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. 2025 Jun 26;41(26):17269–17275. doi: 10.1021/acs.langmuir.5c02116

Structural Effects of Peptide-Type Amines on Ambidextrous Gelation Properties and Their Application to Chiral Recognition

Koichi Kodama 1,*, Toya Hasegawa 1, Yuri Furukawa 1, Masato Obata 1, Shohei Ito 1, Takuji Hirose 1
PMCID: PMC12257581  PMID: 40571287

Abstract

Amino acid-based low-molecular-weight gelators (LMWGs) attract considerable attention for the construction of supramolecular gels with controlled properties. Although most LMWGs behave as either organogelators or hydrogelators, several ambidextrous LMWGs have been reported. However, the factors determining this ambidextrous nature are unclear. Considering that structural differences between LMWGs affect their molecular assembly and gelation ability, analogues of chiral peptide-type amines were developed as LMWGs in this study to investigate the structural effects on their ambidextrous gelation properties. LMWGs with longer spacers behaved as only organogelators and lost their ambidextrous nature. Although the different structures of amide bonds (NHCO or CONH) decreased the ambidextrous nature, replacing one amide group with a urea moiety improved the ambidextrous gelation ability owing to the formation of stronger hydrogen bonds. The self-assembled structures of the gelators were examined, and the relationship between the structure and the gelation ability was elucidated. Finally, the application of the supramolecular gel derived from the LMWGs to the chiral recognition of a carboxylic acid was demonstrated.

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Introduction

Gels are an important class of soft materials with application in the fields of food, lubricants, drug delivery, catalysis, and environmental purification. Owing to their soft and stimuli-responsive properties, gels have recently attracted attention as a platform for visual chiral recognition. − Gels are commonly constructed by immobilizing solvent molecules within nanoscale fibrous networks of gelators. In supramolecular gels, the fibrous network is built up via the self-assembly of low-molecular-weight gelators (LMWGs) through noncovalent interactions such as hydrogen bonds and π–π interactions. , Because the properties of supramolecular gels can be controlled by the molecular design of LMWGs, the development of LMWGs is an active research field.

Amino acids have often been applied to design LMWGs because their carboxy and amino groups can be easily derivatized to other hydrogen-bonding functional groups such as amide, ester, and urea groups with hydrophobic long alkyl chains, which are often necessary to immobilize solvent molecules. − Although naturally derived α-amino acids have been used, relatively fewer LMWGs derived from β-amino acids have been reported despite of their structural diversity. − trans-2-Aminocyclohexanecarboxylic acid (ACHC) is a chiral β-amino acid that has been applied to develop helical β-peptides due to its restricted cyclic conformation. , We previously reported peptide-type LMWGs derived from ACHC. Modification of the amino group of ACHC with a long alkanoyl group afforded a carboxylic-acid-type LMWG that was suitable for the gelation of aromatic organic solvents. The resultant chiral supramolecular gel was applied to the visible chiral recognition of several amine enantiomers. When the carboxy group of ACHC was condensed with β-alanine and alkylamine to form amide bonds, the resultant amine-type LMWG (AB-n) also gelated organic solvents and was successfully applied to the enantiomer separation of racemic naproxen, a pharmaceutical carboxylic acid.

During this study, we found that AB-n was an ambidextrous gelator; that is, it showed gelation ability not only for less polar organic solvents but also for highly polar water. Such a versatile gelator can be advantageous for tuning the gel properties by changing the solvents including the mixed solvents. Because the polarity of the LMWG molecule commonly determines the solvents that can be gelated, most LMWGs behave as either an organogelator or a hydrogelator. Although several ambidextrous LMWGs have been reported, the factors determining this ambidextrous nature are still not fully understood. ,

Considering that subtle structural differences between LMWGs affect their molecular assembly and gelation ability, we synthesized, in this study, analogues of AB-n and investigated the structural effects of the peptide-type amines on their ambidextrous gelation properties. Furthermore, we applied the supramolecular gels derived from these LMWGs to the visual chiral recognition of a carboxylic acid.

