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A rational strategy for the realization of chain-growth supramolecular polymerization

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Science  06 Feb 2015:
Vol. 347, Issue 6222, pp. 646-651
DOI: 10.1126/science.aaa4249

Popping open one by one into polymers

We rarely board airplanes by joining the back of a single well-ordered line. More often, we jostle around in one of several bulging crowds that merge haphazardly near the gate. Roughly speaking, these processes are analogous to the chain growth and step growth mechanisms of polymer assembly at the molecular level. Kang et al. present a strategy to link molecular building blocks through hydrogen bonding in accord with the well-controlled chain growth model. The molecules start out curled inward, as they engage in internal hydrogen bonding, until an initiator pulls one open; that molecule is then in the right conformation to pull a partner into the growing chain, poising it to pull in yet another, and so forth down the line.

Science, this issue p. 646

Abstract

Over the past decade, major progress in supramolecular polymerization has had a substantial effect on the design of functional soft materials. However, despite recent advances, most studies are still based on a preconceived notion that supramolecular polymerization follows a step-growth mechanism, which precludes control over chain length, sequence, and stereochemical structure. Here we report the realization of chain-growth polymerization by designing metastable monomers with a shape-promoted intramolecular hydrogen-bonding network. The monomers are conformationally restricted from spontaneous polymerization at ambient temperatures but begin to polymerize with characteristics typical of a living mechanism upon mixing with tailored initiators. The chain growth occurs stereoselectively and therefore enables optical resolution of a racemic monomer.

Since Staudinger experimentally proved the existence of covalent macromolecular chains in the late 1920s, after a long debate on the controversial concept of colloidal aggregates (1), numerous essential achievements in the field of polymer science have precipitated major innovations in everyday life (24). In the late 1980s, alongside substantial progress in the field of noncovalent chemistry (5, 6), research groups led by Lehn (79) and Meijer (10, 11) breathed life into the controversial concept of colloidal aggregates (1). These authors demonstrated that linear aggregates (i.e., supramolecular polymers) of small molecules that are tailored by complementary hydrogen-bonding (H-bonding) interactions are sufficiently stable, even in dilute solution, to behave like covalent linear polymers under appropriate conditions (10, 12). With a view to reduce the dynamic nature of supramolecular polymerization, Wang et al. reported in 2007 a strategy of using crystallizable monomers upon self-assembly and successfully obtained well-defined block copolymers (13). This achievement, together with some related works reported later (1416), indicated new possibilities of supramolecular polymerization in the context of precision macromolecular engineering. However, because of the preconceived notion that supramolecular polymerization follows a step-growth mechanism (Fig. 1A, upper), the prospect of realizing noncovalent chain-growth polymerization has received little attention until recently. Encouraging reports to this end used thermally cleaved supramolecular polymers as seeds for noncovalently polymerizing the associated monomers, where elongation of polymer chains with incubation time was observed by atomic force microscopy (AFM) and/or transmission electron microscopy (13, 14, 16). Nevertheless, even at this stage, no strategic rationale has been proposed for achieving chain-growth supramolecular polymerization (Fig. 1A, lower). In contrast with step-growth polymerization, chain-growth polymerization uses monomers that do not polymerize spontaneously without initiators (11, 17). In this context, we noticed that a particular compound in our separate work (18) serves as a metastable monomer that is temporarily disabled for spontaneous polymerization in the absence of initiators.

Fig. 1 A monomer-initiator system for supramolecular chain-growth polymerization.

