Single-Chain Polymer Self-Assembly Using Complementary Hydrogen Bonding Units

CommunicationMacromolecular

Rapid Communications

wileyonlinelibrary.com 1 DOI: 10.1002/marc.201300501

1 . Introduction

Polypeptides assume ordered conformations following a hierarchical assembly process. [ 1 ] At the secondary level of assembly, the two most prominent stable con-formations that polypeptides assume are α -helices and β -sheets. Polymer scientists have attempted to mimic these assembly processes using synthetic polymers to yield highly ordered architectures. [ 2–7 ] The exploitation of noncovalent interactions for these studies has provided a simple and reversible medium to tune material prop-erties such as tensile strength, permeability, and tem-perature resilience. [ 8 ] Research has focused primarily on polymers that fold into helical architectures, [ 9–13 ] with few reports on synthetic sheets. The realization of sheet-like structures remains elusive, owing to synthetic chal-lenges involved and also limitations in characterization techniques to assess the conformations achieved. Of the reported synthetic sheet-forming oligomers and polymers, most utilize β -amino acids or their synthetic analogues as building blocks to exploit their directional self-assembly to achieve well-defi ned structures. [ 14,15 ] There remains a need

to develop synthetic approaches to fold single-chain poly-mers derived from non-natural building blocks into sheet structures in order to approach a higher order of com-plexity (i.e., tertiary and quaternary structure) exhibited in natural systems.

Hydrogen bonding is the most exploited noncovalent interaction used for directed self-assembly. [ 16 ] There has been growing interest to engineer synthetic polymers with the propensity to fold into single-chain-ordered structures using well-known complementary hydrogen bonding motifs. [ 5,6,17 ] Barner-Kowollik and co-workers [ 6,18 ] and Meijer and co-workers [ 5,17 ] reported the utilization of two different orthogonally associating motifs (cyanuric acid/ N , N ′-bis[6-(alkanoylamino)pyridin-2-yl] isophthala-mide and thymine/diaminopyridine; self-association of 2-ureidopyrimidinone and benzene-1,3,5-tricarboxamide, respectively) to direct the single-chain folding of polymers into compact structures. These studies present signifi cant steps toward the development of synthetic single-chain polymers that assemble into well-ordered aggregates uti-lizing hydrogen bonding. They also introduce a toolbox of characterization techniques to provide evidence of the ordered assemblies obtained.

In an effort to fully comprehend the complex assembly of natural systems, the research described in this con-tribution aims to direct the intramolecular single-chain self-assembly of a triblock norbornene-based copolymer

A triblock copolymer containing the complementary hydrogen bonding recognition pair urei-doguanosine–diaminonaphthyridine (UG–DAN) as pendant functional groups is synthesized using ring-opening metathesis polymerization (ROMP). The norbornene-based DAN monomer is shown to allow for a controlled polymerization when polymerized in the presence of a modi-fi ed-UG molecule that serves as a protecting group, subsequently allowing for the fabrication of functionalized triblock copolymers. The self-assembly of the copolymers was characterized using dynamic light scattering and 1 H NMR spectroscopy. It is demonstrated that the polymers self-assemble via complemen-tary hydrogen bonding motifs even at low dilutions, indicating intramolecular interactions.

Single-Chain Polymer Self-Assembly Using Complementary Hydrogen Bonding Units

Joy Romulus , Marcus Weck *

J. Romulus, M. Weck Department of Chemistry and Molecular Design Institute , New York University , New York, NY 10003 , USA E-mail: [email protected]

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amidation of compound S12, [ 22 ] followed by coupling of the resulting product S13 to the functionalized norbornene S3 using standard EDC/DMAP conditions (see Supporting Information for complete synthetic procedures).

Monomers 1 and 2 were evaluated to determine if they polymerize in a controlled fashion. Polymerizations were carried out in varying solvents using Grubbs’ third-gen-eration initiator. Monomer 1 precipitated out of solution when polymerized in chloroform and would not allow for complete monomer conversion at a degree of polymeri-zation above 10, which we attributed to self-association. Monomer 1 also did not polymerize to completion in polar solvents such as DMF or DMSO. These solvents have been shown to coordinate to the ruthenium metal center, thereby poisoning the catalysts and reducing catalytic activity. [ 24 ] Monomer 2 did not polymerize at all, which we hypothesized to be due to the coordination of the lone pair electrons of the pyridine units to the metal center of the catalyst, diminishing catalyst activity.

