Preferential intermolecular interactions lead to chiral recognition: Enantioselective gel formation and collapse

Article abstract of DOI:10.1039/c8cc06471g

Interesting self-assembly of an amino acid based molecular material into a hydrogel in the presence of selective enantiomeric chiral amines leading to chiral recognition has been demonstrated. Moreover, collapse of a metallogel formed from the same material in the presence of selective enantiomers validated its enantioselective affinity. Importantly, in addition to relevant experimental techniques, DFT studies have been successfully explored to establish chiral recognition through enantioselective gelation.

Full text of DOI:10.1039/c8cc06471g

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Preferential intermolecular interactions lead to
chiral recognition: enantioselective gel formation
and collapse†
Cite this:DOI: 10.1039/c8cc06471g
Received 8th August 2018,
Accepted 9th September 2018
a
a
a
a
Diksha Gambhir,
Rik Rani Koner
Sunil Kumar,
Gourab Dey,
Venkata Krishnan
and
b
*
DOI: 10.1039/c8cc06471g
rsc.li/chemcomm
Interesting self-assembly of an amino acid based molecular material enantiomers over the other into the gel network formed by the
into a hydrogel in the presence of selective enantiomeric chiral amines interaction between the carboxylic acid of the second generation
leading to chiral recognition has been demonstrated. Moreover, L-lysine dendron with the chiral amine.26 Zheng and co-workers
collapse of a metallogel formed from the same material in the showed enantioselective gel formation by L-2,3 dibenzoyltartaric
presence of selective enantiomers validated its enantioselective acid attached to calix[4]arene in the presence of chiral amines.28
affinity. Importantly, in addition to relevant experimental techniques, Pu et al. reported a BINOL-terpyridine-Cu(II) metallogel and its
DFT studies have been successfully explored to establish chiral enantioselective collapsing behavior in the presence of (S)-phenyl-
recognition through enantioselective gelation.
glycinol while in the presence of (R)-phenylglycinol it remained
intact.29 However, we have not come across any report that demon-
Owing to the importance of enantioselectivity in biology, phar- strates chiral recognition through both gelation as well as collapse.
macology and even industrial applications, supramolecular Moreover, DFT studies have not been explored yet to support visual
chiral recognition,1–4 the ability of receptor to interact profusely enantioselective differentiation through preferential gelation.
with one enantiomer over the other, has garnered immense
Chiral amines are basic building blocks of biological molecules
interest over the years. It has been noticed that particularly one and are also useful intermediates for alkaloid natural product
enantiomer of chiral compounds usually possesses more therapeutic synthesis.30 Therefore, enantioselective recognition of chiral amines
properties than the other, which might even have adverse effects. For is of utmost importance. In this contribution, we wish to report the
example, (S)-citalopram is an inhibitor of serotonin reuptake while first example of enantioselective gel formation as well as metal
the (R)-enantiomer is 30-fold less potent.5 Various analytical induced gel collapse as a powerful tool for selective visual detection
techniques including chiral HPLC,6 mass spectrometry,7 NMR,8,9 of enantiomers.
electrochemical measurements,10,11 CD,12–14 UV/Vis15 and
In this context, a histidine tagged alkyl functionalized carbazole
fluorescence16–18 have been commonly explored for chiral recogni- based reduced Schiff base was developed and employed for chiral
tion. In this endeavor several chiral hosts have been developed recognition. The active compound (CL1, Fig. 1(a)) was synthesized
including polymers,19 Langmuir–Blodgett films,20 Metal Organic by refluxing 9-hexyl-carbazolecarboxaldehyde with L-histidine
Frameworks (MOFs)21 and fluorescent chemosensors.22 However, in methanol for 12 h leading to the formation of the Schiff
conspicuous detection methods either through color change, base followed by NaBH4 mediated reduction (Scheme S1, ESI†).
precipitation or by gel formation and collapse have only recently
gained significant importance.23 To date, a variety of chiral gels
with diverse potential are reported in the literature, but chiral
gels for recognition of particularly one enantiomer from its
mirror image isomer are very scarce in the literature.24,25
In this regard, a few innovative chiral gels have been developed
and demonstrated to have potential for chiral recognition.26–29 The
Smith group reported the selective incorporation of one of the
a School of Basic Sciences, Indian Institute of Technology Mandi, Mandi-175001,
H.P., India
Fig. 1 Molecular structure of CL1, CL2, CL3 (a), CD1 (b), (R)-a-methyl-
benzylamine (c), (S)-a-methylbenzylamine (d), (R)-cyclohexylethylamine
(e), (S)-cyclohexylethylamine (f), (R)-4-methoxy-a-methylbenzylamine (g)
and (S)-4-methoxy-a-methylbenzylamine (h).
b School of Engineering, Indian Institute of Technology Mandi, Mandi-175001, H.P.,
India. E-mail: rik@iitmandi.ac.in; Fax: +91 1905 237924; Tel: +91 1905 267220
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8cc06471g
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The structure of CL1 was fully characterized using various spectro-
scopic techniques such as FT-IR, NMR, and HRMS (Fig. S1–S7,
ESI†). The newly synthesized ligand CL1 contains a hydrophobic
tail and amino acid (L-histidine) group which facilitates hydrogen
bonding and also assists the gelation process.
