New 2-aminoethylimidazole-based dicarboxylic acid receptor derived from cholestane

Article abstract of DOI:10.1016/j.tetlet.2010.09.030

A new facial amphiphile cholestane-based receptor 1 containing a 2-imidazolylethylamino moiety at the 3α and 7α positions of cholestane was synthesized. Recognition selectivity of the new receptor 1 with various dicarboxylic acids was assessed by ¹H NMR titration. Maleic acid showed the highest binding constant among all the tested acids (K _a = 9.36 × 10⁴ M^-1).

Full text of DOI:10.1016/j.tetlet.2010.09.030

Tetrahedron Letters 51 (2010) 5954–5958
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New 2-aminoethylimidazole-based dicarboxylic acid receptor derived
from cholestane
⇑
Jyoti Ramesh Jadhav, Md. Wasi Ahmad, Hong-Seok Kim
Department of Applied Chemistry, Kyungpook National University, Daegu 702-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 July 2010
Revised 6 September 2010
Accepted 10 September 2010
Available online 16 September 2010
A new facial amphiphile cholestane-based receptor 1 containing a 2-imidazolylethylamino moiety at the
3
a and 7a positions of cholestane was synthesized. Recognition selectivity of the new receptor 1 with
various dicarboxylic acids was assessed by 1H NMR titration. Maleic acid showed the highest binding
constant among all the tested acids (Ka = 9.36 Â 104 MÀ1).
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Molecular recognition
Dicarboxylic acid
Maleic acid
2-Aminoethylimidazole
Cholestane
During the last decade, many receptors for neutral molecules
based on properly oriented hydrogen-bonding sites have been
reported. In particular, numerous studies have been devoted to
the design and synthesis of receptors to be used as sensing probes
for dicarboxylic acids and dicarboxylate anions constituting impor-
tant components of various metabolic, biological, and environmen-
tal processes.1 To date, several receptors containing different
functional groups for selective recognition of carboxylic and dicar-
boxylic acids have been reported.2 More specifically, Hamilton and
other research groups have designed and synthesized numerous
Among the dicarboxylic acids, maleic acid is one of the most
attractive targets owing to its central role in biology.7a,b Maleic
acid, the cis isomer of fumaric acid, has long been known to be a
potent inhibitor of enzyme systems in vitro: the inhibition of suc-
cinodehydrogenase and coenzyme activity of glutathione.7c It has
also been used as an alternative method for bonding orthodontic
brackets.7d
The design of a steroid-based receptor capable of selectively
recognizing a variety of guests is of particular interest because of
their rigid framework, facial amphiphilicity, and suitably oriented
functional groups.8 Recently, novel steroid-based receptors have
been synthesized in this laboratory. These receptors contain urea
and amide groups, recognized to act as pendant donors at different
receptors for dicarboxylic acids.3,4 Receptors containing
a-amino-
pyridine as a binding site and spacers, such as quinoline5a and
triphenylamine5b have also been reported. In many of these recep-
tors, the
a
-aminopyridine unit is located in a suitable position to
positions of bile acids and 5
anions and have been evaluated by 1H NMR titration.9 Herein, a
-cholestane-based platform was chosen as a building block in
a-cholestane-based platforms for
bind the carboxylic acid. Challenging developments in this area
have led to the development of a variety of host molecules for
dicarboxylic acids, that are functionalized with various groups,
for example, calix[4]arene,6a ferrocene,6b and thiourea-based6c,d
systems. Thus, in designing a receptor for dicarboxylic acids, a
number of valuable insights can be obtained from the vast related
literature. First, the rigidity of the host molecule and the number
of preferable binding sites for hydrogen-bonding interactions
between the host and guest molecules have to be considered. Addi-
tionally, the distance between two binding sites within specific
binding subunits needs to be considered.
