Nucleobase Containing Synthetic Polymers: Advancing Biomimicry via

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Nucleobase Containing Synthetic Polymers: Advancing Biomimicry via Controlled Synthesis and Self-Assembly Ronan McHale and Rachel K. O’Reilly* Department of Chemistry, Library Rd., University of Warwick, Coventry, U.K. CV4 7AL S Supporting Information *

ABSTRACT: The hydrogen-bonding recognition interactions of nucleobases are a fundamental property of nucleic acid chemistry and associated transcription, translation, and replication functions. Nucleobase interactions are central in protein biosynthesis, yielding sequence- and stereospecific macromolecules capable of assembly into precisely defined, complex shapes and morphologies that make up the machinery of life. As the understanding of nucleobases and their significance developed in the past century, chemists have inevitably sought to extend their function from a biological setting onto wholly synthetic platforms. Recent advances point to a burgeoning area of study which may soon bear fruit in some of the holy grails of polymer synthesis, namely sequence (and stereo) control, single chain manipulation, and controlled polymer folding. This Perspective seeks to summarize recent developments in the area of nucleobase containing polymers (including nucleobase mimics), with particular emphasis on controlled polymerization, self-assembly, and templating polymerization.

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INTRODUCTION Seminal work of early scientists such as Albrecht Kossel, who began identifying, isolating, and naming the nucleobases in the 1880s (Nobel Laureate in Physiology/Medicine 1910), and Hermann Emil Fischer, who first synthesized purine in 1898 (Nobel Laureate in Chemistry 1902) laid crucial groundwork in our understanding of these vital biological molecules. When the structure of DNA was fully elucidated in the early 1950s as an intricate polymeric double helix bound together through specific H-bonding of complementary nucleobases,1 synthetic chemists were inspired, with biomimetic syntheses beginning in earnest thereafter. Realizing the vast potential inherent in nucleobases, it was inevitable that their recognitive functionality (and associated multitude of structural, storage, and replicative applications) would ultimately be harnessed in wholly synthetic platforms. Early synthetic work in the field centered on the attachment of nucleobases to preformed natural polymers such as cellulose.2,3 Subsequently, significant advances were made with the development of synthetic monomers bearing nucleobase functionality by Pitha and T’So4 and Takemoto and Imoto et al.5 Radical polymerization of such monomers, of which N-vinyl derivatives of the purines and pyrimidines represent early examples (see Table S1 (Supporting Information) for structures),4,5 allowed for the first preparation of wholly synthetic nucleic acid analogues. With the synthesis and polymerization of more conventional vinyl analogues, such as methacrylic nucleobase derivatives (Table S1),6 following swiftly, the field was well placed to expand. It was realized at © XXXX American Chemical Society

an early stage that nucleobase functionality had a significant role to play in mechanistic and kinetic aspects of polymerization, with observations such as cyclopolymerization in the radical homopolymerization of N-vinyluracil7 and alternation of sequence in the radical copolymerization of the complementary methacryloyloxyethyl derivatives of adenine and thymine.8 The former involved radical addition to the vinyl functionality inherent in the uracil heterocycle while the latter was attributed to hydrogen bonding between complementary monomer pairs playing a role in the propagation step. Such hydrogen bonding, certainly the primary inspiration for much of the work using these functionalities, was again utilized in one of the earlier examples of a template polymerization; an acceleration effect was observed in the polycondensation of thymine-functionalized activated esters (Table S1) with diamines in the presence of a poly(vinylbenzyladenine) template.9 While the historic progress of this field undoubtedly makes for interesting reading, the current intention is to focus on more recent developments, namely the controlled polymerization of nucleobase containing monomers (and other nucleobase inspired H-bonding monomers) and the selfassembly and template polymerization potential of the resultant polymers. As such, readers are at this point directed to comprehensive reviews by Inaki10 and Smith11 (and references Received: May 3, 2012 Revised: July 16, 2012

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Figure 1. Uridine (left) and adenosine (right) (R = H (acryloyl) or Me (methacryloyl)) nucleoside monomers.12,17,19

generation of well-defined poly(nucleoside) macromolecules.17 The same authors followed up soon thereafter with another report detailing the ATRP of nucleobase functionalized monomers on silica supports. While the separation of polymers replicated along these tethered templates was identified as a desired end goal, no such experiments were reported in this contribution.19 A noteworthy feature of the monomers used in the above studies12,17,19 is the inclusion of a deoxyribose linker between vinyl and nucleobase functionalities (Figure 1). While such a structure is clearly an accurate mimic of that seen in DNA, it is unknown what role such a linker may play in desired applications such as recognition and/or template polymerization. Inherent problems with monomer/polymer solubility, hence the need for hydroxyl protection, and a relatively complex enzyme assisted synthesis suggest monomers employing simpler alkyl or ethylene glycol based linkers may ultimately be more practical.

therein) on progress with synthetic nucleic acid analogues up to the mid 1990s.

