Helicity Inversion of Supramolecular Hydrogels Induced by Achiral

Nov 15, 2017 - Probing the supramolecular chirality of assemblies and controlling their handedness are closely related to the origin of chirality at t...
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Helicity Inversion of Supramolecular Hydrogels Induced by Achiral Substituents Guofeng Liu, Xin Li, Jianhui Sheng, Pei-Zhou Li, Wee Kong Ong, Soo Zeng Fiona Phua, Hans Ågren, Liangliang Zhu, and Yanli Zhao ACS Nano, Just Accepted Manuscript • DOI: 10.1021/acsnano.7b06097 • Publication Date (Web): 15 Nov 2017 Downloaded from http://pubs.acs.org on November 16, 2017

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Helicity Inversion of Supramolecular Hydrogels Induced by Achiral Substituents Guofeng Liu,†,# Xin Li,‡,# Jianhui Sheng,†,§ Pei-Zhou Li,† Wee Kong Ong,† Soo Zeng Fiona Phua,† Hans Ågren,‡ Liangliang Zhu,§ and Yanli Zhao*,†,ǁ †

Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, 637371, Singapore ‡

Division of Theoretical Chemistry and Biology, School of Biotechnology, KTH Royal Institute of Technology, SE10691 Stockholm, Sweden § State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai 200433, P.R. China ǁ School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, 639798, Singapore ABSTRACT: Probing the supramolecular chirality of assemblies and controlling their handedness are closely related to the origin of chirality at supramolecular level and the development of smart materials with desired handedness. However, it remains unclear how achiral residues covalently bonded to chiral amino acids can function in the chirality inversion of supramolecular assemblies. Herein, we report macroscopic chirality and dynamic manipulation of chiroptical activity of hydrogels self-assembled from phenylalanine derivatives, together with the inversion of their handedness achieved solely by exchanging achiral substituents between oligo(ethylene glycol) and carboxylic acid groups. This helicity inversion is mainly induced by distinct stacking mode of the self-assembled building blocks, as collectively confirmed by scanning electron microscopy, circular dichroism, crystallography and molecular dynamic calculations. Through this straightforward approach, we were able to invert the handedness of helical assemblies by merely exchanging achiral substituents at the terminal of chiral gelators. This work not only presents a feasible strategy to achieve the handedness inversion of helical nanostructures for better understanding of chiral self-assembly process in supramolecular chemistry, but also facilities the development of smart materials with controllable handedness in materials science. KEYWORDS: achiral substituent, helicity inversion, hydrogel, self-assembly, supramolecular chirality

The helical chirality of nanoscale architectures in polymer and supramolecular self-assembly systems is important not only for better understanding the role of chirality in medical and biological environments,1-4 but also for extending their applications in areas of chiral recognition,5-7 chiroptical switches,8,9 asymmetric 10,11 catalysis, and optoelectronics.12-17 To date, numerous right-handed and left-handed helical assemblies have been obtained by molecular self-assembly of either chiral or achiral small molecular building blocks, which are usually indispensable with the participation of chiral components.18-22 However, understanding how achiral factors or guests affect the chirality of supramolecular coassemblies is still under its early stage of study.23 In addition, the underlying mechanism and factors determining the twisting tendency and handedness development from molecular scale to supramolecular level and above have not yet been well understood. Moreover, it remains a high challenge to control the helical sense or even invert the macroscopic chirality of nanostructures triggered by achiral factors during the

Scheme 1. Schematic illustration for the chirality inversion of helical assemblies obtained between D/LPF and D/LPFEG as well as D/LCHF and D/LCHFEG.

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Figure 1. CD and corresponding UV absorption spectra of hydrogels of (a) D/LPF, (b) D/LPFEG, (e) D/LCHF, and (f) D/LCHFEG obtained by using a 0.1 mm path length of quartz cuvette with a gelator concentration of 2.0 mg/mL. CD spectra of (c) D/LPF (0.02 mg/mL), (d) D/LPFEG (0.02 mg/mL), (g) D/LCHF (0.05 mg/mL), and (h) D/LCHFEG (0.05 mg/mL) in molecularly aqueous solution obtained by using a 10 mm path length of quartz cuvette.

