Water-soluble aminocalix[4]arene receptors with hydrophobic and hydrophilic mouths

Article abstract of DOI:10.1016/j.tetlet.2010.03.073

We report the new water-soluble aminocalix[4]arene hosts 1 and 2 with deep hydrophobic cavity facilitating hydrophobic mouth and hydrophilic mouth, respectively. The ¹H NMR titrations revealed that host 1 shows high selectivity for neutral guests 9 and 10, with log K of 4.2 and 4.6, respectively. The host 2 shows log K of 4.9 for binding with guest 15. Moreover, the binding ability of the host 2 for guest 14 is stronger by a factor of 1000 than that of the host 1.

Full text of DOI:10.1016/j.tetlet.2010.03.073

Tetrahedron Letters 51 (2010) 2840–2845
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Water-soluble aminocalix[4]arene receptors with hydrophobic
and hydrophilic mouths
Satish Balasaheb Nimse a, Van-Thuan Nguyen a, Junghoon Kim b, Hyung-Sup Kim b, Keum-Soo Song b,
Woon-Young Eoum b, Chan-Yong Jung b, Van-Thao Ta a, Sudhakara Reddy Seelam a, Taisun Kim a,
*
a Institute for Applied Chemistry and Department of Chemistry, Hallym University, Chuncheon 200-702, Republic of Korea
b Biometrix Technology, Inc. 202 BioVenture Plaza, Chuncheon 200-161, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the new water-soluble aminocalix[4]arene hosts 1 and 2 with deep hydrophobic cavity
facilitating hydrophobic mouth and hydrophilic mouth, respectively. The 1H NMR titrations revealed that
host 1 shows high selectivity for neutral guests 9 and 10, with log K of 4.2 and 4.6, respectively. The host 2
shows log K of 4.9 for binding with guest 15. Moreover, the binding ability of the host 2 for guest 14 is
stronger by a factor of 1000 than that of the host 1.
Received 9 February 2010
Revised 16 March 2010
Accepted 18 March 2010
Available online 21 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Molecular recognition
Receptors
Host–guest systems
Cation–p interactions
Pi-interactions
1. Introduction
groups for molecular recognition can be attached. Cyclophanes were
the first examples with polar solubilizing groups.9 Receptors based
Mimicry of the molecular recognition features of naturally
occurring proteins by synthetic receptors is one of the challenging
research topics of supramolecular chemistry.1 Biological receptors
consist of large linear molecules that form three dimensional struc-
tures by specific intramolecular interactions. The recognition site
offers a precise stereochemistry and exhibits very efficient recogni-
tion processes by means of specific functional groups that consti-
tute the entrance and inner surface of the cavity.2 The presence
of specific functional groups at the mouth of the cavity suggests
their role for accessibility of substrates into the cavity.3,4
on clefts,10 porphyrins,11 calixarenes/resocinarenes12,13 have fol-
lowed, and yielded a collection of the thermodynamically stable
host–guest complexes. Examples of good binding selectivity and
kinetic stability in water remain elusive.10–14 Among the various
calixarene derivatives, water-soluble calixarenes have become
increasingly important after their introduction by Ungaro15 and
Shinkai16 in the field of supramolecular chemistry. Water-soluble
calix[4]arene derivatives allowed the study of basic forces involved
in the host–guest recognition processes, in a solvent where, all bio-
logical processes take place.17
Once the substrate enters the gorge it is guided to the active site
and there it is held almost exclusively by aromatic residues.5 The
quaternary ammonium functions of substrates do not permit the
use of conventional hydrogen bonds or salt bridges; rather, typi-
These features of the substrates and enzymes have inspired the
synthesis of deep hydrophobic pocket synthetic receptors. Recently
we have reported the synthesis and molecular recognition proper-
ties of water-soluble iminecaix[4]arene derivative.18 The imine
bonds in iminecalix[4]arene were found to be fragile, limiting its
use as a receptor. Here, we report new, highly stable, water-soluble
aminocalix[4]arene hosts, the one with hydrophobic function and
the other with hydrophilic function on the top of the deep hydro-
phobic cavity (Fig. 1).
We developed a new approach based on the calix[4]arenes.
According to our concept, the calix[4]arene is applied not only
for its cavity but also as a platform on which a molecular cleft
can be constructed by selective functionalization. The imineca-
lix[4]arene derivatives 3 and 4 obtained by selective modification
of the wide rim of aminocalix[4]arene, keeping narrow rim free
cally presents a cation–
p
interaction.6 It is of particular interest
then how the aromatic amines and ammonium ions are recognized
by receptors, considering their relative abundance in nature.7
However, the electronic effects, steric effects, and conformational
aspects of pyridine derivatives seem to be the most crucial for their
recognition by receptors.8
A possible strategy for synthetic receptors comprises a combina-
tion of medium-sized organic building blocks to which functional
* Corresponding author. Tel.: +82 33 258 6098; fax: +82 33 256 3421.
E-mail address: tskim@hallym.ac.kr (T. Kim).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.073

