Visual chiral recognition of mandelic acid and α-amino acid derivatives by enantioselective gel formation and precipitation

Article abstract of DOI:10.1016/j.tetlet.2012.08.025

Novel chiral receptors based on l-phenylalanine and l-valine have been synthesized and their chiral recognition properties toward mandelic acid and N-tosyl α-amino acids are studied. The phenylalanine-based receptor undergoes enantioselective gel formation with R-mandelic acid and N-tosyl-d-valine, whereas the valine-linked receptor in their presence results in the formation of precipitates.

Full text of DOI:10.1016/j.tetlet.2012.08.025

Tetrahedron Letters 53 (2012) 5745–5748
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Tetrahedron Letters
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Visual chiral recognition of mandelic acid and
a-amino acid derivatives
by enantioselective gel formation and precipitation
⇑
Anamica Tripathi, Anjul Kumar, Pramod S. Pandey
Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel chiral receptors based on
ognition properties toward mandelic acid and N-tosyl
based receptor undergoes enantioselective gel formation with R-mandelic acid and N-tosyl-D-valine,
whereas the valine-linked receptor in their presence results in the formation of precipitates.
L
-phenylalanine and
L
-valine have been synthesized and their chiral rec-
-amino acids are studied. The phenylalanine-
Received 2 May 2012
Revised 5 August 2012
Accepted 6 August 2012
Available online 12 August 2012
a
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Chiral recognition
Gel formation
Anion recognition
Mandelic acid
Amino acid
Chiral recognition of
a-hydroxy and
a-amino acids has received
mandelic acid and
a-amino acid derivatives through enantioselec-
considerable attention in recent years because of their relevance to
biology, organic synthesis, and asymmetric catalysis.1 Considerable
progress has been made in the design and development of syn-
thetic receptors that can recognize these molecules with high
enantioselectivity. Analytical techniques such as NMR, UV/Vis,
and fluorescence spectroscopy have been commonly used to study
the chiral recognition.2 Recently, conventional visual detection
methods, such as color change and precipitation, have gained sig-
nificant importance in chiral discrimination.3 Although supramo-
lecular gel formation and collapsing have attracted much
attention in recent years as a means of visual detection of anionic
species,4 there are only a few cases wherein their potential for chi-
ral recognition has been realized. Zheng and co-workers have re-
ported the recognition of chiral amines through enantioselective
gel formation of the L-2,3-dibenzoyltartaric acid appended ca-
lix[4]arene.5 Pu and co-workers have reported the chiral visual
sensing of amino alcohols by enantioselective gel collapsing of
the gels of chiral BINOL-terpyridine-Cu(II) complexes.6 Tu et al.
have used enantioselective metallogel collapsing for the chiral rec-
ognition of binaphthyl derivatives.7 Further, Yashima and co-work-
ers have reported the enantioselective gel formation ability of
some poly(phenylacetylene)s bearing a cyclodextrin residue in re-
sponse to a chiral amine, 1-phenylethylamine.8
tive gel formation and precipitation.
Receptors 6a and 6b were synthesized as shown in Scheme 1.
Compound 2 was synthesized by the hydrolysis of compound 1.9
a
-Amino amides 5a and 5b were synthesized according to the lit-
erature procedure.10 Thus, the reactions of N-boc-protected
L
-ami-
no acids (phenylalanine and valine) with 2-naphthylamine in ethyl
acetate in the presence of DCC followed by treatment with TFA in
DCM gave compounds 5a and 5b, respectively. Treatment of com-
pound 2 with triethylamine and ethyl chloroformate followed by
refluxing with compounds 5a and 5b gave compounds 6a and
6b, respectively in 45–50% yields.
We studied the interaction of receptor 6a and 6b with tetrabu-
tylammonium salts of R- and S-mandelic acid. We have found that
receptor 6a selectively forms a gel with R-enantiomer of mandelic
acid salt in 10% DMSO/CHCl3 (Fig. 1a). The gel formation by recep-
tor 6a (8.3 Â 10À3 M) with TBA salt of R-mandelic acid was ob-
served at 8.5 Â 10À3 M solution of R-mandelate, whereas no gel
formation was observed with S-mandelate even at its much higher
concentration (up to 1.9 Â 10À2 M). On the other hand, the interac-
tion of receptor 6b (9.0 Â 10À3 M) having
L-valine as a chiral center
with R-mandelate (4.4 Â 10À3 M) results in the formation of a pre-
cipitate, whereas with S-mandelate, the solution remains clear up
to 2.2 Â 10À2 M of S-mandelate (Fig. 1b). However, such property
of gel/precipitate formation of a particular receptor was not ob-
served with the solutions of their enantiomeric mixtures.
Herein, we report novel acyclic chiral receptors 6a and 6b based
on L-phenylalanine and L-valine which recognize enantiomers of
The gel which is formed from the interaction of 6a with R-man-
delic acid salt changes into solution phase upon heating, and the
resultant solution reversibly changes to the gel upon cooling to
⇑
Corresponding author. Tel.: +91 11 2659 1506; fax: +91 11 2658 2037.
E-mail address: pramod@chemistry.iitd.ac.in (P.S. Pandey).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.025

