPMAb-MEO3MA), cationic core cross-linked (CCL) nanoparticles were developed by covalently linking the hydrophobic PFPester core with an amine-containing spermine cross-linker. Those cross-linked particles oﬀered promising ability to complex and deliver siRNA into cells.371,372 Additionally, the presence of activated esters within the core enabled installation of ﬂuorescent dyes that allowed tracking of siRNA−particle complexes inside the cells. Temperature-induced phase transition of thermoresponsive block copolymer, PEO-bpoly(NIPAM-co-NHSA), produced micellar aggregates featuring well-solvated PEO coronas and reactive P(NIPAM-coNHSA) cores that could be cross-linked by cystamine and later cleaved by DDT (Scheme 52).373 Those particles revealed opposite thermoresponsive phase behavior in ionic liquids.374 When a disulﬁde-based cross-linker373,375,376 was used, nanoparticles showed reversible disruption−reformation abilities in the presence or absence of DTT. Such particles can be transformed into ratiometric Hg2+ ion sensors by installing additional naphthalimide-based Hg2+-reactive moieties within the thermoresponsive block.377 Li et al.378 decorated the outer surface of single-walled carbon nanotubes (SWCNs) with CCL micelles by covalently attaching a polyDMA-b-poly(NIPAM-coNHSA) on the surface of the nanotube. The polymer was attached by its azide functionality at the polyDMA chain end that could adhere to the nanotube by a nitrene addition reaction upon decomposition of the azide. Thermoresponsive nanoparticles obtained along the walls of the nanotubes were stabilized by core cross-linking with diamines. Shell cross-linked (SCL) nanoparticles can be constructed from both reactive di- or triblock copolymers. In a diblock copolymer, the activated ester unit is incorporated within the

6. FUNCTIONAL MATERIALS BY POSTPOLYMERIZATION MODIFICATION The easy and mild reaction conditions of converting an activated ester with amines into the respective amide has led to the utilization of activated ester chemistry in various areas of functional materials. Examples include particles, hydrogels, numerous bioconjugation ligations, metal polymer complexes, and functional surfaces. 6.1. Cross-Linked Particles

Stimuli-responsive polymeric nanoparticles show great promise as therapeutic materials.163,359−361 However, for delivery applications an important consideration is to overcome invariable disassembly/dissociation of these polymeric nanostructures into single chains once their concentration is diluted under physiological conditions, a cause for premature drug release.362 An approach to address this problem is the use of cross-linked particles, reported as early as 1996.363 A general method for tailoring such cross-linked nanoparticles146,364,365 is by supramolecular assembly of amphiphilic block copolymers into core−shell micelles, followed by covalent cross-linking within the core or shell to ensure particle stability.366,367 Tailormade polymeric approaches have enabled engineering of advanced multifunctional cross-linked nanoparticles with precisely controlled architecture, shape, size, and functional group display. In this context, activated ester-based chemistry has been utilized for designing such polymeric nanostructures, where the role of the activated ester group is either to install the cross-linker or immobilization of functional/stimuli-sensitive molecules within the particle. In addition, rationally designed selective core or shell cross-linked particles can be fabricated by judicial placement of the activated ester moiety within the hydrophobic or the hydrophilic domain of the respective block copolymer. 1464

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polyNHSA-b-polySt, with a pH-sensitive ﬂuorescent pyrazine cross-linker.386,387 SCL polymeric micelles obtained from the triblock copolymer, poly(OEGMA-b-NHSMA-b-MAETC), by covalent attachment of an acid labile ketal-based diamino crosslinker enabled a selective binding and pH-dependent release of anticancer drug cisplatin (Scheme 54).388 Highly emissive nanoparticles prepared from ABA type bolamaphiphilic triblock copolymers were used as photonic nanoprobes for protease sensing. 389 The polymer core featured rigidly packed conjugated chromophores, while the shell was comprised of polynorbornenes with pendent NHS-esters groups. Crosslinking of the shell by a protein linker caused luminescence quenching due to aggregation-induced quenching phenomenon. The ﬂuorescence turned on again by enzymatic cleavage of the cross-linkers with protease.

Scheme 52. Schematic Representation for TemperatureResponsive Core Cross-Linked Micelle Formation and Its Disassembly in the Presence of DTTa

6.2. Hydrogels

a

Hydrogels are 3-dimensionally cross-linked polymer networks that can retain a substantial amount of water by maintaining their overall chemical structure. Such soft materials have been extensively explored in biomedical applications390−393 as a delivery vehicle and for tissue engineering, biosensors, medical devices, and other applications as they can sequester watersoluble drugs, proteins, or other biomaterials for targeted release. The most common method for preparation of robust and mechanically strong hydrogels involves the polymerization of water-soluble monomers in the presence of divinyl crosslinkers. Alternatively, physically cross-linked hydrogels utilize noncovalent interactions such as ionic, hydrogen-bonding, hydrophobic, or host−guest interactions to form the polymeric networks. However, these hydrogels tend to have weaker mechanical strength compared to hydrogels obtained from chemically cross-linked polymers. Environmental-sensitive hydrogels394,395 can alter their shapes and volumes when exposed to external stimuli such as pH, temperature, light, or certain chemicals and therefore hold great promise for triggered drug release when responding to physiological stimuli. In this regard, injectable hydrogels396 that can be generated in situ under physiological conditions by virtue of physical or chemical cross-linking are potential drug reservoirs that oﬀer a convenient method for administration of bioactive materials. Considering these application aspects of hydrogels, new

Reprinted from ref 373. Copyright 2007 American Chemical Society.

hydrophilic block,379 while for triblock copolymers,380it forms a separate segment that tethers the hydrophobic and hydrophilic chains. Wooley and co-workers381 prepared SCL micelles from amphiphilic diblock copolymer, polyMA-b-poly(NHSA-coNAM), by cross-linking the hydrophilic segment with diamino linkers. Replacing hydrophobic poly(methyl acrylate) core with hydrolytically degradable poly(lactic acid) (PLLA) triggered enzymatic hydrolysis of the PLLA core without degrading the overall nanostructure assembly (Scheme 53).382 Reversible SCL micelles were prepared from amphiphilic triblock copolymers, PEO-b-poly(DMA-co-NHSA)-b-polyNIPAM obtained from a PEO-based macro-CTA.383 Thermoresponsive phase transition produced micelles with polyNIPAM core, a PEO corona and reactive shell featuring NHS-ester groups. Particles were stabilized by covalent cross-linking with cleavable cystamine-based difunctional primary amines for controlled drug release study.384 A ratiometric pH sensor was developed from ﬂuorescent SCL nanoparticles,385 prepared by covalently cross-linking an amphiphilic triblock copolymer, PEO-b-

Scheme 53. Pictorial Representation of the Shell Cross-Linked Micelles Containing Polylactide Core Showing Enzymatic Degradationa

a

Reprinted from ref 382. Copyright 2012 American Chemical Society. The structure is redrawn for clarity. 1465

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Scheme 54. Synthetic Scheme for Acid-Degradable SCL-Particles Bound to Cisplatin Drug