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BRINGING CONTROLLED SYNTHESIS TO NUCLEOBASE CONTAINING POLYMERS The concluding years of the 20th century witnessed ever increasing interest in nucleobase containing polymers. A report describing the template-directed polymerization of protected 5′-acryloylnucleosides (Figure 1 and Table S1; deoxyribose and nucleobase functionality) underlines some fundamental considerations for the pursuit of improved fidelity of information transfer.12 Notably, it was shown that a uracil-based template was superior to its adenine counterpart due to selfcomplementary association in the latter (likely intramolecular) which prevented efficient alignment of complementary monomers. Further, an experiment was conducted wherein an adenine-based monomer was shown to preferentially polymerize along its complementary template in the presence of the uracil-based monomer. In this initial report from Khan et al.,12 a traditional free-radical polymerization mechanism was utilized both in the formation of the nucleobase containing templates and in the subsequent template polymerizations. An obvious next step was alignment with the then newly emerging controlled/living radical polymerization (CLRP) technologies.13−16 One of the earliest CLRP studies of a nucleobase containing monomer was the atom transfer radical polymerization (ATRP) of protected 5′-(meth)acryloylnucleosides (Figure 1; TMS and TBDMS protection was necessary to impart solubility in preferred nonpolar polymerization solvents, e.g., toluene).17 Lowest polydispersity index (PDI) values were observed in the polymerization of the TMS protected 5′-methacryloyluridine with values in the range of 1.12−1.17 depending on the choice of ligand. Polymerization of TBDMS protected 5′-methacryloyladenosine was less successful using similar conditions (PDI range of 1.35−1.44). The authors noted at the time that such broadening may be due to interactions between the adenine containing polymers and the column during SEC analysis using THF as eluent. Further to that possibility, it is also discussed in due course that judicious choice of ligand is crucial in ensuring negligible interaction between nucleobase containing monomers and ATRP catalysts.18 More conventional monomers (methyl methacrylate (MMA) and styrene (St)) were also polymerized using nucleobase functionalized ATRP initiators (Table S1; thus introducing nucleobase functionality to the termini of well-defined polymers)17 with good control achieved using both adenine and uracil containing initiators. Overall, this study confirmed ATRP compatibility with the range of functionalities present in nucleoside containing monomers and initiators, allowing for the

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SELF-ASSEMBLING NUCLEOBASE CONTAINING POLYMERS The turn of the millennium saw the emergence of work from the Rotello group involving the first inevitable crossovers between synthetic self-assembly and nucleobase containing polymers. Preliminary work with nucleobase mimics involved the incorporation of side-chain functionalities such as diaminotriazine or diaminopyridine (Table S1)20,21 into vinyl polymers and elegant demonstration of the assembly of individual chains via intramolecular H-bonding interactions. Good control over tertiary polymer structure in solution was demonstrated via isolation of an electroactive nucleobase functionalized guest (6-ferrocenyluracil; Table S1) in the pocket of a unimolecular diaminotriazine functionalized polymeric “micelle”. Encapsulation of such electroactive species represents a notable starting point toward the synthesis of metalloenzymes.20 Continuing with a similar theme, so-called “plug and play” diaminopyridine polymers were also introduced by the Rotello group.21 Interestingly, efficiency of recognition between such polymers and added guest molecules could be readily tuned by adjusting the balance between intra- and intermolecular interactions. It was shown that judicious choice of H-bonding moieties is crucial; intramolecular interactions within polymer chains are reduced when diacyldiaminopyridine is used instead of diaminotriazine (both adenine type mimics), thus allowing for more efficient recognition and uptake of added complementary molecules.21 Such considerations are closely related to the aforementioned intramolecular association difficulties in using a poly(adenine) based macromolecule as a polymer template.12 B

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Figure 2. Giant vesicle formation on mixing a diacyldiaminopyridine-based polymer (R = CO2Et) with a thymine-based polymer. The image on the right is a differential interference contrast (DIC) optical micrograph showing spherical aggregates 3.3 ± 0.9 μm in diameter. Reproduced with permission from ref 22.

demonstrating a highly selective molecular “lock and key” control over higher order assembly and recognition processes.24,26