(A) Schematic representations of step-growth (upper) and chain-growth (lower) polymerizations. In step-growth polymerization, propagation involves coupling of multiple combinations of monomers and oligomers of varying lengths. Chain-growth polymerization requires an initiator that reacts with a monomer to produce a dimer carrying a reactive terminus; subsequently, polymer chains grow exclusively by sequential monomer addition to these termini. The growth of a polymer occurs only at its reactive terminus with the monomer. (B) Chemical structures of C5-symmetric corannulene-based chiral initiators and monomers carrying amide-appended thioalkyl side chains and a schematic representation for the bowl-to-bowl corannulene inversion. The arc-shaped arrows represent tentative definitions of the clockwise and counterclockwise H → R substituent arrays along the corannulene periphery. (C) Schematic representations of the conformational and configurational aspects of the initiator and monomer families. The corannulene core of the monomer family adopts a cagelike closed conformation with a small activity for the bowl-to-bowl inversion due to an intramolecularly H-bonded amide network. By contrast, the initiator family adopts an open conformation with a large activity for the bowl-to-bowl inversion at the corannulene core because its side-chain amide groups are N-methylated and cannot form such an intramolecular, cyclic H-bonded network. (D) Schematic representation of the chain-growth supramolecular polymerization of monomer M initiated with I, where the chain growth is accompanied by the H-bond reorganization of M. The growing polymer carries an initiator unit at one end (the initiating end), whereas the other end [the growing (active) end] adopts a structure analogous to I, with free amide C=O groups. This structural feature prevents bimolecular coupling of the propagating ends.

Here we report the realization of chain-growth supramolecular polymerization involving defined initiation and propagation steps. Figure 1B illustrates the metastable monomers and tailored initiators used for the present study, all of which carry a corannulene core with five amide-appended thioalkyl side chains (1820). Although these corannulene derivatives are chiral because of their C5-symmetric nonplanar bowl shape, bowl-to-bowl inversion, leading to racemization, can occur thermally even at 25°C. Recently, we reported that compound M (Fig. 1B) adopts a cagelike closed conformation (Fig. 1C, right) in low-polarity media such as methylcyclohexane (MCHex), because the bowl-shaped core orients the side-chain amide units to facilitate their intramolecular H-bonding interactions (18). Consequently, unlike disk-shaped triphenylene analogs (11), monomer M does not self-assemble (polymerize) in solution. However, during the course of this study, we found that M spontaneously polymerizes into a one-dimensional polymeric assembly upon heating in MCHex. Unexpectedly, even without further heating, this polymer continued to grow when a fresh feed of M was provided.

From these observations, we hypothesized that M is metastable and temporarily restricted from spontaneously polymerizing but possesses the capacity to undergo chain-growth polymerization (Fig. 1A, lower). As highlighted in this paper, we discovered that compound I (Fig. 1B), an N-methylated derivative of M, can initiate the polymerization of M (Fig. 1D) in MCHex at 25°C. The polymerization proceeds with characteristics typical of a living process (17). Initiator I lacks the capacity for intramolecular H-bonding (Fig. 1C, left) and does not self-assemble but serves as a proton acceptor for H-bonding interactions.

As a typical example of the polymerization, 10 μl of a solution I (1.0 mM in MCHex) were added to 500 equivalents of M (5 ml of a 1.0 mM solution in MCHex), and the mixture was allowed to stand at 25°C for 6 hours, during which M gradually transformed into a supramolecular polymer with a small polydispersity index (PDI). As observed by dynamic light scattering (DLS), the average hydrodynamic diameter of the polymer increased continuously whenever a fresh feed of M was added to the system after a certain interval (Fig. 2A). Diffusion-ordered spectroscopy (DOSY) nuclear magnetic resonance (NMR) measurements in deuterated MCHex indicated that the diffusion coefficient (D) of the polymer decreases nonlinearly upon increment of the total monomer-to-initiator mole ratio ([M]total/[I]0) (Fig. 2B and fig. S10). According to a diffusion theory of polymers (21), a cube root of the molecular weight of a polymer is proportional to D−1 using M as a reference. As shown in Fig. 2B, the Dp values thus estimated are in good agreement with the ratios of [M]total/[I]0. Figure 2C exemplifies tapping-mode AFM images on silicon wafers of air-dried polymerization mixtures formed at [M]0/[I]0 = 1000 and 2000. Their height profiles (0.9 nm) confirm that the polymer molecules thus visualized are unimolecularly dispersed. In accord with the results of DLS and DOSY NMR measurements, the polymer chains formed at [M]0/[I]0 = 2000 (Fig. 2C, bottom) are clearly longer than those at [M]0/[I]0 = 1000 (Fig. 2C, top). As shown by the histogram in Fig. 2D, the contour lengths of polymers formed at [M]total/[I]0 = 250, 500, 1000, and 2000 were successfully evaluated by measuring the lengths of 100 randomly selected polymer chains at individual [M]total/[I]0 ratios (fig. S11). We confirmed that their average chain lengths are proportional to the ratios of [M]total/[I]0 employed (Fig. 2D, inset). Because the overall noncovalent interaction, operative in a single polymer chain, is rather strong (see below), the polymerization can be traced by size-exclusion chromatography (SEC) on a polystyrene gel column under optimized conditions at 4°C using MCHex/CHCl3 (1/1 v/v) as an eluent. Figure 2E shows that, as the [M]total/[I]0 ratio increased, the elution peak of the produced polymer, though exhibiting a little broadening, shifted stepwise toward a region of higher molecular weight (22). The average Dp values of the polymers formed at individual stages, as estimated using polystyrene standards for calibration, scaled linearly over a wide range with [M]total/[I]0 (Fig. 2F, circles). Equally important, the PDI values of the polymers were all determined to lie in a range of 1.2 to 1.3 (Fig. 2F, squares), which is much smaller than that of a polymer formed upon heating without initiator I (fig. S12).