S. B. Nimse et al. / Tetrahedron Letters 51 (2010) 2840–2845
2841
Figure 1. Hosts 1 and 2, (A) host 1 (side view), (B) host 2 (side view).
for further modifications, were used as precursors. The receptors 1
and 2 were prepared from the iminecalix[4]arene 3 and 4, respec-
tively, in three steps.
observation of a distinct signal at d = 30.8 ppm for the methylene
carbon in the 13C NMR spectrum.19 A similar pattern was found for
the compound 1.
Reductions of 3, 4 to the respective aminocalix[4]arene 5, 6 with
BH3ÁTHF complex, and the subsequent reaction of 5, 6 with ethyl 2-
bromoacetate in acetonitrile in the presence of K2CO3 at 80 °C
afforded compounds 7, 8 with 87.5–89.4% yields. The ester then
hydrolyzed with KOH in ethanol and water mixture (2:1) to pro-
vide water-soluble aminocalix[4]arene derivatives 1 as the octapo-
tassium salt, and 2 as dodecapotassium salt in 96.6% and 97.6%
yields, respectively (Scheme 1, see the Supplementary data). The
negatively charged carboxylate functions found on the upper rim,
lower rim, and, or on the body of the receptors 1 and 2 enable their
solubility in water at pH/pD 7.3 at levels up to 50 mM–100 mM.
A 1 mM sample of 2 in D2O provides a NMR spectrum that has
sharp signals and shows the characteristics and symmetry expected
for a time-averaged C4v conformation. The1H NMRspectrumof com-
pound 2 showed a typical AB pattern for methylene bridge protons
represented by two pairs of doublets at d = 3.13 ppm (J = 12.6 Hz)
and d = 4.38 ppm (J = 12.6 Hz) for the axial and equatorial protons,
The preformed cavities with the hydrophobic and hydrophilic
mouths in hosts 1 and 2, respectively, are stabilized by the four
aminoacetate functions found on the body of the hosts. These func-
tions point outward and interact with water, making the aromatic
groups to form walls on the wide rim of calix[4]arene nucleus to
generate an architecture with deep hydrophobic cavity. In water,
the hydrophobic aromatic rings in host 1 come close to each other
to reduce the hydrophobic surface, forming hydrophobic mouth on
the top of the deep cavity. However, in the case of host 2, the four
carboxylate functions on the top of the cavity interact with water,
forming hydrophilic mouth on the top of the deep cavity as illus-
trated in (Fig. 1).
When one equivalent of host 2 was added to a 1 mM solution of
benzyltrimethylammonium bromide (13) (Scheme 2) in D2O, a sig-
nal for the encapsulated trimethylammonium moiety appeared at
d = 1.19 ppm, which shifted d = 1.93 ppm upfield of the free guest
(Fig. 2d). The large anisotropy experienced by the bound guest
shows that it is included deep within the pocket, surrounded by
aromatic walls. NMR titrations in deuterated buffer solution
respectively, this indicates that compound
2 existed in a
symmetrical cone conformation. It was further confirmed by the
Scheme 1. Synthesis of hosts 1 and 2. Reagents: (i) BH3ÁTHF, p-toluenesulfonic acid, THF; (ii) Br-CH2COOCH2CH3, K2CO3, CH3CN, Ar, reflux, 8 h; (iii) aq KOH, EtOH/water (2:1).