Scheme 55. Synthetic Scheme for Preparation of (a) Pamidronate and (b) Phospholipid Conjugated Hydrogels

cross-linked enzyme degradable hydrogel.398 An antigensensitive hydrogel403,404 has been prepared by chemical grafting of antigen (Rabbit IgG) and its corresponding antibody to NHSA and subsequent copolymerization of the resulting monomers with acrylamide.405 Noncovalent cross-linking was introduced within the copolymer by speciﬁc complementary interaction between the antigen and the antibody, which could be cleaved by competitive binding with free antigens. DNAimmobilized divinyl cross-linkers have been prepared by reacting PFPMA with 5′-amino-modiﬁed nucleotide. Copolymerization of acrylamide with such DNA-cross-linker in the presence of an additional divinyl monomer containing disulﬁde bonds resulted in a dual-responsive hydrogel that could respond to speciﬁc DNA sequences or be cleaved under reducing conditions.406,407 Reactive polyNIPAM obtained by copolymerizing NIPAM with NHSA happens to be the most popular constituent for creating thermoresponsive hydrogels.408,409 Such systems render double-network structures where the physical crosslinking occurs due to hydrophobic collapse of polyNIPAM above LCST, while the method for chemical cross-linking varies from system to system. In some cases, the polymer chains are cross-linked by conjugating the reactive NHS-ester sites with polymeric diamines such as diamino PEGs.21 A trithiol-based

synthetic techniques have been employed to generate biologically active hydrogels. Along this line, activated ester chemistry has been utilized in constructing pharmaceutically important hydrogels. The most commonly used method for preparing polymeric hydrogels involves copolymerization of activated ester monomers with water-soluble, biocompatible monomers, where the role of the activated ester is speciﬁc. Either it can be used to introduce a cross-linker subsequent to the polymerization step or it can act as an anchor for covalent attachment of biologically active ingredients within the preformed gel network. There are also examples where reactive monomers have been pretransformed into biologically signiﬁcant new monomers that upon polymerization create polymeric hydrogels.397−400 For example, therapeutic hydrogels comprised of pamidronate drugs have been prepared by copolymerizing pamidronate acrylate developed from NHSA with NIPAM using a bis(acrylamide) cross-linker (Scheme 55a).401 Molecules containing bisphosphonate groups can eﬀectively chelate calcium ions and thus can be used as active drugs for curing several bone diseases. Similarly, phospholipid−hydrogel conjugates have been prepared from acrylate-based lipid anchors obtained from NHSA (Scheme 55b).402 Free radical copolymerization of methacryloylated polyamino acids with HEMA resulted in a covalently 1466

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Scheme 56. Synthesis Scheme for siRNA-Loaded Nanoparticle Hydrogel from polyPFPA Block Copolymer

Scheme 57. Synthetic Scheme for Peptide Conjugation and Hydrogel Formation from a DMA Copolymer Featuring Coumarin Side Chains

polyNIPAM oﬀers easy access to hydrogels by thiol−ene click coupling (Scheme 58).423−425 While incorporating two

cross-linker has been reported to be very robust due to its high reactivity toward NHS-esters.411 Examples where the crosslinker itself is a targeted protein for delivery such as polylysine,412 collagens,413 elastins,414 or microtubule415 are also known. Amphiphilic block copolymer poly(PFPMA-bMEO 3 MA) was chemically cross-linked with spermine produced cationic hydrogel particles that revealed eﬃcient electrostatic complexation with siRNA for gene delivery (Scheme 56).371,372,416 In some cases, the polymerization and cross-linking takes place simultaneously when a divinyl monomer is employed, while the role of the activated ester is to immobilize biologically active molecules within the gel matrix.417−420 Polymeric hydrogels comprised of hydroxamic acid groups were prepared from a cross-linked precursor polyNHSA that showed high aﬃnity for iron binding under acidic pH. These hydrogels can be potentially exploited as a polymeric drug for overloading of gastrointestinal iron.421 Other biologically relevant hydrogels were prepared by copolymerizing NHSA and DMA with a coumarin-based monomer (Scheme 57).422 The linear polymer obtained in the ﬁrst step was photo-cross-linked through coumarin moieties, while the reactive NHS-ester sites were available for modiﬁcation with a cell adhesive peptidyl ligand Arg-Gly-AspSer (RGDS). Another strategy includes preparation of hydrogels by twostep PPM in which the reactive site initially allows incorporation of two amine-based complementary chemical handles that can react with each other in the following step to form the chemical network. Thiol−ene coupling is one such reaction that operates under very mild physiological conditions. Incorporation of thiol and vinyl groups at the reactive sites in

Scheme 58. PolyNIPAM Hydrogel Preparation by Networking through Thiol−Ene Click Reacton

complementary supramolecular handles such as cholic acid and β-cyclodextrin at the reactive sites can lead to noncovalently cross-linked, self-healing supramolecular hydrogels occurs through inclusion complex formation.426 Naturally occurring hyaluronic acid (HA)-based glycopolymers are often used as raw materials for hydrogelation. They are an interesting biomimetic scaﬀold for delivery of stem cells and or other morphogenic proteins for tissue engineering.427 The common approach involves stepwise treatment of HA with dihydrazides and subsequent treatment with NHSA to obtain acrylated hyaluronic acid. It is then connected with a dithiol- or tetrathiol-based cross-linker to generate a network structure for aqueous imbibition under physiological conditions (Scheme 59).428−435 Functionalized injectable thermoresponsive hydrogels414,436 have been prepared by copolymerizing NIPAM, acrylic acid, and NHSA with macromer polylactide−hydroxyethyl methacrylate437 or hydroxyethyl methacrylate−poly1467

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Scheme 59. Synthesis of Hydrogel from Hyaluronic Acid Acrylates by Thiol−Ene Click Reaction

Scheme 60. Synthesis of Boronic-Acid-Based Gluocose-Responsive Hydrogels from PFPA Copolymer

(trimethylene carbonate)438 by free radical polymerization. Gelation takes place under physiological temperature due to a change in hydrophilic/hydrophobic balance inside the body as a result of hydrophobic collapse of the NIPAM segment. For those systems, the activated ester moiety oﬀers chemical tool for immobilization of collagen peptides of varying concentration to improve the cytocompatibility of those bioactive gels. Such degradable hydrogels have been successfully used as a biomimetic scaﬀolds for coencapsulation and release of growth factors (bFGF) and mesenchymal stem cells (MSCs) for regeneration of heart cells.438,439 Besides temperature, other environmental-sensitive hydrogels were prepared by introducing new reactive functional groups within the polymer chain by PPM. Such examples include glucose-responsive boronic-acidbased hydrogels, obtained by physical cross-linking of two DMA copolymers featuring boronic acid and dopamine, introduced via PPM. Those gels revealed self-healable properties at neutral and acidic pH (Scheme 60).440 Dual pH- and temperature-sensitive microgel particles were fabricated from poly(PNPA-co-NIPAM) by precipitation copolymerization.441,442 The activated ester site allowed covalent conjugation of pyridine and folic-acid-functionalized amines for anticancer drug delivery.443 In the recent past, reactive surface- immobilized hydrogels have attracted signiﬁcant interest as biomimetic matrices to study the inﬂuence of diﬀerent physiological signals (both chemical and mechanical) on the cell behavior.444,445 These artiﬁcial matrices frequently rely on hydrogel ﬁlms; their tunable swelling properties depend upon the extent of crosslinking. Cross-linked density happens to be an essential parameter that controls the stiﬀness of these materials, providing opportunities to study cellular response as a function of tailored mechanical signals, while the activated ester sites allow covalent bonding of biologically active molecules that

release chemical signals for cells. Also, surface-attached hydrogels featuring activated ester motifs have been eﬀectively used as tools for microarray446−448 or electrical microswitches.449 Usually, those systems were prepared by copolymerizing an activated ester monomer with a watersoluble monomer in the presence of a cross-linker on a solid surface. PEG-based 3D hydrogels containing activated ester groups coated on glass surfaces showed high eﬃciency as small molecule microarrays over conventional 2D hydrogels.450 Biotin-functionalized amines were immobilized at the activated ester sites on the hydrogel surface and probed with a ﬂuorescent dye, avidin. Those surface-immobilized hydrogel materials revealed stronger ﬂuorescence signal and prominent spot morphology, illustrating their potential for protein microarray experiments. However, following this technique, ligand proteins bound to the hydrogel are not quantitatively available for binding with the analyte protein. To address this issue, loosely bound protein−polymer hybrid hydrogels have been fabricated. The technique required spotting a mixture of protein IgG and a copolymer of poly(NAM-co-NHSA) on a Au surface functionalized with NHS-ester motifs. Covalent binding of the amine functionality of the protein with NHS-ester of the polymer and/or substrate resulted in highly porous cross-linked networks.451 Photopolymerization of NHSA, acrylamide, and a cross-linker on top of 2D polystyrene particle array followed by selective removal of PS beads resulted in 2D hole array on hydrogels.452 Such reactive 2D array hydrogels were used as photonic crystal sensors for sensing avidin when functionalized with biotin ligands. Enzyme-immobilized composite hydrogel membranes can be used in biocatalytic reactions.453,454 To this end, enzymetically triggered injectable hydrogels are particularly attractive. Horseradish peroxidase (HRP)-mediated radical polymerization has been exploited in formulating tough nanocomposite hydrogels 1468