Fig. 2 Multistage chain-growth supramolecular polymerization of monomer M with initiator I in MCHex at 25°C.

Reactions were conducted by stepwise addition of fresh feeds of M, after a certain interval, to a 10 μl initiator solution ([I]0 = 1.0 mM) at varying [M]total/[I]0 ratios. (A) DLS profiles in MCHex at 25°C of polymers formed at [M]total/[I]0 = 50 (green), 250 (orange), 500 (pink), and 1000 (red). The vertical dashed line represents the peak-top position of M. a.u., arbitrary units. (B) Plots of the diffusion coefficients D of polymers formed at [M]total/[I]0 = 50 (green), 250 (orange), 500 (pink), and 1000 (red), evaluated with DOSY NMR in deuterated MCHex at 20°C, and their degrees of polymerization Dp theoretically calculated using the D value of M as a reference. (C) Tapping-mode AFM images on a silicon substrate with height profiles of air-dried polymers formed at [M]total/[I]0 = 1000 and 2000. (D) AFM-based histogram of the counter lengths of randomly selected 100-polymer chains formed at [M]total/[I]0 = 250 (orange), 500 (pink), 1000 (red), and 2000 (blue). (Inset) Average polymer chain lengths (Ln). (E) SEC traces of polymers formed at [M]total/[I]0 = 50 (green), 250 (orange), 500 (pink), and 1000 (red), monitored using an UV detector at 290 nm. The vertical dashed line represents the peak-top position of M. (F) Plots of the Dp and PDI versus [M]total/[I]0, as estimated from the SEC-UV traces using polystyrene standards for calibration.

We posit that the monomer units in the polymer chain are intermolecularly H-bonded at their side-chain amide groups. Infrared spectroscopy (fig. S13) demonstrates that the polymerization is accompanied by a shift of an H-bonded amide C=O vibration from 1650 to 1642 cm–1. Simultaneously, the amide NH groups that are H-bonded to C=O shifted from 3331 to 3326 cm–1. Thus, the H-bonds formed intermolecularly in the polymer chain are more robust than those oriented intramolecularly in the monomer state. As expected from the non–self-assembling behavior of I (the N-methylated derivative of M) in MCHex, corannulene derivatives without H-bonding side-chain motifs hardly stack, even in the solid state (23). Considering also that the electronic absorption spectrum of the polymer is substantially the same as that of M (fig. S14), the van der Waals contributions, including a π-electronic interaction, between the constituent monomer units are rather weak in this solvent (11). MCHex is an excellent solvent for the supramolecular polymerization of M. In this low-polarity medium, the H-bonds in the polymer chain are stable at ambient temperatures and, even upon 10-fold dilution ([M] = 0.1 mM), the polymer obtained upon initiation by I did not exhibit any substantial change in its SEC profile (fig. S15). However, when the MCHex solution was annealed at 100°C for 1 hour, the polymer underwent quick depolymerization. As expected, the heated mixture underwent repolymerization when it was allowed to cool to 25°C. In this case, particularly when the cooling rate was as small as 1.0°C min–1, the elution profile of the resultant mixture in SEC became more complicated than that before the thermal treatment (fig. S16), indicating that the polymerization of M with I is driven kinetically and is pathway-dependent (16, 24). In sharp contrast, in polar media (including moderately polar CHCl3, in which H-bonding interactions are destabilized), the polymer, once formed in MCHex, dissociated within a few minutes, even without heating (fig. S17). Accordingly, M did not polymerize.

