Chiral benzimidazole-derived mono azacrowns: Synthesis and enantiomer recognition studies with chiral amines and their ammonium salts

Article abstract of DOI:10.1016/j.tetasy.2013.04.021

Benzimidazole fused chiral mono aza-15-crown-5 2, was obtained in a single step from (S)-(-)-2-(α-hydroxyethyl) benzimidazole 1. This new class of aza-crown has a unique structure with the chiral unit being held in a stable conformation due to adjacent benzimidazole ring contributing to its stereodiscrimination ability. The interactions between the host aza-crown and enantiomerically pure amine guests in ionic and neutral forms exhibited the enantio-discrimination ability. The preliminary evaluation of the chiral sensing was monitored using ¹H NMR and circular dichroism (CD) analysis of the complexes at their molar equivalence. The binding parameters were determined using electronic absorption spectroscopy.

Full text of DOI:10.1016/j.tetasy.2013.04.021

Tetrahedron: Asymmetry xxx (2013) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral benzimidazole-derived mono azacrowns: synthesis and
enantiomer recognition studies with chiral amines and their
ammonium salts
⇑
Anita Pandey, Hasan Mohammed, Anil Karnik
Department of Chemistry, University of Mumbai, Vidyanagari, Santacruz (East), Mumbai 400098, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online xxxx
Benzimidazole fused chiral mono aza-15-crown-5 2, was obtained in a single step from (S)-(ꢀ)-2-(
a-
hydroxyethyl) benzimidazole 1. This new class of aza-crown has a unique structure with the chiral unit
being held in a stable conformation due to adjacent benzimidazole ring contributing to its stereodiscrim-
ination ability. The interactions between the host aza-crown and enantiomerically pure amine guests in
ionic and neutral forms exhibited the enantio-discrimination ability. The preliminary evaluation of the
chiral sensing was monitored using 1H NMR and circular dichroism (CD) analysis of the complexes at their
molar equivalence. The binding parameters were determined using electronic absorption spectroscopy.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
ammonium ions.19–21 Azacrowns offer several advantages such as
better binding with wider range of cations, including the softer
Understanding and unravelling the concepts of the origin of life
and the associated physiological processes are at the heart of chiral
recognition.1–3 Synthetically designed chiral receptors to study the
stereochemical integrity of biologically significant molecules such
as amino acids, sugars, drugs etc, and are being continuously devel-
oped world wide. It is possible to identify certain structural fea-
tures that are desired for high levels of enantio-discrimination.
Among these the cavity size,4 symmetry,5 additional binding sites,6
metal cations and a binding to the neutral guests; these features
are noticeably different from oxacrown ethers.22,23 Several chiral
azacrowns with heterocylic residues such as pyridine, pyrimidine,
and phenazine have been developed and investigated for their rec-
ognition abilities toward chiral amines and amino acids in their
neutral and ionic forms.16–18
2. Benzimidazole as a chiral synthon
conformational rigidity,7 and availability of a
p-rich unit near the
stereogenic center are considered to be essential features for the
prospective receptors.8 Molecular recognition in the neutral state
of the guest is relatively uncommon.9–11 Amines are a group of
small molecules found extensively in biosystems and in drugs of
abuse and therapeutic relevance. Thus monitoring the chemical
and enantiomeric purity/assay of amines has gained wide recogni-
tion in biochemistry.12 Chiral recognition is a stringent measure of
small energetic differences between diastereomeric complexes and
is a consequence of dissimilar extents of stereochemical interac-
tions between a receptor and guest enantiomers.
For the practical development of a receptor two considerations
are vital; the availability of inexpensive synthons and high yielding
simple synthetic protocols. Benzimidazole motifs have found wide
applications in chemosensing, catalysis, and pharmaceuticals and
so on. The fabrication of benzimidazole derivatives and their appli-
cations in chiral processes have been an area of interest for us, with
one of the most successful applications being the kinetic resolu-
tions of racemic amines and aminoester.24,25 Earlier experience in
the development of crown ether containing furo-fused BINOL and
its effective performance as a chiral discriminator of amines and
aminoesters26 motivated us to synthesize chiral azacrown ether
Enantiomerically pure chiral macrocycles have proven to be
useful synthetic hosts for chiral discrimination.13–15 Heterocycles
containing chiral macrocycles are interesting as they offer multiple
containing
(S)-(ꢀ)-2-(
a
benzimidazole ring as
a
heterocyclic residue.
can be obtained
a
-Hydroxyethyl) benzimidazole 1
conveniently27,28 in a single step reaction between o-phenylenedi-
amine and (S)-lactic acid. This molecule has good configurational
stability. The molecule offers a b-hydroxy amino moiety, which
has been used extensively for construction of several azacrowns.29
A noteworthy feature of the proposed azacrown molecule, is the
mutually shared C–N bond between the heterocycle and the
ligating sites in addition to aromatic p–p interactions.