Efficient recognition processes, i.e., stoichiometric alignment of small molecules along polymeric templates, are essential if the full potential of nucleobase containing polymers (and their analogues) is to be realized in templating applications. The Rotello lab summarize such considerations in the following sentence − “implicit in the bimolecular recognition of intramolecularly associated polymer is a decrease in the ef f iciency of intermolecular binding. This inef f iciency arises f rom the requirement for polymer uncoiling prior to the recognition event.”21 In other words, intramolecular association between polymer strands must be sufficiently weak to allow for unwinding of polymer chains to accept added guest molecules. Such inefficiencies are clarified when one considers that a diaminotriazine based polymer binds flavin (a thymine mimic; Table S1) with an association constant over an order of magnitude lower than the equivalent association constant for diaminotriazine small molecule and flavin. Subsequent to the above early studies with nucleobase analogues, the focus in the Rotello group shifted to native nucleobases with the demonstration of giant vesicle formation in chloroform on mixing thymine/uracil functionalized polystyrene22 or polynorbornene23 (for rigidity) with diacyldiaminopyridine functionalized equivalents (Figure 2 and Table S1). Mono- and multivalent interactions within such vesicles were investigated. Monovalent interactions resulted in swelling followed by dissociation of the vesicles due to competitive binding of complementary monovalent small molecule N(3)-methylflavin. On the other hand, multivalent complementary guests (thymine functionalized gold nanoparticles) were incorporated into the vesicular walls without dissociation of overall structure; i.e., the gold nanoparticles existed as bridges between numerous polymer strands within the vesicle wall.24,25 Building on the idea of multivalent interactions, and in a departure from polymer−polymer mixing, bis-thymine functionalized small molecules were also used to cross-link and stabilize diacyldiaminopyridine polymer aggregates, forming well-defined microspheres in a paper published in 2003.26 The cross-linking procedure was found to be fully reversible, with the cross-linking/deformation process repeated numerous times.26 Overall, the described studies from the Rotello lab illustrate the varied synthetic possibilities inherent in the dynamic nature of nucleobases and their analogues,

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NUCLEOBASE CONTAINING POLYMERS VIA ROMP (AND ALKYNE COUPLING): FURTHER SELF-ASSEMBLY The crossover of self-assembly and synthetic nucleobase systems has been further investigated in the Sleiman group. With an emphasis on ring-opening metathesis polymerizations (ROMP), rod morphologies were observed on assembly of adenine containing block copolymers prepared from adenine derivatized norbornene (Table S1).27 An interesting aspect of this work is the necessity for the addition of a complementary small molecule (succinimide; Table S1) in order to prevent coordination of the ruthenium based ROMP catalyst with adenine functionality in the monomer. Not only does the addition of succinimide act as a noncovalent protection strategy, it also serves to increase the solubility of the resultant polymer, allowing propagation to higher conversion. Complementary small molecule additives are also thought to be advantageous in preventing similar interaction with ATRP catalysts.28 The recurring theme of adenine:adenine association is also evident in this work, allowing the assembly and stabilization of adenine containing block copolymers via adenine:adenine interactions. The formation of cylindrical (rod) like morphologies was unexpected given the core:corona ratio (1:10). While it was suggested that the existence of some crystallinity in the polymers may afford this morphology, a mechanism involving the self-complementary behavior of adenine and its propensity for aromatic π-stacking was favored.27 Work on nucleobase containing polymers in the Sleiman group is also interspersed with nucleobase mimics. One such contribution involved the synthesis and self-assembly (into spherical aggregates) of dicarboximide (Table S1) containing block copolymers via ROMP.29 Dicarboximide functionality is known to selectively bind adenine functionality, acting as a mimic to thymine and/or uracil in interactions with nucleic acids. The observed spherical particles are too large to be considered individual micelles, with the authors suggesting a large compound micellar structure. Interestingly, the spheres C

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Figure 3. Assembly of complementary PEG-b-poly(nucleobase; A and T) polymers in water. Reproduced with permission from ref 37. Copyright 2006 John Wiley and Sons.

from this study was a rate enhancement in the polymerization of the adenine monomer in the presence of either a thymine containing polymer or a thymine containing small molecule (1hexylthymine; Table S1). The authors ascribed their findings not to a template effect but to an interaction between the adenine monomer and the added thymine functionality which prevented association of the adenine monomer with the copper ATRP catalyst (Cu/2bpy system), an effect similar to that observed in the Sleiman group for ROMP catalysts.27 Notably, the polymerizations were performed in DMSO, a relatively polar solvent, in order to maintain polymer solubility. Despite the choice of solvent, which might be expected to interfere considerably with the H-bonding regime of complementary nucleobases, sufficient interaction occurred for the observed acceleration effects to operate (polymerizations were performed at ambient temperature). These findings underline how nucleobases can operate and interact effectively in a range of solvent conditions. Depending on the application and, hence, the degree (strength) of interaction necessary, such adaptability promises a wide range of end uses for systems utilizing these and analogous methodologies.28 A subsequent contribution from the Van Hest group focused on the aqueous self-assembly of poly(ethylene glycol; (PEG))b-poly(nucleobase) block copolymers (prepared by ATRP) (Figure 3).37 The primary driving force for this work was the postulation that the noncovalent interaction would enhance the ability of the block copolymers to assemble and provide stabilization. In fact, a contrary effect was observed, wherein the noncovalent interaction was deemed detrimental in selfassembly. Critical aggregation concentrations (CAC) were initially assessed for aqueous solutions of adenine and thymine containing block copolymers, with little apparent effect of differing nucleobases observed in the self-assembly regime. On mixing the complementary block copolymers the CAC increased. This perceived increased hydrophilicity (lesser tendency to self-assemble) was attributed to complementary interactions which shielded the hydrophobic methacrylic backbone, thus rendering the polymers overall more soluble in the surrounding aqueous media. It was concluded that two

