L-Amino acid derived pyridinium-based chiral compounds and their efficacy in chiral recognition of lactate

Article abstract of DOI:10.1039/c5ra00017c

A series of pyridinium-based chiral compounds 1-6 have been designed and synthesized. l-Amino acids have been used as the chiral source in the molecules. Among the chiral compounds, an l-valine derived compound 1 was found to exhibit enantioselective recognition of d-lactate in fluorescence. Structural tuning of this derivative, either by replacing l-valine with l-alanine or l-phenylglycine or by reducing the number of chiral centres around the binding site, does not result in any significant change in enantioselectivity in the recognition process. Change of the urea site to amide introduces compound 6 that displays good enantiodiscrimination for lactate (enantiomeric fluorescence difference ratio ef = 28.33 for d-lactate), even better than that of the l-valine derived compound 1 and of other reported structures in the literature.

Full text of DOI:10.1039/c5ra00017c

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PAPER
L-Amino acid derived pyridinium-based chiral
compounds and their efficacy in chiral recognition
of lactate†
Cite this: RSC Adv., 2015, 5, 24499
*
Kumaresh Ghosh and Anupam Majumdar
A series of pyridinium-based chiral compounds 1–6 have been designed and synthesized. L-Amino acids
have been used as the chiral source in the molecules. Among the chiral compounds, an L-valine derived
compound 1 was found to exhibit enantioselective recognition of D-lactate in fluorescence. Structural
tuning of this derivative, either by replacing L-valine with L-alanine or L-phenylglycine or by reducing the
number of chiral centres around the binding site, does not result in any significant change in
enantioselectivity in the recognition process. Change of the urea site to amide introduces compound 6
that displays good enantiodiscrimination for lactate (enantiomeric fluorescence difference ratio ef ¼
28.33 for D-lactate), even better than that of the L-valine derived compound 1 and of other reported
structures in the literature.
Received 1st January 2015
Accepted 20th February 2015
DOI: 10.1039/c5ra00017c
www.rsc.org/advances
metabolism and can result in acidosis and decalcication.6
Thus the enantioselective binding of lactate or its derivatives is
crucial, although there are few reports in the literature.5g,7
Introduction
Enantioselective recognition of chiral analytes is an important
topic in chiral recognition.1 Chiral recognition is unavoidably
signicant as chiral biomolecules such as proteins, nucleic
acids and carbohydrates play a vital role in life. In this area,
synthetic receptors that are capable of discriminating a partic-
ular isomer from its mirror image isomer through photo-
physical changes have attracted much attention. Of the
different photophysical processes, uorescence is noteworthy
because of high sensitivity and thus its application in chiral
recognition has been studied for several decades.2 Chiral
uorescence-based sensors can be used in the rapid determi-
nation of enantiomeric composition as well as in high-
throughput catalysis for asymmetric synthesis.3 Thus the
development of uorescence-based enantioselective sensors for
distinguishing chiral amines,4a amino alcohols,4b–c chiral
acids,4d chiral amino acids4e–h and carbohydrates4i–j etc., has
begun to attract research attention. In past several years,
enantioselective recognition of biologically signicant a-
hydroxycarboxylic acids5 as well as of a-amino acids and their
derivatives4e–h has been much explored. Of the different a-
hydroxycarboxylates, lactate is a simple example which is bio-
logically relevant. While the isomer L(+)-lactate is important in
biological metabolism, D(ꢀ)-lactate is harmful to human
Recently, we have reported L-valine derived pyridinium-based
chiral receptor 1, which shows enantioselective binding of
lactate by exhibiting signicant change in emission in the
presence of D-lactate over L-lactate in CH3CN.8 In relation to this,
we wish to report in this full account a series of pyridinium-
based chiral hydrogen bonding receptors 2–6 and their chiral
recognition properties towards hydroxycarboxylates in detail,
emphasizing the importance of structural tuning to achieve
good chiral discrimination.
Department of Chemistry, University of Kalyani, Kalyani-741235, India. E-mail:
ghosh_k2003@yahoo.co.in; Fax: +91 3325828282; Tel: +91 3325828750 ext. 306
† Electronic supplementary information (ESI) available: Figures showing the
change in uorescence and UV-vis titrations of receptors 1–6 with various chiral
anions, Job plot, binding constant table, 1H NMR titration and other spectral
data. See DOI: 10.1039/c5ra00017c
It is to be pointed out that the exploration of 3-amino-
pyridine in devising chiral sensors for the enantioselective
recognition of carboxylate-based substrates is unknown in the
literature except for our recent example of structure 1.8
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Results and discussion
Compounds 1–6 were synthesized according to Schemes 1 and
2. Following our reported reaction protocols for the synthesis of
1,8 compounds 2 and 3 were synthesized (Scheme 1). Boc pro-
tected L-amino acids such as valine 7a, alanine 7b and phenyl
glycine 7c were reacted with 3-aminopyridine in the presence of
dicyclohexylcarbodiimide (DCC) to give the coupled products
8a–c, respectively. Removal of the Boc-groups in 8a, 8b and 8c
using triuoroacetic acid (TFA) gave the amines 9a, 9b and 9c,
respectively, which individually upon reaction with 1-naphthyl
isocyanate, obtained from the reaction of 1-naphthylamine with
triphosgene, yielded the respective urea derivatives 10a, 10b
and 10c. For quarternization of the pyridine ring nitrogens in
10a–c, the chloroamides 11a–c, which were obtained from the
reactions of methyl esters of amino acids with chloroacetyl
chloride, were used. Individual reux of compounds 10a–c in
the presence of the corresponding chloroamides 11a–c in dry
CH3CN for 4 days afforded the chloride salts of 1–3. Next, anion
exchange reactions of the chloride salts of 1–3 were pursued
using NH4PF6 to give the desired compounds 1, 2 and 3. On the
other hand, reaction of 10a with benzyl bromide in dry CH3CN
Scheme 2 (a) (i) 1-Naphthylamine, triphosgene, Et3N, CH2Cl2, 18 h; (ii)
11a, CH3CN, reflux, 4 days; (iii) NH4PF6, CH3OH–H2O; (b) (iv) 1-
naphthylacetyl chloride, CH2Cl2, Et3N, 12 h; (v) 11a, CH3CN, reflux, 3
days; (vi) NH4PF6, CH3OH–H2O.