Crown ethers16–18 and azacrown ethers have gained importance
as an efficient class of sensors for metal ions and (alkyl)
⇑
Corresponding author. Tel.: +91 22 265206091x585; fax: +91 22 26528547.
E-mail address: avkarnik@chem.mu.ac.in (A. Karnik).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.04.021
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A. Pandey et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
H
N
N
CH3
H
O
N
CH3
OH
O
O
O
dry THF, NaH
reflux, 8 hrs.
+
O
O
N
H
TsO
OTs
O
1
2
(S)-(-)-2-(α-hydroxyethyl) benzimidazole
mono aza-15-crown-5
Figure 1. Synthesis of mono aza-15-crown-5 (2).
macrocyclic cavity of crown. We anticipated that this arrangement
of atoms would result in a highly strained geometry of the crown
ring in the vicinity of the benzimidazole ring. This feature was con-
sidered to be potentially useful to monitor the associated electronic
transitions during recognition events. This unique and novel mole-
cule was worth exploring as a chiral sensor for biomolecules, the
efficiency of which would depend on the combined interplay of
noncovalent intermolecular interactions such as hydrogen bonding,
steric effects, and aromatic
enantiomers.
p–p interactions with the guest
Herein we report the synthesis of a chiral mono azacrown ether
(Fig. 1), and also present our preliminary 1H NMR and circular
dichroism (CD) spectroscopic studies on the enantiomeric recogni-
tion of the azacrown with the enantiomers of 1-naphthylethyl-
amine and 1-phenylethylamine and their ammonium perchlorate
salts along with UV titration studies in order to determine the
association constants. These studies revealed that the chiral (S)-
Figure 2. ORTEP representation of the X-ray crystal structure of 2.
(ꢀ)-2-(
a-hydroxyethyl) benzimidazole 1 derived azacrown ether
displayed high enantioselectivities for the (S)-enantiomers of chi-
3.2. X-ray crystallographic data of monoaza-15-crown-5 2
ral organic amines and their ammonium salts.
Single crystal XRD studies of mono aza-crown 2 revealed that
the benzimidazole backbone provided conformational rigidity to
the crown cavity, while the portion of macrocycle away from the
heteroaryl ring exhibited two major conformations (Fig. 2). As ex-
pected, the stereogenic center seemed to be acquiring much
needed conformational stability.
One of the nitrogen atoms, N-2 from the benzimidazole ring
along with the hydroxyl group present at the stereogenic center
are involved in the formation of the chiral azacrown ring. Thus,
the N-2 nitrogen atom is shared by the azole as well as the aza-
crown cavity providing a highly rigid geometry at the interface of
the two rings, while another nitrogen atom N-1 is seen in the hy-
drated form in the single crystal X-ray. This association of the
water molecule (neutral) with the azacrown unit was considered
interesting since it exhibited its ability to bind to appropriate
guests in a neutral state.
3. Results and discussion
3.1. Synthesis of benzimidazole derived mono aza-15-crown-5 2
The enantiopure benzimidazole-derived mono aza-15-crown-5
2 was synthesized in a single step (Fig. 1). (S)-(ꢀ)-2-(
a-Hydroxy-
ethyl) benzimidazole 1 was treated with tetraethylene glycol
ditosylate in the presence of sodium hydride as the base and anhy-
drous THF as the solvent at reflux under high dilution conditions
under an inert atmosphere. This gave the desired chiral mono
aza-15-crown-5 2 as a white crystalline solid. The racemic aza-
crown was prepared in a similar manner by starting from racemic
2-(a
-hydroxyethyl) benzimidazole 1.