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Scheme 61. Schematic Representation of Synthesized Lipopolymers Starting from Lipophilic ATRP Initiators and the PolymerSupported Bilayers Made There From

monomers, such as n-octadecylacrylamide as a lipophilic unit. The lipopolymers insert via their lipophilic group into giant liposomes and allow temperature-induced shape changes of these self-assembled aggregates.461 Besides stabilizing liposomes, lipopolymers can induce a pH-triggered transmembrane release, as described by Chiu and co-workers. They partially converted polyNHSA with mPEG-NH2 followed by hydrolysis of remaining NHS-esters to produce anionic polymers that assembled with cationic lipids.120,462,463 Stabilizing lipid membranes on surfaces by polymersupported lipid bilayers has been investigated over several decades. Such supported lipid bilayers are suited for biophysical investigations.464 Essentially, activated ester chemistry has been utilized for the synthesis of thin polymerized hydrogel layers or hydrophilic polymeric monolayers equipped with lipid-anchor groups. Again, NHSA has been employed for the synthesis of monomeric lipids457 to be included in hydrogels. However, also PFPA when copolymerized with 4-benzoylphenyl methacrylate was used to prepare reactive thin ﬁlm networks. Subsequently, those ﬁlms were eﬃciently modiﬁed to result in proteintethered bilayer lipid membranes via functionalization with nickel chelating nitrilotriacetic acid (NTA) groups to which cytochrome c oxidase (CcO) was bound via a his-tag.456 Synthesis of statistical copolymers featuring a hydrophilic polymer backbone while being equipped with a lipophilic group and a surface anchor (e.g., disulﬁde for Au surfaces) has been a common approach that utilized PPM of polyNHSA.459,465−467 In combination with controlled radical polymerization techniques, this concept was expanded to the synthesis of end-functionalized lipopolymers by utilizing NHSA for synthesis of a short end block that allowed for immobilization of the lipolymers on surfaces (Scheme 61).458 Those lipopolymer supports were used for ﬁxing lipid vesicles to form polymersupported bilayers. 6.3.2. Glycopolymers. Glyocolated structures play an important role in biology in speciﬁc recognition events. Therefore, as a possibility to mimic natural oligosaccharides, glycoproteins, or glycolipids, carbohydrate-containing polymers, so-called glycopolymers, have attracted increased attention. The actual binding aﬃnities are a common example of polyvalency, which require multiple copies of the same or diﬀerent carbohydrates. Even though the direct polymerization of glycomonomers is convenient, there have been numerous

from a mixture of silica nanoparticles, acryloylated human serum albumin, and DMA that displayed high enzyme activity and catalytic performance in organic medium.455 Stable, longlived bilayered lipid membranes (BLMs) can be engineered by covalent attachment of lipid bilayers to reactive hydrogel supports that oﬀer the possibility for investigating functional membrane proteins.456 Those artiﬁcial cytoskeletons were also prepared by copolymerizing an acrylate-modiﬁed lipid with a PEG-based dimethacrylate that led to concomitant formation of gel and conjugation of lipid to the gel matrix.457 The acrylated lipid membrane was obtained by treating diphytanoylphosphatidylethanolamine (DPhPE) with NHSA. This complements work on polymer-supported lipid membranes that utilized lipo-polymers, often prepared from reactive polyNHSA.458−460 6.3. Bioconjugated Polymers

Activated ester polymers have been employed as synthetic handles in the preparation of bioconjugated polymers. These include areas of (i) lipopolymers, (ii) DNA-polymer conjugates, (iii) glycopolymers, and (iv) protein−polymer conjugates. It is noteworthy to state that early studies almost exclusively utilized NHS-ester containing polymers, while in recent years the exploitation of PFP-ester derivatives has become increasingly popular. However, also other activated esters have found accepted use in the synthesis of numerous bioconjugates. The following paragraphs are not intended to provide the reader with a full and exhaustive overview of the applications but rather focus on synthetic possibilities of activated ester polymers and their valuable contribution to the synthesis of bioconjugated polymers. In many aspects, the discussed solutions are complementary to other eﬃcient ligation chemistries. 6.3.1. Lipopolymers. Lipopolymers have been explored in stabilizing liposomes that can be used for self-assembling surrogates. Early approaches followed copolymerization of water-soluble monomers with polymerizable lipids. Often such monomeric lipids were synthesized by reacting amino-lipids, such as 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE) or ﬂuorescence-labeled derivatives 1-myristoyl-2-[6[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]caproyl]-sn-glycero3-phosphoethanolamine (PE-NBD), with NHSA.402 Alternatively, for the synthesis of stimuli-responsive lipopolymers, NHSA was copolymerized with NIPAM and hydrophobic 1469

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followed by a CuAAC with, for example, 1-azido-β-Dgalactose.488 The group of Kiessling could also demonstrate that numerous glycopolymers can also be synthesized by ROMP of norbornene monomers featuring an activated ester.489−491 Again, this approach can also be utilized in a sequential PPM, by reacting the activated ester ﬁrst with an amino−azide linker, followed by a CuAAC with propargyl β-D-galactoside.492 6.3.3. DNA-Polymer Conjugates. Nucleic acid detection has become very important in recent years, and hence, it comes as no surprise that numerous routes have been developed to conjugate oligonucleotides (ODNs) to polymers. In order to enable a conjugation of ODNs via activated ester chemistries, a terminal amino group at the ODNs is required. In most studies, ODNs are synthesized by β-cyanoethyl phosphoramidite chemistry using modern synthesizers and an accessible amino group is introduced via a 5′-aminohexyl modiﬁcation using the phosphoramidite derivative of triﬂuoracetylaminohexanol, which after deprotection yielded a primary amino group. This allowed the conjugation to various NHSA-derived copolymers493−495and NHSMA copolymers.496 When densely grafting oligo-DNA on a polymer backbone, cylindrical brushes can be obtained.497 The group of Ke Zhang could show that triblock copolymer brushes with functionalized ODN sequences at the ends allowed for polycondensation via a head-to-tail connection by DNA hybridization forming supramolecular nanostructures (Scheme 63).203 Another important area of nucleic acid conjugation is found for RNA delivery. Here, often amphiphilic block copolymers featuring a hydrophobic activated ester block are utilized to prepare core−shell structures with a cationic charged core that can complex siRNA and a hydrophilic shell.182,498,499 However, microcapsules have also been obtained from DNA-grafted polyNIPAM micelles, where NHSA copolymers were used as reactive intermediates.500 Further, RNA-functionalized γ-Fe2O3 nanoparticles have been prepared by coating the inorganic nanoparticles with multifunctional polymers, which were synthesized via sequential aminolysis of activated ester polymers.501 Similarly, DNAcoated MnO nanoparticles have been prepared and utilized as speciﬁc cellular cargos.502,503 Those selected examples nicely document the versatility of preparing highly speciﬁc and multifunctional polymers by a simple series of aminolysis steps using an activated ester precursor polymer. In eﬀorts to detect speciﬁc DNAs, various sensing approaches have been presented. Among those, DNAresponsive hydrogels that show a distinct swelling in response to speciﬁc DNAs have been reported.406 Here, NHSMA has been utilized as a reactive monomer for the synthesis of ssDNA cross-linked hydrogels. This approach has been taken further for the synthesis of polymer−DNA hydrogels that respond to a speciﬁc ODN and a nonspeciﬁc trigger, enabling dual-input and mutiscale responses.504 The most common route to DNA detection is the preparation of microarray chips. For this amphiphilic block copolymers featuring reactive NHSA and surface anchor units are used for polymer supports.193,448 On these supports ODN polymer conjugates are prepared. Planar supports as well cellulose-derived ﬁbers have been used in such a functionalization scheme.505 Alternatively, electrochemical DNA biosensors have been prepared using activated ester chemistry. For example, poly(MMA-co-PEGMA-co-NHSMA) has been synthesized to noncovalently bind to CNTs.506 Attachment of

