Synthesis and binding studies of bowl-shaped hosts for quaternary ammoniums

Article abstract of DOI:10.1246/cl.2002.1166

Two bowl-shaped hosts for quaternary ammonium salts were synthesized and their binding properties, along with the anion effect, were systematically examined and compared in CDCl₃.

Full text of DOI:10.1246/cl.2002.1166

1166
Chemistry Letters 2002
Synthesis and Binding Studies of Bowl-Shaped Hosts for Quaternary Ammoniums
Kyu-Sung Jeong,ꢀ Kwang Hoon Shin, and Soong-Hyun Kim
Department of Chemistry, Yonsei University, Seoul 120-749, Korea
(Received August 12, 2002; CL-020678)
Two bowl-shaped hosts for quaternary ammonium salts were
synthesized and their binding properties, along with the anion
effect, were systematically examined and compared in CDCl3.
Finally three amide carbonyl groups are directed to the cavity of
the host in a convergent way (Figure 1).
A large number of artificial hosts for quaternary ammoniums
(QA’s) have been studied for the last decade, and provided much
experimental evidence for the nature of noncovalent forces,
especially the cationꢁꢀ interaction.1;2 The hosts contain a rigid
cavity for the QA binding surrounded by aromatic surfaces, like in
calixarenes and cyclophanes.2 Because QA salts exist as ion pairs
in organic solvents, the coexisting counteranions have a
significant influence on the binding of QA to the host. The
electrostatic interaction of the ion pair may have either a negative
or a positive effect on the QA binding as recently demonstrated by
several groups including ours.3 We herein prepared two new
bowl-shaped hosts for QA and investigated systematically their
binding properties with QA salts in CDCl3.
The basic scaffold of the hosts is a hexasubstituted benzene
that has been widely used as a molecular building block for the
construction of artificial hosts.4 The synthesis of hosts is outlined
in Scheme 1. 2,4,6-Triethyl-1,3,5-tris(acetic acid) (1)5 and tert-
butyl 4-amino-3,5-dimethylbezoate (2)6 were prepared from
commercially available 1,3,5-triethylbezene and 1,3,5-trimethyl-
benzene, respectively. After reaction with oxalyl chloride, the
acid 1 was coupled with the amine 2 to give the N–H host 3, which
was in turn converted into N–Me host 4.7
Figure 1. Energy-minimized (Tripos, Sybyl 6.3) structures of
the N–H host 3 (left) and the N–Me host 4 (right).
The binding studies were first performed with N–H host 3 and
benzyltrimethylammonium (BTMAþ) halides (5, Xꢁ=Clꢁ, Brꢁ,
and Iꢁ). Upon addition of the host 3 (ꢂ3 equiv) in CDCl3, the
signals for NþCH3 and NþCH2 of BTMAþÁClꢁ were signifi-
cantly upfield shifted (Áꢁ ¼ 1:5 and 1.8 ppm, respectively). This
is a strong evidence for the QA guest locating inside the cavity
surrounded by aryl surfaces of the host. However, the magnitude
of the shifts is highly anion-dependent; Áꢁ = ꢂ1 ppm for
BTMAþÁBrꢁ and <0:3 ppm for BTMAþÁIꢁ when equal amounts
of the host 3 were added. Quantitative binding affinities were
determined by nonlinear least squares fitting of 1H NMR
chemical shift changes observed by diluting a 1 : 1 mixture of
host and guest in CDCl3 at 23 Æ 1 ꢃC. The association constants
(Ka’s) were calculated to be >3  104, 3.4 ðÆ0:2Þ Â 103, and 1.7
ðÆ0:2Þ Â 103 Mꢁ1 for BTMAþClꢁ, BTMAþBrꢁ, and
BTMAþIꢁ, respectively.
As suggested previously,3 this anion dependence may be
rationalized by hydrogen bonds between the amide NH hydrogen
of thehost 3 and the anion Xꢁ of the guest.8 The hydrogen-bonded
anions may exert electrostatic interactions with the oppositely
charged ammonium ions, especially in a less polar organic
solvent, CDCl3. Second, the hydrogen bond may increase the
electron density on the amide carbonyl oxygens and consequently
strengthen the cation–dipole and/or C–HÁ Á ÁO interactions.9
Next, we have prepared the N–Me host 4 that cannot directly
interact with anions through hydrogen bonds. As seen in Figure 1,
the energy-minimized structure10 of the host 4 is very close to that
of the N–H host 3. When the host 4 was added to a CDCl3 solution
of various QA salts, the 1H NMR signals of the NþCHn hydrogen
were gradually upfield shifted (Áꢁ ¼ 0:3{0:5 ppm), but the
degree of the shifts is smaller compared with the N–H host 3. The
association constants are calculated by nonlinear least-square
fitting of 1H NMR titration curves11 and the results are
summarized in Table 1. Job’s plots also confirm a 1 : 1 complex
formation between the host 4 and each of the guests 5–8.12
Trends in the binding affinity are as follows. The magnitude