To overcome the noncontrolled polymerization behavior of 1 and 2 and to be able to synthesize the desired triblock copolymers, we developed a protecting group strategy. [ 25 ] An acylated guanosine-derivative ( S14 ) was synthesized to serve as a receptor as well as a pro-tecting group to the recognition motifs of 2 , potentially circumventing the coordination of 2 to the ruthenium catalyst. We monitored the titration of the protecting group (2.0 equivalents) to 2 by 1 H NMR spectroscopy and observed the characteristic downfi eld shifts of the DAN amide protons from 8.93 to 11.45 ppm, and the downfi eld shifts of the UG–NH protons from 10.20 and 12.09 ppm to 11.50 and 13.58 ppm, respectively. [ 26 ] Excess of the pro-tecting group was added to ensure that the pyridine was fully protected. Upon addition of Grubbs’ third-genera-tion initiator, the polymerization of the protected 2 pro-ceeded to completion and the polymer remained in solu-tion (Scheme 1 ).

To test whether the protected 2 polymerized in a con-trolled fashion, a series of polymerizations were carried out with varying [M]:[I] (40:1, 60:1, 80:1, 100:1) using Grubbs’ third-generation initiator in chloroform [Note: M represents the equivalents of 2 only]. The controlled nature of the 2 - S14 complex was indicated by a linear relationship between M̄n and [M̄n ]:[I] (Figure 2 ).

The target sheet-type structure was envisaged to arise from the single-chain folding of a triblock copoly mer bearing complementary units on the two end blocks. The triblock copolymer was achieved by the copolymerization of 2 - S14 , norbornene octyl ester (NOE), and 1 . Since the polymerization of the 2 - S14 com-plex was demonstrated to be controlled, it was poly-merized fi rst, followed by NOE (previously shown to be living), [ 27 ] and fi nally 1 (Scheme 2 ) resulting in a soluble triblock copolymer. Removal of the protecting group

using hydrogen bonding. In particular, the ureidoguano-sine–diaminonaphthyridine (UG–DAN) recognition motif is utilized as complementary side-chain units. [ 19–21 ] The self-assembly of the triblock copolymers into single-chain-folded structures is evidenced by 1 H NMR spectros-copy and dynamic light scattering (DLS).

2 . Results and Discussion

We required a controlled polymerization technique to allow for the formation of block copolymers bearing pen-dant functional groups. The triblock copolymer synthe-sized in this study was designed that the A and C blocks contained complementary hydrogen bonding units on each repeat unit, while the middle block served as a fl ex-ible spacer, vide infra. The complementary supramolecular recognition motifs are based on a substituted UG–DAN motif. The UG–DAN complex has a high association con-stant K a ≈ 10 7 M −1 in halogenated solvents as well as low self-association constants ≤200 M −1 . [ 19 ] This is critical to allow for intramolecular aggregate formation, potentially single-chain sheet-formation, as opposed to an extended ladder-type assembly (Figure 1 left and right, respectively).

The synthetic routes used for the UG and DAN hydrogen bonding motifs were adapted from literature procedures. [ 19,22 ] The polymerizable group S3 was accessed by methylation of the acid of aminocapronic acid, fol-lowed by coupling to norbornene exo-acid [ 23 ] using standard EDC/DMAP (1- ethyl- 3- (3- dimethylaminopropyl)carbodiimide/4- dimethylaminopyridine)conditions, and fi nally deprotection with trifl uoroacetic acid. The guano-sine monomer 1 was synthesized by coupling compound S7 [ 19 ] to the polymerizable group S3 using standard DCC (N,N′- dicyclohexylcarbodiimide)/DMAP conditions. Simi-larly, the naphthyridine monomer 2 was accessed by

Figure 1. Schematic representation of potential self-assembled structures achieved from triblock copolymers functionalized with side-chain recognition units: (left) intramolecular association of a complementary recognition pair; (right) intermolecular associa-tion of recognition units.



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With the deprotected triblock copolymer in hand, the hydrogen bonding self-assembly was investigated. DLS is a powerful technique that provides size distributions of molecules suspended in solution. A concentration study (from 50 × 10 −3 M down to 1 × 10 −3 M ) was carried out to determine if it was possible to determine the concentra-tion at which the predominant structures in solution were single-chain self-folded polymers, i.e., no larger aggregates are visible. At concentrations of 50–30 × 10 −3 M , two signals were detected by DLS corresponding to 10.5 and 18.9 nm. From concentrations of 20–10 × 10 −3 M , only a single signal was detected corresponding to 0.5 nm. Below 10 × 10 −3 M , no aggregates were detected. This sug-gests that the polymer solutions at concentrations below

S14 was achieved by dialysis in DMSO. DMSO competes for the hydrogen bonding between the complemen-tary UG–DAN pair, thereby releasing the protecting group from the triblock copolymer. Figure S1 (Sup-porting Information) shows a partial 1 H NMR spectrum for the titration of S14 to 2 in DMSO-d 6 . The signals of the interacting protons on the small molecules remain at the same chemical shifts even up to 3.0 equivalents of S14 (Figure S1A, Supporting Information), contrary to the characteristic downfi eld shifting demonstrated in CHCl 3 (vide infra). [ 19,26 ] The 1 H NMR spectrum of the triblock copolymer following dialysis in DMSO shows the removal of the UG-protecting group (Figure S2, Sup-porting Information).

