Tetramidocavitand: strong anion receptor by well-organized four -(C{double bond, long}O)N-H?X- interactions

Article abstract of DOI:10.1016/j.tetlet.2009.12.144

Resorcin[4]arene-based tetramidocavitands containing four secondary amide groups on their upper rim showed strong RSO₃^- (R = methyl or ethyl) binding properties. The caviplex formation through hydrogen bonds of -(C{double bond, long}O)N-H?X^- was supported by ¹H NMR and crystal structure analyses. In a mixture of C₂D₂Cl₄/DMSO/D₂O = 5:15:2 at 25 °C, the thermodynamic parameters for caviplex CH₃ SO₃^-@1, ΔG (kcal mol^-1), ΔH (kcal mol^-1), and ΔS (cal K^-1 mol^-1), are -3.7, -8.6, and -16.7, respectively.

Full text of DOI:10.1016/j.tetlet.2009.12.144

Tetrahedron Letters 51 (2010) 1291–1293
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Tetrahedron Letters
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Tetramidocavitand: strong anion receptor by well-organized
four –(C@O)N–Hꢀ ꢀ ꢀXꢁ interactions
Nak Shin Jung, Jaeok Lee, Sang Beom Choi, Jaheon Kim, Kyungsoo Paek
*
Department of Chemistry, Soongsil University, Seoul 156-743, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Resorcin[4]arene-based tetramidocavitands containing four secondary amide groups on their upper rim
ꢁ
Received 16 November 2009
Revised 22 December 2009
Accepted 24 December 2009
Available online 11 January 2010
showed strong RSO3 (R = methyl or ethyl) binding properties. The caviplex formation through hydrogen
bonds of –(C@O)N–Hꢀ ꢀ ꢀXꢁ was supported by 1H NMR and crystal structure analyses. In a mixture of
C2D2Cl4/DMSO/D2O = 5:15:2 at 25 °C, the thermodynamic parameters for caviplex CH3SO3ꢁ@1,
DG
(kcal molꢁ1),
D
H (kcal molꢁ1), and
D
S (cal Kꢁ1 molꢁ1), are ꢁ3.7, ꢁ8.6, and ꢁ16.7, respectively.
Ó 2010 Elsevier Ltd. All rights reserved.
The concave organic receptors, cavitands have great potentials as
an attractive host due to their versatile hydrophobic cavity as well as
a variety of functional groups attachable on their rims.1 These resor-
cin[4]arene-based cavitands are capable of functions as neutral
molecular receptors2 or molecular capsules.3 Even, some of them
can recognize and bind anions with limited accomplishments
though.4 Using hydrogen bonding interactions, Y–Hꢀ ꢀ ꢀXꢁ (Y = C,5
O,6 or N;7 Xꢁ = anions) is an efficient manner for recognizing anions,
which has got a great attention recently. Especially, amide,8 urea,9
and pyrrol10 groups can convey those interactions and work effi-
ciently in many strong and selective anion receptors. Here, we pres-
ent resorcin[4]arene-based tetramidocavitands that can recognize
and capture effectively organic sulfonates by forming multiple
hydrogen bonds comprising amido donors and oxygen acceptors.
Resorcin[4]arene-based tetramidocavitands which could form
well-organized four –(C@O)N–Hꢀ ꢀ ꢀXꢁ hydrogen bonds upon the
addition of Xꢁ were designed and characterized. Tetramidocavit-
ands 1–3 were synthesized from tetrakis(chlorocarbonyl)cavitand
44b and t-butylamine, p-nitroaniline, or N,N-dimethylamine in
the presence of triethylamine at room temperature in CHCl3
(Scheme 1). Pure compounds of 1, 2, and 3 were obtained by re-
crystallization from the mixtures of CH2Cl2 and MeOH in 40%,
45%, and 50% yields, respectively, and were characterized by 1H
NMR, 13C NMR, MALDI-TOF, and elemental analyses.