5a
the design of a receptor for dicarboxylic acids. This choice is based
on the fact that this platform offers exactly the same bond length
attachment of ligands at C3 and C7 in an axial manner, which is
not possible using the same positions within the 5b-configura-
tion.10 The introduction of an axial amino group at C3 and C7 could
be derivatized rapidly in and quantitatively by reductive amination
of 3,7-diketosteroid.9d Thus a 5
a-cholestane-based scaffold with a
rigid structure, simple derivatization, and easy one-pot reductive
amination at the 3 and 7 positions with various amino groups
can be used as the building block for the construction of receptor
molecules.
In this Letter, we report on the synthesis of a new 2-aminoethy-
limidazole receptor 1 bearing two binding imidazole units at the
⇑
Corresponding author. Tel.: +82 53 9505588; fax: +82 53 9506594.
E-mail address: kimhs@knu.ac.kr (H.-S. Kim).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.030

J. R. Jadhav et al. / Tetrahedron Letters 51 (2010) 5954–5958
5955
C3 and C7 positions of 5
the recognition of dicarboxylic acids. To establish the role of both
imidazole groups in the complex formation, an alternative 5
cholestan-3 -imidazolylethylamino-7 -phenylamino receptor 2
(Fig. 1), in which one of the imidazole rings was replaced with a
phenyl ring while keeping all the other groups fixed, is examined.
The binding abilities of receptors 1 and 2 with various dicarboxylic
acids were subsequently determined by 1H NMR titration. In most
a-cholestane; this receptor can be used for
1.2
1.0
0.8
0.6
0.4
0.2
0.0
Maleic acid
Oxalic cid
a
-
a
a
Malonic acid
Phthalic acid
D-tartaric acid
L-tartaric acid
Fumaric acid
Succinic acid
L-aspartic acid
Propionic acid
of the receptors, the
a-aminopyridine groups connected with dif-
ferent spacers were used as important hydrogen-binding sites for
dicarboxylic acid recognition.2–5 On the other hand, in the case of
the imidazole receptor, its acidic H-2 proton was used for anion
recognition.11 The present study revealed that imidazole groups
containing acidic H-2 protons and free –N atom (N-3) as binding
sites were more suitable for the recognition of dicarboxylic acids.
To the best of the authors’ knowledge, this is the first synthetic
receptor whose imidazole groups can be utilized for dicarboxylic
acid recognition. This significant result was obtained owing to
the better-defined substrate-binding sites, their reduced structural
flexibility, and increased uniformity.
0
2
4
6
8
Mole fraction [G]o/[H]o
Figure 2. 1H NMR titration curves of receptor 1 with various dicarboxylic acids
dissolved in DMSO-d6.
L
-tartaric acids,
the largest downfield shift of the imidazole H-2 protons (from d
7.78 to 8.93 ppm ( d = 1.15 ppm)) upon the addition of 8 equiv
proportions of maleic acid. The oxalic and malonic acids also
caused significant downfield shifts of d = 0.71 and 0.46 ppm,
respectively, with respect to 1. Furthermore, their association
constant values were estimated to be comparable to that of other
acids, as depicted in Table 1. However, all other acids were
characterized by relatively small chemical shift changes
L-aspartic, and propionic acids, maleic acid showed
Imidazole receptor 1 was prepared by one-step reductive ami-
nation of 5a
-cholestane-3,7-dione 39d with 1-(2-aminoethyl)imid-
azole12 in the presence of NaBH(OEh)3, whereas receptor 2 was
D
synthesized by two-step reductive amination as shown in Scheme
1. The structure of receptors 1 and 2 were confirmed by 1H and 13
C
D
NMR and fast atom bombardment (FAB)-mass analysis.13
Owing to the poor solubility of dicarboxylic acids in CDCl3, the
binding properties of 1 with dicarboxylic acids were investigated
by 1H NMR titration in DMSO-d6. In the 1H NMR spectrum, we noted
that the H-2 protons of both imidazoles had shifted considerably
downfield from their original positions as compared to the other
imidazole protons (H-4 and H-5). Significant downfield chemical
shifts of all the imidazole protons of 1 clearly revealed the com-
plexes formed with dicarboxylic acids. The 1H NMR titration curves
of 1 with various dicarboxylic acids are shown in Figure 2.
(
D
d = 0.004À0.11 ppm) and association constant values were
obtained by titration of 1.