examples of employing PPM for the synthesis of glycopolymers.468 A recent review on this account summarizes nicely various approaches in this respect but leaves out the utilization of activated ester chemistries. Most commonly, acrylic or metharylic derivatives have been used as monomers, but also norbornene derivatives have been reported. NHS-ester-based chemistry is still dominating the area of glycopolymer synthesis. For example, NHSA and NHSMA monomers have been utilized in the synthesis of complex (meth)acrylamide monomers and their direct polymerization for the synthesis of Fucoidan-mimetic glyopolymers469 or mannan trisaccharide hapten gyclopolymers.470 Early studies utilized polyNHSA for the synthesis of monosaccharide-derived glycopolymers by attachment of ω-aminoalkylglycosides471,472 or amino-diethylene glycolglycosides.473 Later, attachment of monosaccharides was conducted with reaction of polyNHSA, for example, with galactosamine,69 glucosamine,474 or sialic acid.475 However, pepitdoglycans have been attached via this route to polymers for the synthesis of polyacrylamide copolymers.476 As glycopolymers that are suited for speciﬁc binding or recognition events are mostly copolymers, the attachment of larger units, such as speciﬁc disaccharides477,478 or trisaccharides479 for the synthesis of copolymers has been described. The group of Brocchini even reported the attachment of larger complexes, such as Amphotericin B.480 The group of Bovin very early on focused on the use of polyPNPA as an activated ester platform for the attachment of ω-aminoalkylglycosides.481,482 However, also disaccharides483 and trisaccharides484 have been attached following this approach. In recent years, the use of PFP-esters became very popular as well. Similar to polyNHSA, glycopolymers can be prepared by simple aminolysis of polyPFPA with, for example, glucosamine, resulting in poly(glucose acrylamide).485 It had been shown that PFPA-containing polymers can also be used for an eﬃcient surface modiﬁcation of porous polymers486 and polymer ﬁbers,487 allowing modiﬁcation with galactose and mannose derivatives. Via an arm-ﬁrst method, star glycopolymers have been prepared by aminolysis of polyPFPA arms with galactose amine and glucose amine (Scheme 62).228 If azido-functionalized saccharides are only available, a sequential PPM can be conducted by aminolysis of the activated ester polymer with propargyl amine or 2-[2-(prop-2-ynyloxy)ethoxy]ethanamine, Scheme 62. Synthesis of PFPA-Derived Star Polymer Using an Arm-First Approach

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Scheme 63. Synthesis of the Hairpin DNA−Polymer Brush Conjugates and Their Polycondensation into Wormlike Nanostructures via DNA Hybridizationa

a

Reprinted from ref 203. Copyright 2014 American Chemical Society.

enzyme surfaces enabled a labeling of enzymes with diﬀerent polymers by taking advantage of triple bioorthogonal ligation chemistries, while activated ester chemistry520 was heavily used for the monomer synthesis. To graft polymers precisely onto enzymes requires often polymers that feature an activated ester at one chain end.242 Alternatively, initiators or chain transfer agents for ATRP or RAFT polymerization can be conjugated onto the enzyme surface that enable grafting-from polymerization.243 For further details, the reader is referred to recent reviews of such protein−polymer conjugates.521,522 Utilizing a PPM approach, polyPFPMA has been functionalized with numerous moieties that even allow the formation of antibody− polymer conjugates.523 Conjugation of peptides onto polymer chains follows very much the same route as for proteins. Activated esters can be easily prepared by activation from poly(acrylic acid) units within polymers with DCC coupling of NHS524 or by direct polymerization of the respective activated ester monomers (see section 2) and subsequent PPM with peptide fragments. Because of the possibility for altering LCST of thermoresponsive polymers upon recognition events or the elegant thermoprecipitation of peptide−polymer conjugates, many polyNIPAM copolymers have been investigated. Commonly starting from a copolymer of NIPAM and NHSA, peptide attachment was straightforward, following established PPM protocols. The thermoresponsive behavior has then been utilized for puriﬁcation or recognition events.149,525−528 However, also copolymers of NHSMA and HPMA have been utilized for the synthesis of biocompatible peptide−polymer conjugates.73 More recent studies take advantage of the activated ester polymers based on PFPMA529 in a sequential postmodiﬁcation by ﬁrst reaction with allylamine and then attachment of cysteine thiol side group (Scheme 64). The synthetic protocols to attach peptide segments onto polymer chains via activated ester chemistries enabled an eﬃcient synthesis of polyvalent conjugates.288 Such polyvalent peptide−polymer conjugates found application in areas such as enhancing inhibitors,530,531 HIV-1 entry inhibitors,532 promo-

ssDNA allowed the electrochemical sensing of complementary DNA strands due to the charge-trapping nature of base pairs in hybridized DNA. Another electrochemical sensing utilized hydrophobic poly(nBA-co-NHSA) microspheres, which were functionalized with ssDNA, during diﬀerential pulse voltametry using anthraquninone-2-sulfonic acid monohydrate sodium salt (AQMS) as the electroactive hybridization label.507 6.3.4. Peptide/Protein Polymer Conjugates. Proteins or peptides are ideal candidates that can be linked via activated esters to form protein− or peptide−polymer conjugates. The inherent amino group at the N-terminus of a polypeptide chain allows conjugation to activated ester polymers. While this essentially allows synthesis of a practically inﬁnite number of conjugates, it is the intention in the following section to highlight a number of selected examples to provide the reader with a categorization of areas that heavily utilize activated ester polymers. These areas include (a) grafting-from/to enzymes, (b) peptide conjugates, (c) incorporation of peptide recognition sites, (d) peptide-coated particles, and (e) peptidecoated surfaces. The group of Hoﬀman intensively studied protein−polymer conjugates, often conjugated to PNIPAM, to take advantage of the varying LCST properties of the protein−polymer conjugates.508−511 For this they mostly used copolymers derived from NHSA and NIPAM. Their work has inspired numerous other scientists to study similar PNIPAM conjugates that all were prepared using NHSA-derived copolymers.512−514 Alternatively, enzymes have also been immobilized within a polymer gel,515−517 which ﬁnd application either as catalysts or as responsive sensors. To be reasonably applicable, such a covalent enzyme immobilization has been performed on highly porous monoliths that were prepared from a polymerized high internal phase emulsion.518 In ways to stabilize enzymes, they have been covered by a polymer network around them.519 For this NHSA has been reacted with lysine groups exposed at the enzyme surface, and subsequent polymerization led to a thin permeable shell around the enzyme. Taking advantage of diﬀerent functionalities on 1471