With the detailed characterization of CL1, an interesting
phenomenon was noticed, when an aqueous solution of CL1
was mixed with (R)-a-methylbenzylamine (MBA), the formation of
a gel was observed. Therefore, the enantiopure chiral nature due
to the presence of L-histidine motivated us to investigate the
interaction of CL1 with different chiral amines through gelation
studies. Interestingly, it has been observed that the addition of CL1
(0.06 M) into an aqueous solution of (R)-a-methylbenzylamine
(MBA) (0.082 ꢀ 10ꢁ3 M) led to gelation at room temperature
whereas precipitation was observed for (S)-MBA under identical
conditions (Scheme 1). It is worth pointing out that very weak or
no gelation was observed in the case of high amine/ligand ratio. In
contrast, high ligand to amine ratio resulted in good enantio-
selective gelation (Fig. S8, ESI†).
Rheological studies were performed at constant strain and
varying frequency values to check the gelatinous behaviour of
the developed gel (Fig. S9, ESI†). The observed higher storage
modulus (G0) than the loss modulus (G00) in the experimental
frequency range (0.1–100 rad sꢁ1) confirmed the gel nature of
our system.
Scanning Electron Microscopy (SEM) was performed to
study the self-assembly behavior of the gel and the precipitates
obtained with chiral amines, respectively (Fig. 2). The morphology
of the gel depicted the sheet like structures which would favour the
formation of long fibres to assemble into a gel, whereas the
precipitates obtained with (S)-MBA had thin and perturbed fibres.
The developed gel exhibited thermoreversibility i.e. the gel
transformed into a solution upon heating and again turned
back into a gel when left to rest at room temperature within a few
minutes (Fig. S10, ESI†). This gel–sol transition was observed up
to four cycles with good thermoreversibility. To gain insight
into the mechanical property of the gel after each thermocycle
amplitude sweep measurement was performed in which the
storage modulus and loss modulus were plotted with increasing
Fig. 2 SEM image of the (a) gel formed by the interaction of CL1 with (R)-
MBA (inset: photograph of the gel) and (b) precipitates formed by inter-
action of CL1 with (S)-MBA (inset: photograph of the precipitates).
strain (Fig. S11 and S12, ESI†). The yield stress (g), the point of
intersection of the two curves (G0 = G00), was determined. Higher
g stated high strain bearing capability, resulting in a more
mechanically stable gel. It was noticed that the value of g decreased
(Table S1, ESI†) on increasing the thermocycle, demonstrating the
weak nature of the gel, which was further corroborated by SEM
analysis. As shown in Fig. S13 (ESI†) the breakage of the gel fibres
was observed with each consecutive cycle.
Circular Dichroism (CD) spectra were examined for evaluating
the chiral recognition behaviour of CL1 with (R)-MBA and (S)-MBA.
Equimolar concentrations of both the enantiomers were used. A
positive cotton effect band was observed at 228 nm in the case of
(R)-MBA while a negative band was recorded in the case of (S)-MBA
(Fig. 3). Addition of CL1 (1–5 eq.) to the above solutions led to
decrement in the CD absorption bands in both cases. However,
while (R)-MBA experienced a decrease of almost 99%, the decrease
for (S)-MBA was only 50%. This indicated that (R)-MBA interacted
with CL1 more favourably, which may be due to a better interaction
between the chiral host and guest.
In order to gain a deep insight into the interactions responsible
for CL1-amine gelation/precipitation, 1H NMR experiments were
performed. As shown in Fig. 4 upon addition of gelator (CL1) to the
deuterated solution of (R)-MBA and (S)-MBA, the NH proton of the
chiral amine experienced a downfield shift in both cases. However,
this shift was 0.177 ppm more for (R)-MBA as compared to that of
(S)-MBA. This indicated the involvement of –NH protons in chiral
recognition and also supported the strong interaction of NH in the
case of (R)-MBA as observed in CD studies.
Subsequently, we recorded FTIR spectra of the pure gelator
(CL1), xerogel (CL1 + (R)-MBA) and precipitates (CL1 + (S)-MBA).
The gelator CL1 showed several strong characteristic peaks.
Scheme 1 Schematic representation of the enantioselective behaviour
of CL1.
Fig. 3 CD spectra of (R)-a-methylbenzylamine (10ꢁ2 M) (a) and (S)-a-methyl-
benzylamine (10ꢁ2 M) (b) under different sample amounts of CL1 (0–5 eq.).