When 1 was titrated with fumaric acid, the chemical shift
changes of the imidazole protons were negligible. Owing to the fact
that a trans-ethene group was flanked by dicarboxylic acid groups
that are anti to each other when dissolved in fumaric acid, the
desirable free orientation of the carboxylic acid group toward
the binding sites could not be achieved. However, cis geometry of
In the case of 1, among the tested dicarboxylic acids that in-
cluded oxalic, malonic, succinic, maleic, fumaric, phthalic, D- and
HN
NH
HN
NH
H
H
1
N
N
N
2
N
N
N
Figure 1. Structures of cholestane-based 2-aminoethylimidazole receptors 1 and 2.
SC
SC
SC
i
i or ii
O
O
HN
O
HN
NH
H
3
H
4
H
1, 2
R1
R1
R2
1: R1, R2 = Im
2: R1 = Im, R2 = Ph
4: R1 = Im
SC =
Scheme 1. (i) Amine, NaBH(OEh)3, AcOH, THF, rt; (ii) amine, NaBH3CN, AcOH, THF–MeOH 1:1, rt.

5956
J. R. Jadhav et al. / Tetrahedron Letters 51 (2010) 5954–5958
Table 1
1 to chiral dicarboxylic acids, such as D- and L-tartaric acids was
Association constants (Ka) of receptor 1 with various dicarboxylic
also worth investigating, but a comparative study of these two
acids did not offer distinguishable data. The chemical shift differ-
ences and binding constant values obtained for both stereoisomers
are nearly the same, as depicted in Table 1. Lastly, the chemical
shift differences obtained for aspartic and propionic acids were
so small that it was not possible to calculate the corresponding
acidsa
Carboxylic acid
Association constant (Ka)
Maleic acid
Oxalic acid
Malonic acid
9.36 Â 104
6.46 Â 104
2.46 Â 104
2.56 Â 104
L-Tartaric acid
binding constants (Dd <0.01 ppm).
2.63 Â 104
D-Tartaric acid
The role of both imidazole groups could be analyzed by titrating
2 with maleic acid. More specifically, receptor 2 titrated with
maleic acid showed a very small chemical shift difference of the
Succinic acid
Phthalic acid
Fumaric acid
1.10 Â 101
1.72 Â 102
3.10 Â 101
NCb
H-2 proton (Dd = 0.05 ppm), which might have been due to one-
L-Aspartic acid
side binding of dicarboxylic acid to the imidazole ring. On the other
hand, negligible chemical shifts were observed in the case of the
protons of the other arm of 2. The comparison of 1 and 2 provided
sufficient evidence that the two imidazole groups are essential for
the selective binding of dicarboxylic acids. The changes observed in
the partial 1H NMR spectra of 2 after the addition of 1 equiv of
maleic acid are shown in Figure S-1. The significantly lower associ-
ation constant Ka value (1.22 Â 102 MÀ1) calculated for 2 with re-
spect to the H-2 proton of imidazole was comparable to the
value obtained in the case of binding maleic acid with 1. Thus,
the large downfield shifts of H-2 protons and the significant shifts
of the H-4 and H-5 protons of both imidazole rings in 1 clearly
show that both O–H and C@O oxygens of dicarboxylic acids partic-
ipated in the binding process. The direct hydrogen binding of O–H
in the carboxylic acid with the N-3, and C@O oxygen with the H-2
protons of imidazoles through @C–HÁ Á ÁO@C and @NÁ Á ÁH–O bonds
could potentially clarify the shifting of all imidazole protons. This
Propionic acid
NC
Determined in a DMSO-d6 at 298 K, [host] = 4.5 Â 10À3 M,
a
[guest] = 4.5 Â 10À2 M. Errors were estimated to be 610%.
b
NC: not calculated.
the maleic acid makes it possible for the dicarboxylic acid groups
to shift toward the binding sites of 1. During the complexation of
1 with maleic acid, both acidic sharp H-2 protons of 1 gave rise
to a broad peak with a comparatively large downfield shift, imply-
ing that both acidic imidazole protons contributed to the complex
formation. Figure 3 shows the partial 1H NMR spectra of 1 before
and after the successive addition of maleic and fumaric acid. It is
worth noting that 1 binds selectively to maleic acid rather than
to isomeric fumaric acid. Oxalic acid and malonic acid also showed
a comparatively large chemical shift difference with respect to
other dicarboxylic acids owing to the strong binding of the dicar-
boxylic acid’s –OH group with the N3 of both imidazole pendants.