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copolymerization of NHSA with NIPAM, a thermoreversible cell attachment could be observed.540 The cell adhesive RGD peptide could also be used to deliver a drug cargo that can be released upon thermal stimulation of polyNIPAM copolymer to induce cell death.541 Polymers displaying the desintegrin domain of fertilin β, Glu-Cys-Asp (ECD), mediate inhibition of mammalian fertilization.542,543 Functionalization of particles has been conducted in order to immobilize enzymes. Commonly, emulsion polymerization was used to prepare latex (nano)particles that contain NHSesters.544 After successful immobilization of various enzymes, the particles have been used as catalysts.545,546 Utilizing conducting polymer nanoparticles that have been functionalized with collagen mimetic peptides enabled the sensitive ﬂuorescence imaging of collagen strands.547 Equipping polymer opals that were assembled from reaction colloids featuring activated esters on their surface enabled immobilization of Histagged silicatein.548 Such reactive photonic crystals provide a versatile platform as sensors. A route to detect proteases has been reported by the group of Swager. They prepared luminescence-quenched shell cross-linked nanoparticles utilizing peptide strands as cross-linkers.549 Upon exposure to protease, these cross-links are cleaved and luminescence is recovered. Micellar nanoparticles have been prepared from polymer−peptide block copolymer amphiphiles, which had been synthesized by attachment of peptide sequences on activated ester polymer chains.550 Through a phosphorylation− dephosphorylation cycle, the morphology changes in response to proteolysis. Lastly, activated ester polymers have been investigated as linkers to conjugate enzymes onto inorganic nanoparticles, which have been used for bioseparation or catalysis.551−553 Similar to the enzyme immobilization on nanoparticle surfaces, proteins and peptides have been linked to planar surfaces. Most commonly the terpolymer derived from NHSA, DMA, and 3-(trimethoxysilyl)propyl methacrylate has been utilized to coat glass slides with a reactive polymer layer that enables covalent attachment of proteins and peptides within microarrays.554−557 As an alternative route, the plasma surface modiﬁcation via plasma polymerization of PFPMA generates a reactive surface that has been used to covalently immobilize protein layers, as shown for bovine serum albumin (BSA).558 Last but not least, also other functional groups have been conjugated to polymers via activated ester chemistries. As long

Scheme 64. Synthesis of Peptide−Polymer Conjugates by Sequential Postpolymerization Modiﬁcationa

a

Reprinted with permission from ref 529. Copyright 2011 American Chemical Society.

tors for cellular internalization,533 directing ﬁbrillar assembly,534 or activation of cell signaling.535 Polymer−glycopeptides conjugates have been suggested as potential antitumor vaccines.209 Alternatively, polymer−drug conjugates have been described taking advantage of an enzymatically cleavable peptide linker.68 In combination with the formation of disulﬁde cyclic bridges via cysteine linkages within peptide sequences, complex single polymer chain topologies have been reported.536 Polymer−peptide conjugates have also been found to feature interesting self-assembly properties. pHresponsive coil to α-helix transitions of topological diﬀerences in grafted ABA peptide−PEO conjugates showed a clear inﬂuence on the transitions.219 Also, collagen-like peptidecontaining block copolymer conjugates have been prepared utilizing activated ester end group modiﬁcations of linear polymer chains.269 The obtained structures showed an interesting temperature-dependent self-assembly of nanostructures (Scheme 65).270,537 Probably the most commonly attached peptide sequence is the arginine-glycine-aspartic acid (RGD) peptide, which is a common element in cellular recognition and involved in cellular attachment via integrins. Polymer thin ﬁlms expressing the RGD sequence after attachment via activated esters support strongly cell attachment.538,539 When combined with the thermoresponsive properties of PNIPAM ﬁlms, prepared by

Scheme 65. Conjugation Scheme Showing the Synthesis of the Triblock Hybrid via the Reaction of the Activated EsterTerminated PDEGMEMA with Telechelic Amine-Functionalized Collagen Peptide and Their Proposed Self-Assemblya

a

Reprinted from ref 270. Copyright 2012 Royal Society of Chemistry. 1472

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Scheme 66. Synthesis of Lanthanide Ion Binding Terpyridine Polymers

Scheme 67. Synthesis of Novel DOTA(Gd3+)−Polymer Conjugates

directly copolymerized to achieve similar targets.566,565 The ability of the terpyridine motifs to complex with lanthanide ions such as Eu3+ and Tb3+ produced metal-functionalized polymers that exhibit strong emission of pink and green light for Eu3+ and Tb3+ ions, respectively.567 The color of the emissive light could be tailored by incorporating a mixture of these two ions within the polymer backbone. Heating the polymer above 50 °C also conferred thermochromic properties to those materials. Multichromophoric metallopolymers obtained by anchoring ruthenium(II) polypyridine complexes to polyNHS4VB side chains grafted from reduced graphene oxide (RGO) sheets revealed enhanced photovoltaic performance.568 Gadolinium (Gd), an important element in the lanthanide series, has been used as a contrasting agent in magnetic resonance imaging (MRI) application. The contrasting eﬃciency of Gd3+ ions can be improved signiﬁcantly by immobilizing them with high molecular weight compounds that enhance the relaxivity of the macrocontrasting agents. For this purpose, various Gd3+ chelating ligands such as DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) or DTPA (diethylenetriaminepentaacetic acid) have been covalently attached to activated ester-containing water-soluble copolymers through their amine functionality (Scheme 67).569 Lowe, Davis, and Boyer570 developed gadoliniumfunctionalized gold nanoparticles as bimodal contrasting agent for computed X-ray tomography (CT) and magnetic resonance imaging (MRI). The hybrid nanoparticles were prepared by covalently attaching the Gd3+ ligands, DO3A-tBu-Et-NH2, to the PFP-ester sites of reactive oligoethylene glycol-based statistical copolymers, synthesized by RAFT. Grafting of the Gd3+-chelated polymer onto gold nanoparticles was achieved through its free thiol residue obtained by reducing the dithiocarbonate unit at the ω-chain end of the polymer. A single nanoscale theragnostic device was developed from polymer−Gd metal organic framework (MOF) nanoparticles

as the functional group of choice is equipped with an accessible amine (best primary amine) group, attachment is very straightforward. Examples include tamoxifen-conjugated polymers,559,560 folate−polymer conjugates,441,443,561 biotinylated polymers,196,562,563 or simply ﬂuorogenic polymers.288 6.4. Metal Polymer Complexes

Metal-based polymers564,565,3 have for long been a topic of interest especially in the area of bioanalytical chemistry, sensors, wastewater treatment, catalysis, and photovoltaics. Integrating metal chelating ligands into macromolecules has bestowed a variety of advanced polymeric materials with unique properties, depending upon the sequestered metal ions. However, the synthetic challenges in carrying out polymerization reactions with monomers featuring metal complex comes from their bad solubility, undesired side reactions, poor yield, and so forth. As a result, the ﬁeld of metallopolymers was comparatively much less developed until the advent of postpolymerization functionalization. It turned out to be one of the most versatile approaches in the context of metal chelating polymer synthesis, oﬀering the easiest way to introduce a library of diﬀerent metal complexing ligands into the side chains of polymer backbones. With this advancement, lanthanide-containing polymers as luminescent probes, biosensors, and contrasting agents for magnetic resonance imaging (MRI) have become available. For a long time, terpyridine−lanthanide complexes have been known to impart strong luminescence properties along with other features such magnetism and thermochromism. Nevertheless, to utilize these complexes as an active component in materials applications, they are required to be embedded within a polymer matrix to make them soluble and processable for device fabrication. Tew et.al developed polymers with terpyridine-functionalized side groups by reacting NHS-ester containing homo- or copolymers with amine-based terpyridine ligands (Scheme 66).169,78 Also, monomers featuring terpyridine residues were 1473