self-assembly process,7,8,24 although many chirality inversion of supramolecular aggregates have been successfully achieved by changing the chiral structures of amphiphiles,25,26 tuning the sequence of nucleic acids or amino acids,27 and applying an external stimulus such as pH,28 light,29-31 temperature,32-34 solvent,35-40 and metal coordination.41-43 Thus, it is urgently in demand to explore the chirality transfer and handedness inversion of selfassemblies triggered by achiral factors to deepen the understanding of helicity inversion of supramolecular assemblies and the chirality transformation from molecular scale to supramolecular level in self-assembly systems. Inspired by appealing chirality features of supramolecular gels where the assemblies are collectively driven by various noncovalent interactions44,45 and the helical handedness of assemblies could be finely controlled, herein, we present an interesting chirality inversion of hydrogels self-assembled from phenylalanine based gelators before (DPF, LPF, DCHF, and LCHF) and after (DPFEG, LPFEG, DCHFEG, and LCHFEG) modifications with achiral oligo(ethylene glycol) groups. D represents the gelators obtained from D-phenylalanine derivatives, while L stands for gelators originated from Lphenylalanine derivatives. As shown in Scheme 1, the introduction of achiral oligo(ethylene glycol) groups can trigger apparent chirality inversion of helical nanostructures by either altering achiral substituents or changing absolute configuration of phenylalanine residues in both 1,4-phenyldicarboxamide (short as P) and 1,4-cyclohexanedicarboxamide (short as CH) based hydrogel systems. To the best of our knowledge, this is a very rare example of the chirality inversion of supramolecular self-assemblies triggered by achiral substituents covalently bonded to phenylalanine acid based hydrogelators.46

D/LPF and D/LCHF centered with 1,4phenyldicarboxamide bear two L/D-helicogenic phenylalanine motifs and achiral COOH at each terminus of the phenylalanine arms. D/LPFEG and D/LCHFEG were synthesized through the esterification of D/LPF and D/LCHF with achiral diglycol respectively, according to previously reported procedures.4,47,48 All the synthesized compounds were fully characterized by 1H and 13C NMR spectra as well as high-resolution mass spectrometry (Figures S1-S6). All of them can form self-supportive and homogeneous hydrogels by heating-to-cooling and inversion tests in vials (Figure S7). Circular dichroism (CD) spectra of these hydrogels were first measured at room temperature. As shown in Figure 1a, the CD spectrum of DPF hydrogel displayed an apparently negative dichroic signal at 237 nm and a strong positive CD peak at 268 nm corresponding to the absorption region of 225-300 nm. As compared with the molecular CD spectra (Figure 1c) of DPF and LPF in dilute aqueous solution, both DPF and LPF showed strong signals with positive and negative Cotton effects at 299 nm respectively, i.e., at the absorption region of the aromatic unit, indicating the formation of helical superstructures with preferred handedness. Interestingly, the CD spectrum of DPFEG hydrogel showed a positive Cotton effect at 227 nm and a negative Cotton effect at 268 nm (Figure 1b), which revealed distinctly inverted helicity with respect to the one in DPF hydrogel. Thus, an apparent helix inversion occurred between DPF hydrogel and DPFEG hydrogel, although they possess the same helicogenic R-phenylalanine residue. Similarly, the CD spectrum of LPFEG hydrogel presented a strong negative Cotton effect at 227 nm and a positive CD signal at 268 nm, which was opposite to the case of LPF (positive maximum at 237 nm and negative minimum at 268 nm), indicating that the helical sense of the assemblies in LPF hydrogel switched to opposite handedness in LPFEG hydrogel. The contribution of linear dichroism (LD) on

RESULTS AND DISSCUSSION 2

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ACS Nano compared with DCHF hydrogel, a perfect mirror-imaged CD curve was observed from LCHF hydrogel. By contrast, the CD spectrum of DCHFEG hydrogel showed positive, negative, and negative Cotton effects at around 194 nm, 202 nm, and 250 nm, respectively (Figure 1f ). Opposite to positive CD signals of DCHF above 225 nm, DCHFEG hydrogel showed well-define negative Cotton effects. These observations indicate that supramolecular chirality inversion also occurs between DCHF and DCHFEG hydrogels, which is similar to the helicity inversion observed in 1,4-phenyldicarboxamide based hydrogel systems. In addition, the supramolecular chirality inversion of gels was further confirmed by the molecular CD measurements of DCHF and DCHFEG (Figure 1g,h), both of which showed negative Cotton effects at around 198 nm and 214 nm. The chirality inversion effect of the CD signals induced by achiral substituents could also be found between hydrogels of LCHF and LCHFEG. Thus, intriguing chirality inversion indeed occurs between the hydrogels assembled from gelators having carboxylic acid and oligo(ethylene glycol) units with the same chirality of the phenylalanine residue. Considering that the only difference between DPF and DPFEG as well as LPF and LPFEG is the achiral terminal substituents of carboxylic acid and oligo(ethylene glycol) units (similarly in CH based gel system), it is reasonably inferred that the helicity inversion of these hydrogels is induced by the alteration of achiral substituents in gelators.