The extraordinary stability of the polymer in MCHex is essential for achieving the living character of polymerization. Equally important to consider is an end-capped structure of the polymer. As described, initiator I was derived from M by N-methylation of the side-chain amide groups (Fig. 1B). Owing to the initiation mechanism illustrated in Fig. 1D, the produced polymer should be end-capped with initiator I at the initiating end. This capped initiating end lacks the capacity for H-bonding interactions because the C=O groups at its N-methylated amide units are H-bonded with the amide NHs of its neighboring monomer unit. Hence, this capped end neither interacts with incoming M nor recombines with the other polymer terminus, although bimolecular recombination often occurs in conventional supramolecular polymerization and enlarges the PDI (22). To support the importance of this end-capped structure, we cleaved the polymer chain using sonication in MCHex to generate terminally uncapped, short polymer chains (fig. S18, A and B) and then allowed the resultant mixture to stand at 25°C. SEC showed that these short polymer chains recombined spontaneously (fig. S18C), whereas no recombination took place when initiator I, capable of end-capping, was immediately added to the sonicated mixture at [I]/[M]total = 1/5 (fig. S18, D and E). Therefore, we conclude that our design strategy for chain-growth supramolecular polymerization operates as intended.

We next explored the possibility of stereoselective polymerization using chiral initiators (25). Unlike M, compounds MR and MS, together with their respective N-methylated derivatives IR and IS (Fig. 1B), carry chiral side chains, and each chain has a stereogenic center in proximity to the H-bonding amide unit. We found that MR and MS polymerize in a precise stereoselective manner using IR and IS, respectively, as chiral initiators (Fig. 3A and figs. S19 to S21). For example, when IR was added at 25°C to a MCHex solution of MR at [MR]0/[IR]0 = 500, MR polymerized in the same way as M, thereby yielding a polymer with a small PDI in 6 hours (Fig. 3B, i). In stark contrast, the opposite enantiomer MS did not polymerize with IR (Fig. 3B, ii), even with a prolonged reaction time, whereas it polymerized readily upon mixing with initiator IS (fig. S22). Namely, the polymerization occurs only when the stereogenic centers of the monomer and initiator in their chiral side chains are matched in configuration. Such precise enantioselection of chiral monomers MR and MS indicates a large energetic penalty for stereochemical mismatching in the polymer sequence (26).

Fig. 3 Stereoselective chain growth polymerization of chiral monomers.

(A) Schematic representation of the stereoselective chain-growth supramolecular polymerization of monomers MR and MS with initiators IR and IS (Fig. 1B), respectively, where the monomers and initiators both carry chiral side chains. The polymerization proceeds only when the absolute configurations of their side-chain stereogenic centers are identical to one another. (B) SEC-UV traces at 290 nm of the supramolecular polymerization of MR (i) and MS (ii) using IR as the initiator at the initial monomer-to-initiator mole ratio of 500 in MCHex at 25°C for 6 hours. (C) Schematic representation of the optical resolution of racemic monomer Mrac by stereoselective polymerization initiated with IR. (D) SEC-UV and SEC-CD traces at 290 nm of Mrac (i) and its polymerized mixture initiated with IR at [Mrac]0/[IR]0 = 500 in MCHex at 25°C for 6 hours (ii). The flow rate of the eluent for SEC was set at 0.5 ml min–1 except for the case of Fig. 3D, for which the flow rate was 0.2 ml min–1 (23).