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polymer side chain. Hydrogels prepared by chelating Fe3+ ions with polymers containing pendent hydroxamic acid groups could act as potential chelators for excess iron in the gastrointestinal tract.421 This approach was extended to polymers containing other metal binding ligands introduced by PPM. Terpyridine functional polyNIPAMs, obtained from precursor poly(NIPAM-co-NHSMA), was cross-linked with Mn2+ or Co2+ to produce supramolecular metal gels.170,582,583 Gelation properties of those gels were dependent on the strength of metal−ligand interactions, which were found to be greater than hydrogen-bonding interactions-based supramolecular cross-linking. Cu 2+ or Fe 3+ served as potentially biodegradable cross-linkers for polymeric nanoparticles comprised of poly(N-methyl methacryloyl hydroxamic acid) with PEO-grafts prepared from a polyNHSMA precursor.584 Internalization of those metal ions within the polymer core through the hydroxamic acid chelates could be expressed inside the cells by a transchelation mechanism happening due to intracellular bioreduction of the metal ions. This resulted in degradation of the nanoparticles under physiological conditions, prerequisite for drug delivery. Fe3+ binding catechol ligands introduced at the chain end of thermoresponsive polyNIPAM resulted in Fe3+-ion-induced solubility switch of polyNIPAM. This is essentially an alternative to a temperature stimulus that has tremendous signiﬁcance in treatment of neurodegenerative disorders.585 Besides various aforementioned biomedical applications, water-soluble metal binding polymers that can selectively chelate toxic and heavy transition metal ions are eﬀective in ultraﬁltration and wastewater treatments. Reactive PolyNIPAM displaying NHS-ester groups were utilized for covalent attachment of 3-hydroxy-2-pyridinone or hydroxamic-acidfunctionalized ligands that complexed with a trace amount of Fe3+ ions in aqueous solution. Metal ions were removed by thermal precipitation of the polymer that could be regenerated by treatment with ethylenediaminetetraacetate (EDTA).586 For removal of Fe3+ from the organic phase, hydroxamicacid-based ﬂuorinated polymers were employed that could be removed from organic layers by liquid/liquid phase separation following ﬂuorous biphasic conditions.586,587 There has been a major impetus toward detection and removal of toxic Hg2+ ions, whose presence in the environment can cause severe cellular dysfunction. Therefore, Hg2+-responsive solid-state probes were developed by covalent attachment of aminocontaining spirolactam rhodamine derivatives on polyPFPMA, grafted on cellulose ﬁlter papers by surface-initiated ATRP (SIATRP).588 The response of the functionalized ﬁlter papers to Hg2+ was analyzed by the change in color and ﬂuorescence of the ﬁlter paper that operated as a disposable solid-state sensor for detection of Hg2+ ions. Aluminum-ion-sensitive optical imaging ﬁbers were developed to investigate in situ localized corrosion of galvanic aluminum−copper couple.589 The optical sensor was created by immobilizing pH-sensitive ﬂuorescent dye, SNAFL-SE, and Al3+ chelating morin ligand on the imaging ﬁber modiﬁed with (3-aminopropyl)triethoxysilane and poly(acrylamide-co-NHSA). For a long time polymeric supports have been exploited in chemical synthesis.590 One such popular example includes solid-phase peptide synthesis using Merriﬁeld resins. However, most heterogeneous systems suﬀer from prolong ﬁltration and a tiresome workup for the recovery of the catalyst. An attractive alternative would be one where the reaction can proceed under solution-phase pseudo-homogeneous conditions. Also, the

for cancer therapy and diagnosis through both magnetic resonance as well as ﬂuorescence microscopy.571 Unlike previous examples, where the activated ester group was used to introduce ligands for metal ions, Boyes et al. grafted ﬂuorescent tagged copolymer poly(NIPAM-co-NHSAco-ﬂuorescein-O-methacrylate) by means of its thiolate end group to the vacant orbitals on the Gd3+ ions at the surface of the Gd−MOF nanoparticles. Those NHS-ester groups were employed for attachment of therapeutic agent and cell targeting ligand. Besides bioimaging by MRI, positron emission tomography (PET) imaging with radioactive isotopes is another powerful tool for diagnosis. Hawker and co-workers572 prepared amphiphilic graft copolymer PMMA-co-PNHSMA-gPEG that self-assembled in water into polymeric nanoparticles. Covalent anchoring of DOTA at the NHS-ester sites followed by chelation of radioactive 64Cu nuclei allowed analysis of the biodistribution of these nanoparticles in medical imaging. Metal chelating polymers have been extensively exploited in bioassays.573 Modiﬁcation of poly(acrylamide-co-NHSA) with nitrilotriacetic acid (NTA) ligand allowed immobilization of Ni2+ ions. The resulting polymers were employed as protein assays for detection of hexahistidine-tagged proteins that can bind selectively with Ni2+ ions through their imidazole sites. Integrating an additional thiol-based ligand, 3-(methylthio)propylamine (MTP), further supported immobilization of such metal-bound polymer−protein conjugates on gold nanoparticles.574 Lanthanide-bound polymeric ligands have been exploited as elemental tags to develop highly sensitive bioassays, where the signal for the lanthanide isotopes were analyzed by inductively coupled plasma mass spectrometry (ICP-MS).575−577 Gd3+ and Eu3+ chelating ligand-functionalized polymers, tagged with lectines578 and antibodies,579 respectively, through the free thiol group at the chain end were used for diﬀerentiation of various biomarkers such as glycoproteins and individual cells targeting proteins. The presence of multiple copies of the bound lanthanide isotopes attached as side groups of a single polymer chain oﬀers greater sensitivity of polymer-supported elemental tags compared to ﬂuorescence-based bioassays, making this technique more advantageous for immunoassays. Also, Ni3+ and Gd3+ chelating polymeric ligands obtained by treating poly(NHSA-co-MMA) with Nα,Nα-bis(carboxymethyl)-L-lysine have been exploited as disposable polymeric pMALDI chips for selective identiﬁcation of phosphoproteins by MALDI-TOF/MS.580 However, massspectroscopy (MS)-based analysis of phosphoproteins suﬀers from certain disadvantages such as poor ionization of phosphopeptides due to the presence of nonphosphorylated counterparts in positive-ion mode. Also, the collision-induced dissociation process leads to the instability of the phosphate groups on phosphopeptides that suppress their identiﬁcation by MS techniques. Immobilized metal aﬃnity chromatography (IMAC) columns have been projected as a better alternative for phosphoproteome analysis. NHS ester-functionalized monolithic IMAC matrix was treated with nitrilotriacetic acid (NTA) to immobilize Ti4+ or Zr4+ that revealed higher aﬃnity for phosphoproteins.581 Incorporating strong and directional metal−ligand interactions within macromolecular domains has been extensively investigated in making supramolecular cross-linked polymeric networks. These are useful materials in self-healing, shape memory, or controlled release soft adhesive substrates to name a few. The binding strength of the cross-linker is dictated by the selection of metal ions and the ligand immobilized on the 1474

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Scheme 68. Modiﬁcation of Poly(NODAM-co-NHSA) into Diﬀerent Metal Binding Polymers for Catalyzing Organic Reactions

between iodobenzene and phenylboronic acid in biphasing conditions.597 Product puriﬁcation and catalyst regeneration was achieved by the thermoresponsive phase transfer of the catalytically active nanoparticle from organic to aqueous phase upon temperature drop.