exchange in 15 using NH4PF6 gave the desired compound 6 in
appreciable yield. All the compounds were characterized by
usual spectroscopic methods.
Chiral recognition requires multiple-point interaction.9
Analysis of the structures 1–6 reveals that the pyridinium cation
is the principal binding site in all cases. Around this motif,
other different functional groups have been considered in
different ways to have diverse chiral receptor structures that are
capable of attaining multiple-point interaction. Variation of the
amino acid in the design strategy has been considered to
account for the steric requirements in the binding site for good
chiral discrimination. The naphthalene moiety has been used
as the uorescence signaling unit to assess the chiral recogni-
tion behavior of the molecules. It is to be pointed out that the 3-
aminopyridinium motif is important in anion recognition as it
provides hydrogen bond donors from different anchoring
groups and also a polarized C–H bond at the ortho position to
the anion and the complex is further stabilized by charge–
charge interaction. Its widespread use in anion recognition by
different researchers and also by us has recently been thor-
oughly reviewed.10
ꢀ
followed by Brꢀ exchange with PF6 gave compound 4.
Compounds 5 and 6 were synthesized according to Scheme
2. Triphosgene mediated reaction of 3-aminopyridine, followed
by addition of 1-naphthylamine in Scheme 2a gave the urea 12,
which on further reaction with the chloroamide 11a, gave the
chloride salt 13. Chloride exchange in 13 using NH4PF6 gave the
desired compound 5. On the other hand, the amine 9a was
coupled with 1-naphthylacetyl chloride to give the amide
derivative 14, which, under reux in CH3CN in the presence of
chloroamide 11a, gave the chloride salt 15. Next, chloride
To study the chiral recognition properties of the receptor
structures 1–6, tetrabutylammonium salts of D- and L-hydroxy
acids such as lactic and mandelic acids were used. In our earlier
report8 we showed that compound 1 selectively recognizes D-
lactate over L-lactate with an ef [ef ¼ (ID ꢀ I0)/(IL ꢀ I0) where I0
represents the uorescence emission intensity in the absence of
the chiral substrate, IL and ID are the uorescence intensities in
the presence of L- and D-lactates, respectively] of 5.32. To
understand the structural role of L-valine (chiral source) in 1, we
studied compound 2, which bears L-alanine instead of L-valine.
The uorescence study of 2 (c ¼ 3 ꢁ 10ꢀ5 M) in CH3CN revealed
poor enantiodiscrimination. Upon gradual addition of guests to
the solution of 2 in CH3CN, the emission of 2 at 378 nm
increased with a red shi of ꢂ28 nm. But the change in emis-
sion for each pair occurred to nearly the same extent (Fig. S1,
ESI†). Only in the case of D-lactate it was slightly more (ef ¼
1.16). Fig. 1, in this regard, shows the change in emission of 2 in
the presence of 20 equiv. of D/L-lactates and mandelates in
Scheme 1 (i) 3-Aminopyridine, DCC, CH2Cl2, 20 h; (ii) TFA, CH2Cl2, 3
h; (iii) 1-naphthylamine, triphosgene, Et3N, CH2Cl2, 16 h; (iv) (a) 11a–c,
CH3CN, reflux, 4 days; (b) NH4PF6, CH3OH–H2O; (v) (a) benzyl
bromide, CH3CN, reflux, 18 h; (b) NH4PF6, CH3OH–H2O.
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show chiral discrimination of the guests studied. In the case of
receptor 4, although the lactate-induced change in emission
was greater than the cases with mandelates, the enantiomers of
lactate were discriminated with ef ¼ 1.65 (Fig. 3a). In compar-
ison, chiral receptor 5 under identical conditions in CH3CN did
not exhibit any uorescence selectivity between lactate and
mandelate. But the enantiomers of lactate were poorly
discriminated with an ef of 1.18 (Fig. 3b). These observations
underline the fact that the presence of L-valine as a single unit
either at the ring nitrogen or at the amine function of 3-ami-
nopyridine does not do much to cause enantiodiscrimination of
lactate.
Fig. 1 Change in fluorescence ratio of 2 (c ¼ 3 ꢁ 10ꢀ5 M) upon
addition of 20 equiv. of guests in CH3CN at 406 nm (lexc ¼ 300 nm).