the CD signals of all the four hydrogels was also studied. The intensity of LD signals (Figure S8) was obviously lower than that of corresponding CD signals, indicating that the LD contribution could be negligible in these hydrogels. To correlate the CD spectra between hydrogel and solution phases, all of the samples (D/LPF, D/LPFEG) were subjected to molecular CD measurements in their dilute aqueous solutions with the gelator concentration of 0.02 mg mL-1. For the CD spectrum of DPF molecule in aqueous solution, negative, positive, and positive Cotton effects were observed at 218 nm, 235 nm, and 258 nm, respectively (Figure 1c). Consistent with our expectation, the CD spectrum of DPFEG molecule in aqueous solution was very similar to the CD spectrum of DPF, in which a negative Cotton effect occurred at 217 nm and two positive Cotton effects appeared at 235 nm and 252 nm (Figure 1d). This observation means that there was almost no obvious difference of molecular chirality in CD spectra between DPFEG and DPF, since the alteration between carboxylic acid and ester group did not induce observable changes of the UV absorption (both of them showed the same UV absorption peak around 250 nm with similar intensity). Similarly, the CD spectrum of LPFEG molecule in aqueous solution displayed positive, negative, and negative Cotton effects at 217 nm, 235 nm, and 252 nm respectively, which is also analogous with molecular CD signals of LPF as illustrated in Figure 1c. There are obvious differences of the CD signals between hydrogel and solution phases. Taking DPFEG as an example (Figure 1b,d), the CD spectrum of DPFEG molecule in dilute aqueous solution (0.02 mg mL-1) displayed negative, positive, and positive Cotton effects at 217 nm, 235 nm, and 252 nm respectively, while the CD spectrum of DPFEG hydrogel (2.0 mg mL-1) exhibited shifted positive and negative Cotton effects at 227 nm and 268 nm, respectively. Meanwhile, the CD signal intensity of the hydrogel is almost 100 times higher than corresponding molecular signal intensity in the region of 220-300 nm. By contrast, the molecular CD spectrum of DPF in aqueous solution showing negative, positive, and positive Cotton effects at 218 nm, 235 nm, and 258 nm is similar to the CD spectrum of DPF hydrogel displaying negative and positive dichroic signals at around 237 nm and 268 nm, except for an obvious difference in the signal intensity. These observations suggest that the chiroptical activity of monomers ended with carboxylic acid and oligo(ethylene glycol)ester groups is almost identical in molecular CD spectra when they possess the same chiral phenylalanine residue. However, after the gelation, the CD spectrum of DPFEG presented changes in both the intensity and property of the Cotton effects. To study if this interesting substituent effect is also applicable to other systems, hydrogels self-assembled from DCHF, LCHF, DCHFEG, and LCHFEG centered with the 1,4-cyclohexanedicarboxamide unit were also investigated in detail. As shown in Figure 1e, the CD spectrum of DCHF hydrogel displayed negative, negative, and positive Cotton effects at around 199 nm, 216 nm, and 235 nm respectively, related to the UV absorption region of 190-250 nm. As

Figure 2. SEM images of helical fibers obtained from xerogels. (a) Left-handed (M) helical nanofibers of DPF with a pitch of ~100 nm (inset). (b) Right-handed (P) helical nanofibers assembled from LPF with a pitch of ~85 nm (inset). (c) P helical nanofibers assembled from DPFEG with a pitch of ~450 nm (inset). (d) M helical nanofibers assembled from LPFEG with a pitch of ~500 nm (inset).

To visualize the chirality inversion of helical assemblies, scanning electron microscopy (SEM) experiments of the xerogels (Figure 2 and Figures S9-S16) were conducted. The images showed the formation of micrometer-long helical fibers with highly uniform diameters from these hydrogels. As shown in Figure 2a, nanofibers from the DPF gel revealed exclusively left-handed (M-type) twist with a diameter of 36±1 nm and a helical pitch around 100 nm. By contrast, the LPF gel organized into uniformly right-

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The helical inversion of chiral nanostructures was also found in the xerogels self-assembled from DCHF, LCHF, DCHFEG, and LCHFEG with 1,4-cyclohexane center. As shown in Figure S13, the left-handed nanoribbons were observed in DCHF with widths varying between 30 and 45 nm and the pitch in the range of 110-130 nm, whereas helical nanoribbons from LCHF displayed completely opposite handedness (Figure S14) but with nearly the same width and pitch with respected to DCHF. To our delight, the handedness of assemblies in DCHF is the same as the one in DPF. More interestingly, right-handed helical nanofibers were observed from SEM images of DCHFEG hydrogel (Figure S15), showing opposite handedness of helical nanostructures to DCHF. By contrast, LCHFEG presented left-handed helical nanofibers with a width at around 50 nm and a helical pitch around 55 nm as depicted in Figure S16.