catalyst can be easily recovered and reused as in heterogeneous catalysis, essential for environmental concern and economic advantages. Immobilization of catalysts and reagents on polymer support oﬀered multiple advantages such as easy separation of the molecules attached to the polymer, enabling recovery of costly ligands and catalyst, and simplifying the puriﬁcation steps. In addition, the use of polymer supports increased the surface area of the microenvironment for the catalyst or the reagents, which led to an improvement of the reaction conditions. Activated ester-containing polymers have been employed for developing polymeric supports for homogeneous catalysis. The activated ester residues act as anchors to attach those ligands that can selectively bind to certain transition metal ions, whose choice essentially depends on the nature of the reaction that will be catalyzed. Following this technique, Bergbreiter and coworkers developed a polymer-bound SCS−Pd(II) Heck catalyst for C−C coupling reaction by treating reactive poly(NODAMco-NHSA) with amine-based SCS-ligands followed by complexation with Pd(II) species (Scheme 68a).591 Such versatile and generalized design allows immobilization of other ligands to carry out diﬀerent reactions from the same precursor polymer. This was exempliﬁed by attachment of phosphine ligands to the same polymer for sequestering of Rh(I) or Pd(0) to catalyze alkene hydrogenation or allylic substitution reactions, respectively (Scheme 68b).592 Even phenanthroline-appended polymers could immobilize Cu species for a Huisgen 1,3-dipolar cycloaddition reaction (Scheme 68c).593 Owing to their multivalent supramolecular substrate binding capability, cyclodextrin-functionalized polymers prepared from polyNHSA revealed eﬀective mass transfer ability. Those properties have been judicially utilized for Rh-catalyzed hydroformylation of hydrophobic oleﬁns in aqueous biphasing catalysis.594 To ensure maximum recovery and reuse of the catalyst, a biphasing condition is usually created either by perturbing the solution or by addition of another immiscible solvent that separates the polymer from the catalyst or the product.595,592 For air- or moisture-susceptible polymeric catalyst, additional introduction of a closed and continuous microﬂuidic loop system in conjunction with thermomorphic multicomponent system conditions was found to be more advantageous.593 For a polyNIPAM support, catalyst recovery was achieved by simply varying the reaction temperature or salt concentration that aﬀected the LCST of polyNIPAM and conferred stimuliresponsive precipitation of the polymer-bound catalyst.596 PolyNIPAM−cobalt hybrid nanoparticles were employed as amphiphilic supports for covalent anchoring of a Pd− phosphine complex to catalyze Suzuki cross-coupling reactions

6.5. Functionalized Surfaces

The modiﬁcation of surfaces has been a vibrant research area to design functional surfaces with numerous applications. Yet, it comes as no surprise that postpolymerization modiﬁcation reactions have also been employed for the modiﬁcation of surfaces.598 Besides the formation of polymer brushes599 and their postmodiﬁcation, various other routes are commonly used in the formation of polymer thin ﬁlms. Various approaches also utilize activated ester chemistries to enable an eﬃcient postmodiﬁcation of polymer thin ﬁlms. For example, thin polymers ﬁlms containing PFP-esters were obtained by plasma polymerization of PFPMA (Scheme 69),600−602 making PFPMA a unique monomer suitable Scheme 69. Plasma Polymerization of PFPMA and BSA Attachment on the Obtained Layersa

a

Reprinted from ref 558 . Copyright 2013 American Chemical Society.

because of its volatile character. Such ﬁlms found application for the immobilization of biomolecules, such as peptides and proteins.336,603,604 Postmodiﬁcation yielding swellable hydrogel thin ﬁlms found application in cell studies.605 An alternative route has been presented by Lahann and co-workers, who utilized a CVD copolymerization of [2.2]paracyclophanes featuring pentaﬂuorophenyl ester groups and alkyne groups to prepare orthogonally reactive surfaces, which can be used to coimmobilize diﬀerent biomolecules and cells.334,340,606,607 Polymer ﬁbers spun from a PCL/polyPFPMA blend had been described, allowing a versatile surface functionalization of the ﬁbers.487 In contrast, NHSA could only be grafted from polypropylene substrates by gamma irradiation, and the resulting poly(NIPAM-co-NHSA) ﬁlms provided a useful biological plat1475

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form.608 However, polyNHSA polymer ﬁlms can be grown from conductive substrates by an electrografting method.609,610 This allowed the growth of polymer chains from an AFM tip, which subsequently enabled the deposition of single polyNHSA chains onto amino-coated substrates.327 Additionally, the postpolymerization modiﬁcation of the grafted polyNHSA chains on the AFM tip allowed the preparation of chemically modiﬁed AFM tips by simple conversion with various amines.611 As an alternative, the group of Schönherr utilized reactive microcontact printing on polyNHSMA ﬁlms with the transfer of amino end-functionalized PEG, yielding biomolecular patterns.612,613 Copolymerization of NHSA, NAM, and bis-acrylamidoprop1-yl-PEG1900 in the presence of a glass slide that has been modiﬁed with 3-(trimethoxysilyl) propyl methacrylate to aﬀord a suﬃcient attachment yielded NHS-ester hydrogel-coated glass slides.450 Similarly, PNPA has been utilized for the formation of functional hydrogel layers.614 Rather than pretreating the glass surface with 3-(trimethoxysilyl)propyl methacrylate, direct copolymerization of dimethylacrylamide, 3-(trimethoxysilyl)propyl methacrylate, and NHSA (Scheme 70) led to polymers

and essentially depend on the amine used for the functionalization, for example, antibacterial surfaces632 and molecular recognition probes.611 Theato and co-workers presented a very versatile approach by combining a graftingto and postmodiﬁcation step on the basis of polysilsesquioxanebased hybrid polymers, which consist predominately of polyPFPA chains grown from a polysilsesquioxane precursor polymer. Secondary condensation reactions of the polysilsesquioxane part upon annealing allow for the deposition onto various surfaces. The subsequent conversion with amines results in surfaces with adjustable wettability347,633,634 or biological activity.635 The group of Klok demonstrated the grafting of PFPMA from a surface via RAFT polymerization, following a detailed investigation of the subsequent postpolymerization functionalization.98 Surface-initiated ATRP (SIATRP) of PFPM and postfunctionalization of the obtained polymer brushes had also been reported.588 The group of Locklin utilized activated ester polymer brushes grafted-from surfaces in a double PPM (Scheme 71).81 First, the activated ester polymer brushes were reacted with an amine-functionalized cyclopropenone, which was then successfully used in a second functionalization step via a catalyst-free cycloaddition reaction with azides.82 Besides the functionalization of macroscopic planar surfaces, activated ester polymers have also been valuable synthetic tools as polymeric ligands for nanoparticles. For example, polymers bearing either NHSMA or PFPA units have been used to decorate magnetic nanoparticles, which can then be the basis for an eﬀective bioseparation process or immobilization process of proteins.551 Similarly, NHSA has been grafted from mesoporous silica nanoparticles via a grafting-from RAFT polymerization.636 Activated ester polymers on the basis of polyPFPA have been used for the synthesis of polymeric ligands for a variety of diﬀerent nanoparticles.501,502,553,637,638 Diﬀerent binding ligands have been incorporated, depending on the inorganic nanoparticle. Similar to the coating of planar surfaces, tercopolymers of NHSA, DMA, and 3-(trimethoxysilyl)propyl methacrylate were used to stabilize CdSe−ZnS quantum dots in water.639 A library of polymer-coated (core−shell-type) gold nanoparticles utilizing polyPFPMA prepared by RAFT polymerization has been presented by the group of Klok.640,641 Carbon nanotubes (CNTs) have also been functionalized by utilizing polymeric activated esters as precursors, which, for example, allowed the modiﬁcation with DNA.506 Incorporation of pyrene side groups provided a good stabilization of CNTs, and further conversion of the activated ester units into a polyNIPAM resulted in stimuli-responsive CNTs, whose solubilization can be triggered by changes in temperature.132,133 Polymer conjugation onto CNTs via azides has also been achieved.378 Alternatively, PFPMA could be attached to the CNT surface via plasma polymerization.642 Lastly, semiconducting thin ﬁlms of polythiophene or polypyrrole derivatives featuring activated ester groups have been described,300,310,313−315,643 and no real diﬀerentiation between the various activated esters (PFP or NHS) has been observed. Such reactive polythiophene layers have been used for protein immobilization644 or as electrochemical DNA sensors.318,645

