Allosteric binding of anionic guests to a bicyclic host which imitates the action of a 'turnstile'

Article abstract of DOI:10.1039/b506883e

A bicyclic host 1, which has a diethynyl tetrafluorophenyl axis and is expected to behave as an anion-binding 'turnstile', has been designed. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b506883e

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Allosteric binding of anionic guests to a bicyclic host which imitates the
action of a ‘turnstile’{
Osamu Hirata, Masayuki Takeuchi* and Seiji Shinkai*
Received (in Cambridge, UK) 16th May 2005, Accepted 6th June 2005
First published as an Advance Article on the web 28th June 2005
DOI: 10.1039/b506883e
A bicyclic host 1, which has a diethynyl tetrafluorophenyl axis
and is expected to behave as an anion-binding ‘turnstile’, has
been designed.
The design of artificial allosteric systems is of great significance to
regulate the complexation ability or the catalytic activity of
artificial receptors in a nonlinear fashion.1,2 Especially, in a positive
Fig. 1 Cooperative acetate binding to 1 with the energy-minimized
homotropic system, the guest binding information in one subunit
could be passed to all other subunits in unison.3 We have recently
structures of free 1, 1?acetate 1 : 1 complex and 1?(acetate)2 1 : 2 complex.
designed dimeric and oligomeric porphyrins with an axle moiety
Taking acetate anion as a guest, the structures of 1, its 1 : 1
potentially capable of displaying positive homotropic allosterism,
complex and 1 : 2 complex have been energy-minimized (Insight II,
which can be utilized as a new concept to achieve nonlinear
Discover 3). It is clearly seen from Fig. 1 that two cavities in 1 can
amplification of binding events and chemical signals towards high
be sterically filled up by a ‘turnstile’ tetrafluorophenyl group and
guest selectivity and high guest affinity.4 In these systems, the
two ‘frame’ tetrafluorophenyl groups, but when the first acetate
porphyrins can rotate (or oscillate) relative to each other like two
anion is bound, the residual cavity is largely opened and
wheels around a central metal ion,5 a bridging C(sp2)–C(sp2) bond,6
preorganized. The F atoms in the ‘turnstile’ and ‘frame’ phenyl
butadiyne,7 ethynylene8 or terphenyl group9 which act as an axle.
groups are introduced to increase the steric crowding for the closed
We report herein that a bicyclic host 1 having two bisamide-type
state.
anion-binding sites with a diethynyltetrafluorophenyl ‘turnstile’10
displays a cooperative response towards anions.11,12 Anion
Compound 1 was synthesized according to Scheme 1 and
identified by 1H NMR, 19F NMR and HR-FABMS spectroscopic
recognition events are ubiquitously seen in nature and have
evidence.{
frequently been investigated for designing artificial receptors.13,14 It
Upon addition of anion [acetate, phosphate, dibenzylphos-
is often difficult to control selectivity and sensitivity among anions
phinate (Bz2P), hydrogensulfate and halides as n-tetrabutyl-
because of their wide range of geometries, low charge to radius
ammonium salts] to a solution of 1 in THF-d8–DMSO-d6 5 : 1
ratios and high solvation energies.13h Initially, 1 adopts a closed
state which prevents the approach of guest anions, but when the
first anion is bound to one site, the ‘turnstile’ is forced to rotate to
give an open state which elicits the cooperative binding of a second
anion to another site (Fig. 1).
Scheme 1 Reagents and conditions: (i) NaNO2, KI, conc. HCl(aq),
0 uC 79%; (ii) 3-methyl-1-butyne-3-ol, Pd(PPh3)2Cl2, CuI, NH(i-Pr)2,
reflux 39%; (iii) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline,
Department of Chemistry and Biochemistry, Graduate School of
Engineering, Kyushu University, 6-10-1 Hakozaki, Higashi-ku,
K2CO3, THF, reflux 67%; (v) NaOH, THF–EtOH, r.t 93%.; (vi) SOCl2,
Fukuoka, 812-8581, Japan. E-mail: taketcm@mbox.nc.kyushu-u.ac.jp;
Pd(dppf)Cl2, Na2CO3, DME–H2O, reflux 73%; (iv) ethylbromoacetate,
reflux quant.; (vii) NaOH, toluene, reflux 93%; (viii) 1,4-diiodotetrafluor-
seijitcm@mbox.nc.kyushu-u.ac.jp; Fax: +81-92-642-3611
obenzene, Pd(PPh3)2Cl2, CuI, NH(i-Pr)2, reflux 62%; (ix) 9, 2,6-lutidine,
{ Electronic supplementary information (ESI) available: experimental
CH2Cl2, r.t. under high dilution conditions, 24%.
details. See http://dx.doi.org/10.1039/b506883e
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Chem. Commun., 2005, 3805–3807 | 3805