handed (P-type) twist with a diameter of 36±1 nm and a helical pitch of approximately 85 nm (Figure 2b). Interestingly, nanofibers with width of 60–70 nm and pitch of 450–500 nm obtained from DPFEG and LPFEG displayed exclusively right-handed and left-handed twists respectively, showing opposite handedness to corresponding chiral nanostructures in DPF and LPF, respectively (See more detailed morphologies of helical nanofibers in Figures S9-S12). For peptides and amino acid derivatives, the chirality of constituent amino acids is widely regarded as a key factor controlling the handedness of their supramolecular organizations. According to previous reports,17 specific one-dimensional nanofibers self-assembled from L-phenylalanine derived gelators normally show left-handedness. Specially, LPF exhibited exclusively right-handed nanofibers with uniform diameter and helical pitch, whereas DPF revealed exclusively left-handed nanofibers. More interestingly, apparently opposite handedness of helical assemblies was observed between DPF and DPFEG hydrogels, although their gelators possess the same R-type chiral center of phenylalanine residue. This helicity inversion was in good correlation with the chirality inversion of chiroptical activity observed in the CD spectra of hydrogels. It should be pointed out that the width and helical pitch of nanofibers between DPF and DPFEG are not the same, since these two gelators are not exactly enantiomers.

The results discussed above indicate how slight changes in the molecular structure of building blocks could obviously influence overall supramolecular chirality of corresponding aggregates in hydrogel systems. The chirality of aggregates presented here is not only controlled by the absolute configuration of the phenylalanine residue, but also influenced by the achiral substituents covalently bonded at each terminus of gelator structures. These factors collectively play vital roles in guiding these gelators to organize into single- handed helical assemblies and show unexpected chirality

Figure 3. Temperature-dependent CD spectra of (a) DPF, (b) LPF, (c) DPFEG, and (d) LPFEG samples obtained by using a 1 mm path length of quartz cuvette with a gelator concentration of 0.4 mg/mL in aqueous solution.

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inversion. Due to the same R-type phenylalanine stereocenter within DPF and DPFEG, it was reasonably anticipated that the achiral peripheral groups of oligo(ethylene glycol) and carboxylic acid are indispensable for the chirality inversion of self-assemblies between D/LPF and D/LPFEG. To obtain further insight into the helical inversion of hydrogels by the alteration of achiral peripheral groups, dynamic CD spectra of these samples were recorded with the concentration of gelators at 0.4 mg mL-1 in a quartz cuvette with a path length of 1 mm. Since gelators with low concentration can be completely dissolved in water, their CD signals are mainly attributed to the monomeric chirality. For solutions of gelators with higher concentration, gelators could self-assemble into dimers, unidirectional assemblies, or even helical nanofibers, which might present supramolecular chirality of helical assemblies with the chirality amplification.49 The conversion between gelators (monomers) and gels (nanofibers) as well as the chirality transition between monomeric chirality and supramolecular helicity are illustrated in Scheme 2. Two chiral monomers (m) could aggregate into a dimer (M2) via intermolecular noncovalent interactions, subsequently organize into supramolecular assemblies (Mn), and finally assemble into helical nanofibers displaying the supramolecular chirality. In addition, the heating run for DPFEG in water (0.5 mg mL-1) was carried out to obtain a plot of the fraction of aggregates (αagg) against temperature (Figure S17), where the heating curves (0.5 K min-1) could be fitted with a nucleation-elongation model proposed by van der Schoot, Schenning and Meijer,50,51 and the elongation temperature (Te) and the enthalpy corresponding to the aggregation process (ΔHe) were calculated to be 337.1 K and –96.7 kJ mol-1, respectively. The associationdissociation process of a chiral self-assembly is reversible, since the main driving forces are intermolecular noncovalent interactions (mainly constituted with hydrogen bonding interaction here). Thus, the chirality transformation of gel-to-sol could be controlled dynamically by finely tuning the environmental temperature.