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was carried forward to understand the destabilization in the
geometry of CLD1 by optimizing its geometry in the presence
of chiral amines (R) and (S) as shown in Fig. 5. In the presence of
(R)-MBA, the H-bond which is responsible for the dimer form did
not undergo H-bond rupturing and hence no destabilization of
the dimer molecule was observed (Fig. 5c). Moreover, the NH
group of (R)-MBA was noticed to have interaction with CLD1 and
formed a H-bond (1.71 Å) (Fig. 5c). While (S)-MBA lacked such
close H-bonding due to the steric hindrance arising from the
methyl group of (S)-MBA (Fig. 5(d)). Thus, we could ascertain that
the chiral environment of (R) and (S) MBA is the responsible
factor for the gel and precipitation as observed, respectively. As
reported in the literature, such heterochiral assemblies lead to
gelation.28
Fig. 4 The NMR spectra of a-methylbenzylamine (a), CL1 with (S)-MBA (b)
and CL1 with (R)-MBA (c).
To understand the role of hydrophobicity in effective gelation,
two more chiral hosts were developed by varying the alkyl chain
length, namely C4H9 (CL2) and C2H5 (CL3). It was noticed that
with increasing length of the alkyl chain the formation as well
as stability of the gel in terms of yield strength got enhanced
(Fig. S11 and S19, ESI†). It is worth mentioning that the ligand
with a C2H5 group led to precipitation upon addition of amine
guest. This may be attributed to insufficient hydrophobic inter-
action which is required for the gel formation.31 Therefore, the
structure property relationship studies enabled us to establish
the importance of hydrophobicity to induce the desired gelation.
The involvement of functional groups toward chiral recogni-
tion through H-bonding inspired us to investigate the effect of
metal ions for gel formation as well as chiral recognition.
Interestingly, CL1 was capable of forming a metallogel in the
presence of Zn2+ metal ions over other bivalent metal ions such
as Cu2+, Ni2+, Cd2+ etc. (Fig. S20, ESI†). The reason may be
attributed to the strong binding affinity of Zn2+ with a carboxylate
group and imidazole NH.32,33 The Gaussian theoretical optimized
geometry of the Zn complex in a 1 : 2 metal : ligand ratio
confirmed the bonding interactions with the carboxyl and
–NH group of the ligand (Fig. 6). Mass spectra analysis also
revealed the formation of a complex with metal ligand ratio 1 : 2
(Fig. S21, ESI†).
The stretching frequencies of groups –CQO and –NH were
observed at 1624 cmꢁ1 and 3137 cmꢁ1 respectively (Fig. S16, ESI†).
Interestingly, the stretching frequency of the –NH group for the
xerogel with (R)-MBA was significantly shifted to 3110 cmꢁ1 (–NH).
The changes associated with the FTIR spectra were mainly due to
the formation of strong hydrogen bonds between the OH group of
the carboxylic acid of CL1 and the –NH2 groups of the chiral
amine. In the case of (S)-MBA, the observed precipitates showed a
shift of the –NH peak from 3058 cmꢁ1 to 3048 cmꢁ1. This result
again confirmed that interaction between –NH and –OH mainly
played a vital role in chiral recognition.
DFT calculations have been performed to further validate
the mechanism of interaction. As a first step, the gelator (CL1)
was optimized in a monomer form followed by its optimization
in a dimer form to understand the hydrogen bonding in the
dimer form (CLD1). In the dimer, it could be observed that
the molecules are held together by hydrogen bonding between
the –COOH group of one molecule and the imidazole NH– unit of
other molecules (2.02 Å) (Fig. 5a and b). Furthermore, the study
In addition, we examined the interactions of the metallogel
with different enantiomers. When (R)-MBA (0.082 ꢀ 10ꢁ3 M)
was added to the metallogel, the gel remained intact while the
metallogel collapsed upon the addition of equimolar concentration
of (S)-MBA. This may be ascribed to the formation of hydrogen
Fig. 5 Optimized geometry of dimer CLD1 (a), close view of hydrogen
bonding in the dimer (b), dimer interaction with (R)-MBA (c) and dimer
interaction with (S)-MBA (d).
Fig. 6 Optimized geometry of CL1 with Zn(II) (inset: close view of inter-
action of Zn(II)).
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bonded assembly between the Zn2+ coordinated metallogel and We thank the Director, IIT Mandi, for research facilities. The
(R)-MBA. It has already been noticed that the gelator (CL1) has a support from the Advanced Materials Research Centre (AMRC),
strong tendency to form H-bonds with (R)-MBA which led to IIT Mandi, for the sophisticated instrument facility is sincerely
strengthening/stabilizing the gel. On the other hand, when acknowledged.
(S)-MBA was added into the metallogel, it weakened the inter-
molecular H-bonding network which was responsible for self-
Conflicts of interest
assembly of the metallogel structure and thus, collapse of the
gel was observed.
There are no conflicts to declare.
Additionally, the gelation phenomenon was also studied
using a mixture of enantiomers of guest amines to explore the
effectiveness of the CL1 ligand for enantiomeric excess deter-
mination. It was found that pure gel formation got retained up
to 70 : 30 mixture of R and S amines respectively. Afterwards, a
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