To evaluate the potentiality of the urea functionality in the
design, we then considered amide analogue 6. A thorough
uorescence study of 6 (c ¼ 3 ꢁ 10ꢀ5 M) was carried out in
CH3CN. As can be seen from Fig. 1, receptor structure 2 shows
preferential binding to the isomers of lactates than to man-
delate. But the enantioselection was insignicant. This was also
true in the ground state. In a UV-vis study, no marked difference
CH3CN. Like urea analogue 1, compound
6 selectively
discriminated the stereoisomers of lactates. Upon gradual
in absorption spectra of 2 during titration was observed (Fig. S2, addition of D-lactate to a solution of 6 in CH3CN, while the
ESI†).
emission at 338 nm decreased to a small extent, a new emission
Under identical conditions, a uorescence study of 3 (c ¼ 3 ꢁ at 425 nm appeared with signicant intensity. In comparison, a
10ꢀ5 M), which contains L-phenyl glycine as the chiral source, small increase in emission at 425 nm with the addition of L-
also revealed poor enantiodiscrimination in CH3CN. On addi-
tion of the guests to a solution of 3 in CH3CN the emission of 3
at ꢂ400 nm increased (Fig. S3, ESI†) to the same extent and in
the case of L-lactate it was a little more (ef ¼ 1.08). Fig. 2
lactate was observed. Fig. 4 represents the titration spectra for 6
with both D- and L-lactates. Under identical conditions, titration
experiments for 6 with D- and L-mandelates were performed and
negligible changes in emission were found. No peak at 425 nm
represents the change in emission ratio of 3 in the presence of 6 was noticed during interaction (Fig. S9, ESI†). It is thus
equiv. of D/L-lactates and mandelates in CH3CN. Further addi- presumed that the peak at 425 nm in the presence of the
tion of guests to the receptor solution decreased the emission lactates is due to the formation of an intermolecular excimer
gradually (Fig. S3, ESI†). Similar to 2, in UV titration no char- between the naphthalenes.11 Mandelate, being more bulky than
acteristic difference in the absorption spectra of 3 was observed
in the presence of the guests (Fig. S4, ESI†).
Thus, these results corroborate that in the present study,
valine with its steric isopropyl substituent at the a-carbon is
lactate, is weakly involved in binding and thus is unable to
participate in intermolecular chelation, responsible for excimer
emission.
Fig. 5 shows the emission ratio of 6 in the presence of D/L-
superior to alanine and phenyl glycine with methyl and phenyl lactates and mandelates in CH3CN. As can be seen from Fig. 5,
groups, respectively, in chiral recognition to discriminate the while the receptor 6 shows sharp uorometric discrimination
enantiomers of lactate.
between D- and L-lactates at 425 nm, enantiomers of mandelate
Aer establishing L-valine as the suitable chiral source in the are scarcely discriminated. The enantiomeric uorescence
series, we moved further to understand its positional role
around the pyridinium motif in the chiral discrimination of a-
hydroxycarboxylate. For this, compounds 4 and 5 were synthe-
sized. While in 4 the L-valine unit is present at the 3-position of
difference ratio, ef, is determined to be 28.33, which is
considerably greater than the case with 1. Even, the ef value is
signicantly greater than that for the salen-based chiral uo-
rescent sensor reported by Song et al.5g It is further to be pointed
the pyridinium motif, in compound 5 it is present on the pyr- out that the quantum yield12 of 6 is much more enhanced upon
idinium ring nitrogen. Fluorescence titrations of these two interaction with D-lactate than with L-lactate. The increment is
compounds in CH3CN revealed that both 4 and 5 were unable to
Fig. 3 Change in fluorescence ratio of (a) 4 (c ¼ 3 ꢁ 10ꢀ5 M) upon
addition of 13 equiv. of guests in CH3CN at 402 nm (lexc ¼ 300 nm),
Fig. 2 Change in fluorescence ratio of 3 (c ¼ 3 ꢁ 10ꢀ5 M) upon and (b) 5 (c ¼ 3 ꢁ 10ꢀ5 M) upon addition of 19 equiv. of guests in
addition of 6 equiv. of guests in CH3CN at 405 nm (lexc ¼ 300 nm).
CH3CN at 401 nm (lexc ¼ 300 nm).
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less than the binding constant value for D-lactate. However, due
to poor change in emission, we were unable to t the titration
data to a nonlinear equation to determine the binding constant
values for both the stereoisomers of mandelates. A comparison
of the binding constant values as shown in Table S2 (ESI†)
shows that the receptor 6, among the designs, exhibits stronger
binding towards D-lactate.
However, the enantioselective response of 6 towards a
particular stereoisomer of lactate was further realized from the
change in emission of 6 in the presence of its mirror image
isomer. Fig. 7, in this context, demonstrates these features. L-
Lactate induced change in emission of 6 was further perturbed
to a considerable extent upon addition of D-lactate (Fig. 7a). The
reverse addition was observed to be insignicant (Fig. 7b).
For practical applications, we also investigated the chiral
recognition behaviour of 6 with the same guests in aqueous
CH3CN (CH3CN : H2O ¼ 4 : 1 v/v). Surprisingly, guest-induced
minor change in emission indicated its inefficiency in chiral
recognition in aqueous organic solvent (ESI, Fig. S13†).
Fig. 4 Fluorescence titration spectra for 6 (c ¼ 3 ꢁ 10ꢀ5 M) in CH3CN
with tetrabutylammonium salts of (a) D- and (b) L-lactic acids (in all
cases 6 ꢁ 10ꢀ4 M is a maximal concentration of anion applied; lexc
¼
285 nm).
Prior to studying the interaction of 6 with the lactate isomers
via 1H NMR, a NOESY spectrum of 6 was recorded in CD3CN to
identify the positions of the different protons (ESI, Fig. S14†).