were observed to aggregate into necklace like morphologies which may be intermediary between spheres and rod-like structures.29 Further work involved the ROMP preparation of self-complementary triblock copolymers30 containing dicarboximide functionality and the complementary diacyldiaminopyridine functionality used in Rotello’s work. Strikingly, it was observed that block order plays a critical role in the selfassembly regime; small micelles were observed when the diacyldiaminopyridine and dicarboximide blocks were separated by a nonfunctional central block, while no aggregates were observed when the complementary functional blocks were adjacent in the triblock copolymer.30 A more comprehensive study involving triblock copolymers composed of diacyldiaminopyridine and thymine containing outer blocks was also conducted more recently.31 A range of small molecule functionalities were examined for their effects in terms of micellar retention, modification, or destruction, with an associated set of guidelines providing valuable information for future nucleobase containing responsive micellar design.31 Additional work from the Sleiman group in 2008 described the synthesis (via Cu-catalyzed alkyne coupling) of watersoluble π-conjugated poly(p-phenylenebutadiynylene) (Table S1) containing both a thymine and poly(ethylene glycol) functionality at every repeat unit.32 Interaction studies of this polymer with DNA resulted in a dramatic change in the secondary structure of the DNA guest, indicating significant compatibility/interaction between the native and synthetic poly(nucleobase) formats. The water solubility inherent in this nucleobase containing polymer underlines a likely future direction for the field, opening the way to further possibilities in hybrid polymer−DNA and/or nucleobase-mediated polymer−biomolecule interactions.33−35

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BROADENING THE SCOPE: EXPLORING NEW MONOMERS AND NUCLEOBASES The Van Hest laboratory has also explored the controlled polymerization of nucleobase containing monomers,18,28,36,37 initially concentrating on the ATRP of adenine and thymine functionalized methacrylates (Table S1).28 A notable finding D

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Figure 4. DNA-like melting behavior in mixtures of adenine and thymine containing polymers. Selected absorption spectra of an equimolar mixture in 1,4-dioxane in the temperature range 298−368 K (3 × 10−5 M). The arrows indicate the changes observed upon increasing the temperature. The inset shows the temperature dependence of the intensity at 268 nm of the first derivative absorption spectra of the mixture. Reproduced with permission from ref 41.

interaction on cooling. Crucially, control of the polymerization was observed to be as good as that attained using unsupported catalysts.

antagonistic parameters contributed to the net effect observed, the amphiphilic nature of the diblocks, and their associative noncovalent interaction.37 The range of nucleobase functionality available in vinyl monomer format was extended in another contribution from the same group,18 with unprotected cytosine and guanine methacrylic derivatives added to the repertoire (Table S1). Interactions with the copper catalyst (Cu/2bpy) were observed for both new monomers during ATRP (polymerizations in DMSO from ambient to 40 °C). In the case of the guanine derivative, the polymerization was not noticeably hindered. However, in the case of the cytosine analogue, a stronger copper binding ligand, PMDETA, was necessary to gain control over the polymerization.18 Overall, PDI values ranged from ∼1.15 to 1.20 for all four monomers with associated molecular weights (Mn) of ∼6000 g/mol. The Shen group has also explored the ATRP and subsequent assembly of nucleobase containing methacrylic polymers (Table S1).38−40 A particularly interesting contribution38 detailed the development of a zipper-like copolymer wherein poly(methacrylic thymine) and poly(methacrylic adenine) blocks were anchored on the ortho positions of a pyridine ring via a consecutive two-step ATRP process (Table S1). Such strategic positioning of complementary nucleobase containing polymers appeared to enhance their relative association when compared with simple mixtures of the corresponding homopolymers. The diblock was insoluble in most solvents, with sparing solubility attained only in DMSO. Interestingly, DLS studies indicated an anisotropic structure rather than a random coil structure. This observation was further corroborated by an AFM experiment wherein the diblock was observed to adopt a V-shaped topology. Further work from the Shen laboratory39 notes an enhanced propagation rate in the ATRP of a diaminopyrimidine methacrylate derivative (DMP) in the presence of a highly soluble uracil containing polymer (poly[6-undecyl-1-(4vinylbenzyl)uracil]; PUVU) (Table S1), while another interesting contribution details a nucleobase containing “catalyst sponge” wherein maleimide or thymine functionalized polystyrene gel was used as a solid support to “mop up” diaminopyridine derivatized ATRP catalysts (Table S1) postpolymerization.40 The latter concept centered on the proviso that the catalyst is released from the solid support sponge only at the higher temperature (60 °C) required for ATRP, while it is readsorbed onto the support via a H-bonding