Chiral HPLC analysis indicated that the mono aza-15-crown-5 2
was obtained in high enantiomeric excess when prepared from (S)-
(ꢀ)-2-( -hydroxyethyl) benzimidazole 1. The newly synthesized
a
3.3. Enantiomer recognition studies
crown was characterized by suitable spectroscopic techniques,
including single-crystal XRD analysis. The azacrown was obtained
in 48% yield. The 1H NMR and 13C NMR showed that the crown had
been built by typical signal pattern due to the methylene groups in
addition to the aromatic benzimidazole part. The COSY spectrum
exhibited correlations for signals due to the CH protons and the
methyl protons at the stereogenic center, clearly indicating their
proximity. Similarly the signals due to protons present on the aro-
matic rings correlated among themselves. Apart from the correla-
tions observed in the COSY, the NOE spectrum exhibited energy
transfer among the methyl signal at the stereogenic center and
the cluster of signals due to the –CH2 protons of the crown ring,
which also displayed energy transfer to signals due to the aromatic
protons, thus confirming their proximity through space. Single
crystal XRD analysis confirmed the structure (Fig. 2).
Enantiomer recognition potential for the azacrown was evalu-
ated by various spectroscopic techniques. The preliminary enantio-
mer sensing ability of the azacrown was evaluated by 1H NMR and
circular dichroism methods.30,31 The UV–vis titration was per-
formed with the azacrown and chiral amines/ammonium perchlo-
rates in order to determine the binding parameters.
Azacrown ethers have been successfully applied for the chiral
sensing of amines and amino acids using NMR spectroscopy.29a,32
The interaction of benzimidazole derived azacrown 2 with enantio-
pure perchlorate salts of 1-a-phenylethyl amine and 1-a-naph-
thylethyl amine confirmed the enantiomeric purity of the
azacrown molecule as well as displaying the preferential complex-
ation with (S)-(ꢀ)-enantiomers of organic ammonium perchlo-
rates. A higher upfield chemical shift
Dd = (0.079 ppm) of the
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A. Pandey et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
3
Figure 5. CD spectra of azacrown 2 and 1:1 complexes of 2 (R)-(+)-PEA perchlorate
and (S)-(ꢀ)-PEA perchlorate.
acids and so on, has been widely studied using CD.34 The UV–vis
and CD spectra of benzimidazole containing azacrown offers the
scope to study H-bonding and
exciton couplets in the CD spectrum.
p–p interactions from the strong
Figure 3. UV–vis and CD (inset) spectral studies of azacrown 2 in acetonitrile
(2 ꢁ 10ꢀ5 M).
methyl doublet at the stereogenic center of 2 in the complex of 2
3.4. CD studies of azacrown 2
with (S)-(ꢀ)-
pared to 2 with (R)-(+)-
complex d = (0.074 ppm) confirmed the chiral discrimination
ability of 2. The diastereomeric complex formed between 2 and
1- -naphthylethylamine perchlorates resulted in downfield
chemical shift of the methyl doublet. A small difference for d of
0.004 ppm was observed for the two diastereomeric complexes
of the two enantiomers of 1- -naphthylethylamine perchlorate
salts and the crown 2 complex.
a-1-phenylethylamine perchlorate salt when com-
a-1-phenylethylamine perchlorate salt
The ECD spectrum of azacrown 2 was studied in acetonitrile
(2 ꢁ 10ꢀ5 M) (Fig. 3, inset-B). The Near UV-CD region consists of
weak exciton couplets. The Far UV-CD region displays intense cot-
ton effects in the region around 220 nm associated with n ? p⁄ and
D
a
a
p
?
p⁄ electronic transitions due to –C@N bonds of benzimidazole.
D
An intense bisignate couplet was observed with a negative band at
217 nm and a positive band at 221 nm, corresponding to the
n ? p⁄ transitions.
a
Circular dichroism (CD) is a powerful tool for understanding the
structural changes that occur at a molecular level ranging from
small organic molecules to bulky bioploymers upon their interac-
tion with other molecules. The mutual interaction of the chro-
mophores present in the two interacting species (host and guest)
results in electronic perturbations and if a stereogenic center is
in the vicinity of the chromophore, these interactions result in an
appreciable difference in the diastereomeric interactions of chiral
guest enantiomers, which can be discriminated by CD.30,31,33 The
enantio-discrimination behavior of a chiral host toward the enan-
tiomers of biologically significant molecules such as amines, amino
3.4.1. Analysis of the ECCD spectra of host–guest complexes
The discriminating efficiency of host 2 was probed by exciton
coupled circular dichroism (ECD) spectroscopy using enantiomers
of amines and their ammonium salts. The ECD spectra of azacrown
2 were recorded with 1-
amine, and their perchlorate salts in acetonitrile. Chiral azacrown
2 was treated with one molar equivalent of (S)-(ꢀ)-1- -phenyleth-
ylamine and (R)-(+)-1- -phenylethylamine and the CD spectra
a-phenylethylamine, 1-a-naphthylethyl
a
a
were recorded. The CD spectrum of host 2 in the absence and pres-
ence of the guest enantiomers was recorded separately. The first
Figure 4. CD spectra of azacrown 2 and 1:1 complexes of 2 (R)-(+)-PEA and (S)-(ꢀ)-
Figure 6. CD spectra of azacrown 2 and 1:1 complexes of 2 with (R)-(+)-1-
a-NEA
PEA.