in spectral range of achiral aromatic moieties, indicating the formation of helical superstructures with a preferred handedness. Upon heating, the CD signal at 296 nm with the positive maximum gradually decreased up to 70 °C, and completely disappeared upon further heating. The phenomenon demonstrates that the main driving force of helical supramolecular assembly is intermolecular hydrogen bonding interaction. The CD spectrum of DPF sample at 20 °C is similar to the CD spectrum of DPF hydrogel shown in Figure 1a. Both of CD curves displayed negative CD signs around 227 nm and positive CD signs at 260 nm. It should be noted that the signal intensity presents some differences, since the concentration of the gelator and the path length of measurement cells were different. Interestingly, the Cotton effect bands of DPF sample at 90 °C revealed obvious blue shifts to 218 nm and 258 nm respectively, which are similar to those observed from molecularly dissolved DPF aqueous solution in Figure 1c. It should be mentioned that the CD spectrum of DPF sample at 90 °C still differs a little from that in Figure 1c, because some dimers or fine assemblies may remain after the dissociation of most helical superstructures upon heating. This fact was further supported by the spectroscopic investigation shown in Figure 3a, where the negative Cotton effect of DPF sample at 227 nm at 90 °C still red-shifted with respect to the negative CD signal of molecular DPF at 218 nm shown in Figure 1c. For DPFEG sample shown in Figure 3c, the CD intensity at around 225 nm and 266 nm weakened gradually upon heating from 20 to 70 °C. The maximum wavelength was blue-shifted, and the maximum intensity of the CD signal was decreased, indicating the gel-to-sol transition. Interestingly, the CD signal at 266 nm with the negative minimum decreased up to 50 °C and completely reversed to a positive Cotton effect of molecular CD signal upon further heating (Figures 3b and S18), which clearly revealed the chirality transformation from the supramolecular level into molecular scale accompanied with the chirality inversion. The chirality inversion was also supported by the transformation of the CD signal at 212 nm from a positive sign to negative minimum upon heating (Figure 3c). As compared with the mere decrease of the CD intensity in DPF sample, the chirality inversion during the gel-to-sol process in DPFEG sample fully demonstrates supramolecular helicity inversion between DPFEG and DPF hydrogels as illustrated in Figure 1a,b. Similarly, the CD signals of LPF at approximately 230 nm, 260 nm, and 296 nm dropped dramatically upon heating to 70 °C (Figures 3b and S18a), whereas for LPFEG sample, not only the intensity of Cotton effects at 228 nm and 270 nm decreased gradually as the temperature increase, but also the chirality inversion occurred upon heating to 65 °C (Figures 3d and S18b). Thus, the molecular chirality could be transferred into the helicity of assemblies at supramolecular level accompanied by the chirality amplification during the self-assembly process. In addition, the observed chirality in CD spectra is the collective results of monomers, dimers, assemblies and helical fibers, which can be

Scheme 2. Schematic representation for the associationdissociation process of a chiral self-assembly. m represents monomer, n represents the number of monomers, and Mn represents assemblies aggregated by n monomers.

As presented in Figure 3a, the CD spectrum of DPF sample at 20 °C showed the induction of a positive Cotton effect at higher wavelengths (around 260 nm and 296 nm)

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reversibly regulated by tuning the system temperature due to the formation and destruction of hydrogen bonding interaction. Based on the results discussed above, it was concluded that the intriguing chirality inversion of these assemblies could be undoubtedly attributed to the achiral substituents of carboxylic acid and oligo(ethylene glycol). The chiroptical activity and handedness inversions of helical assemblies might be due to the stacking propensity of gelators induced by these achiral substituents. To explore the underlying mechanism of the helix inversion and better understand the molecular arrangement of self-assembly, single crystals of DPF and LPF were grown in tetrahydrofuran/para-xylene/H2O (3:5:0.1, v/v/v) solution at room temperature (Figure S19). As shown in Figure 4a, there are two water molecules, one para-xylene molecule, and one LPF molecule in each unit cell of LPF single crystal. The crystal structure and packing diagram of LPF suggest that the main driving forces for the self-assembly are four types of intermolecular hydrogen bonding interactions according to the structural parameters (Figure 4b-d, and Table S1). The crystal structure of LPF exhibited that each two adjacent central phenyl rings of LPF molecules were perpendicular to each other (Figure S20a), and the two terminal phenyl groups were arranged in a trans fashion as phenyl group in LPF was nearly parallel to an adjacent para-xylene molecule with the smallest intermolecular