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ASSEMBLY AND DISASSEMBLY So-called “DNA-like melting” of adenine and thymine functionalized polystyrene (Table S1) and dodecyl methacrylate (DMA) copolymers (Figure 4; synthesized via conventional free-radical polymerization)41 represents the starting point for contributions from the Lutz laboratory to the field.41−44 DMA was chosen as comonomer for two reasons: (i) long alkyl chains enhance solubility in many organic solvents, and (ii) reactivity ratios predict an alternating copolymerization, thus suggesting a homogeneous chain composition and regular distribution of nucleobases. Three solvents were chosen to perform spectrophotometric measurements of adenine and thymine containing polymers: trifluoroethanol (TFE), chloroform (CHCl3) and 1,4-dioxane. In the solvent of highest polarity (TFE) no evidence of intramolecular association was observed, a finding which was rationalized by the strong tendency of TFE to compete in H-bonding to the nucleobases. In CHCl3, a relatively complex picture emerged wherein intermolecular association was only observed above a threshold concentration (∼4 × 10−5 M). At concentrations lower than this value, hypochromic absorption effects, which are diagnostic of base-pairing interactions, were not observed. In 1,4-dioxane, the solvent of lowest polarity, distinctive nucleobase interactions were observed across the range of concentrations studied. Temperature-dependent studies in this latter solvent indicated DNA melting behavior on increasing the temperature from room temperature to 368 K. The exact temperature of melting was found to be concentration dependent, going from 315 K at lower concentrations (1 × 10−5 M) to 325 K at the highest concentration studied (3 × 10−5 M). Further analysis of self-organization and colloidal fusion of these nucleobase containing copolymers has also been reported using fluorescence microscopy and turbidimetry measurements.44 A subsequent paper from the Lutz group detailed an improved, controlled synthesis (via ATRP) of poly(1-(4vinylbenzyl)thymine (VBT)-co-DMA) and poly(1-(4(vinylbenzyl)adenine (VBA)-co-DMA) copolymers analogous to those described above. A catalyst system comprising CuCl/ N,N′-bis(pyridine-2-ylmethyl-3-hexoxo-3-oxopropyl)ethane1,2-diamines (BPED) was found effective in the ATRP E

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highly soluble 1-octylthymine in CH2Cl2 at −78 °C as mediator, the syndiospecific radical polymerization of complementary acrylamide monomer [(N-(6-acetoamidopyridin-2yl)acrylamide] yielded syndiotactic rich polymers up to r = 84%. RAFT-mediated polymerizations in the presence of the same thymine-based mediator yielded lower r values (73 and 76%) due to the necessity to conduct these polymerizations at higher temperatures. Nonetheless, this approach is certainly promising for simultaneous control over MW and tacticity using specific nucleobase interactions. The latter synthesis is deemed noteworthy in that tacticitycontrol is invoked using a monomer:small molecule interaction, i.e., a nonpolymeric template. Such an approach shows parallels with the copolymerization of N-6-methacryloyloxyethyl derivatives of adenine and thymine (discussed in the Introduction)8 wherein it is proposed the small molecule monomer:monomer interaction directs the polymerization to an alternating propagation mechanism. Future investigations may focus on how such small molecule interactions between comonomers could simultaneously control regio- and stereochemistries.

copolymerizations.42 This metal−ligand pairing was chosen to overcome possible metal−nucleobase interactions, similar to those discussed previously.18 Self-assembly studies of the copolymers in either CHCl3 or 1,4-dioxane revealed micrometer-sized spherical superstructures via optical microscopy. An interesting study was carried out on the poly(VBT-co-DMA) comprised superstructures wherein the effect of addition of increasing levels of the complementary monomer (VBA) was monitored via 1H NMR spectroscopy. A distinctive downfield shift of the NH signal of VBT was observed. This shift, coupled with an increase in resolution/intensity with increasing VBA concentrations, indicated the breakup of the superstructures with the onset of significant A−T base pairing. Similar findings were observed in the case of the poly(VBA-co-DMA) superstructures on addition of VBT. Overall, these observations confirm the self-assembly is driven by relatively weak A−A or T−T interactions in solutions of individual polymers, whereas A−T interactions are expected to predominate when the copolymers are mixed.42 A biological mechanism involving the UV activated 2+2 cycloaddition of the vinyl functionality inherent in thymine has also been elegantly utilized by Saito and Warner et al. to stabilize thymine containing polymeric nanostructures.45−48 Notably, it has further been shown that the cycloaddition is reversible,49 opening up possibilities for reversible crosslinking and capture/release protocols using these materials.