5746
A. Tripathi et al. / Tetrahedron Letters 53 (2012) 5745–5748
LiOH/THF/H2O
O
O
O
O
O
O
O
O
O
O
O
OH
OH
1
2
O
O
NH2
R
NH2
NH
TFA/DCM
O
R
O
NH
NH
O
R
O
NH
DCC, EtOAc
OH
3a: R= -CH2Ph
3b: R= -CH(CH3)2
4a: R= -CH2Ph
4b: R= -CH(CH3)2
5a: R= -CH2Ph
5b: R= -CH(CH3)2
O
O
O
O
1.ClCOOC2H5/Et3N/THF
R
O
NH
NH
HN
HN
R
O
O
O
OH
O
O
2. compound 5a or 5b/reflux
OH
2
6a: R = -CH2Ph
6b: R = -CH(CH3)2
Scheme 1. Synthesis of compounds 6a and 6b.
(a)
(a)
(b)
6a
6a+R
6a+S
(b)
6b
6b+R
6b+S
Figure 2. (a) SEM image of the gel formed by receptor 6a with TBA salt of R-
mandelic acid; scale bar: 10 m. (b) SEM image of the precipitate formed by
receptor 6b with TBA salt of R-mandelic acid; scale bar: 1 m.
l
l
Figure 1. (a) photograph of the organogel formed by receptor 6a (8.3 Â 10À3 M) in
(10%) DMSO/CHCl3 with TBA salt of R-mandelic acid (8.5 Â 10À3 M); (b) photograph
of the precipitate formed by receptor 6b (9 Â 10À3 M) in (10%) DMSO/CHCl3 with
TBA salt of R-mandelic acid (9 Â 10À3 M).
The average diameter of spherical particles is in the range of 30–
40 nm (Fig. 3).
Further, to get more insight into the binding behavior of recep-
tor 6a with enantiomers of mandelic acid salts, 1H NMR experi-
ment was carried out. The changes in the spectrum of receptor
6a on addition of R- and S-mandelic acid salts (1.1 equiv) have
been shown in Figure 4. It is observed that in both cases, there is
a similar downfield shift in the -NHb protons of receptor 6a on
addition of the enantiomers of mandelic acid salt. However, there
is a significant difference in the downfield shifts of the chiral –
CH protons of the enantiomers of mandelic acid salt. In the pres-
ence of R-mandelate, the chiral –CH of mandelic acid salt shifted
from 4.77 ppm to 4.89 ppm, whereas in the case of S-mandelate,
room temperature, showing that the gel formation and collapsing
are thermoreversible. The [T-gel] was found to be 49 °C.
To know the aggregation behavior of the gel and the precipitate
formed by receptors 6a and 6b with R-mandelic acid salts, micro-
scopic studies were carried out. The SEM images of these showed
different aggregation patterns. The morphology of the gel was
not well defined (Fig. 2a), whereas the precipitate showed a fibrous
morphology (Fig. 2b).
The TEM image of the gel formed by receptor 6a in the presence
of R-mandelic acid salt showed a nano-size spherical morphology.