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distance of about 3.9 Å and was simultaneously close to another adjacent para-xylene molecule with a dihedral angle of 60° (Figure 4b). Along the a-c plane, every two of adjacent LPF molecules contacted with two water molecules via multiple hydrogen bond interactions (Figure 4c). The detailed information of these multiple hydrogen bonds is as follows: each oxygen atom of water molecule formed two hydrogen bonds with one hydrogen atom from the amide group of an adjacent LPF molecule (N-H···O-H, bond length: 2.975–2.997 Å, Table S1) and with another hydrogen atom from the carboxylic group of the other neighboring LPF molecule (CO-O-H···O-H, bond length: 2.605–2.613 Å, Table S1). The intermolecular hydrogen bonds show antiparallel conformation along the b axis (Figure 4b). In addition, two other kinds of intermolecular hydrogen bonding formed between hydrogen atoms of a water molecule and an oxygen atom of the amide group on one side of LPF molecule (HNC=O···H-O-H, bond length: 2.683–2.696 Å) as well as an oxygen atom of the carboxylic group (O=C-OH) on the other side of the same LPF molecule (HO-C=O···H-O-H, bond length: 2.708–2.710 Å, Table S1). These four types of multiple intermolecular hydrogen bonds are the main driving forces to stabilize the single crystal framework of LPF (Figures 4b and S21), which enable the stacking of LPF molecules to form right-handed helix (Figure S20b). Similarly, the crystal structure of DPF was depicted in Figure 4c, which showed a similar unit cell of single

Figure 4. Single-crystal structures of (a) LPF and (c) DPF obtained from a mixture solution of tetrahydrofuran/para-xylene/H2O (v/v/v, 3:5:0.1), and corresponding packing structures of (b) LPF and (d) DPF stabilized by intermolecular hydrogen bonds (black dashed lines) in the single crystal state.

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ACS Nano are perpendicular to each other and simultaneously linked by two water molecules via multiple hydrogen bonds. However, we didn’t obtain the single crystals of DPFEG and LPFEG, probably due to the flexible nature of oligo(ethylene glycol) groups located at the periphery. To further corroborate the chirality inversion triggered by achiral substituents, the general Amber force field (GAFF) was employed to simulate and optimize the dimer structures of LPF and LPFEG. The dimer structure of LPF was extracted from its crystal structure. For LPFEG dimer, the structure was generated according to a report in literature.23 Here, we focused our investigation only on the properties of LPF and LPFEG, because of experimental mirror-imaged CD spectra between LPF and DPF, as well as DPFEG and LPFEG. The optimized structures of LPF and LPFEG dimers are shown in Figure 5a,b, respectively. In the LPF dimer, the central phenyl rings are nearly perpendicular to each other, and the peripheral phenyl rings are in a “trans” arrangement. While in the LPFEG dimer, the two central phenyl rings are almost parallel to each other via a fully overlapped packing arrangement, and the two phenyl rings are in “cis” positions (Figure 5b). This structural difference may be attributed to their different side chains. In the LPF dimer, multiple hydrogen

crystal with respect to LPF. The packing diagram of DPF was also stabilized by four kinds of intermolecular hydrogen bonds (N-H···O–H, bond length: 3.055–3.058 Å; CO–O–H···O–H, bond length: 2.619–2.627 Å; HN– C=O···H–O–H, bond length: 2.721–2.726 Å; HO–C=O···H– O–H, bond length: 2.718–2.728 Å, Figures 4d, S22 and S23, and Table S2), which revealed a left-handed packing mode along the b axis in the single crystal state (Figure S22b). Furthermore, the self-assembly mechanism of LPF was investigated in both xerogel and single crystal states by using wide angle X-ray diffraction (WAXD). Analogous WAXD patterns with peaks at 6.6°, 14.6°, 16.0°, 18.4°, 20.4°, 21.4°, 23.0°, and 26.8° were obtained from single crystal and xerogel states of LPF, although the intensity of signals in xerogel was lower than that of single crystal (Figure S24a). Therefore, a similar stacking mode was assumed for LPF in xerogel and single crystal states, which was mainly driven by intermolecular hydrogen bonding interactions. Since DPF and LPF are enantiomers, the crystal structure and packing diagram of DPF are almost the same as that of LPF (Figure S24b). Thus, exclusively right-handed helical assembly in LPF should be resulted from special stacking mode of LPF molecules, where they

Figure 5. Optimized structures of dimers of (a) LPF and (b) LPFEG. Both side view and top view are shown. Black dashed lines represent intermolecular hydrogen bonding formed from the self-assembly of LPF and LPFEG gelators. TDDFT calculated CD spectra of (c) LPF and (d) LPFEG dimers.