new peaks for an amido proton Ha of 1 and methyl protons of
the methanesulfonate appeared at 7.64 and ꢁ1.81 ppm, respec-
tively, which is strongly indicative of the formation of a caviplex,
CH3SO3ꢁ@1. It is noticeable that the signal for the inner proton
Hin of the dioxymethylene bridge (O–CHinHout–O) also moved to
downfield slightly (Dd = 0.25 ppm). This observation suggests that
there is a weak interaction between –Hin and ꢁO3SCH3.4a When
1 equiv TBACH3SO3 was added to 1, the peaks Hb and Hin for the
free cavitand 1 disappeared and only the peaks for caviplex
CH3SO3ꢁ@1 remained. There were no further chemical shift
changes for caviplex CH3SO3ꢁ@1 by the addition of 2 equiv
TBACH3SO3, which confirms that cavitand 1 and methanesulfonate
ion form a 1:1 complex.
For the caviplex CH3SO3ꢁ@2 in CDCl3: DMSO-d6, 1H NMR spec-
tra showed the upfield shift of the –NHa signal from 10.48 to
9.76 ppm (
D
d = ꢁ0.72 ppm) upon complexation. This implies that
a hydrogen bonding partner of the amido group was changed from
DMSO-d6 to a methanesulfonate donor. As shown in the case of 1,
the inner proton Hin of 2 moved also to downfield from 4.68 to
5.05 ppm
(
D
d = 0.37 ppm). The guest peak for cavipleꢁx
CH3SO3ꢁ@2 appeared at ꢁ1.40 ppm, which indicates that CH3SO3
in caviplex CH3SO3ꢁ@2 nests less snugly than that in caviplex
CH3SO3ꢁ@1.
When cavitand 1 or 2 was titrated in CDCl3 at 25 °C with tetra-
butylammonium ethanesulfonate, only caviplex CH3CH2SO3ꢁ@2
was formed. It is presumable that the blocking t-butyl groups of
cavitand 1 limit the size of guest. 1H NMR spectrum of caviplex
CH3CH2SO3ꢁ@2 shows that methyl peak of complexed ethanesulf-
onate appeared at –1.54 ppm. It is upfield shift of 2.70 ppm from
that of free ethanesulfonate at 1.16 ppm which is rather small
compared to that of methanesulfonate, 4.08 ppm. The negative
mode MALDI-TOF Mass spectra of caviplex CH3SO3ꢁ@1 and
CH3SO3ꢁ@2 showed strong peaks at 1,419.9 for [CH3SO3ꢁ þ 1]
and 1680.8 for [CH3SO3ꢁ þ 2], respectively.
Figure 1 shows 1H NMR spectral changes of 1 by the addition of
tetrabutylammonium methanesulfonate (TBACH3SO3) in CDCl3 at
25 °C, and the chemical shift changes of the hydrogen atoms near
the cavity are summarized in Table 1. When 0.5 equiv TBACH3SO3
was added to 1, the peaks of Hb and Hin were split into two 1:1
peaks for free and complexed hosts, respectively. In addition, two
* Corresponding author. Tel.: +82 2 820 0435; fax: +82 2 826 1785.
E-mail address: kpaek@ssu.ac.kr (K. Paek).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.144

1292
N. S. Jung et al. / Tetrahedron Letters 51 (2010) 1291–1293
Cl
Cl
Cl
Cl
O
O
Hin
O
O
Hout
X
X
X
X
O
O
O
O
O
O
O
amine
O
O
O
O
O
O
O
O
O
O
O
O
O
NEt3, CHCl3, rt,
Hb
C7H15
C7H15
C7H15
C7H15
C7H15
C7H15
C7H15
C7H15
4
1: X = (CH3)3C-NHa
2: X = 4-NO2-
NHa
Hc
3: X = (CH3)2N-
Scheme 1. Syntheses of tetramidocavitands 1, 2, and 3.