and (S)-(ꢀ)-1- -NEA.
a
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A. Pandey et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
Figure 7. CD spectra of azacrown 2 and 1:1 complexes of 2 (R)-(+)-1-
a-NEA
perchlorate and (S)-(ꢀ)-1- -NEA perchlorate.
a
Figure 8. UV–vis spectral changes upon spectrophotometric titration of
(1 ꢁ 10ꢀ5 M) with (S)-(ꢀ)-1-phenylethyl ammonium perchlorate (1 ꢁ 10ꢀ6
2 ꢁ 10ꢀ5 M).
2
–
set of weak oppositely signed bands was seen between 196.3 nm
(11.872) and 200 nm (ꢀ7.7261). The second pair of the prominent
bisignate band was observed at 211.5 nm (ꢀ6.459) and 213.5 nm
(8.197) while the third pair of bisignate band was observed be-
tween between 224.7 nm (ꢀ1.524) and 226.7 nm (0.144) bonds
(Fig. 4).
Similarly crown 2 when treated with (R)- and (S)-isomers of 1-
-naphthylethyl amine, the ECD spectra revealed the diastereo-
meric nature of interactions (Fig. 6).
a
Comparing the amplitudes (A) of the couplet at 224.5 and
235.4 nm, in the ECD spectra of diastereomeric complexes
The bands observed at 211.5 nm (ꢀ6.459) and 213.5 nm (8.197)
showed noticeable differences upon complexation with chiral
guest molecules. These bands are most likely due to n ? p⁄ and
D
A = 2475.7 cm2 mmolꢀ1 was found to be reasonably good for
(S)-(ꢀ)-(ꢀ)-1-
a-naphthylethylamine upon interaction with 2 in
the neutral form.
p
?
p⁄ transitions associated to C@N, the part closer to the chiral
The ECD spectra of diastereomeric complexes of 2 with 1-a-
unit.
naphthylethyl ammonium perchlorate enantiomers displayed
prominent cotton effects between 223.6 and 234.0 nm (Fig. 7).
The large magnitude of the amplitude A, but smaller difference in
The amplitudes (A) of the couplet at 213 and 211 nm, in the
ECCD spectra of diastereomeric complexes were compared, where
amplitudes
D
A = 1516.6 cm2 mmolꢀ1, indicates strong complexa-
Amplitude, A = (
R
|
D
emax
|
of the couplet) A(ꢀ)PEA
=
complex
{|(11,762) ꢀ (14,802.6)| cm2 mmolꢀ1} = (32,564.6 cm2 mmolꢀ1).
tion of 2 with NEA perchlorate salts but lower discrimination
among both the enantiomers. The details of CD analyses are pro-
vided for all of the complexation experiments carried out in
Table 1.
Thus, as expected based on the structural features, the chiral
azole chromophore containing part of the crown backbone exhib-
ited the chiral discrimination by forming diastereomeric com-
plexes with primary organic amines and their ammonium
perchlorates. Such molecules have found wide application in chro-
matographic separation science.35
Conversely
A(+)PEA
cm2 mmolꢀ1
2 with (R)-1-a-phenylethyl amine; Amplitude,
complex = {|(7608.34)ꢀ(ꢀ2750)| cm2 mmolꢀ1} = (10,358.1
)
and
D
A = {A(ꢀ)PEA
complex ꢀ A(+)PEA
complex};
D
A = 22,205.5 cm2 mmolꢀ1 was found to be reasonably high and
indicated the difference in the extent of the complexation of the
azacrown between the two enantiomers of 1- -phenylethyl amine.