Among the different protons, the interacting protons of 6 were
identied in the 1H NMR spectrum by observing the positional
movement of the signals in the presence of D- and L-lactates. In
relation to this, Fig. 8 highlights the spectral changes of 6 in the
presence of D-lactate. All the amide protons of types ‘a’, ‘b’ and
‘c’ underwent downeld chemical shis in the presence of D-
lactate. The amide proton of type ‘a’ became invisible in the
presence of a small amount of the guest and this is presumed to
be due to its strong participation in hydrogen bonding that
makes the signal broaden. On the other hand, while the amide
proton of type ‘c’ is signicantly shied downeld, the amide
proton of type ‘b’ exhibits a small change in chemical shi upon
complexation. The participation of the pyridinium motif in
complexation was also recognized from the downeld chemical
shis of the ortho protons of types ‘d’ and ‘e’. The plot in the
inset of Fig. 8 shows the change in chemical shis of the
different interacting protons with guest concentration. It is of
note that, during interaction, some signals for naphthalene ring
protons (asterisks marked in Fig. 8; for details see Fig. S14†) in
the regions 7.93 ppm and 7.50 ppm underwent an upeld
chemical shi when D-lactate was gradually added. Guest-
Fig. 5 Change in fluorescence ratio of 6 (c ¼ 3 ꢁ 10ꢀ5 M)) upon
addition of 17 equiv. of guests in CH3CN at 425 nm.
considerable with respect to the receptor 1 (ESI, Table S1†).
Thus the amide analogue 6 is established to be more efficient
than 1 in the enantioselective recognition of lactate.
In the interaction process, the stoichiometry of the interac-
tion of 6 with both D- and L-lactates was determined to be 1 : 1,
as conrmed by Job plot13 (Fig. S11, ESI†). In this context, it is to
be pointed out that the appearance of the intermolecular exci-
mer between the naphthalenes in Fig. 4 may originate from the
equilibrium species with the stoichiometry of adducts 1 : 1
(polymeric assembly), 2 : 2 or others. However, the binding
constant value14 was determined from a nonlinear t of the
emission titration data and found to be (1.55 ꢃ 0.19) ꢁ 104 Mꢀ1
for D-lactate (Fig. 6). For L-lactate, it was determined to be (5.29
ꢃ 0.89) ꢁ 103 Mꢀ1 (Fig. S12, ESI†) and this is about three times
Fig. 7 Fluorescent response of 6 (c ¼ 3 ꢁ 10ꢀ5 M) to (a) D-lactate (c ¼
6 ꢁ 10ꢀ4 M) in the presence of L-lactate (c ¼ 6 ꢁ 10ꢀ4 M) and (b) L-
Fig. 6 Nonlinear curve fitting of the fluorescence titration data for 6 lactate (c ¼ 6 ꢁ 10ꢀ4 M) in the presence of D-lactate (c ¼ 6 ꢁ 10ꢀ4 M)
with D-lactate.
in CH3CN.
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Fig. 9 DFT optimized geometries of the complexes of (a) 6 D-lactate
(hydrogen bond distances in A˚: a ¼ 1.60, b ¼ 1.95, c ¼ 2.19 and d ¼
1.78); and (b) 6 L-lactate in the gas phase (hydrogen bond distances in
A˚: a ¼ 1.52, b ¼ 1.92, c ¼ 2.39 and d ¼ 1.79).
Conclusions
In summary, we have designed and synthesized a series of
pyridinium-based chiral receptors 1–6 of which structures 1 and
6 have been established as chiral receptors for the enantiose-
lective sensing of D-lactate over its mirror image. Both the
structures contain an L-valine unit as the chiral source, which
brings good enantioselectivity in the recognition process. Other
amino acids such as L-alanine and L-phenyl glycine as the chiral
source in the designed structures 4 and 5, respectively, did not
bring any enantioselectivity. The steric features of the side chain
of the a-amino acid, hydrogen bonding effects and charge–
charge interactions play important roles in the recognition
process. It is further of note that between 1 and 6, the receptor
structure 6, with an amide functionality at the site of the
naphthalene instead of a urea, shows greater enantioselectivity
(ef ¼ 28.33) towards D-lactate and establishes its efficacy in the
chiral recognition of lactates. Further insight along this direc-
tion is underway in our laboratory.
Fig. 8 Partial 1H NMR (400 MHz, CD3CN) spectra of 6 (c ¼ 1 ꢁ 10ꢀ2 M)
in the absence and presence of D-lactate [inset: change in chemical
shift values for the interacting protons with guest concentration].
induced intermolecular chelation of the receptors in solution
probably gives a situation where the naphthalene ring experi-
ences p-stacking interaction. This is in accordance with the
observation of an excimer emission peak11 at 425 nm in uo-
rescence (see Fig. 4). A similar observation in the 1H NMR
spectra of 6 was noted upon gradual addition of L-lactate,
although the changes in chemical shis of the interacting
protons were less compared to those in the case of D-lactate
(Fig. S15, ESI†).
Generally the selectivity of a chiral environment towards the
two enantiomers of a chiral species is due to the formation of
transient diastereomeric adducts, which differ in both energetic
and structural aspects. In the present case, in spite of the several
possibilities of stoichiometries of the adducts (1 : 1, 2 : 2 or
others) in solution, we became interested to study the hydrogen
bonding features of the receptor 6 with the lactate isomers and
also the corresponding stabilities of the discrete 1 : 1 adducts in
the gas phase through DFT calculations. DFT optimization15
was done in the gas phase using the B3LYP function and 3–21
basis set (Fig. 9). Like structure 1,8 receptor module 6 also
showed a preference for D-lactate over its mirror image isomer.