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these experimental and computational results that the inversion of helical chirality in hydrogels is exclusively induced by the exchange of achiral substituents between carboxylic acid and oligo(ethylene glycol) groups.

bonding interactions are formed between O=C of carboxylic acid and H-N of amide groups. In the case of LPFEG, more hydrogen bonds are formed between side chains and peripheral phenyl rings, forcing them to stay in the “cis” arrangement. The hydrogen bonding interaction also leads to different twisting angles between the central phenyl rings, which are around 90° for the LPF dimer and 60° for the LPFEG dimer. In turn, molecules of LPF or LPFEG stack on top of each other with mutual rotation in a unidirectional mode to form helical fibers. Moreover, time-dependent density functional theory (TDDFT) results suggested that such structural difference results in opposite signals in their CD spectra (Figure 5c,d). To gain insight into the electronic excitations occurred in the dimer systems, the participating molecular orbitals were plotted in Tables S3 and S4. In the LPF dimer, the CD signals are mainly contributed by the S2 and S10 states, which correspond to HOMO-2–›LUMO and HOMO-2–›LUMO+1 transitions, respectively. As shown in Table S3, the LUMO and LUMO+1 orbitals of the LPF dimer show significant mixing between the two monomers, and exhibit opposite twisting patterns. The LUMO of LPF dimer, which is lower in energy, shows lefthand twisting, while the LUMO+1 presents right-hand twisting. This different twisting leads to a pair of negative/positive CD signals from longer wavelength to shorter wavelength, which is consistent with the experimental CD spectrum of LPF hydrogel shown in Figure 1a. Differently in the LPFEG dimer, the most significant CD signals are contributed by the S6 and S8 states, corresponding to HOMO-1–›LUMO and HOMO-1– ›LUMO+1, respectively (Table S4). In contrast to that in the LPF dimer, the LUMO and LUMO+1 of the LPFEG dimer show right-hand and left-hand twisting respectively, leading to a pair of positive/negative CD signals from longer wavelength to shorter wavelength. To our delight, the simulated results are in a good agreement with the experimental results of LPFEG hydrogel shown in Figure 1b. Thus, the calculations fully support experimentally observed helical inversion. What’s more, the calculations also illustrate how distinct CD signals of the assembled structures are arisen from a small change in the twisting angle of the central phenyl rings. Since both LPF and LPFEG possess the same S-type stereocenter within the L-configuration of phenylalanine units, distinctly opposite CD signals between dimers of LPF and LPFEG indicate that their supramolecular selfassembly could lead to the formation of helical aggregates with opposite handedness. According to our experimental results, LPF can assemble into right-handed helical nanofibers, while LPFEG aggregates into left-handed ones. Thus, the intriguing chirality inversion of these helical nanostructures was successfully achieved by the self-assembly of phenylalanine-based gelators with the same molecular chirality, indicating that the supramolecular chirality of helical nanostructures is not only controlled by the absolute configuration of phenylalanine residues, but also highly influenced by peripherally achiral substituents. It was concluded from

CONCLUSIONS In conclusion, the helix inversion of assemblies based on phenylalanine derivatives has been successfully achieved by altering the peripherally achiral groups. The chiral inversion is mainly attributed to the stacking mode of the self-assembled building blocks exclusively triggered by achiral substituents of carboxylic acid and oligo(ethylene glycol), as collectively confirmed by electron microscopy, optical spectroscopy, crystallography and computational calculations. This study discloses a straightforward approach through the self-assembly of small molecule-based hydrogelators into helical nano-assemblies together with helical inversion of their handedness, and provides a compelling selfassembly mechanism for the development of helical nanostructures with desirable chirality. Having the generality of this approach demonstrated for both 1,4phenyl- and 1,4-cyclohexane-centered building blocks, it is expected that this approach could be applicable to various building blocks for constructing chiral nanostructures with desired helical topologies. Further investigations using this strategy to design chiral materials would not only bring insights into better understanding of chiral assembly processes in supramolecular chemistry, but also be in favor of applying these chiral materials in the fields of asymmetric catalysis and chiroptical switches.

EXPERIMENTAL DCHF: 1,4-Cyclohexanedicarboxylic acid (1.73 g, 10.00 mmol) was added to dry dichloromethane containing thionyl chloride (20 mL). The reaction mixture was stirred at 100 °C for 4 h. The solvent was evaporated under vacuum, and the residue liquid was collected to give 1,4cyclohexanedicarbonyl dichloride. 1,4Cyclohexanedicarbonyl dichloride (2.0 g, 9.66 mmol) in dry dichloromethane (100 mL) was added dropwise to a dichloromethane solution (100 mL) containing Dphenylalaninemethyl ester hydrochloride (5.0 g, 23.18 mmol) and trimethylamine (3.6 mL, 26.00 mmol) in an ice-water bath. After finishing the addition, the solution was stirred at room temperature overnight. The solvent was evaporated under vacuum, and the residue was subsequently dissolved in dichloromethane (100 mL). After washing with water, the organic phase was dried by anhydrous MgSO4. The organic solvent was removed to give the dimethyl ester of DCHF. For the hydrolysis, aqueous NaOH (10 mL, 2.0 M) was added to a cooled suspension of dimethyl ester having DCHF (5.43 g, 6.14 mmol) in MeOH (20 mL). The mixture was gradually heated to room temperature and stirred for 24 h. A clear solution was then obtained. The solution was acidified with 3.0 M HCl until the pH value was less than 3.0, and gel-like precipitate was formed. The gel phase was