This comparison of the differences in the chemical shift and asso-
ciation constant of 1 with respect to a variety of dicarboxylic acids
revealed that it is a suitable receptor for undersized dicarboxylic
acids.
Studying the binding properties of 1 with phthalic and succinic
acids led to a unique result. The spatial hindrance caused by the
phenyl groups of phthalic acid seems to have been out of reach
for the two pendants of 1 that interacted only with the carboxylic
groups. Because of the increase observed in the bond length be-
tween the two methylene groups (1.52 Å) connecting the two car-
boxylic groups and the orientation of the hydrogens of the
methylene group in succinic acid, the latter may not have been via-
ble in terms of binding with the imidazole groups. The response of
verifies that 5a-cholestane bearing axially two 2-aminoethylimi-
dazole pendants at the 3 and 7 positions is a good receptor for
dicarboxylic acid recognition. The association constants were cal-
culated from the chemical shift changes of the H-2 protons of imi-
dazoles by using the WinEQNMR2 software,14 which suggested a
1:1 complex formation. The results are summarized in Table 1.
The 1:1 stoichiometry of the maleic acid bound with 1 was further
confirmed by its Job’s plot (see Fig. S-2).
The selectivity of 1 toward dicarboxylic acids was also evalu-
ated by treating 1 with FÀ, ClÀ, BrÀ, IÀ, H2PO4À, CH3CO2À, and
À3
HP2O7 (2 equiv) in the form of tetrabutylammonium salts, as 1
contains two acidic imidazole protons. None of these anions in-
duced any changes in the chemical shift of the imidazole H-2 pro-
ton. This behavior could be attributed to the distance between the
Figure 3. Partial 1H NMR spectra of 1 after successive addition of (a) maleic acid and (b) fumaric acid in DMSO-d6.

J. R. Jadhav et al. / Tetrahedron Letters 51 (2010) 5954–5958
5957
Figure 4. Energy-minimized structures of (a) 1 and (b) 1 treated with maleic acid.
two binding subunits and the orientation of the two imidazole
References and notes
pendants. In other words, comparing the response of 1 to all differ-
ent acids and anions confirmed its relatively rigid structure and
high binding affinity for dicarboxylic acids.
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Org. Chem. 2008, 4, 52; (b) Ghosh, K.; Masanta, G. Tetrahedron Lett. 2006, 47,
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In order to better understand the nature as well as the binding
mode of 1 with maleic acid, we calculated the energy-minimized
structure. For this purpose, the geometries of all compounds in-
volved were subjected to optimization at the Hartree-Fock 3-21G
15
*
( ) level using Spartan 04 software. It is evident from the opti-
mized geometry of the complex of 1 shown in Figure 4 that the
guest was bound strongly in the open cleft involving a large num-
ber of hydrogen-bonding interactions. The distances between the
two H-2 and N-3 atoms of imidazole and 3,7-amino N–H in the
uncomplexed structure were estimated to be equal to a = 2.82,
b = 4.98, and c = 3.62 Å, as shown in Figure 4a. However, after com-
plexation with maleic acid, these values changed to 6.90, 6.53, and
5.30 Å, respectively, thus providing an open cavity for the guest
molecule.
The distances for the hydrogen bond interactions of 1 with
maleic acid are indicated by the dotted lines in Figure 4b
(d = 1.78, e = 3.01, f = 1.69, g = 2.62, h = 2.10, and i = 3.18 Å). As
predicted by 1H NMR titration both the O–H and the –C@O
groups of dicarboxylic acid formed hydrogen bonds with the
imidazole-binding sites as well as the 3,7-amino N–H protons.