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We analyzed the plot for acetate in Fig. 3 with a nonlinear least-
squares method assuming the stepwise formation of 1 : 1 and 1 : 2
complexes and the association constants are summarized in
Table 1. The association constants thus obtained are K1
5
144 M21 for the 1 : 1 complex and K2 5 66 M21 for the 1 : 2
complex (formation from the 1 : 1 complex), which satisfy the
prerequisite for positive homotropic allosterism, K2 . 0.25K1
although the cooperativity is not so high.17 The Hill coefficients
and association constants for four other anions were evaluated by
both Hill’s equation and a nonlinear least-squares method
(Fig. S4{). It is seen from the results summarized in Table 1
that (i) dibenzylphosphinate (Bz2P2), bromide and hydrogensul-
fate also have n 5 1.4–1.5 comparable with that for acetate
anion and the K1 and K2 values also satisfy the prerequisite
for positive homotropic allosterism and (ii) the magnitudes of
the K1 and K2 values correlate to the basicity of each guest
anion.
Fig. 2 1H NMR spectra (600 MHz) of 1 (4.0 mM) in THF-d8–DMSO-
d6 (5 : 1, v/v) upon addition of acetate anion at 25 uC.
(v/v) mixed solvent, the peak for the NH protons in 1H NMR and
those for the F atoms in 19F NMR both shift to lower magnetic
fields with an increase in the anion concentration (Figs. 2, S1 and
S2{).15 A typical example for tetra-n-butylammonium acetate is
shown in Fig. 2. In Table 1, we summarize the Dd values for the
NH protons and F atoms in the saturated region of the titration
experiments. The results in Table 1 show that the shift width
correlates to the basicity of each guest anion.
There are two exceptions, however. Firstly, complexation of 1
with chloride did not satisfy the allosteric binding mode, having
n 5 1.1 and K2 (518 M21) , 0.25K1 (527 M21), indicating that
there is no cooperativity. The K1 value for chloride is sufficiently
high among anions tested herein. Probably, the ion size of the
chloride anion is not large enough to regulate the ‘turnstile’
tetrafluorophenyl group and the first guest binding cannot
provide the preorganized open cavity advantageous to the second
guest binding.18 This result means that the slight difference in the
From plots of DdNH against guest concentration one can
estimate the complexation mode and the association constants
(Fig. 3). A plot of DdNH vs. [1]/([1] + [acetate]) (Job plot16) gave a
maximum at 0.33 (Fig. S3), indicating that the complex consists of
1 : 2 1 : acetate stoichiometry. Although the sigmoidal curvature
characteristic of a positive homotropic system is not clearly seen in
Fig. 3, the Hill plot for 1 and acetate provides evidence with n (Hill
coefficient) 5 1.4, showing that the acetate binding to 1 is taking
place cooperatively.17
ion size between chloride (the radius of chloride anion in an
13h
octahedral environment is 1.67 A ) and bromide (1.82 A13h) has
˚
˚
a
decisive influence on the cooperativity. Secondly, upon
addition of fluoride salt, the colour of the solution of 1 turned
from yellow to orange with significant UV-Vis spectrum change,
which was not observed for the addition of other anions.
1
Furthermore, the H NMR spectrum in the presence of fluoride
gave the complicated split patterns. This colour change is
rationalized by the acid–base reaction between the NH protons
in 1 and fluoride anion rather than the hydrogen-bonding
interaction19 (Fig. S5{).
Table 1 Anion binding parameter of
(5 : 1, v/v) at 25 uC
1 in THF-d8–DMSO-d6
Binding constantb/M21 Dd of 1?X2 complex/ppmc
2
na K1
K2
N–H
Ar–F
In conclusion, we have succeeded in the molecular design of a
new dynamic host having an allosteric anion-binding function,
motivated by the action of a ‘turnstile’. Furthermore, the designed
host is able to recognize anionic guests, the allosteric binding of
which has scarcely been investigated so far in spite of its biological
importance. We are now extending this dynamic recognition
system to anion-binding in an aqueous system, aiming at the
design of an allosteric interface with biologically-important guest
anions.
CH3COO2 1.4 144 ¡ 2
66 ¡ 3
71 ¡ 4
18 ¡ 2
18 ¡ 5
9 ¡ 2
2.34
2.02
1.64
0.73
0.18
0.93, 0.32
Bz2P2
Cl2
1.4 196 ¡ 5
1.1 110 ¡ 2
1.5 50 ¡ 3
1.4 28 ¡ 1
b
0.46, 0.28
0.35, 0.22
Br2
HSO4
2
a
c
, 10%. Saturation point of anion
Hill coefficient. Errors
titration curve.
We would like to thank Dr. Kazunori Sugiyasu for initial efforts
on this project. The present work is partially supported by a
Grant-in-Aid for Scientific Research B (17350071) and the 21st
Century COE Program, ‘Functional Innovation of Molecular
Informatic’ from the Ministry of Education, Culture, Science,
Sports and Technology of Japan.
Notes and references
{ 1H NMR (600 MHz, THF-d3, d/ppm, J/Hz) 1.38 (s, 18H), 4.85 (s, 8H),
7.41 (s, 4H) 7.56 (d, J 5 8.3, 8H), 7.68 (d, J 5 8.3, 8H), 9.29 (s, 4H). 19
NMR(500 MHz, THF-d8, TFA); 261.1, 281.9 ppm. HR-FABMS
(matrix: NBA) calcd. (found) for C74H50F12N4O8 1350.3437 (1350.3430).
F
Fig. 3 Plots of DdNH of 1 as a function of added anion.
3806 | Chem. Commun., 2005, 3805–3807
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This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 3805–3807 | 3807