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filtered, washed with deionized water, and finally dried in a vacuum oven to afford DCHF (2.8 g, 6.0 mmol, 64.4%). 1 H NMR (300 MHz, DMSO-d6, ppm): δ = 12.62 (s, 2H, COOH), 8.03 (d, 2H, CONH), 7.22 (m, 10H, Ar-H), 4.40 (s, 2H, CH), 3.05 (m, 2H, CH2), 2.84 (m, 2H, CH2), 2.06 (s, 2H, CH), 1.59 (d, 4H, CH2), 1.19 (d, 4H, CH2). 13C NMR (75 MHz, DMSO-d6, ppm): δ = 178.52, 175.30, 138.28, 129.57, 128.52, 126.77, 53.57, 43.34, 37.16, 28.50-28.66. EI-MS for C26H30O6N2 calcd 466.2104; found 467.2163 [M + H]+. DCHFEG: DCHF in diglycol (60 mL) was added to concentrated HCl (0.5 mL). The mixture was stirred at 130 °C for 3.5 h, and the achieved clear solution was poured into a water/ice mixture (300 mL). The gel-like precipitate was collected on a filter, washed with water, and dried in a vacuum oven to afford DCHFEG (2.6 g, 4.0 mmol, 66%). 1 H NMR (300 MHz, DMSO-d6, ppm): δ = 1.17-1.25 (m, 4H, CH2), 1.52-1.68 (m, 4H, CH2), 2.06 (m, 2H, CH), 2.85-2.93 (m, 4H, CH2), 3.42-3.49 (m, 12H, CH2), 4.12-4.44 (m, 4H, CH2), 4.43-4.44 (m, 4H, CH2), 7.20-7.27 (m, 10H, Ar-H), 8.17-8.20 (d, J = 8.0 Hz, 2H, CO-NH). 13C NMR (75 MHz, DMSO-d6, ppm): δ = 175.51, 172.18, 137.82, 128.46-129.62, 126.93, 72.77, 68.59, 64.33, 60.65, 53.77, 43.27, 37.06, 28.54. EI-MS for C34H46O10N2 calcd. 642.3152; found 643.3216 [M+H]+. LCHFEG: By using a similar procedure abovementioned, LCHFEG was obtained as a white solid (2.8 g, 4.3 mmol, 72%). 1H NMR (300 MHz, DMSO-d6, ppm): δ = 1.14-1.20 (m, 4H, CH2), 1.52-1.69 (m, 4H, CH2), 2.07 (m, 2H, CH), 2.85-2.93 (m, 4H, CH2), 3.43-3.48 (m, 12H, CH2), 4.13-4.14 (m, 4H, CH2), 4.43-4.44 (m, 4H, CH2), 7.20-7.27 (m, 10H, Ar-H), 8.16-8.19 (d, J = 8.0 Hz, 2H, CO-NH). 13C NMR (75 MHz, DMSO-d6, ppm): δ = 174.63, 171.31, 136.93, 128.68, 127.75, 126.06, 71.90, 67.72, 63.45, 59.78, 52.89, 42.40, 36.20, 27.67. EI-MS for C34H46O10N2 calcd. 642.3152; found 643.3254 [M+H]+. Hydrogel preparation: The DCHFEG hydrogel formed from 0.2 wt. % DCHFEG was employed as an example to describe the preparation procedure. DCHFEG (2.0 mg mL1 ) was suspended in a septum-capped 4.0 mL glass vial and heated until a homogeneous solution was obtained. The solution was solidified into a hydrogel after standing for an hour at room temperature.

ACKNOWLEDGMENT This research is supported by the Singapore Academic Research Fund (RG112/15, RG19/16, and RG121/16), and partially supported by the National Natural Science Foundation of China (21628401).

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ASSOCIATED CONTENT Supporting Information Experimental procedures, characterization spectra, CD and LD spectra, SEM images, crystal structures, PXRD, and computational details. This material is available free of charge via the Internet at http://pubs.acs.org. #

These authors contributed equally to this work. The authors declare no competing financial interests.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

ORCID Yanli Zhao: 0000-0002-9231-8360 Guofeng Liu: 0000-0003-1911-8546

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