When 2 was subjected to complexation with one molar equiv-
alent of ammonium perchlorate salts of 1-
a
a
-(R)-(+)- and (S)-(ꢀ)-
phenylethylamine, the ECD spectra displayed a weak, oppositely
charged couplet at 216.1 and 218.3 nm due to transitions associ-
ated with –C@N (Fig. 5).
3.5. Determination of the binding parameters by UV/vis
spectroscopy
The bisignate wave couplet between 202.9 and 205 nm was
analyzed to better understand the chiral discrimination. The
amplitudes (A) of this couplet in the ECD spectra of diastereomeric
UV/vis spectroscopy is a powerful tool for examining chiral
sensing protocols36. An effective sensor should absorb light of dif-
ferent wavelengths in non-bound and complexed forms. The differ-
ence in the characteristic absorbance of the host and chiral
complexes were compared,
to be reasonably good and indicative of the preferential complexa-
D
A = 4596.65 cm2 mmolꢀ1 was found
tion of 2 with (S)-(ꢀ)-1-
a-phenylethyl ammonium perchlorate.
Table 1
CD data of benzimidazole derived aza-crown 2 and its 1:1 complexes with chiral amines and their ammonium perchlorates
Host
2
Guest
k[nm] (
D
e
)
k[nm] (
D
e
) (cm2 mmolꢀ1
)
A = (
R
|
D
e
max|of the couplet)
D
A = [A(S)complex] ꢀ [A(R)complex
]
(S)-PEA
(R)-PEA
(S)-PEA salt
(R)-PEA salt
(S)-NEA
(R)-NEA
(S)-NEA salt
(R)-NEA salt
213(ꢀ17762)
211(14802.6)
32,564.6
10,359.1
8601.99
4005.34
4515.1
2039.4
16,672.38
18,189.05
22,205.5
4596.6
2475.7
1516.6
213(7608.34)
211(ꢀ2750.76)
202.97(1355.4)
202.97(ꢀ2080.46)
235.4 (1128.73)
235.4(2246.8)
2234.0(19674.51)
234.0(ꢀ15253.47)
205.5(ꢀ7246.59)
205.44(1924.88)
224.5 (ꢀ3386.4)
224.5(4286.2)
223.6(1485.47)
223.6(1418.9)
2
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A. Pandey et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
5
Table 2
Spectrophotometric titration experiments of the aza-crown sensor
with organic amines and ammonium perchlorate enantiomers were
carried out and changes in absorption profile were monitored. The
Binding constants K(S) or K(R), enantioselectivities K(S)/K(R) and Gibbs free energy
changes (ꢀ
DG0) for the diastereomeric complex of 2 with enantiomers of amines and
their ammonium perchlorates in acetonitrile at 25 °C
typical UV spectroscopic changes upon the addition of (S)-(ꢀ)-
a-
Host
Guesta
Ka (Mꢀ1
)
K(S)/K(R)
ꢀ
D
G0
ꢀ
DDG0
1-phenylethyl amine to 2, are represented in Figure 8.
b
(kJ molꢀ1
)
(kJ molꢀ1
)
The association constants of the enantiomers with the crown
molecule were calculated according to the modified Benesie–Hil-
debrand equation, (Eq. 2)
Azacrown
(2)
(S)-PEA
(R)-PEA
(S)-PEA
ion
(R)-PEA
ion
(S)-NEA
(R)-NEA
(S)-NEA
ion
4.054 ꢁ 105 11.9
32
26
30
6.14
3.4 ꢁ 104
( 0.229)
1.711 ꢁ 105 3.03
2.75
( 0.068)
½Hꢃ0½Gꢃ0
1
aD
½Gꢃ0
5.64 ꢁ 104
27
¼
þ
De
ð2Þ
D
A
K
e
1.602 ꢁ 105 1.122
29
30
27
0.43
0.30
Further modification results in an equation where a double recipro-
1.428 ꢁ 105 ( 0.033)
cal plot can be made with 1/
>>>[H]0}. (Eq. 3)
DA as a function of 1/[G]0. {where [G]0
7.848 ꢁ
1.193
( 0.015)
104
(R)-NEA
ion
6.576 ꢁ
104
28
1
1
1
½Gꢃ0
¼
þ
De
ð3Þ
D
A
K
aD
e
½Hꢃ0½Gꢃ0
a
PEA =
NEA = (1-
rate.
G0 = ꢀRT ln K.
DDG0 = ꢀ G0(S)
a
a
-phenylethylamine, PEA ion =
a
-phenylethylammonium perchlorate.