Scheme 70. Structure of a Terpolymer Comprised of Dimethylacrylamine, 3-(Trimethoxysilyl)propyl Methacrylate and NHSA

that allow direct deposition of activated ester-containing polymers onto substrates.554,615,616 Similar surface functionalizations have been achieved with the tercopolymer prepared from NHSA, 3-(trimethoxysilyl)propyl methacrylate, and PEGMA617 or other variations to alter surface wetting properties618−621 or enable biomolecule conjugation.622,623 In particular, this approach has been used for the preparation of DNA microarray sensors.615,624−626 The biocompatibility of these approaches has also led to the exploration of NHSA in dental adhesives.627 Noteworthy, the trimethoxysilyl group provides an eﬃcient possibility not only for the attachment onto SiO2 surfaces but also for the modiﬁcation of AFM cantilevers yielding molecular recognition sensors.628 The activated ester moiety can also be utilized to enable covalent attachment of functional copolymers onto aminofunctionalized surfaces. For example, poly(NIPAM-co-NHSA) has been attached onto amino-modiﬁed silica nanoparticles, and the remaining activated ester moieties have then been used in deposition of covalent layer-by-layer self-assembly of these coated nanoparticles with polyethylenimine (PEI), resulting in stimuli-responsive nanocomposite ﬁlms.629,630 Similarly, such a covalent cross-linking approach has also been utilized for the formation of nanostructured protein hydrogel ﬁlms. For this a copolymer of NHSA and NAM was deposited simultaneously with a protein, wherein the amino groups exposed at the protein surface reacted with the activated ester groups, resulting in a cross-linked hydrogel ﬁlm.451,631 There have also been reports focusing on more precisely prepared reactive polymers ﬁlms by grafting-from approaches. The potential applications of these surfaces can be numerous

7. CONCLUDING REMARKS Activated esters have been used in polymer synthesis frequently and an established synthetic tool for more than 40 years. The rich structural variations of the diﬀerent activated esters that 1476

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Scheme 71. (a) Grafted Poly(NHS4VB) from a SiO2 Surface and Attachment of Cyclopropenone (1); (b) UV-Irradiated Activation into the Dibenzocyclooctyne (2) and Its Cycloaddition with Azides

to other click chemistries, making them very powerful synthetic handles in eﬃcient, one-pot modiﬁcations. In this regard, further intensive use can be expected in the future. The excellent compatibility of activated ester chemistry with numerous polymerization methods, ranging from free radical polymerization, controlled radical polymerizations, ring-opening metathesis polymerizations, and other ring-opening polymerizations to plasma polymerization and electrochemical polymerizations, provides the basis of a very broad applicability in materials science and life science. Now, is there still something remaining to be done in basic research on activated esters in polymer chemistry? When looking at the monomer map, one can identify several empty areas that urgently need to be addressed. (A) Not all activated esters have been explored in all areas. Here their compatibility remains to be tested. (B) The possibility to conduct activated ester−amine conversions in water is another very challenging area. Even though some potential approaches have been presented, e.g., 4-sulfotetraﬂuorophenyl (STP) esters,64,65 so far, mostly sulfonated NHS-esters are used. However, it has to be noted that sulfonated NHS-esters are semistable aminereactive esters. (C) Activation of activated esters. The intrinsic existing reactivity of activated esters is synthetically very valuable; however, it would be exciting to have access to an activated ester that is dormant under normal conditions and can be activated upon exposure to a physical stimulus. One example has been reported in the literature;109 however, it is only a change from an activated ester into a deactivated ester, and the deactivation is irreversible. A reversible process is highly needed.

have found application in polymer synthesis document its lasting success. Activated esters represent an extremely successful method when it comes to postpolymerization modiﬁcations. The broad availability and accessibility of amines and the mild reaction conditions (catalyst free, room temperature) speak to the fact that conversions of activated esters with amines are superior in several aspects to other click reactions. However, one should also note the intrinsic disadvantage of activated ester−amine conversions. It remains a substitution reaction and becomes only economically viable when recycling the released auxiliary alcohol. The choice of activated ester depends on several factors. NHS-esters are historically the most frequently used activated esters in polymer chemistry; however, the suﬀer from the fact that their respective acrylate or methacrylate polymers are only soluble in DMSO or DMF. When used within copolymers, solubility is not an issue anymore. Modern times have seen a vital revival of activated ester applications with the advent of PFP-esters. Their solubility as well as their hydrolytic stability is advantageous when compared to NHS-esters. The additional charm of utilizing 19F NMR spectroscopy as a sensitive analytical tool has additionally contributed to the increased use of PFP-esters. When 1H NMR spectroscopy is required for detailed analysis, the use of tetraﬂuorophenyl esters may come in handy but at a higher cost of the required chemical compounds. A comparable alternative is the use of PNP-esters. Noteworthy, most polymers containing activated ester groups are stable, can be stored without special precaution, and can easily be shipped. It is worthwhile to note that activated ester−amine conversions are very compatible and often also fully orthogonal 1477

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Polymeric activated esters have been and will be attracting a lot of attention because of their synthetic potential for the synthesis of new functional polymer materials that ﬁnd application in many research areas. The recent trend in combining postpolymerization modiﬁcations with modern advances in precision polymerization will result in an increasing use of activated ester chemistries.

within the WCU program. In 2011, he accepted a prize senior lectureship at the University of Sheﬃeld. Shortly after he moved to the University of Hamburg, where he is currently an associate (W2) professor for polymer chemistry. He has edited 2 books and authored or coauthored more than 180 publications. His research interests are postpolymerization modiﬁcations, stimuli-responsive polymers, surface modiﬁcations, energy storage, functional nanoobjects, and nanoﬁbers.

AUTHOR INFORMATION

ACKNOWLEDGMENTS A.D. is indebted to the Alexander-von-Humboldt Foundation for postdoctoral fellowship.

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing ﬁnancial interest.

REFERENCES

Biographies

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Dr. Anindita Das was raised in Kolkata, India. After receiving her B.Sc. and M.Sc. degrees in Chemistry from the University of Calcutta she joined the research group of Dr. Suhrit Ghosh at Indian Association for the Cultivation of Science where she obtained her Ph.D. degree in 2014. The topic of her doctoral thesis was “hydrogen-bonding-induced assembly of aromatic donor−acceptor gelators and chromophore− conjugate amphiphilic macromolecules”. Currently, she is working as an Alexander von Humboldt Postdoctoral Fellow in the research group of Prof. Patrick Theato at the University of Hamburg. Her current research is focused on precise polymer assemblies by directional noncovalent interactions.

Prof. Patrick Theato studied chemistry at the University of Mainz and the University of Massachusetts, Amherst, and obtained his doctoral degree from the University of Mainz in 2001. After postdoctoral studies at Seoul National University supported by a Feodor Lynen Postdoctoral Research Fellowship and at Stanford University, he completed his Habilitation at the University of Mainz in 2007. From 2009 to 2012 he held a joint appointment at Seoul National University 1478

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Activated Ester Containing Polymers: Opportunities and Challenges

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