Table 2
Thermodynamic parameters of caviplexes G@1 and G@2 at 25 °C
Host
1
Guest
Solution
Ka
D
Gb
D
Hb
D
Sc
ꢁ
ꢁ
CH3SO3
C2D2Cl4/DMSO/D2O
= 5:15:2
C2D2Cl4/DMSO/D2O
= 5:15:4
C2D2Cl4/DMSO
= 9:1
C2D2Cl4/DMSO
= 8:2
560
ꢁ3.7
ꢁ1.6
ꢁ3.5
ꢁ2.4
ꢁ2.1
ꢁ8.6
ꢁ6.7
ꢁ7.1
ꢁ6.6
ꢁ5.3
ꢁ16.7
ꢁ17.1
ꢁ12.2
ꢁ14.1
ꢁ10.9
14
380
61
2
CH3SO3
ꢁ
CH3CH2SO3
C2D2Cl4
36
a
b
c
Mꢁ1
,
kcal molꢁ1
.
cal Kꢁ1 molꢁ1
.
respectively. All the binding processes in Table 2 are enthalpy dri-
ven. Caviplex G@1 is much more inert than caviplex G@2 which dis-
sociates completely in a mixture of C2D2Cl4/DMSO/D2O = 5:15:2 at
25 °C. The corresponding thermodynamic parameters of caviplex
CH3SO3ꢁ@2 in C2D2Cl4: DMSO = 9: 1 are ꢁ3.5, ꢁ7.1, and ꢁ12.2,
respectively. Caviplex CH3CH2SO3ꢁ@2 shows an equilibrium shift
even in C2D2Cl4 and those corresponding thermodynamic parame-
ters are ꢁ2.1, ꢁ5.3, and ꢁ10.9, respectively. Caviplex CH3SO3ꢁ@2
is much more stable than caviplex CH3CH2SO3ꢁ@2.
Figure 1. The partial 1H NMR spectra showing the chemical shift changes of
cavitand 1 by the addition of tetrabutylammonium methanesulfonate (G) in CDCl3
at 25 °C; (a) 0.0 equiv G, (b) 0.5 equiv G, (c) 1.0 equiv G, (d) 2.0 equiv G.
Table 1
Chemical shift changes of selected protons of cavitands 1 and 2 in 1H NMR spectra by
the addition of TBACH3SO3 (G) in CDCl3 for cavitand 1 and CDCl3/DMSO-d6 for
cavitand 2 at 25 °C
The crystal structure of caviplex CH3SO3ꢁ@1 shown in Figure 2
supported the spectroscopic observation studied in solution.11
The anion is captured in the host with its methyl group directing
to the inner cavity, and the three sulfonate oxygen atoms are ly-
ing on the plane defined by four amide N atoms of 1. The closest
distances between amide H atoms and three oxygen atoms in
Cavitand
Chemical shift (d in ppm) of proton
ꢁ
CH3SO3
Ha
Hb
Hin
Hc
Free
Complexed
ꢁ
No G
1
2
1
2
1
2
—
7.00
7.50
6.93
7.41
4.75
4.68
5.00
5.05
+0.25
+0.37
—
7.86
—
7.95
—
0.09
—
—
2.68
2.68
—
—
—
ꢁ1.81
ꢁ1.40
ꢁ4.49
ꢁ4.08
CH3SO3 are in the range of 2.054–2.284 Å (av. 2.140 Å) (Fig. 3).
10.48
7.64
9.76
—
These values are within the range of normal hydrogen bonding
distance, 1.2–2.2 Å.12 In addition, the oxygen atoms (O1G, O2G,
and O3G) seem to involve with non-conventional hydrogen bonds
with C–Hin groups, too; their distances are 2.541, 2.450, and
2.341 Å (av. 2.444 Å), respectively, which are within the range
of weak hydrogen bonding distance, 2.2–3.2 Å.12 All these hydro-
gen bonds play a cooperative role in holding the guest because
O1G and O2G interact, respectively, with a pair of one CH and
one NH while O3G does with a pair of one CH and two NH groups
as shown in Figure 3. The bulky tetrabutylammonium is apart
from the cavity of 1 as expected.