In relation to the stereoselective nature of polymerization described above, we also investigated the polymerization of M using chiral initiators IR and IS (Fig. 4A). As described previously, monomer M, identical to MR and MS, carries an asymmetric center at the C5-symmetric corannulene core, but it is devoid of chiral side chains and therefore exists as a racemic mixture (Fig. 1B). The main interest here is whether IR and IS can differentiate the enantiomeric forms of M in the polymerization (25, 27). Thus, a solution of a mixture of M and IR and at [M]0/[IR]0 = 500 in MCHex ([M] = 1.0 mM) was incubated at 25°C, wherein M was completely consumed in 6 hours, as observed by SEC, to yield a polymer in a manner analogous to the case of using I as the initiator. As expected, the results were the same when IS was used as the initiator instead of IR under conditions otherwise identical to those described above. In a SEC trace monitored with a circular dichroism (CD) detector at 290 nm (SEC-CD) (Fig. 4B), the resultant polymers exhibited positive (red) and negative (blue) chiroptical responses when IR and IS were used as the initiators, respectively. As shown in Fig. 4C (right), the vibrational circular dichroism (VCD) spectroscopy displayed a positive or negative band at ~1000 cm–1 due to the corannulene skeleton of polymeric M. Figure 4D shows that the polymers are also CD-active, displaying mirror image spectra of one another. Furthermore, the CD spectra intensified with time monotonically at the initial stage and then fell off gradually to reach a plateau in 5 hours. Although the time to reach such a plateau region became shorter when [M]0/[IR]0 was reduced from 500 to 250 and then 50, at a constant [M]0 of 1.0 mM the CD intensities finally attained were substantially the same as one another (Fig. 4E). Note that the CD spectral pattern is almost identical to that of monomeric MR or MS (fig. S23). Together with the VCD spectral profile in Fig. 4C (right), the CD spectra in Fig. 4D most likely reflect the genuine chiroptical feature of the corannulene skeleton rather than of the intermolecular exciton couples (28). By applying the molar ellipticity of the enantiomerically pure C5-symmetric corannulene skeleton (18), the enantiomeric excess of M in the polymer chain was estimated as close to 100% in MCHex at 25°C (tables S2 and S3).

Fig. 4 Characterization of homochiral polymers from conformationally flexible monomers with achiral side chains.

(A) Schematic representation of the stereospecific chain-growth supramolecular polymerization of monomer M using initiators IR and IS carrying chiral side chains (Fig. 1B), where right- and left-handed helical polymers formed with IR and IS, respectively. (B and C) SEC-CD traces (290 nm) of the polymerized mixtures of M using IR and IS at the initial monomer-to-initiator mole ratio of 500 in MCHex at 25°C for 6 hours (B) and their vibrational circular dichroism (VCD; upper) and infrared (IR; lower) spectra (C). The vertical dashed line in (B) represents the peak-top position of M in its SEC-CD trace. Abs, absorption. (D) CD spectra of polymerized mixtures at [M]0/[IR]0 = 500 ([M]0 = 1.0 mM) in MCHex at 25°C in 0 (black), 1 (blue), 2 (light blue), 3 (green), 4 (orange), and 5 (red) hours. The dashed curve represents the CD spectrum of a polymerized mixture of M using IS under conditions otherwise identical to those described above. (E) Plots of molar ellipticity at 290 nm ([θ]290) against incubation time in the polymerization of M with IR at [M]0/[IR]0 = 50 (red), 250 (orange), and 500 (green) ([M]0 = 1.0 mM) in MCHex at 25°C.