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ENHANCED THERMAL AND VISCOSITY PROPERTIES Recently, an informative feature article was published by the Long group with a primary focus on combining nucleobase and electrostatic interactions.52 A key theme in this groups work involves polymers containing nucleobase mimics, so-called multiple hydrogen-bonded polymers (MHB) consisting of welldefined polystyrenes, isoprenes,53 or poly(ethylene-co-propylene),54 end-terminated with methylisocytosine functionality. A urea linkage between the polymer and the isocytosine functionality (Figure 6 and Table S1; first described by Meijer et al.55,56 and termed ureidopyrimidone (UPy) motifs) ensures four H-bonding sites at the chain end. The significant strength of the UPy:UPy interaction yields increased thermal resistance and increased viscosities in the melt state. The melt viscosity, for example, of the modified polymers was higher than that of similar nonfunctionalized polymers with twice the numberaverage molecular weight (Mn), indicating significant interaction even in the melt state.53 The Long group subsequently investigated nucleobase containing polymers, using nitroxide-mediated polymerization (NMP) to control the synthesis of triblock copolymers containing a long thermoplastic elastomeric chain (poly(nbutyl acrylate)) and outer blocks of either poly(vinylbenzyladenine) or poly(vinylbenzylthymine). Polymer mixtures again exhibited dramatic viscosity enhancements (through increased effective molecular weight) and evidence of a complementary A−T hard phase in the solid state. Complementary interactions allowed for selective uptake into nucleobase-containing domains, pointing to potential applications in drug delivery and/or biological applications.57 Four-arm star-shaped poly(DL-lactide)s containing adenine or thymine functionality were also investigated as thermally reversible viscosity modifiers (Table S1). Hydroxyl-terminated poly(lactide) chains were converted to acrylate derivatives via coupling with acryloyl chloride, followed by Michael addition of nucleobases to the unsaturated acrylic end groups to form tetranucleobase functional stars.58 Additional work from the Long group involved the use of nucleobase interactions for the noncovalent attachment of ionic functionality into triblock copolymers creating so-called ionomers.59 A novel uracil

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STEREOCHEMISTRY: CONTROLLING TACTICITY The Kamigaito lab has recently explored the exciting concept of controlling both the MW and tacticity in radical polymerizations of H-bonding monomers in the presence of a complementary small molecule (Figure 5 and Table S1). This

Figure 5. Directing tacticity via monomer:small molecule complementary interactions. Reproduced with permission from ref 50.

approach was first demonstrated during the polymerization of N-(6-acetoamidopyridin-2-yl)acrylamide in the presence of a range of cyclic imides, yielding syndiotactic polymers. Simultaneous MW control was demonstrated by RAFT polymerization in the presence of the small molecule mediator.50 A nucleobase-mediated stereospecific radical polymerization has also been reported by the same group,51 further underlining the significant potential of nucleobase interactions in controlling primary chain structure. Utilizing the F

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Figure 6. Urea linkage combined with nucleobase analogue (methylcytosine) to give four H-bonding sites at polymer termini.53,55

Figure 7. Copying the chain length and polydispersity of living polymers into conjugated polymers. Reproduced with permission from ref 60.

Figure 8. Self-assembly of template block copolymers PSt-b-PVBT yields a stable monodisperse micellar system with poly(VBT) cores. Addition of complementary adenine monomer (VBA) and heating induces dynamic exchange of VBA loaded template unimers. Initiation and polymerization yield a stable (nondynamic) larger micelle containing high-MW, low-PDI poly(VBA) daughter polymer.61

containing phosphonium salt (Table S1) was observed to associate with adenine containing triblock copolymers

(described above) influencing surface morphology, solution viscosity, and mechanical properties. G

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thermosensitive materials with, for example, film and fiber forming properties.65 Another contribution in this area came from Binder et al.,69 who described supramolecular poly(ether ketone; PEK)− poly(isobutylene; PIB) pseudoblock copolymers in a report from 2004. Thymine or cytosine moieties were attached onto PIB chain ends and 2,6-diaminotriazine functionality onto PEK termini (Table S1), with the resultant mixtures analyzed in both liquid and solid states. Interestingly, nanophase structure was observed only in the system containing the higher binding constant (thymine/2,6-diaminotriazine) with no such structure observed in the lower binding cytosine/2,6-diaminotriazine system.69 The Zhu lab has recently reported a nucleobase-mediated supramolecular approach to amphiphilic block copolymers and their subsequent higher order assembly.70 Adenine-terminated poly(ε-caprolactone) and uracil-terminated poly(ethylene glycol) assembled in water on association of their complementary termini to form well-defined micelles capable of doxorubicin uptake. As expected, the supramolecular nucleobase association broke down in acidic conditions akin to those observed in tumors to release the drug cargo. Considering the supramolecular block copolymers were formed in water from only one nucleobase-mediated interaction, the well-defined, stable assemblies observed are somewhat unexpected in our opinion. It is worth noting that such an approach may not be generally applicable to all block copolymer pairs and/or may not represent a wholly stable assembly in the long term for ideal delivery applications (possible storage issues, etc.). Other interesting concepts involving synthetic supramolecular systems derived from lower molecular weight (small molecule) functionalized base pairs have also been reviewed by Sessler and Jayawickramarajah. 71 Numerous ideas and associated applications are discussed, including duplex small molecule systems, self-replication, receptors, and electron/ energy transfer.71 A final fundamental avenue of exploration going forward should also be highlighted herein, i.e., the interaction of synthetic nucleobase containing polymers with DNA and RNA and associated applications in gene targeting, assembly, etc. In this regard, peptide nucleic acids (PNAs) (Table S1), consisting of a peptide backbone and pendant nucleobase functionalities, have shown significant potential.72,73 PNAs exhibit extraordinary binding behavior with cDNA. In fact, PNA−DNA complexes have been observed to have stronger binding affinities than the corresponding DNA−DNA complex, with PNA binding to double-stranded DNA by strand displacement.72,73 The matching of such diverse backbones offers undoubted hope in tailoring vinyl and other wholly synthetic backbones toward comparable levels of affinity with DNA.