Experimental Section

General Methods

All reagents and solvents were purchased and used as received. Enantiopure ACHC was synthesized according to a previously reported procedure in the form of hydrochloride salt. 1H and 13C NMR spectra were recorded using Bruker 300, 400, or 500 MHz NMR spectrometers. IR spectra were recorded in reciprocal centimeters. Melting points were measured using a Mitamura Riken Kogyo MEL-TEMP apparatus and reported uncorrected. MALDI-TOF mass spectra were recorded by using a Bruker Autoflex III mass spectrometer. Powder X-ray diffraction (XRD) analyses were performed using a Bruker D8 ADVANCE ECO instrument with Cu Kα radiation. Scanning electron microscopy (SEM) images were obtained with a HITACHI S-2400 microscope using xerogel samples coated with a Pt/Pd thin layer. Optical rotation values were measured with a JASCO DIP-370 or P-2100 polarimeter.

Examination of the Gelation Ability

A small amount of gelator (∼3 mg) was dissolved in the appropriate solvent by heating. In the case that insoluble solid remained, it was denoted as “I” (insoluble). If the solid was dissolved, then the solution was allowed to stand at room temperature. If a precipitate was formed, it was denoted as “P” (precipitate). Gelation was confirmed by performing a flow in the tube inversion test. If the solution was completely dropped, it was denoted as “S” (soluble); if a drop was not observed, it was denoted as “G” (gel). Upon gel formation, the above procedure was repeated with the addition of a solvent until no gelation was observed to determine the lowest concentration of the gelator required to afford a gel, which was defined as the minimum gelation concentration (MGC, g/L).

Single-Crystal XRD Analysis

Single crystals of AA-16 suitable for XRD analysis were obtained via recrystallization from its acetonitrile solution. XRD data were collected on a Bruker D8 Quest ECO diffractometer using graphite monochromate Mo Kα radiation at 150 K. The crystallographic information was deposited in the Cambridge Structural Database (CCDC 2434907).

Results and Discussion

Effect of the Spacer Length between Two Amide Groups on the Gelation Ability

In general, the construction of fibrous structures from gelators is essential for the immobilization of solvent molecules and efficient gel formation. In the case of AB-n, the two amide moieties must form a one-dimensional (1D) supramolecular assembly via hydrogen bond formation. First, the effect of the length of the spacer between the two amide moieties in the AB-n gelators was investigated.

Gelators AA-16, AG-16, and AD-16 were synthesized by condensing N-protected enantiopure ACHC with the corresponding hexadecyl amide of linear α-, γ-, and δ-amino acids followed by deprotection (Scheme S1). The gelation ability of these compounds for selected solvents with different polarities was examined, and the results are summarized in Table . Compound AA-16 with a shorter alkyl spacer than AB-16 showed gelation ability only for less polar organic solvents, i.e., toluene and CCl4, with much higher MGC values. Conversely, AG-16 and AD-16 containing longer alkyl spacers showed higher gelation ability than did AB-16 for those less polar organic solvents. They could gelate not only less polar solvents but also polar organic solvents such as acetone and ethyl acetate (AcOEt). In particular, the MGC value of AD-16 for toluene was as low as 1.1 g/L. However, all of these gelators lost the gelation ability for water, with only AB-16 with a two-carbon spacer showing an ambidextrous nature.

1. Gelation Ability of AB-16 and Its Analogues AA-16, AG-16, and AD-16 with a Different Spacer and Boc-AB-16 for the Solvents with Their Corresponding Melting Points ,

graphic file with name la5c02116_0008.jpg

  AA-16 AB-16 AG-16 AD-16 Boc-AB-16
Mp (°C) 139–141 136–138 123–126 139–142 197–200
H2O P G (6.7) P P I
MeOH S S S S G (32)
acetone P P G (18) G (12) I
AcOEt P P P G (3.3) I
CHCl3 S S S S G (33)
toluene G (21) G (3.2) G (4.8) G (1.1) G (3.7)
CCl4 G (78) G (14) G (1.7) G (1.5) G (4.8)
hexane P I P P I
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a

G: gel, P: precipitate, S: soluble, I: insoluble.

b

Values in the parentheses indicate minimum gelation concentration (g/L). The results of AB-16 were reported previously.