D-Lactate is observed to be complexed 4.56 kcal molꢀ1 more
strongly than the L-isomer. Fig. 9 represents the DFT optimized
structures in the gas phase with the hydrogen bonding
schemes.
Experimental
Compounds 8a, 10a, 11a and 1 were obtained according to our
earlier reported procedure.8 Synthetic procedures and charac-
terization data of these compounds are further given in the
ESI.† Compounds 2, 3 and the intermediates such as 8b and c,
10b and c and 11b and c were prepared according to the same
procedure as followed for 1 (ESI†).8
Compound (4)
To a stirred solution of 10a (0.1 g, 0.275 mmol) in CH3CN (15
mL), was added benzyl bromide (0.06 g, 0.35 mmol) and the
mixture was reuxed for 18 h. Aer completion of reaction,
purication of the crude reaction mixture by preparative TLC
using ethyl acetate as eluent gave the bromide salt of 4 as a
gummy product (0.11 g, yield: 74%). In the next step, based on
the procedure of anion exchange as followed in the case of 1, the
ꢀ
bromide ion was exchanged with the PF6 ion using NH4PF6
(0.1 g, 0.61 mmol) in MeOH–H2O (20 mL) to give the desired
compound 4 (0.115 g, yield: 93%), mp 120 ꢄC, [a]D25 ¼ 19.41 (c ¼
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0.618 g/100 mL, CH3CN), 1H NMR (400 MHz, CDCl3 containing 163.8, 152.6, 140.9, 137.8, 134.3, 133.9, 133.1, 132.5, 128.5,
two drops d6-DMSO): d 10.80 (s, 1H), 9.36 (s, 1H), 8.52 (s, 1H), 127.4, 127.1, 125.9, 125.5, 125.0, 121.1, 119.7, 62.3, 58.0, 52.0,
8.33 (d, 1H, J ¼ 5.20 Hz), 8.23 (d, 1H, J ¼ 8 Hz), 8.08 (d, 1H, J ¼ 4 30.6, 18.8, 17.8 (one carbon in the aromatic region is unre-
Hz), 7.84 (d, 1H, J ¼ 8 Hz), 7.79–7.76 (m, 1H), 7.58–7.52 (m, 2H), solved); FT-IR: n cmꢀ1 (KBr): 3379, 3286, 3099, 2967, 1736, 1703,
7.46–7.43 (m, 3H), 7.39–7.33 (m, 5H), 7.01 (d, 1H, J ¼ 8 Hz), 5.51 1656, 1598, 1533, 1504; HRMS (TOF MS ES+): calcd for (M ꢀ
(s, 2H), 4.47 (t, 1H, J ¼ 8 Hz), 2.23–2.18 (m, 1H), 1.08–1.05 (m, PF6)+: 435.2027, found: 435.2032.
6H); 13C NMR (100 MHz, CDCl3 containing two drops d6-
DMSO): d 173.3, 156.7, 139.8, 138.1, 134.4, 134.06, 134.0, 133.9,
132.0, 130.0, 129.5, 129.0, 128.3, 128.1, 126.8, 125.8, 125.74,
125.70, 123.7, 121.5, 118.7, 65.2, 60.0, 30.9, 19.4, 18.0; FT-IR: n
cmꢀ1 (KBr): 3631, 3367, 3095, 2966, 1707, 1655, 1595, 1547,
1504; HRMS (TOF MS ES+): calcd for (M ꢀ PF6)+: 453.2285,
found: 453.2233.
(S)-3-Methyl-2-(2-(naphthalene-1-yl)actamido)-N-(pyridine-3-
yl)butanamide (14)
To a stirred solution of 1-naphthylacetic acid (0.2 g, 1.07 mmol)
in dry CH2Cl2 (15 mL), was added oxalyl chloride (0.2 mL, 2
equiv.) and two drops of dry DMF and the stirring was
continued for 6 h. Then solvent was evaporated off in vacuo to
give the desired 1-naphthylacetyl chloride. This was directly
used in the next step. 1-Naphthylacetyl chloride was dissolved in
1-(Naphthalene-1-yl)-3-(pyridine-3-yl)urea (12)
To a stirred solution of triphosgene (0.5 g, 1.68 mmol) in dry dry CH2Cl2 (10 mL) and to this solution amine 9a (0.25 g, 1.2
CH2Cl2 (5 mL), was added 3-aminopyridine (0.16 g, 1.7 mmol) mmol) in dry CH2Cl2 (10 mL) containing Et3N (0.25 mL, 1.5
dissolved in dry CH2Cl2 (25 mL), dropwise using a dropping equiv.) was added. The reaction mixture was stirred for another
funnel for 30 min. Aer complete addition of 3-aminopyridine, 12 h. Aer completion of the reaction, the solvent was removed
triethylamine (0.62 mL, 2.5 equiv.) was added and the reaction under reduced pressure, water was added to the residue, and
mixture was stirred for another 40 min. Then 1-naphthylamine the product was extracted with CHCl3 (25 mL ꢁ 2) and dried
(0.27 g, 1.89 mmol) in dry CH2Cl2 (25 mL), was added to the over anhydrous Na2SO4. Evaporation of the solvent gave the
reaction mixture. Stirring of the reaction mixture was continued crude product, which was puried by silica gel column chro-
for 16 h. Aer completion of reaction, CH2Cl2 was evaporated matography using petroleum ether–ethyl acetate (1 : 9, v/v) as
ꢄ
off and water was added to the residue. The aqueous layer was eluent to give the product 14 (0.25 g, yield: 64%), mp 196 C,