TOWARD BIOMIMICRY: TEMPLATE POLYMERIZATIONS Recently, the Sleiman lab focused on template polymerization, arguably the most fundamental, and synthetically rewarding, goal in the field of nucleobase containing polymers.60 This paper describes the templated Sonogashira coupling of an adenine containing monomer in the presence of a thymine containing block copolymer template prepared by ROMP (Figure 7).60 The chain length (DP ∼ 20) and polydispersity of the parent template were copied into the conjugated daughter polymer, representing one of few examples of conjugated polymers with controlled molecular weight distribution and perhaps the first example of a relatively well-controlled templated polymerization using a poly(nucleobase) template. The success of this synthesis represents a noteworthy breakthrough, underlining how accurate transfer of information can occur between a nucleobase containing synthetic template and daughter strand. Significantly, the polymerization mechanism used in this synthesis was a step-growth mechanism. It is conceivable that such mechanisms are better suited to template polymerization relative to alternative polymerization mechanisms containing active propagating species, i.e., chain-growth polymerizations. Another prominent feature of this templated polymerization is the relatively rigid nature of the template backbone, which may be crucial in attaining the fidelity of information transfer which was reported. It is apparent that Nature has perfected templating polymerizations through the alignment of nucleobase containing polymers (DNA, mRNA, tRNA) with segregation processes. Segregation is used to isolate reactive components in individual compartments, preventing deleterious interaction/ reaction with other species. We have recently combined nucleobase-mediated templating polymerization with selfassembly induced segregation to achieve unprecedented control over free-radical polymerizations to high MW (Figure 8).61 Polymerization of a nucleobase containing vinyl monomer (vinylbenzyladenine) in the presence of a low-MW complementary block copolymer template (poly(styrene-b-vinylbenzylthymine; PSt-b-PVBT; prepared via NMP) yields high MW (up to ∼400 000 g/mol) extremely narrow polydispersity (PDI ≤ 1.08) daughter polymer. Control is attained by segregation of propagating radicals in discrete micelle cores (via assembly of dynamic template polymers). Significantly reduced bimolecular termination, combined with controlled propagation along a defined number of templates, ensures unprecedented control to afford well-defined high-MW polymers.

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OTHER SUPRAMOLECULAR NUCLEOBASE CONTAINING SYSTEMS Prior to our concluding remarks, we now briefly summarize a few supramolecular nucleobase containing systems which are deemed somewhat beyond the primary scope of this article but nonetheless warrant discussion given their importance to the future directions of the field. Supramolecular polymerization using nucleobases,62 i.e., noncovalent linking of nucleobase containing monomers (polymers) to form high(er) molecular weight species, has received much attention of late. The Rowan lab has, in particular, made notable contributions,62−68 with one such example detailing the solid-state assembly of low molecular weight poly(tetrahydrofuran; THF) chains terminated in nucleobase derivatives (Table S1).63,65 A combination of weak hydrogen bonding and phase segregation yielded

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OUTLOOK Having summarized the extent and variety of advancements in controlled synthesis and self-assembly of nucleobase containing polymers, it is clear that this is an expanding field of considerable promise. We now reflect on some fundamental synthetic goals for the future using these and similar polymers. The authors' (and colleagues) recently reported results,61 for example, serve as a proof of concept in manipulating individual chains as they propagate; i.e., careful and exacting segregation from other propagating chains prevents bimolecular termination in radical polymerization. Such control over the propagation step in a chain growth polymerization promises H

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polymerizations proceed from one monomer to the next linearly along a template or randomly within a coiled template. Such mechanistic questions were considered in another paper from Saito et al., elegantly taking advantage of the considerable differences in reactivity of styrenes and methacrylates during ATRP.96 While research to date has overcome many obstacles in the field, it is clear that many opportunities remain for future exploration. The targets and considerations outlined above seek merely to initiate the intellectual process. In due course it is likely that polymer chemists will ask (and answer) even more complex questions concerning, for example, the basic level of synthetic polymer machinery necessary to construct a vinyl Holliday junction or a synthetic G-quadruplex, or the possibility of error correction in vinyl template polymerizations. Indeed, one must consider whether a synthetic ribosome (and its associated mechanisms) is a stereotypical, even clichéd goal of synthetic biologyshould we be broadening our pursuits? In conclusion, it is worth remembering that Nature, while inordinately complex, wonderful, and life-giving, is neither intelligent nor efficient. Evolutionary time scales were necessary to perfect current biological mechanisms through a process of trial and error. Conversely, while chemists do not operate in an evolutionary time scale, we have intelligence and an enormous range of chemistries relative to the comparatively small natural toolbox. We should play on these strengths to bypass evolutionary pitfalls and inefficiencies in designing the synthetic world of tomorrow.