Scheme 1. a) i) HBr/(CH2O)n/ZnBr2, 42% ii) NaCN/EtOH–
H2O, 95% iii) 50% aqueous H2SO4, 72%, b) i) fuming HNO3/
CH3COOH, 97% ii) CrO3–H2SO4/H2O–CH3COOH, 14% iii)
SOCl2, then t-BuOH–DMAP/CHCl3, 83% iv) H2, Pd–C/MeOH,
96%, c) (COCl)2, then 2/DMAP(cat), 45%, d) MeI–KOH/DMSO,
71%.
According to molecular modeling studies (Tripos, Sybyl 6.3),
the hosts present the following features. First, three benzoate
walls are all positioned to the same side as the result of alternative
up and down conformation of adjacent substituents in the central
benzene. Second, 3,5-dimethyl substituents of the benzoate walls
enforce the aryl plane to be perpendicular to the amide plane and
consequently the cavity becomes surrounded by the aryl surfaces.
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
1167
(2002).
5
C. Walsdorff, W. Saak, and S. Pohl, J. Chem. Res., Synop.,
1996, 282.
6J. P. Schaefer and T. Miraglia, J. Am. Chem. Soc., 86, 6 4
Table 1. Association constants (Ka Æ 10%) between the N–Me
host 4 and ammonium guests in CDCl3 at 23 Æ 0:5 ꢃC
(1964).
7
Physical and spectroscopic properties of the N–H host 3:
mp > 300 ꢃC; 1H NMR (250 MHz, CDCl3) ꢁ 7.67 (br s,
3NH), 7.59 (s, 6H), 3.93 (s, 6H), 2.80 (q, J ¼ 7:3 Hz, 6H),
2.13 (s, 18H), 1.53 (s, 27H), 1.29 (t, J ¼ 7:3 Hz, 9H); 13C
NMR (63 MHz, CDCl3) ꢁ 169.2, 165.3, 143.1, 137.6, 135.1,
130.8, 130.4, 129.5, 81.2, 28.3, 18.6, 15.0; FABMS m=z =
968.5 (7%) for [MÁNa]þ, 944.5 (12%) for [M-H]þ; Anal.
Calcd for C57H75N3O9: C, 72.35; H, 7.99; N, 4.44. Found: C
72.38; H, 7.95; N, 4.45. Physical and spectroscopic properties
of the N–Me host 4: mp > 192–193 ꢃC; 1H NMR (250 MHz,
CDCl3) ꢁ 7.79 (s, 6H), 3.17 (s, 6H), 3.14 (s, 9H), 2.36–2.29
(m, 24H), 1.61 (s, 27H), 0.92 (t, J ¼ 7:2 Hz, 9H); 13C NMR
(63 MHz, CDCl3) ꢁ 171.1, 165.3, 144.9, 141.1, 136.1, 131.7,
130.4, 129.4, 81.6, 34.7, 28.3, 17.5, 14.3; FABMS m=z =
988.7 (100%) for [MH]þ, 987.5 (45%) for [M]þ; Anal. Calcd
for C60H81N3O9: C, 72.92; H, 8.26; N, 4.25. Found: C 72.96;
H, 8.26; N, 4.25.
The formation of the hydrogen bond is evident in the 1H NMR
spectra. When ꢄ3 equivalents of BMTAþXꢁ were added to a
CDCl3 solution of the host (1 mM), large downfield shifts of
the NH signal were observed, Áꢁ ¼ 2:4, 1.9, and 0.7 ppm for
X=Cl, Br, and I, respectively. For hydrogen bonding
interaction between anions and amide NH’s, see: a) F. P.
Schmidtchen and M. Berger, Chem. Rev., 97, 1609 (1997). b)
K. Choi and A. D. Hamilton, J. Am. Chem. Soc., 123, 2456
(2001).
Guest
Ka/Mꢁ1
Guest
Ka/Mꢁ1
5ÁClꢁ
5ÁBrꢁ
5ÁIꢁ
570
8ÁIꢁ
490
140
no binding
no binding
1160
1780
3300
2200
Et4NþÁIꢁ
Bu4NþÁIꢁ
t-BuOH
6ÁIꢁ
7ÁIꢁ
of the association constants between host 4 and BTMAþÁXꢁ is the
order of Clꢁ < Brꢁ < Iꢁ, exactly opposite to that seen with the
N–H host 3. This is expected because tightening the ion pair
weakens the cation binding to the cavity, like in the host 4 having
no hydrogen-bonding site for anion. Second, two hosts 3 and 4
show nearly identical association constant (ꢄ1700 Mꢁ1) toward
BTMAþÁIꢁ, implying that iodide ion is poor hydrogen-bonding
acceptor and exerts negligible anion effect. Third, the host 4 binds
strongly to the small QA guests but negligibly either to a large
guest Bu4NþÁIꢁ or to a neutral guest tert-butanol.
8
In conclusion, the coexisting counteranions have a large
influence on the QA binding in organic solvents, but the
magnitude depends on the nature of the host as well as the anion.
This work was supported by Korea Research Foundation
(KRF-2000-041-D00190).
`
a) S. Tomas, M. C. Rotger, J. F. Gonzalez, P. M. Deya, P.
Ballester, and A. Costa, Tetrahedron Lett., 36, 2523 (1995). b)
´
`
9
References and Notes
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10 This structure is the energy-minimized one of the host 4 when
complexed with tetramethylammonium guest inside the
cavity. In the 1H NMR spectroscopy, the free host 4 contains
a small amount (ꢄ5%) of conformational isomer in CDCl3,
but only one set of 1H NMR signals was observed upon the
complex formation. Therefore, the guest binding seems to
induce the host structure in a way of maximizing inter-
molecular noncovalent interactions.
11 a) R. S. Macomber, J. Chem. Educ., 69, 375 (1992). b) K.-S.
Jeong, Y. L. Cho, S.-Y. Chang, T.-Y. Park, and J. U. Song, J.
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Am. Chem. Soc., 123, 1258 (2001).
3
4
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12 K. A. Corners, ‘‘Binding Constants,’’ John Wiely & Sons,
New York (1984), p 24.