A. Tripathi et al. / Tetrahedron Letters 53 (2012) 5745–5748
5747
O
O
O
O
O
O
O
O
O
HN
NH
NH
HN
OH
H
O
H
O
O
O
O
H
O
H
H
H
H
N
N
O
O
N
N
6a:S-TBAMA
6a:R-TBAMA
Figure 5. Proposed binding models for the interaction of TBA salts of R- and S-
mandelic acid with receptor 6a.
Figure 3. TEM image of the gel formed by receptor 6a with TBA salt of R-mandelic
acid; scale bar: 100 nm.
For the R-isomer, due to gel formation, binding constant could not
be determined. The Ka for 6b:S-mandelate was found as 30 3 MÀ1
.
The organogel was also characterized by FTIR spectroscopy. The
FTIR spectrum of receptor 6a shows two sharp characteristic N–H
stretching bands at 3425 and 3272 cmÀ1 and a carbonyl band at
1661 cmÀ1. After the gel formation with TBA salt of R-mandelic
acid, the NH bands change into a broad band, whereas the carbonyl
band shifts from 1661 cmÀ1 to 1650 cmÀ1. The shift in the carbonyl
stretching frequency to lower frequency (11 cmÀ1) after the gel
formation indicates that the amide group is involved in the inter-
action through H-bonding during the gel formation. The precipitate
formed by 6b and TBA salt of R-mandelic acid was also character-
ized by 1H NMR and FTIR. The 1H NMR spectrum of the precipitate
in DMSO-d6 showed 1:1 complex formation. The IR spectrum of the
precipitate shows the shift in the carbonyl band from 1650 cmÀ1 to
1629 cmÀ1 (see Supplementary data).
O
O
O
O
HN
NH
a
a
b
OH
c
c
Ph
COOH
O
NH
HN
O
d
b
R/S
6a
We also examined the behavior of receptors 6a and 6b toward
d
TBA salts of various N-tosylated
We have found that these receptors show chiral discrimination be-
tween - and -enantiomers of N-tosylvaline salts. The receptor 6a
forms a partial gel, whereas receptor 6b forms a precipitate with
TBA salt of N-tosyl- -valine, respectively. No discrimination be-
a-amino acids listed in Table 1.
i)
D
L
d
a
a
b
D
ii)
c
tween the enantiomers was observed with other amino acid deriv-
d
atives. The binding constants for receptors 6a and 6b with TBA salt
b
c
of N-tosyl-
L
-valine were found to be 250 25 MÀ1 and 50 5 MÀ1
,
iii)
respectively.
The SEM image of the gel formed by 6a and TBA salt of
indicated a folded sheet like morphology (Fig. 6a), whereas the pre-
D
-valine
a
b
c
iv)
cipitate formed by 6b and D-valine salt showed a fibrous morphol-
ogy (Fig. 6b).
10
8
6
[ppm]
The FTIR spectral studies of the partial gel and the precipitate
were also conducted. The gel formation shows the shift in the C–
O stretching frequency from 1661 cmÀ1 to 1648 cmÀ1. In the pre-
cipitate formation the shift of the carbonyl band is from
1650 cmÀ1 to 1645 cmÀ1. The 1H NMR spectrum of the precipitate
in DMSO-d6 showed 1:1 complex formation between 6b and TBA
Figure 4. 1H NMR spectra in (10%) DMSO-d6/CDCl3 (i) TBA salt of R(À)-mandelic
acid; (ii) receptor 6a (10 mM) + S-mandelic acid salt (1.1 equiv); (iii) receptor 6a
(10 mM) + R-mandelic acid salt (1.1 equiv); (iv) receptor 6a (10 mM).
it is unaltered and appeared at 4.77 ppm. This difference in the
NMR patterns clearly indicates that the chiral –CH proton of the
R-isomer is involved in hydrogen bonding with 6a perhaps through
C––H––O interaction.
salt of N-tosyl derivative of
In addition, we also synthesized the receptors with
anine and -valine, and studied their gel/precipitate formation
D-valine.
D
-phenylal-
D
behavior with TBA salts of the enantiomers of mandelic acid and
N-tosylvaline. It is found that these receptors form similar gel or
precipitate with the opposite enantiomers.
The proposed binding models for the interaction of TBA salts of R-
and S-mandelic acid with receptor 6a are given in Figure 5. In the
case of R-mandelate, the chiral –CH proton is hydrogen-bonded with
C@O groups of the receptor, and hence the OH group is free to inter-
act with the solvents particularly DMSO to induce gel formation.
Whereas, in the case of S-mandelate, the OH group is oriented to-
ward carbonyl groups of the receptor and may be hydrogen-bonded
(C@O––H––O–C). Hence, it is not free for the interaction with the
solvents to initiate the gel formation. The NMR titration with S-man-
Table 1
Response of receptors 6a and 6b with TBA salts of various N-tosylated amino acids
L
D
L
D
L
D
Receptor 6a
Receptor 6b
PG
P
PG
P
Sol
Sol
PG
P
PG
P
PG
P
delic acid salt revealed 1:1 complexation with Ka, 150 15 MÀ1
calculated by WinEQNMR software11 (see Supplementary data).
,
PG: Partial gel; P: Precipitate.

5748
A. Tripathi et al. / Tetrahedron Letters 53 (2012) 5745–5748
Supplementary data
(a)
(b)
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.
025.
References and notes
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Figure 6. (a) SEM image of the gel formed by receptor 6a with TBA salt of
scale bar: 10 m. (b) SEM image of the precipitate formed by receptor 6b with TBA
salt of -valine; scale bar: 1 m.
D-valine;
l
D
l
In conclusion, chiral receptors based on
-valine have been synthesized. These receptors show enantiose-
lective discrimination toward TBA salts of the enantiomers of
mandelic acid and N-tosylvaline in terms of gel formation or pre-
cipitation. The
TBA salts of R-mandelic acid and N-tosyl-
formation, whereas the receptor with -valine on their interaction
results in the formation of precipitates. The receptors with -phen-
ylalanine and -valine show enantioselective gel/precipitate for-
mation with the opposite enantiomers. Hence, these systems
may find their application in the visual sensing of enantiomers of
mandelic acid and N-tosylvaline through gel formation or precipi-
tation of their TBA salts.
L-phenylalanine and
L
L
-phenylalanine-based receptor on interaction with
D
-valine leads to gel
L
D
D
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Acknowledgments
A.T. and A.K. thank UGC and CSIR, New Delhi, respectively, for
their research fellowships. We also thank DST, New Delhi, for
financial support under FIST program for the purchase of Mass
Spectrometer.
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