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S. B. Nimse et al. / Tetrahedron Letters 51 (2010) 2840–2845
Scheme 2. Neutral pyridine (9–11), cationic (12–16) and anionic guests (17–20).
Figure 2. Partial 1H NMR Spectra of complexes between host 1, 2 and molecule of guests 10, 13, and 15. (A) complex between host 1 and guest 13; (B) complex between host
1 and guest 10; (C) complex between host 1 and guest 15; (D) complex between host 2 and guest 13; (E) complex between host 2 and guest 10; (F) complex between host 2
and guest 15. (N) and (H) indicate the changes in protons of guest upon addition of host. In each box, the partial 1H NMR spectra is of free host (top), free guest (middle), and
host–guest complex (bottom).
[pD 7.3] provide a log K of 3.7 and 4.7 for 13 with 1 and 2, respec-
tively (Table 1).
guests 12 and 13 reveals a preference for the binding by the host
2. This interpretation is strongly supported by the 1H NMR and
NOESY (see the Supplementary data) results showing that in
the 12–2 complex the guest is more deeply included into the cav-
ity of the host 2 than into the cavity of the host 1. It is accepted
Similar 1:1 host–guest complexes were formed for 1 and 2
with 12, with log K of 3.4 and 4.0, respectively. The NMR spectra
of each host–guest complexes indicate that the trimethylammoni-
um residue of each guest is bound deep within the aromatic
pocket by the induced fit mechanism. It is clear that the cat-
that the cation–p interactions play a major role in both cases, but
maybe the difference is made by hydrophobic or hydrophilic
mouth in hosts 1 and 2.17a This phenomenon was not clear and
hence, structurally flat neutral aromatic pyridine guests (9–11)
were studied.
ion–p interaction is a powerful force that aids the recognition be-
tween hosts with their guests.20 The direct comparison between
log K values obtained for binding of hosts 1 and 2 with cationic

S. B. Nimse et al. / Tetrahedron Letters 51 (2010) 2840–2845
2843
Table 1
exit of guests 9, 10 into the deep hydrophobic cavity; therefore
the reduced stacking interactions result in the decreased bind-
ing constant.
It is noticeable that host 1 showed stronger binding with pyri-
dine derivatives (9–10) as compared to aromatic quaternary
ammonium ions (12, 13). The hydrophobic mouth of host 1 is con-
sidered to play a major role in the recognition of structurally flat
pyridine derivatives. Further, to put a light on the effect of the
hydrophobic and hydrophilic mouths, more hydrophilic aromatic
ammonium guests (14–16) were studied.
Log K values of complex formation of guests 9–20 by hosts 1 and 2 in water (pD 7.3;
p–p
25 °C)a
Guests
Host 1 4.2 4.6 nsb 3.3 3.7 1.0 3.4 2.4 ns ns ns 2.2
Host 2 3.3 4.4 ns 4.1 4.7 3.8 4.9 4.4 ns ns ns 2.1
9
10
11
12
13
14
15
16
17 18 19 20
a
All solutions were prepared in 200 mM sodium phosphate buffer (pD 7.3). The
guest concentration was kept constant (1 Â 10À3 M) while the host concentration
was varied from 8 Â 10À4 to 3 Â 10À3 M, and the chemical shifts of the protons of
guest were recorded at each concentration. The obtained 1H NMR data was ana-
lyzed by the well-known method of nonlinear least square regression analysis,
which allowed the calculation of association constant (log K).
The 1H NMR titrations revealed that the protons of the methyl
group para to the benzylammoniomethyl moiety in guest 15
showed a maximum (CIUS) of d = 0.61 ppm and d = 2.76 ppm upon
complexation with the hosts 1 and 2, respectively (Fig. 2c and f).
Similar pattern found for 14 and 16 indicates that aromatic nucleus
enters deep into the hydrophobic cavity from position para to the
benzylammonium or phenethylammonium functions in guests 14,
15, and 16, respectively, projecting ammonium moiety outward
from the host’s cavity. The binding of guests 14–16 in this mode
positions the guest’s ammonium moiety in the proximity of the
hydrophobic mouth and hydrophilic mouth of the host 1 and host
2, respectively. Compared to guests 14 and 16, guest 15 is better
complexed by the hosts 1 and 2 (log K = 3.4 and 4.9, respectively).
Interestingly, host 2 showed a preference over the host 1 for the
binding of guests 14–16. Moreover, the binding ability of the host
2 for benzylammonium ion (14) is stronger by a factor of 1000 than
that of the host 1 (Table 1).
b
ns indicates no change in chemical shift of protons in guests upon addition of
hosts.
Guests 9 and 10 enter in the deep hydrophobic cavities of hosts
1 and 2 with the hydrophobic open-chain substituent in pyridine
guests, as 4-methyl and 4-ethyl moieties showed significant chem-
ically induced upfield shift (CIUS) than aromatic protons (Fig. 2b
and e). The guest 11 with hydrophilic ends on both sides did not
show any change upon titration with hosts 1 and 2, respectively.
It is interesting to notice that host 1 showed higher association
constants for guests 9 and 10 as compared to host 2 (Table 1).
Structurally flat guest molecules like guests 9 and 10 enter into
the deep cavity of host 1 through the hydrophobic mouth and
get trapped in the cage formed by four aromatic rings, thus the
optimized
p-p stacking interactions result in the increased binding
constant. The hydrophilic mouth of host 2 allows easy entry and
Figure 3. Functional group selectivity demonstrated by hosts 1 and 2, (A) Host 1 with guests 10, 15, 17, and 19, (B) Host 2 with guests 10, 15, 17, and 19, (C) Comparison
between log K values of hosts 1 and 2 for binding of guests 9, 11, 13, 14, 18.