-naphthylethylammonium perchlo-
-naphthylethylamine), NEAion = 1-
a
Where [H]0 and [G]0 denote the total concentration of crown and
guest molecule, respectively, is the change in the molar extinc-
tion coefficient between the free and complexed crown ether and
A represents the absorption changes of crown ether upon the
D
ꢀ
De
b
D
ꢀ
DG0(R).
D
addition of organic ammonium salts.
For all of the guest molecules examined, plots of 1/DA against 1/
[G]0 values, gave excellent linear relationships, supporting 1:1
binding between the crown and guest enantiomers. can be de-
D
e
rived from the intercept while Ka (association constant) can be cal-
culated from the slope. The binding constants, K(R) or K(S) and
associated free energy changes (ꢀ
DG0) for the host molecules on
complexation were obtained by usual curve fitting analyses (R
>0.9850) of the observed absorbance changes as summarized in
Table 2.
The typical Benesie–Hildebrand plot to determine the binding
parameters upon the addition of (S)-phenylethyl ammonium per-
chlorate to 2 are shown in Figure 9.
The binding constants were determined for the interaction of
host 2 with chiral organic amine enantiomers in their neutral
and ammonium perchlorate forms. It was observed that 2 bonded
to 1-
naphthylethyl amine as indicated by the higher ꢀ
and 1-phenylethyl amine based complexes. It was also interesting
to observe that (S)-(ꢀ)-1- -phenylethyl amine displayed a higher
a
-phenylethyl amine more effectively when compared to 1-
a-
D
G0 value for 2
Figure 9. Benesie–Hildebrand plot of sensor
2
(1 ꢁ 10ꢀ5
M in acetonitrile) in
presence of (R)-(+) and (S)-(ꢀ)-1-PEA salt (1 ꢁ 10ꢀ6 – 1 ꢁ 10ꢀ5 M).
a
association constant compared to (R)-(+)-
a-1-phenylethyl amine
enantiomer by approximately ꢀ6.14 kJmolꢀ1
(
DDG0). Similarly,
complex provides useful information with regard to the extent and
strength of binding in a quantitative manner.
(S)-(ꢀ)-1-
a-phenylethyl ammonium perchlorate displayed a high-
er association constant as compared to (R)-(+)-a-1-phenylethyl
The UV/vis spectrum of the benzimidazole derived azacrown 2
ammonium perchlorate by approximately ꢀ2.75 kJmolꢀ1
(DDG0).
(2.835 ꢁ 10ꢀ5 M in acetonitrile) indicated kmax = 254 nm (
e = 7337)
In the case of 1-a-naphthylethyl amine, it was observed that 2
(Fig. 3A). The prominent band in the UV/Vis spectrum around
bonded to the amine in neutral form more effectively in compari-
220 nm was an interesting region for study, as the characteristic
son to the corresponding ammonium perchlorate salts. (S)-(ꢀ)-1-
n ? p⁄ and
p ?
p⁄ transitions due to C@N bonds of the benzimid-
a-Naphthylethyl amine displayed a higher association constant
azole ring and the ether linkages of the crown ring occurred in this
region. We expected important changes around 220 nm in the spec-
trum upon complexation of 2 with chiral guests. Different enantio-
mers were expected to have different levels of electronic
perturbation due to the proximity of the stereogenic center to the
C@N bond. The absorption at higher wavelengths, that is, 285, 277,
as compared to (R)-(+)-1-a-naphthylethyl amine by approximately
ꢀ0.43 kJ molꢀ1 (ꢀDDG0). Similarly, (S)-(ꢀ)-1-
a-naphthylethyl
ammonium perchlorate displayed a higher association constant
with 2 as compared to (R)-(+)-1-a-naphthylethyl ammonium per-
chlorate by approximately ꢀ0.30 kJmolꢀ1
(DDG0).
and 254 nm is characteristic of aromatic
p ?
p⁄ transitions.