The powder XRD patterns of the xerogels prepared from toluene gels are shown in Figure . The diffraction peaks of AG-16, AD-16, and AB-16 were weak, which suggests the low crystalline nature of these gelators. The ratio of the d-spacing values of the peaks observed for these three gelators was close to 1:1/2, which indicated their lamellar molecular packing. Although the primary d-spacing values of AG-16 and AD-16 were similar (∼22 Å), that of AB-16 was longer (∼30 Å) in spite of its shorter alkyl spacer. This indicates that the molecular conformation and packing of AG-16 and AD-16 are different from those of AB-16, which can explain the loss of the ambidextrous gelation nature of the former two gelators. In contrast, sharp diffraction peaks were observed for the xerogel of AA-16, indicating its crystalline nature. Although AA-16 was expected to be more hydrophilic than AB-16, it produced precipitates from its water solution. In addition, the melting point of AA-16 was higher than that of AB-16 despite its lower molecular weight. These results suggest the presence of stronger intermolecular interactions in AA-16.

1.

1

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Powder X-ray diffraction patterns of the xerogels AA-16, AB-16, AG-16, and AD-16 prepared from their toluene gels.

To investigate the detailed molecular assembly of AA-16 in the solid state, XRD analysis was performed on crystals of AA-16 obtained from its acetonitrile solution. As shown in Figure a, the AA-16 molecules are linked to each other via one hydrogen bond between the amide groups of ACHC to give a 1D assembly along the a axis. This is in contrast to the previously reported 1D hydrogen-bonding network of AB-4, in which the two amide groups participate in the hydrogen bonding. The AA-16 molecule is bent at the glycine moiety to give an L-shaped molecular conformation. Such a bent structure is stabilized by an intramolecular hydrogen bond between the amino nitrogen and N–H on the hexadecyl amide group. The terminal NH of the amino group is involved in an intermolecular hydrogen bond with the oxygen atom of CO on the hexadecyl amide group to combine neighboring 1D networks, affording a layer-like hydrogen-bonding network along the ab plane (Figure b). This intramolecular hydrogen bond occurs more likely owing to the shorter alkyl spacer of AA-16. Moreover, the less stable 1D network can be invoked to explain its low gelation ability. The XRD pattern simulated from these crystallographic data was consistent with that of the xerogel shown in Figure , with the slightly shorter d-spacing values being attributable to the lower temperature of the crystallographic measurement (Figure S1).

2.

2

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Crystal structure of AA-16 (a) viewed along the a axis and (b) viewed from the a axis. Oxygen and nitrogen atoms are represented with red and blue balls. The dotted lines show hydrogen bonds. Hydrogen atoms are omitted for clarity in (b).

To confirm the influence of the terminal primary amino group of AB-16 on its ambidextrous property, the gelation ability of its Boc-AB-16 precursor was examined (Table ). The amino group of AB-16 was protected as a carbamate in Boc-AB-16. As expected, Boc-AB-16 was insoluble in water and lost its ambidextrous nature. It was more hydrophobic and showed good gelation ability for organic solvents. Boc-protected peptides have been previously reported as potential organogelators. , Thus, the Boc group increased the gelation ability for organic solvents, but the primary amino group of AB-16 is clearly essential for the gelation of water.