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S. B. Nimse et al. / Tetrahedron Letters 51 (2010) 2840–2845
Figure 4. Energy-minimized structure of complexes between host 1, 2, and molecules of guests 10, 13, and 15 by SpartanÒ (MM+ Force Field) (A) complex between host 1 and
guest 10 (side view); (B) complex between host 1 and guest 13 (side view); (C) complex between host 1 and guest 15 (side view); (D) complex between host 2 and guest 10
(side view); (E) complex between host 2 and guest 13 (side view); (F) complex between host 2 and guest 15 (side view).
The hydrophobic mouth of host 1 blocks the entrance of hydro-
philic benzylammonium ions, hence the benzyl function cannot get
deep into the cavity of host 1. However, the hydrophilic mouth of
host 2 allows the entry of guest 14 into its deep hydrophobic cavity
and shows stronger binding. Substitution of methyl group at the
para position of benzylammonium function increases the hydro-
phobic area of the guest 15. This methyl function now can get dee-
per into the cavity of host 1, which results in the increased binding
constant as compared to the guest 14.
thus reducing the overall hydrophobic surface to increase its solu-
bility in water. Therefore, guest 16 showed a less association con-
stant as compared to guest 15. Hence, the advantage of the
hydrophilic mouth over the hydrophobic mouth in the recognition
of aromatic ammonium ions is clearly established.
Hosts 1 and 2 also demonstrate the functional group selectiv-
ity—except aromatic quaternary ammonium ions (guests 12, 13),
aromatic ammonium ions (14–16), and neutral heterocycles
(4-methylpyridine 9 and 4-ethylpyridine 10), the aromatic anionic
guests (17–20) do not form stable complexes with hosts 1 and 2
(Table 1, Fig. 3).
Except the difference of a hydrophobic or hydrophilic mouth,
the hydrophobic–hydrophobic interactions, –CH–p interactions,
and stacking interactions can be similar due to the structural
p
–
p
Irrespective of electrostatic interactions, host 1 shows low val-
ues of association constants with guests bearing small hydrophobic
surfaces, as these guests cannot enter through the hydrophobic
mouth. Whereas the hydrophilic mouth of host 2 allows the entry
of guests into its cavity and shows different CH–p, p–p stacking,
and hydrophobic interactions depending upon the depth the guest
similarities of the hosts 1 and 2 for the recognition of guests 14–16.
The ammonium functions of guests 14–16 show favorable electro-
static interactions at the hydrophilic mouth of host 2 in their
respective complexes. In case of host 1, the hydrophobic mouth
blocks the entrance of guests 14–16 and avoids their access to
the deep hydrophobic cavity. As shown in Table 1, it is interesting
to notice that the affinity for guests 14–16 by the hosts 1 and 2 is in
the order of 14 < 16 < 15. This indicates that the substitution of
methyl group at para position increases the strength of binding.
Upon complexation with host 1 the 4-methyl moiety in guest
16 showed less CIUS than the 4-methyl moiety in guest 15, this
indicates that the guest 16 cannot get deep inside the cavity
through the hydrophobic mouth of host 1. However, it enters into
the cavity of host 2 through the hydrophilic mouth, but not to the
depth achieved by guest 15. The extended chain length by one car-
bon atom in 4-(methyl) phenethylammonium moiety in guest 16
puts ammonium function in the vicinity of the aromatic moiety
achieves.
The anions such as 17, 18, and 19 do not show evidence of com-
plex formation with hosts 1 and 2. While the guest 20 with ex-
tended arm of dimethylamino moiety was recognized by hosts 1
and 2 with log K of 2.2 and 2.1, respectively. The hydrophobic
interactions along with –CH–p and p–p stacking interactions im-
prove the binding of guest 20 in the hydrophobic cavities of hosts.
The 1H NMR titration indicates that the dimethylamino moiety
show high value of CIUS as compared to aromatic protons in guest
20, indicating that dimethylamino moiety is exclusively incorpo-
rated into the cavity of hosts 1 and 2, respectively. The binding
of 4-(dimethylamino)benzoate (20) in this mode positions the