2 equiv G
D
d
ꢁ0.07
ꢁ0.72
ꢁ0.09
—
Table 2 shows thermodynamic parameters of caviplexes G@1
and G@2 at 25 °C. Caviplex CH3SO3ꢁ@1 is extremely inert in most
organic solvents and only showed a slow equilibrium shift in an
aqueous solution. In a mixture of C2D2Cl4/DMSO/D2O = 5:15:2 at
25 °C, the thermodynamic parameters,
D
G
(kcal molꢁ1),
D
H
The requirement of the secondary amide groups for anion bind-
ing has been assessed again by the experiments with cavitand 3
(kcal molꢁ1), and
D
S (cal Kꢁ1 molꢁ1), are ꢁ3.7, ꢁ8.6, and ꢁ16.7,

N. S. Jung et al. / Tetrahedron Letters 51 (2010) 1291–1293
1293
solution. In a mixture of C2D2Cl4/DMSO/D2O = 5:15:2 at 25 °C, the
thermodynamic parameters,
D D
G (kcal molꢁ1), H (kcal molꢁ1),
and
D
S (cal Kꢁ1 molꢁ1), are ꢁ3.7, ꢁ8.6, and ꢁ16.7, respectively.
Caviplex G@2 is much less inert than caviplexes G@1. All the bind-
ing processes are enthalpy driven. Various derivatives of tetramid-
ocavitands
1 and 2 and their kinetic and thermodynamic
properties for various anions are being studied to tune their bind-
ing properties.
Acknowledgments
The financial support from Center for Bioactive Molecular
Hybrids (Yonsei University) is acknowledged.
Figure 2. A stereo-view of caviplex CH3SO3ꢁ@1 depicted by ORTEP with 50%
ellipsoids. Hydrogen atoms are omitted for simplicity.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.12.144.
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Figure 3. Crystal structure of (TBA)(CH3SO3ꢁ@1) with selected inter-atomic
distances (Å). The amide and methylene hydrogen atoms (light blue) of 1 are only
shown for clarity.
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having four tertiary amide groups. The addition of 2 equiv TBACH3-
SO3 to cavitand 3 in CDCl3 resulted in no chemical shift changes of
cavitand 3 in 1H NMR spectrum, and no signals for the would-be
ꢁ
complexed CH3SO3 in the range of 0 to ꢁ4 ppm either. When
the energy minimization of a caviplex CH3SO3ꢁ@3 model structure
was conducted using SPARTAN’04 V1.03 (Molecular Mechanics
ꢁ
MMFF), the CH3SO3 ion was ejected from the cavity, indicating
that cavitand 3 cannot act as a methanesulfonate receptor. In this
aspect, it is certain that tetramidocavitands 1 and 2 bind anions
mainly via (C@O)N–Hꢀ ꢀ ꢀXꢁ interactions. This conclusion can lead
to such an interpretation that the combined interaction of the
weak O2HC–Hꢀ ꢀ ꢀXꢁ hydrogen bondings and the size complemen-
tarity between host and guest cannot be enough for the caviplex
formation in the conditions studied here.4a
11. A suitable crystal for the X-ray crystallography was grown by a slow diffusion
In this work, we have presented that resorcin[4]arene-based
tetramidocavitands 1 and 2 containing four secondary amide
groups on their upper rim showed strong anion binding properties.
These bind strongly CH3SO3ꢁ and CH3CH2SO3ꢁ in a 1:1 ratio mainly
through hydrogen bonds of –(C@O)N–Hꢀ ꢀ ꢀXꢁ supported by 1H
NMR and crystal structure analyses. Both caviplexes G@1 and
G@2 are extremely stable in most organic solvents. Caviplex
CH3SO3ꢁ@1 only showed slow equilibrium shift in an aqueous
of benzene into
a mixed solution of CH2Cl2 and MeOH containing
(TBA)(CH3SO3ꢁ@1). Crystal data of (TBA)(CH3SO3ꢁ@1)ꢀ(C6H6)0.5
: C100H158-
N5O15S, Mr = 1702.37, triclinic, space group P(ꢁ1), a = 17.094(3) Å, b =
17.800(4) Å, c = 19.804(4) Å,
a = 116.32(3), b = 105.02(3), c = 98.39(3), V =
4974.2(17) Å3, Z = 2, dcalc = 1.137 g/cm3, T = 100(2) K, k(MoK ) = 0.71073 Å,
a
2h = 39.56, 8325 independent reflections, GOF = 1.054, R1 = 0.0557 (I > 2
r(I),
7827 reflections), wR2 = 0.1612 (all data).
12. Steed, J. W.; Atwood, J. L. Supramolecular Chemistry, 2nd ed.; John Wiley & Sons
Ltd: UK, 2009. Chapter 1.