extracted with CHCl3 (25 mL ꢁ 3) and dried over anhydrous [a]2D5 ¼ ꢀ1.99 (c ¼ 0.502 g/100 mL, CHCl3), 1H NMR (400 MHz,
Na2SO4. Aer evaporation of the solvent, the crude mass was CDCl3): d 9.05 (s, 1H), 8.55 (s, 1H), 8.30 (d, 1H, J ¼ 4 Hz), 7.91 (d,
puried by silica gel column chromatography using petroleum 1H, J ¼ 8 Hz), 7.86 (dd, 2H, J1 ¼ 8 Hz, J2 ¼ 2 Hz), 7.81 (d, 1H, J ¼
ether–ethyl acetate (2 : 3, v/v) as eluent to give the compound 12 8 Hz), 7.50–7.39 (m, 4H), 7.15 (dd, 1H, J1 ¼ 8 Hz, J2 ¼ 4 Hz), 6.22
(0.3 g, yield: 68%), mp 221 ꢄC, 1H NMR (400 MHz, d6-DMSO): d (d, 1H, J ¼ 8 Hz), 4.47 (t, 1H, J ¼ 8 Hz), 4.08 (dd, 2H J1 ¼ 28 Hz,
9.30 (s, 1H), 8.97 (s, 1H), 8.72 (s, 1H), 8.28 (d, 1H, J ¼ 4.80 Hz), J2 ¼ 16 Hz), 1.98–1.93 (m, 1H), 0.80 (d, 3H, J ¼ 6.80 Hz), 0.62 (d,
8.19 (d, 1H, J ¼ 8 Hz), 8.09–8.00 (m, 3H), 7.75 (d, 1H, J ¼ 8 Hz), 3H, J ¼ 6.80 Hz); 13C NMR (100 MHz, CDCl3): d 171.9, 170.6,
7.69–7.60 (m, 2H), 7.55 (t, 1H, J ¼ 8 Hz), 7.40 (dd, 1H, J1 ¼ 8 Hz, 145.0, 141.5, 134.7, 133.8, 131.8, 130.5, 128.8, 128.5, 128.3,
J2 ¼ 4 Hz); 13C NMR (100 MHz, d6-DMSO): d 153.5, 143.3, 140.3, 127.1, 126.6, 126.0, 125.6, 123.5, 123.4, 59.3, 41.3, 30.8, 19.1,
137.0, 134.4, 134.1, 128.8, 126.7, 126.4, 126.3, 125.6, 124.1, 123.9, 18.1; FT-IR: n cmꢀ1 (KBr): 3257, 3047, 2959, 1660, 1637, 1534;
121.8, 118.6 (one carbon is not resolved); FT-IR: n cmꢀ1 (KBr): mass: (LCMS) 362.0 (M + 1)+.
3263, 3013, 1642, 1587, 1555; mass: (LCMS) 264.0 (M + 1)+.
Compound (6)
Compound (5)
To a stirred solution of 14 (0.15 g, 0.415 mmol) in dry CH3CN (20
To a stirred solution of 12 (0.12 g, 0.455 mmol) in dry CH3CN (15 mL), was added compound 11a (0.11 g, 0.529 mmol) in dry
mL), was added compound 11a (0.12 g, 0.577 mmol) dissolved CH3CN (5 mL) and the reaction mixture was reuxed for 3 days.
in dry CH3CN (5 mL) and the reaction mixture was reuxed for 4 The crude product was puried by preparative TLC using ethyl
days. Aer completion of reaction, the crude product was acetate as eluent to give yellowish gummy compound 15 (0.147
puried by preparative TLC using ethyl acetate as eluent to give g, yield: 62%). Finally, according to the ion exchange procedure
yellowish gummy compound 13 (0.15 g, yield: 70%). Finally, followed for the synthesis of 1, the chloride anion in 15 was
based on the procedure followed in the case of compound 1, the exchanged with the PF6ꢀ ion using NH4PF6 (0.14 g, 0.86 mmol)
ꢀ
chloride anion in 13 was exchanged with the PF6 ion using in MeOH–H2O to give the desired compound 6 (0.15 g, yield:
NH4PF6 (0.15 g, 0.92 mmol) in MeOH–H2O (20 mL) to give the 85%), [a]2D5 ¼ 16.33 (c ¼ 0.612 g/100 mL, CH3CN), 1H NMR (400
desired compound 5 (0.16 g, yield: 86%), mp 160 ꢄC, [a]D25
¼
MHz, CDCl3 containing two drops of d6-DMSO): d 10.68 (s, 1H),
1
ꢀ9.5 (c ¼ 0.524 g/100 mL, MeOH), H NMR (400 MHz, CDCl3 9.19 (s, 1H), 8.41 (d, 1H, J ¼ 8 Hz), 8.30 (t, 2H, J ¼ 8 Hz), 7.99 (d,
containing two drops d6-DMSO): d 9.91 (s, 1H), 9.31 (s, 1H), 8.79 1H, J ¼ 8 Hz), 7.86–7.84 (m, 1H), 7.80 (d, 1H, J ¼ 8 Hz), 7.75–7.71
(s, 1H), 8.69 (d, 1H, J ¼ 8 Hz), 8.43 (d, 1H, J ¼ 8 Hz), 8.31 (d, 1H, (m, 1H), 7.50–7.44 (m, 4H), 6.86 (d, 1H, J ¼ 8 Hz), 5.33 (s, 2H),
J ¼ 5.60 Hz), 8.04 (d, 1H, J ¼ 8 Hz), 7.91–7.88 (m, 3H), 7.69 (d, 4.41–4.35 (m, 2H), 4.11 (d, 2H, J ¼ 16 Hz), 3.73 (s, 3H), 2.21–2.16
1H, J ¼ 8 Hz), 7.56–7.46 (m, 3H), 5.38 (s, 2H), 4.45–4.42 (m, 1H), (m, 1H), 1.99–1.97 (m, 1H), 0.96–0.94 (m, 6H), 0.80 (d, 3H, J ¼
3.73 (s, 3H), 2.21–2.16 (m, 1H), 0.96 (d, 6H, J ¼ 6.40 Hz); 13C 6.80 Hz), 0.71 (d, 3H, J ¼ 6.80 Hz); 13C NMR (100 MHz, CDCl3
NMR (100 MHz, CDCl3 containing two drops d6-DMSO): d 171.5, containing two drops of d6-DMSO): d 171.9, 171.7, 171.6, 163.9,
24504 | RSC Adv., 2015, 5, 24499–24506
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140.0, 138.9, 135.5, 134.5, 133.5, 131.9, 131.3, 128.5, 128.0,
127.9, 127.4, 126.3, 125.8, 125.5, 123.8, 62.3, 59.4, 58.2, 52.1,
30.8, 30.57, 30.50, 19.1, 18.8, 17.9, 17.8; FT-IR: n cmꢀ1 (KBr):
3631, 3406, 3103, 2968, 1740, 1693, 1656, 1596, 1537, 1508;
HRMS (TOF MS ES+): calcd for (M ꢀ PF6)+: 533.2758, found:
533.2750.