Effect of the Hydrogen-Bonding Groups on the Gelation Ability

Among the gelators examined, only AB-16 exhibited an ambidextrous nature; therefore, the effect of the hydrogen-bonding groups was examined in detail. First, the effect of the structure of the amide groups on AB-12 was investigated. One of the two amide bonds of AB-12 was reversed from NHCO to CONH, yielding the structural isomers A*B-12 and AB*-12, which differ in the amide group that is reversed, that is, the one close to the N-terminus and that close to the C-terminus, respectively. These pseudopeptides were synthesized according to the reactions described in Schemes S2 and S3. Their gelation abilities together with those of AB-12 are summarized in Table . A*B-12 could gelate less polar toluene and CCl4 as well as water, thus showing an ambidextrous nature. However, the MGC values for all of the solvents were higher than those of AB-12 and the gelation ability was lower. Meanwhile, AB*-12 also showed ambidextrous gelation ability and gelated organic solvents more efficiently than did AB-12. However, the MGC value for water increased compared with that of AB-12. Therefore, the structure of both amide groups in gelator AB-12 is important for achieving an ambidextrous nature. The melting points of these three LMWGs increased in the order A*B-12 < AB-12 < AB*-12, which corresponds to their MGC values for less polar organic solvents such as toluene (A*B-12 > AB-12 > AB*-12). This suggests that the higher melting point stems from the formation of a more stable hydrogen-bonding network in toluene and that the gel was formed, even with a lower gelator concentration. The powder XRD patterns of the xerogels of A*B-12 and AB*-12 prepared from their toluene gels are shown in Figure S2. Their patterns and d-spacing values were similar to those of AB-12, which suggests that the molecular conformations and packing of these three gelators are similar. The order of the peak sharpness is A*B-12 > AB-12 > AB*-12, which is consistent with the above-mentioned trend of their gelation ability.

2. Gelation Ability of AB-12 and Its Analogues with a Different Hydrogen-Bonding Moiety for the Solvents with Their Corresponding Melting Points ,

graphic file with name la5c02116_0009.jpg

  AB-12 A*B-12 AB*-12 ABU-12
Mp (°C) 141–143 130–132 150–151 149–151
H2O G (8.8) G (21) G (22) G (2.1)
MeOH S S S S
acetone P P G (72.5) G (21)
AcOEt P PG G (11.2) G (1.2)
CHCl3 S S S PG
toluene G (15.4) G (75) G (3.1) G (0.33)
CCl4 G (48.3) G (50) G (7.6) G (2.3)
hexane I I I PG
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a

G: gel, PG: partial gel, P: precipitate, S: soluble, I: insoluble.

b

Values in the parentheses indicate minimum gelation concentration (g/L). The results of AB-12 was reported previously.

The urea moiety forms stronger hydrogen bonds than the amide group; therefore, it has often been used in the design of LMWGs. − Because the ACHC unit is important, ABU-12, in which the C-terminus amide group of AB-12 was replaced with a urea group, was designed and synthesized according to Scheme S4. The gelation properties of ABU-12 are summarized in Table . ABU-12 showed a better gelation ability than AB-12 for both less polar organic solvents and water. The MGC value for water was 2.1 g/L, and toluene could be gelated even at a low ABU-12 concentration of 0.33 g/L. Polar organic solvents were also gelated, with AcOEt in particular being gelated with a low MGC value of 1.2 g/L.

The powder XRD patterns of the xerogels of ABU-12 prepared from its toluene and water gels are shown in Figure S3. Although the diffraction peaks were weak, their patterns were almost the same, which indicates that the molecular assembly of ABU-12 was similar in toluene and water gels. The morphologies of these xerogels were observed via field-emission SEM. As shown in Figure , both xerogels displayed entangled fibrous structures, suggesting the construction of a one-dimensional molecular assembly from ABU-12. The fibers were thinner than those of AB-12 and AB-16, with widths ranging from 20 to 50 nm. The formation of such thin fibers indicates that the high gelation ability of ABU-12 can be attributed to the rapid growth of the 1D assembly.

3.

3

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SEM images of the xerogels of ABU-12 prepared from its (a) toluene gel and (b) water gel.

Because ABU-12 showed a high gelation ability for toluene, the gel-to-sol transition temperatures (T gel) of ABU-12/toluene gels with different concentrations were measured (Figure ). As the concentration of ABU-12 increased, the T gel values became higher, indicating that the self-assembly of ABU-12 resulted in the formation of a thermally stable gel. The T gel value increased up to 80 °C, which is approximately 20 °C higher than those of the AB-n /toluene gels. The high stability of the ABU-12/toluene gel was also supported by the large enthalpy change (ΔH = 88.4 kJ/mol) and entropy change (ΔS = 224 J/mol·K) during the gel-to-sol transition, which were estimated from the van’t Hoff plots (Figure S4).