4. Conclusion
The qualitative evaluation of aza-crown 2 as a prospective chi-
ral discriminator of biologically significant amines and their organ-
ic ammonium salts using 1H NMR and CD spectroscopy studies
encouraged us toward quantitative determination of the binding
parameters. The following equation represents equilibrium be-
tween chiral aza-crown host (H) and the guest amine enantiomers
(G) (Eq. 1):
1H NMR, CD, and UV analyses clearly indicated that the aza-
crown 2 exhibited diastereomeric interactions with the two enan-
tiomers of
1H NMR, CD, and UV analyses indicated that the two enantiomers
of -phenylethyl amine as free bases and as their perchlorate salts
exhibited better enantiomeric discrimination compared to the two
enantiomers of 1- -naphythylethyl amine.
a-phenylethyl amine and 1-a-naphthylethyl amine. The
a
Ka
a
H þ G ꢀ H ꢂ G
ð1Þ
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6
A. Pandey et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
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Reagents were of AR grade and used without further purifica-
tion. (R)-(+)-/(S)-(ꢀ)-PEA and NEA were purchased from Sigma–Al-
drich. The HPLC chromatogram was recorded on Agilent 1200,
Column: ULTRON-ESOVM 4.6 ꢁ 150 mm, (A:B) = 25:75[A = ACN,
B = Ethanol:20 mM KH2PO4 Buffer (pH adjusted to 5.5), 0.7 ml/
min, UV k = 229 nm). Optical rotations were measured on a Ru-
dolph polarimeter. Melting points are uncorrected. IR spectra were
recorded on a Shimadzu FTIR Spectrometer and 1H NMR spectra
were recorded on a 300 MHz Bruker, AV II 300 spectrometer, using
TMS as an internal standard. Chemical shifts are given in ppm rel-
ative to the internal reference for CDCl3; 13C NMR spectra were re-
corded on 75 MHz Bruker, AV II 300 spectrometer. GC–MS
spectrum was recorded on a Thermoelectron spectrometer. UV
spectra were recorded on a Shimadzu UV–visible Spectrophotom-
eter UV-2100. CD spectra were recorded on a J-815 CD spectrome-
ter after calibrating it with D-10-camphorsulfonic acid under a
constant nitrogen flow. Solvents used for UV and CD studies were
of spectroscopic grade.
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5.2. Synthesis of mono aza-15-crown-5 2
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In a nitrogen flushed, dry 250 ml 3-necked round bottomed
flask fitted with a dropping funnel, a reflux condenser and nitrogen
inlet was charged with sodium hydride (240 mg, 6 mmol) and
washed twice with hexane (20 ml). Hexane was decanted and
dry THF (50 ml) was added and the mixture was refluxed under
nitrogen for 30 min. To the refluxing solution was added dropwise
a solution of (S)-(ꢀ)-2-a-hydroxy ethyl benzimidazole 1 (324 mg,
1 mmol) in 75 ml of dry THF in 1 h and the mixture was stirred
and refluxed at 70 °C for 2 h. Subsequently a solution of tetraethyl-
ene glycol ditosylate in 75 ml dry THF was added dropwise to the
reaction mixture in 1hr after which the reaction mixture was re-
fluxed for a further 8 h until the starting material was consumed
(monitored by TLC); the reflux was stopped and THF was then con-
centrated under reduced pressure to afford a light yellow oily res-
idue, which was added to 100 g of ice. The yellow semi solid
residue was extracted with CHCl3 (3 ꢁ 50 ml) and the organic layer
washed with water (2 ꢁ 75 ml), and concentrated in vacuo to pro-
vide a light yellow viscous oil which was purified by column chro-
matography on silica gel using petroleum ether/Chloroform
(40:60) as eluent to afford a white crystalline solid of monoaza-
15-crown-5 2 in 48% yield. Mp 65 °C, ½a D20
¼ ꢀ36:5 (c 1, MeOH),
ꢃ
FTIR(KBr): 3392, 2947, 2867, 2349, 1672, 1616, 1517, 1466, 1452,
1323, 1123, 1096, 749, 735 cmꢀ1. 1H NMR (300 MHz, CDCl3) d: 1.66
(d, 3H, J = 6.6 Hz), 3.5–3.6 (m, 10H), 4.0 (t, 2H, J = 6.6 Hz), 4.3 (m,
1H), 4.5 (m, 1H), 5.0 (q, 1H, J = 6.6 Hz), 7.2–7.7 (Ar, 4H). 13C NMR
(75 MHz, CDCl3) d: 154.2, 141.6, 135.6, 122.8, 122.1, 119.6, 109.9,
71.6, 71, 70.9, 70.1, 70, 69.1, 67.9, 63.6, 44.2, 18.9). GCꢀMS:
319.6 ([M+1]+). Chiral HPLC analyses ee = 92.02% (HPLC, ULTRON-
ESOVM).
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Acknowledgment
A.D.P. is thankful to UGC India, for financial assistance.
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