However, it was not possible to determine the chemical shift
values by NMR titration because of the assimilation of N–H
6. (a) Qing, G. Y.; He, Y. B.; Chen, Z. H.; Wu, X. J.; Meng, L. Z. Tetrahedron:
Asymmetry 2006, 17, 3144; (b) Moriuchi, T.; Yoshida, K.; Hirao, T. Org. Lett.
2003, 5, 4285; (c) Gunnlaugsson, T.; Davis, A. P.; O’Brien, J. E.; Glynn, M. Org.
Lett. 2002, 4, 2449; (d) Yen, Y. P.; Ho, K. W. Tetrahedron Lett. 2006, 47, 1193.
7. (a) Gougoux, A.; Lemieux, G.; Lavoie, N. Am. J. Physiol. 1976, 231, 1010; (b)
Eiamong, S.; Spohn, M.; Kurtzman, N. A.; Sabatini, S. Kidney Int. 1995, 48, 1542;
(c) Morgan, E. J.; Friedmann, E. Biochem. J. 1938, 32, 862; (d) Olsen, M. E.;
Bishara, S. E.; Paul, D.; Jakobsen, J. R. Am. J. Orthod. Dentofacial Orthop. 1997, 111,
498.
protons in the up field area. Nonetheless, similar to
a-aminopyr-
8. (a) Davis, A. P. Chem. Soc. Rev. 1993, 22, 243; (b) Davis, A. P.; Bonar-Law, R. P.;
Sanders, J. K. M. In Supramolecular Reactivity and Transport: Bioorganic Systems;
Murakami, Y., Ed.; Comprehensive Supramolecular Chemistry; Pergamon:
Oxford, 1996; Vol. 4, p 257; (c) Davis, A. P.; Joos, J.-B. Coord. Chem. Rev. 2003,
240, 143; (d) Davis, A. P. Coord. Chem. Rev. 2006, 250, 2939; (e) Davis, A. P.
Molecules 2007, 12, 2106; (f) Brotherhood, P. R.; Davis, A. P. Chem. Soc. Rev.
2010, 39, 3633.
9. (a) Kim, K. S.; Kim, H.-S. Tetrahedron 2005, 61, 12366; (b) Kim, K. S.; Cho, N. J.;
Kim, H.-S. Bull. Korean Chem. Soc. 2006, 27, 739; (c) Kim, K. S.; Jang, H.-S.; Kim,
H.-S. Bull. Korean Chem. Soc. 2006, 27, 1445; (d) Ahmad, M. W.; Jung, Y. M.;
Khan, S. N.; Kim, H.-S. Bull. Korean Chem. Soc. 2009, 30, 2101.
idine and urea group receptors, properly inclined 2-aminoethy-
limidazole groups are also attractive building blocks for
dicarboxylic acids.
In conclusion, a new 5a-cholestane-based 2-aminoethylimidaz-
ole receptor 1 was synthesized in high yield. This new receptor
showed, through hydrogen-bonding interactions, relatively high
selectivity toward maleic acid. The key feature of 1 designed to
bind with dicarboxylic acids is the two axially oriented 2-aminoe-
thylimidazole pendants located at the C3 and C7 positions of cho-
lestane that act both as spacers and as binding units.
10. Bhattarai, K. M.; del Amo, V.; Magro, G.; Sisson, A. L.; Joos, J.-B.; Charmant, J. P.
H.; Kantacha, A.; Davis, A. P. Chem. Commun. 2006, 22, 2335.
11. (a) Boiocchi, M.; Bonizzoni, M.; Abbrizzi, L.; Piovani, G.; Taglietti, A. Angew.
Chem., Int. Ed. 2004, 43, 3847; (b) Kim, S. K.; Singh, N. J.; Kim, S. J.; Swamy, K. M.
K.; Kim, S. H.; Lee, K.-H.; Kim, K. S.; Yoon, J. Tetrahedron 2005, 61, 4545; (c) Jang,
Y. J.; Moon, B.-S.; Park, M. S.; Kang, B.-G.; Kwon, J. Y.; Hong, J. S.; Yoon, Y. J.; Lee,
K. D.; Yoon, J. Tetrahedron Lett. 2006, 47, 2707; (d) Xu, Z.; Kim, S. K.; Yoon, J.
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Acknowledgment
This work was supported by the Kyungpook National University
Research Fund, 2009.