4.

4

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Gel-to-sol transition temperatures (T gel) of the ABU-12/toluene gel and AB-n /toluene gels.

To confirm the effect of the hydrogen-bonding moieties during self-assembly, concentration-dependent 1H NMR spectra of ABU-12 were measured in toluene-d 8 solutions (Figure ). As the concentration of ABU-12 increased, the signals of the amide N–H proton (Ha) and two urea N–H protons (Hb and Hc) showed a downfield shift, suggesting that these three protons of ABU-12 participate in the formation of the hydrogen-bonding network.

5.

5

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Concentration-dependent 1H NMR spectra of ABU-12 in toluene-d 8 solutions.

According to these results, the molecular assembly shown in Figure can be proposed for ABU-12. The robust 1D supramolecular structure is constructed by the formation of hydrogen bonds involving amide and urea groups. The hydrophobic long alkyl chains contribute to the immobilization of less polar organic solvents. During the packing of these 1D structures, the polar primary amino groups approach each other, thereby allowing ABU-12 to immobilize and gelate water and less polar organic solvents.

6.

6

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Plausible one-dimensional molecular assembly of ABU-12 during gel formation.

Finally, the supramolecular gel made of ABU-12 was applied to the chiral recognition of a carboxylic acid. Previously, we demonstrated the visual chiral recognition of amines by a supramolecular gel composed of an acid-type LMWG. Because ABU-12 is an amine-type LMWG based on a chiral ACHC scaffold, the enantiomers of acidic compounds were expected to produce different diastereomeric interactions with ABU-12, enabling their recognition. Mandelic acid (MA) was selected as a target compound because its structure is rather simple and its (−)-(R)-enantiomer is an important precursor of various drugs.

As a preliminary experiment, the two diastereomeric salts ABU-12·(+)-MA and ABU-12·(−)-MA were prepared, and their melting points were recorded. The melting point of ABU-12·(+)-MA (124 °C–126 °C) was higher than that of ABU-12·(−)-MA (87 °C–90 °C), suggesting that the salt with (+)-MA is more stable than that with (−)-MA.

For the chiral recognition experiment, a ABU-12/AcOEt gel was prepared in vial tubes according to the standard procedure, and solutions of (+)-MA and (−)-MA in EtOAc were slowly added on top of the turbid gel at room temperature. After the vial tubes were kept at 50 °C for half an hour, the gel with the (−)-MA solution collapsed to give a clear solution. Conversely, the gel with (+)-MA was preserved and its upper part changed to a clear gel. Thus, the enantiomers of MA could be visually discriminated (Figure ). In contrast, when only the same amount of AcOEt solvent was added to the ABU-12/AcOEt gel, the original turbid gel remained intact after the same operation. These results show that the added MA enantiomers were dynamically soaked into the gels, changing the assembly of ABU-12. Such dynamic behavior is a merit of supramolecular gels, enabling facile and rapid chiral recognition without complicated operations.

7.

7

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Photographs of the appearance changes of ABU-12/ethyl acetate gels by the addition of solutions of mandelic acid (MA) enantiomers.

Conclusions

In this study, the structural effects of peptide-type gelators on their ambidextrous gelation nature were investigated. Although modification of the spacer length and amide structure decreased the gelation ability for water, replacing an amide group with a urea moiety improved the ambidextrous gelation ability. The construction of a 1D hydrogen-bonding network involving the urea and amide moieties plays an important role in efficient gel formation. The resultant supramolecular gel was successfully applied to visual chiral recognition of MA enantiomers.

Supplementary Material

la5c02116_si_001.pdf (18.2MB, pdf)

Acknowledgments

This work was supported by JSPS KAKENHI Grant Number JP23K04716.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.langmuir.5c02116.

  • Experimental details, XRD patterns, van’t Hoff plot, summary of the crystallographic data, and copies of NMR and IR spectra (PDF)

The authors declare no competing financial interest.

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