42, 5984; (f) P. Lustenberger, E. Martinborough,
T. M. Denti and F. Diederich, J. Chem. Soc., Perkin Trans. 2,
1998, 747; (g) W. S. Weiner and A. D. Hamilton, Bioorg.
Med. Chem. Lett., 1998, 8, 681.
2 (a) L. Pu, Chem. Rev., 2004, 104, 1687; (b) G. A. Hembury,
V. V. Borovkov and Y. Inoue, Chem. Rev., 2008, 108, 1.
3 (a) G. A. Korbel, G. Lalic and M. D. Shair, J. Am. Chem. Soc.,
2001, 123, 361; (b) G. T. Copeland and S. J. Miller, J. Am.
Chem. Soc., 1999, 121, 4306; (c) K. D. Shimizu,
M. L. Snapper and A. H. Hoveyda, Chem.–Eur. J., 1998, 4,
1885.
Preparation of anionic guests
All the tetrabutylammonium salts were prepared by adding 1
equivalent of tetrabutylammonium hydroxide in methanol to a
solution of carboxylic acid (1 equivalent) in methanol. The
mixture was stirred at room temperature for 3 h and evaporated
to dryness under reduced pressure. The gummy mass was
further dried under vacuum for 24 h.
4 Fluorescent receptors for chiral amines: (a) T. Kida,
T. Iwamoto, H. Asahara, T. Hinoue and M. Akashi, J. Am.
Chem. Soc., 2013, 135, 3371. Fluorescent receptors for
chiral amino alcohols: (b) X. He, Q. Zhang, X. H. Liu,
L. L. Lin and X. M. Feng, Chem. Commun., 2011, 47, 11641;
(c) J. Jiao, X. Liu, X. Mao, J. Li, Y. Cheng and C. Zhu, New J.
Chem., 2013, 37, 317. Fluorescent receptors for chiral acids:
(d) Z. B. Li, J. Lin, M. Sabat, M. Hyacinth and L. Pu, J. Org.
Chem., 2007, 72, 4905. Fluorescent receptors for chiral
amino acids: (e) H. Qin, Y. He, C. Hu, Z. Chen and L. Hu,
Tetrahedron: Asymmetry, 2007, 18, 1769; (f) M. H. Rodriguez
and E. Juaristi, Tetrahedron, 2007, 63, 7673; (g) Z. B. Li,
J. Lin, H. C. Zhang, M. Sabat, M. Hyacinth and L. Pu, J.
Org. Chem., 2004, 69, 6284; (h) X. Wu, M. Xie, X. Zhao,
X. Liu, L. Lin and X. Feng, Tetrahedron Lett., 2014, 55,
3446. Fluorescent receptors for carbohydrates: (i)
A. Berthod, X. Chen, J. P. Kullman and D. W. Armstrong,
Anal. Chem., 2000, 72, 1767; (j) P. Bako, G. Keglevich,
Z. Rapi and L. Tke, Curr. Org. Chem., 2012, 16, 297.
5 (a) V. D. Jadhav and F. P. Schmidtchen, Org. Lett., 2006, 8,
2329; (b) A. Bencini, C. Coluccini, A. Garau, C. Giorgi,
V. Lippolis, L. Messori, D. Pasini and S. Puccioni, Chem.
Commun., 2012, 48, 10428; (c) F. Han, L. Chi, X. Liang,
S. Ji, S. Liu, F. Zhou, Y. Wu, K. Han, J. Zhao and
T. D. James, J. Org. Chem., 2009, 74, 1333; (d) K. X. Xu,
X. J. Wu, Y. B. He, S. Y. Liu, G. Y. Qing and L. Z. Meng,
Tetrahedron: Asymmetry, 2005, 16, 833; (e) J. Lin,
H. C. Zhang and L. Pu, Org. Lett., 2002, 4, 3297; (f) L. Chi,
J. Zhao and T. D. James, J. Org. Chem., 2008, 73, 4684; (g)
F. Song, G. Wei, L. Wang, J. Jiao, Y. Cheng and C. Zhu, J.
Org. Chem., 2012, 77, 4759 and references cited therein.