Scheme 1. A) Compounds 1 and 2 represent the side-chain-functionalized monomers used in this study. B) Polymerization scheme of guano-sine-protected 2 using Grubbs’ third-generation initiator.

Figure 2. Polymerization data for poly- 2 . a) Comparison between molecular weight and degree of polymerization; b) Polymer data of homopolymers of 2 . Molecular weights were calculated against poly(styrene) standards with DMF as eluant.




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The combined results of DLS and 1 H NMR spectros-copy strongly suggest that the triblock copolymers self-assemble via complementary side-chain hydrogen bonding motifs occur intramolecular and not intermo-lecular, and are consistent with previously reported single-chain-folding polymers characterized via similar techniques. [ 6,8,28– 31 ]

3 . Conclusions

This contribution describes the intramolecular self-assembly of a triblock copolymer using orthogonal hydrogen bonding motifs (UG–DAN) as side-chain recogni-tion units. The polymers were synthesized by ROMP of nor-bornenes. The DAN monomer was shown to polymerize in a controlled fashion when protected. This allowed for the synthesis of triblock copolymers containing the DAN as the fi rst block, NOE as the second block, and UG as the fi nal block. Self-assembly of the triblock copolymers was char-acterized using DLS and 1 H NMR spectroscopy. DLS data showed that the polymers did not form large aggregates at concentrations below 10 × 10 −3 M , suggesting single-chain self-assembly at lower concentrations. 1 H NMR spec-troscopy experiments showed that the hydrogen bonding

10 × 10 −3 M might comprise of smaller nondetectable assemblies.

The hydrogen bonding directed self-assembly of the block copolymer was further investigated by 1 H NMR spectroscopy within the concentration range that did not exhibit aggregation in the DLS (i.e., below 10 × 10 −3 M ). A concentration study of the triblock copolymer was car-ried out from 5 × 10 −3 M to 100 × 10 −6 M in chloroform to monitor if the characteristic downfi eld shifts of the pro-tons involved in the complementary hydrogen bonding can be detected. A signifi cant shift and broadening of the hydrogen bonding UG proton signals was observed even at concentrations of 100 × 10 −6 M (Figure 3 A). At this low concentration, interchain hydrogen bonding becomes less likely suggesting hydrogen bonding between com-plementary side-chain units on the same polymer chain. This is in close analogy to results reported by Barner-Kowollik and co-workers, [ 28 ] where α , ω -functional hydrogen donor/acceptor polymers (functionalized with cyanuric acid/Hamilton wedge, respectively) were shown to self-assemble via intramolecular interactions in dilute concentrations (<1 × 10 −3 M ). Furthermore, the signal shifts observed for the current system are in agreement with the signal shifts observed for the analogous hydrogen-bonded small molecule complex (Figure 3 B).

Scheme 2. Polymerization scheme for the formation of the protected triblock copolymer.



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complex formed even at dilute concentrations of 100 × 10 −6 M . The combined DLS and 1 H NMR spectroscopy data strongly indicate that single-chain folding was achieved. This study provides a rational, straightforward approach for the self-assembly of a single polymer chain, exploiting noncovalent interactions. The realization of reliable tech-niques to characterize sheet-type structures remains a challenge that, if overcome, can attract researchers to target these structures, thereby broadening the scope of current synthetic self-assembled polymers.

Supporting Information

Supporting Information is available from the Wiley Online Library or from the author.

Acknowledgements : Financial support has been provided by the National Science Foundation (CHE-1213743).

Received: June 30, 2013; Revised: July 20, 2013; Published online: ; DOI: 10.1002/marc.201300501

Figure 3. Partial 1 H NMR spectra in CDCl 3 representing the (A) triblock copolymer assembly (100 × 10 −6 M ), (B) assembly of 1 with three equivalents of 2 , (C) monomer 2 , and (D) monomer 1 . Dotted lines represent shifting of amide protons of UG 1 monomer.

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Keywords: hydrogen bonding ; intramolecular folding ; ROMP ; self-assembly

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Single-Chain Polymer Self-Assembly Using Complementary Hydrogen Bonding Units

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