S. B. Nimse et al. / Tetrahedron Letters 51 (2010) 2840–2845
2845
guest’s carboxylate group in proximity to the four carboxylate res-
References and notes
idues that decorate the opening of the pocket of the host 2.
The negatively charged functions of guests 17–20 show unfa-
vorable electrostatic interactions at the hydrophilic mouth of the
host 2. In the case of host 1 the hydrophobic mouth blocks the en-
trance of hydrophilic guests 17–19. Hence, the hydrophobic and
hydrophilic mouths of hosts 1 and 2, respectively, play a vital role
in the recognition of anionic guests too.
As shown in Figure 4, the plausible special orientation of com-
plexes between hosts 1, 2, and molecules of guests 10, 13, and
15 is presented by the energy-minimized structures generated by
SpartanÒ (MM + Force Field), respectively.
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In summary, water-soluble aminocalix[4]arene derivatives with
hydrophobic or hydrophilic mouth were synthesized in prominent
yield. The binding behavior and geometrical properties of host
complexes with aromatic cationic, aromatic anionic, and neutral
pyridine molecules have been investigated in the aqueous medium
where the entire natural processes occur. It was of particular inter-
est to us to investigate how and to what extent the difference of a
hydrophobic mouth and a hydrophilic mouth on the top of the deep
hydrophobic cavity of the hosts affects the binding ability of
hosts. The NMR investigations indicate that hosts 1 and 2 can form
1:1 host–guest inclusion complexes with aromatic cationic guests
and pyridine derivatives with high binding constants. Both hosts
refused to recognize the hydrophilic anionic guests. The host 1
with hydrophobic mouth showed high binding constant for
4-ethylpyridine amongst tested guests. However, the hydrophilic
mouth of host 2 enhances the binding of 4-methylbenzylammoni-
um ion, as the carboxylate functions of the mouth show strong
electrostatic interactions with the ammonium function. It is clear
from the data that the cavity of both hosts has a preference for
structurally flat guests containing methyl groups (either a CH3 in
para position of an aromatic ring or a presence of trimethylammo-
nium group) and very poor for smaller but more hydrophilic
primary ammonium groups, which indeed do not enter the hydro-
phobic cavity.
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Acknowledgments
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This study was financially supported by Technology Develop-
ment Program for Agriculture and Forestry and Ministry for Agri-
culture, Forestry and Fisheries, Republic of Korea.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.03.073.
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