benefits in more complex copolymerization strategies, possibly allowing access to sequence-controlled polymers74−85 and associated applications in controlled polymer folding and single chain manipulation,86−92 etc. While such targets are admittedly ambitious in the short term, it is likely they are attainable given the intense research interest in these areas. Fundamental studies in the laboratory might include an assessment of the minimum degree of sequence necessary for a particular application; i.e., is a single nucleobase:monomer interaction optimal for a templated polymerization (each monomer templated by one nucleobase on the template)? Perhaps seeking to further mimic Nature in designing artificial tRNA analogues that use anticodon:codon recognition (3 nucleobases per monomer unit) will ultimately allow access to a greater variety of orthogonal interactions and hence complexity of sequence. Other recognitive (nonhydrogen-bonding) functionalities may also have an important role to play. See, for example, the one-step (one-pot) orthogonal bifunctionalization of random copolymers using distinct hydrogen bonding (Table S1) and metal−ligand interactions which exhibit complete specificity.93 It is always worth considering whether native nucleobase interactions are optimal for a specific application or set of reaction conditions. It is evident from this Perspective that there are a variety of non-native functionalities in the chemistry toolbox which may allow for more favorable noncovalent interactions in certain cases. One such motif previously discussed herein is the UPy functionality pioneered by Meijer et al.55,56 Another recent contribution of note involves an interesting quadruple acceptor:donor (AAAA−DDDD) array (Table S1) from the Leigh lab which maximizes the strength of hydrogen bonding by placing all the acceptor sites on one molecule and the donor sites on the other.94 The net effect in this case is a bond greater than 20% the strength of a carbon− carbon covalent bond, which is remarkable for a supramolecular complex. Further to the design of the hydrogen-bonding interaction is the associated engineering of such functionality into the monomer/polymer structure. It is conceivable that the styrenic based vinylbenzyl nucleobases, for example, perform better in template polymerizations compared to more flexible methacrylic counterparts (due to possible secondary π−π interactions in the former). Closer study of the biological mechanisms of DNA and RNA inevitably raises further questions going forward. Nature uses site-specific proteins (initiation and termination factors) in protein biosynthesis to ensure defined initiation and termination events, concepts which should certainly be at the forefront of a chemists mind in designing synthetic mimics. An elegant solution from Saito et al. to non-site-specific initiation in a template-mediated polymerization involved the use of a dual functional initiator in the ATRP of methacrylate groups pendant along a vinyl backbone (multivinyl monomer; MVM). Dual initiation, and the associated bidirectional propagation, rendered the site of initiation immaterial.95 Further to initiation and termination processes, the mode of propagation also deserves serious consideration. We have discussed above whether a step-growth polymerization may be favored over a chain-growth mechanism. Another possibility for nucleobase-mediated templating might involve combining a step-growth mechanism with the robustness of a radical polymerization, a polymerization concept illustrated in recent notable work from the Kamigaito group.82 A related consideration to the mode of propagation is whether template

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ASSOCIATED CONTENT

S Supporting Information *

Table S1. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Notes

The authors declare no competing financial interest. Biographies

Ronan was born and raised in Donegal, Ireland. He obtained his B.Sc. (2004) and Ph.D (2007) from the National University of Ireland (Galway) having spent two semesters at Kobe University, Japan, in 2005/2006. His doctoral studies, conducted under the supervision of Dr. Fawaz Aldabbagh (Galway) and Profs. Bunichiro Yamada (Galway/Osaka), Per B. Zetterlund (Kobe), and Masayoshi Okubo (Kobe), centered on the use of addition−fragmentation chain transfer reactions in radical polymerizations and nitroxide-mediated heterogeneous polymerizations in supercritical carbon dioxide. After a year post-PhD working in industry, Ronan returned to academia as a I

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postdoctoral fellow in the group of Dr. Xiaosong Wang at the University of Leeds in early 2009 where he worked on the synthesis of novel coordination polymer nanostructures. Ronan joined the O’Reilly group at Warwick in June 2010 to work on nucleobase containing polymers.

Rachel O’Reilly is currently an EPSRC career acceleration fellow in the Chemistry Department at the University of Warwick. She graduated from the University of Cambridge in 1999 and went on to complete her PhD at Imperial College, London, in 2003. She then moved to the US under the joint direction of Professors Craig J. Hawker and Karen L. Wooley. In 2004 she was awarded a research fellowship from the Royal Commission for the Exhibition for 1851, and in 2005 she took up a Royal Society Dorothy Hodgkin Fellowship at the University of Cambridge. In 2009 she moved to her current position, and in 2012 she was promoted to full professor. Her research focuses on bridging the interface between creative synthetic, polymer, and catalysis chemistry to allow for the development of materials that are of significant importance in medical, materials, and nanoscience applications.

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