12. Caudro, A. M.; Matia, M. P.; Garcia, J. L.; Vaquero, J. J.; Alvarez-Builla, J. Synth.
Commun. 1991, 21, 535.
13. Compound 1:
[
a
]
À17.42 (c 0.06), TLC Rf 0.68 (CH2Cl2–MeOH–NH4OH
D
Supplementary data
15:2:0.5); 1H NMR (CDCl3) d 0.59 (s, 3H, 18-CH3), 0.73 (s, 3H, 19-CH3), 0.84
(d, J = 6.8 Hz, 3H, 26-CH3), 0.85 (d, J = 6.6 Hz, 3H, 27-CH3), 0.87 (d, J = 6.8 Hz,
3H, 21-CH3), 2.51 (bs, 1H, 7b-H), 2.66 (m, 1H, 3b-H), 2.85 (bs, 1H, N–H), 2.95
(m, 4H), 4.01 (m, 2H), 4.15 (t, 2H, J = 6.2 Hz), 6.96 and 6.98 (s, 1H, Im H-5), 7.01
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.09.030.

5958
J. R. Jadhav et al. / Tetrahedron Letters 51 (2010) 5954–5958
and 7.03 (s, 1H, Im H-4), 7.57 and 7.68 (s, 1H, Im H-2); 13C NMR (CDCl3) d 11.2,
7.23 (d, 2H, J = 3.6 Hz, Ph H-1), 7.29 (m, 2H, Ph H-2), 7.59 (s, 1H, Im H-2); 13C
NMR (CDCl3) d 11,3, 12.1, 19.0, 21.1, 22.9, 23.2, 23.7, 24.2, 26.3, 28.4, 31.8, 32.7,
33.1, 36.1, 36.5, 36.9, 38.9, 39.2, 39.7, 43.2, 46.5, 47.8, 48.1, 49.5, 50.7, 52.6,
55.9, 56.4, 61.8, 73.0, 119.5, 126.7, 128.9, 129.2, 129.5, 137.8, 140.0; FAB-mass
Calcd for C39H67N6: 601.5083. Found: m/z 601.5088 (M+H)+.
14. (a) Hynes, J. J. Chem. Soc., Dalton Trans. 1993, 311; (b) WinEQNMR2, version 2.0,
2008.
12.2, 19.0, 21.0, 22.9, 23.2, 24.0, 24.3, 24.9, 28.4, 32.2, 32.4, 32.5, 32.6, 36.2,
36.5, 36.7, 39.2, 39.7, 39.9, 43.0, 46.1, 46.4, 47.9, 48.6, 49.4, 51.0, 51.2, 54.4,
55.6, 56.5, 119.5, 119.7, 128.2, 129.6, 137.9, 138.7; FAB-mass Calcd for
C
39H67N6: 591.5224. Found: m/z 591.5111 (M+H)+. Compound 2: [
a] +14.30
D
(c 0.06), TLC Rf 0.67 (CH2Cl2–MeOH–NH4OH 15:2:0.5); 1H NMR (CDCl3) d 0.62
(s, 3H, 18-CH3), 0.79 (s, 3H, 19-CH3), 0.89 (d, J = 6.8 Hz, 3H, 26-CH3), 0.90 (d,
J = 6.6 Hz, 3H, 27-CH3), 0.91 (d, J = 6.6 Hz, 3H, 21-CH3), 2.64 (m, 2H), 2.88 (m,
4H), 3.01 (m, 1H, 7b-H), 3.04 (bs, 1H, N–H), 3.62 (m, 1H, 7b-H), 3.77 (m, 1H, 3b-
H), 4.07 (m, 2H), 7.01 (s, 1H, Im H-4), 7.06 (s, 1H, Im H-5), 7.21 (bs, 1H, Ph H-3),
15. Energy minimization was carried out using Spartan 04 for Windows
(Wavefunction: Irvine, CA).