6 (a) R. Datta, S. P. Tsai, P. Bonsignore, S. H. Moon and
J. R. Frank, FEMS Microbiol. Rev., 1995, 16, 221; (b)
Y. J. Wee, J.-N. Kim and H. W. Ryu, Food Technol.
Biotechnol., 2006, 44, 163.
Binding constant determination14
Binding constant values were determined using the uores-
cence titration data. The nonlinear t of the titration data was
done using equation: I ¼ I0 + (Ilim ꢀ I0)/2CH{CH + CG + 1/Ka ꢀ
[(CH + CG + 1/Ka)2 ꢀ 4CHCG]1/2} where I represents the intensity;
I0 represents the intensity of pure host; CH and CG are the cor-
responding concentrations of host and anionic guest; Ka is the
binding constant. The binding constant (Ka) and the correlation
coefficient (R) were obtained from a nonlinear least-square
analysis of I vs. CH and CG.
Quantum yield determination
Quantum yields of the compounds were determined in CH3CN
by the relative comparison procedure using naphthalene as
standard (FNap ¼ 0.23 in cyclohexane).12a The general equation
used in the determination of relative quantum yields is as
follows:12b–c
Fu ¼ (Fs ꢁ Fu ꢁ As ꢁ lexs ꢁ hu2)/(Fs ꢁ Au ꢁ lexu ꢁ hs2)
where F is the quantum yield, F is the integrated area under the
corrected emission spectrum, A is the absorbance at the exci-
tation wavelength, lex is the excitation wavelength, h is the
refractive index of the solution and the subscripts ‘u’ and ‘s’
refer to the unknown and the standard, respectively.
Acknowledgements
We thank DST New Delhi, India, for nancial support [project
SR/S1/OC-76/2010(G); Date: 23.08.2011]. A.M. thanks CSIR, New
Delhi, India for a fellowship.
7 (a) M. Almaraz, C. Raposo, M. Martin, M. C. Caballero and
J. R. Moran, J. Am. Chem. Soc., 1998, 120, 3516; (b)
A. Barnard, S. J. Dickson, M. J. Peterson, A. M. Todd and
J. W. Steed, Org. Biomol. Chem., 2009, 7, 1554; (c)
G. K. Budnikov, G. A. Evtyugin, Y. G. Budnikova and
V. A. Alfonsov, J. Anal. Chem., 2008, 63, 2; (d) L. Zhu and
E. V. Anslyn, J. Am. Chem. Soc., 2004, 126, 3676; (e)
N. Seurre, K. L. Barbu-Debus, F. Lahmani, A. Zehnacker,
N. Borho and M. A. Suhm, Phys. Chem. Chem. Phys., 2006,
8, 1007; (f) T. Ema, D. Tanida, K. Hamada and T. Sakai, J.
Org. Chem., 2008, 73, 9129.
References
1 (a) T. D. James, Top. Curr. Chem., 2005, 255, 31; (b) J. Lin,
Q. S. Hu, M. H. Xu and L. Pu, J. Am. Chem. Soc., 2002, 124,
2088; (c) Z. B. Li, J. Lin, Y. C. Qin and L. Pu, Org. Lett.,
2005, 7, 3441; (d) G. W. Gokel, W. M. Leevy and
M. E. Weber, Chem. Rev., 2004, 104, 2723; (e)
M. Matsushita, K. Yoshida, N. Yamamoto, P. Wirscing,
R. A. Lerner and K. D. Janda, Angew. Chem., Int. Ed., 2003,
This journal is © The Royal Society of Chemistry 2015
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View Article Online
RSC Advances
Paper
8 K. Ghosh and A. Majumdar, Tetrahedron Lett., 2013, 54, 5686.
9 L. Salem, X. Chapuisat, G. Segal, P. C. Hiberty, C. Minot,
C. Leforestier and P. Sautet, J. Am. Chem. Soc., 1987, 109,
2887.
10 K. Ghosh, A. R. Sarkar, T. Sarkar, S. Panja and D. Kar, RSC
Adv., 2014, 4, 20114.
11 M. T. Albelda, E. Garcia-Espana, L. Gil, J. C. Lima, C. Lodeiro,
J. S. de Malo, M. J. Melo, A. J. Parola, F. Pina and C. Soriano,
J. Phys. Chem. B, 2003, 107, 6573.
12 (a) A. M. Brouwer, Pure Appl. Chem., 2011, 83, 2213; (b)
R. A. Velapoldi and H. H. Tonnesen, J. Fluoresc., 2004, 14,
465; (c) Y. Wu, X. Peng, J. Fan, S. Gao, M. Tian, J. Zhao and
S. Sun, J. Org. Chem., 2007, 72, 62.
B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato,
X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng,
J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota,
R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr.,
J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd,
E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi,
J. Normand, K. Raghavachari, A. Rendell, J. C. Burant,
S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam,
M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo,
J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,
A. J. Austin, R. Cammi, C. Pomelli, J. Ochterski,
R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth,
P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels,
O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski and
D. J. Fox, GAUSSIAN 09 (Revision A.2), Gaussian, Inc.,
Wallingford, CT, 2009.
13 P. Job, Ann. Chim., 1928, 9, 113.
14 B. Valeur, J. Pouget, J. Bourson, M. Kaschke and
N. P. Eensting, J. Phys. Chem., 1992, 96, 6545.
15 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,
24506 | RSC Adv., 2015, 5, 24499–24506
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