In accord with the posited mechanism in Fig. 1D, initiator IR or IS attaches to the initiating end of polymeric M and serves as a chiral auxiliary to stereochemically bias the polymerization (Fig. 4A). How does this chiral auxiliary at a polymer terminus enable such strong geometrical control over the entire polymer chain? In relation to this question, we noticed that not only the corannulene skeleton but also the H-bonded amide C=O at 1642 cm–1 is VCD-active (Fig. 4C, left), thus indicating that the polymer adopts either a clockwise or counterclockwise helical geometry (Fig. 4A) (29). This helical structure is stabilized by the intermolecular H-bonded amide network. Hence, no racemization resulted when the polymer chain end-capped with IR or IS was cleaved by sonication to transform into uncapped, short polymer chains (fig. S24). We consider that this highly stable helical geometry most likely accounts for the near 100% stereochemical bias of the C5-symmetric corannulene core of M in the polymer chain. After observing the notable stereoselectivity of the polymerization in Fig. 3A, we were motivated to investigate whether Mrac, a racemic mixture of MR and MS, could be optically resolved by the polymerization using IR or IS as the initiator (Fig. 3C). Thus, IR was added at 25°C to a solution of Mrac (1.0 mM) in MCHex at [Mrac]0/[IR]0 = 500, where in 6 hours the SEC–ultraviolet (UV) profile demonstrated the appearance of a polymeric fraction along with the monomer (Fig. 3D, ii, red). By means of SEC-CD, the polymeric fraction was revealed to possess a positive CD sign at 290 nm, whereas the unassembled monomer fraction possessed a negative CD sign (Fig. 3D, ii, blue). Even upon prolonged reaction for 14 days, the residual monomer observed in 6 hours remained without further consumption (fig. S25A).

For the purpose of quantitatively analyzing the SEC-CD profile in Fig. 3D, we prepared two reference samples, a MCHex solution of nonpolymerized MS ([MS] = 0.5 mM) and its polymerized version using IR as the initiator at [MR]0/[IR]0 = 250 ([MS] = 0.5 mM). As shown in fig. S25B, the SEC-CD (ii, blue) and SEC-UV (ii, red) traces in Fig. 3D were perfectly reproduced when the corresponding SEC traces of the above reference samples were superimposed. We thus succeeded in optically resolving MS and MR, using initiator IR to polymerize only MR and vice versa stereoselectively, thus leaving MS or MR unpolymerized (Fig. 3C). This notable stereochemical selection results from the homochiral nature of the polymer with respect to both the chiral side chains and stacked corannulene units. So far, some chiral monomers are known to self-assemble only homochirally. However, this process yields a racemic mixture of right- and left-hand helical polymers (26) because the conventional mechanism does not allow for selection of one enantiomer of the monomer for polymerization. Even for thoroughly studied covalent chain-growth polymerizations, such a high level of optical resolution has been rarely reported (30).

In differential scanning calorimetry (DSC), M unavoidably polymerizes during the heating process. Upon first heating in DSC (fig. S26, blue), monomeric M exhibited an exotherm (20 J g–1) at 82°C and an endotherm at 175°C (27 J g–1). By reference to the DSC profile of polymeric M separately prepared (endothermic peak at 177°C, 27 J g–1) (fig. S26, red), the exotherm and endotherm in fig. S26 (blue) are assigned to the thermal polymerization of M and dissociation of the resulting polymer, respectively. These DSC profiles corroborate the H-bond stability of M, as suggested by comparing its infrared spectrum with that of polymeric M. Although the exotherm in the DSC trace indicates that the polymerization is enthalpically driven, the monomer M does not spontaneously polymerize without initiator I at ambient temperatures because M is metastable with a sufficiently large energetic barrier for the self-opening of its intramolecularly H-bonded cage. We presume that the chain growth proceeds through an H-bond–assisted transition state (Fig. 1D), where M is preorganized with the growing end of the polymer as well as initiator I (both having free amide C=O groups) and transforms its H-bonding mode from intramolecular to intermolecular. This transition state is energetically less demanding than the self-cleavage of the H-bonded amide network in the monomer state. Although the concave structure of the monomer is critical for the present work, further conceptual diversification of metastable monomers for chain-growth supramolecular polymerization may give rise to a paradigm shift in precision macromolecular engineering.

Supplementary Materials

www.sciencemag.org/content/347/6222/646/suppl/DC1

Materials and Methods

Supplementary Text

Figs. S1 to S27

Tables S1 to S3

References (3134)

References and Notes

  1. Acknowledgments: This work was financially supported by a Grant-in-Aid for Specially Promoted Research (25000005) on “Physically Perturbed Assembly for Tailoring High-Performance Soft Materials with Controlled Macroscopic Structural Anisotropy” for T.A and a Grant-in-Aid for Research Activity Startup (25888024) for D.M.
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