A regioselectively bis(thiourea)-substituted dibenzo-diaza-30-crown-10: A new strategy for the development of multi-site receptors

Article abstract of DOI:10.1016/S0040-4039(00)00819-4

Due to our interest in the functionalization of dibenzo-30-crown-10 moiety, a regioselectively dinitro-derived congener 1 was conveniently synthesized. The availability of the compound as a building block to develop new molecular systems allowed us to pre

Full text of DOI:10.1016/S0040-4039(00)00819-4

Tetrahedron Letters 41 (2000) 5219±5223
A regioselectively bis(thiourea)-substituted
dibenzo-diaza-30-crown-10: a new strategy for the
development of multi-site receptors
Tomokazu Tozawa,a Yoshihiro Misawa,a Sumio Tokitaa and Yuji Kuboa,b,
*
aDepartment of Applied Chemistry, Faculty of Engineering, Saitama University, 255 Shimo-ohkubo, Urawa,
Saitama 338-8570, Japan
bForm and Function, PRESTO, Japan Science and Technology Corporation (JST), Department of Applied Chemistry,
Faculty of Engineering, Saitama University, 255 Shimo-ohkubo, Urawa, Saitama 338-8570, Japan
Received 22 March 2000; accepted 19 May 2000
Abstract
Due to our interest in the functionalization of dibenzo-30-crown-10 moiety, a regioselectively dinitro-
derived congener 1 was conveniently synthesized. The availability of the compound as a building block to
develop new molecular systems allowed us to prepare a multi-site receptor 3, desirable for cooperative
complexation of cationic and anionic species in an induced ®t fashion. Indeed, K+ accommodated in the
crowned cavity did not only tune the conformation to bind anions but also associated in the anion binding
eciently. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: crown ethers; macrocycles; molecular recognition; thioureas.
Numerous e€ects have been devoted to the development of synthetic receptors possessing
crown ether units1 since the discovery of crown ether complexes by Pedersen. Moreover, recently,
use of dibenzo-24-crown-8 has attracted much attention for the generation of novel psudorotaxanes.2
However, surprisingly, the study of dibenzo-30-crown-10-derived systems is limited in spite of the
fact that unique complex structures with potassium ion (K+)3 and electron-de®cient pyridinium
derivatives4 were obtained; this may be due to the diculty in modi®cation of the skeleton.
Indeed, the rare examples of disubstituted dibenzo-30-crown-10s5 required multiple stepwise
synthesis involving troublesome protection±deprotection.6 Meanwhile, in our ongoing program
to develop function-tunable molecular systems (e.g. allosteric e€ect),7 we have been intrigued by
the utilization of the highly ¯exible dibenzo-30-crown-10 macrocycle, the large conformation
change of which upon complexation leads us to design the relevant systems. However, according
to the desired property, suitable functional groups should be pre-organized in the system. Based
* Corresponding author. Fax: +81-(0)48-858-3514; e-mail: yuji@apc.saitama-u.ac.jp
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00819-4

5220
on a retro-synthesis, we succeeded in synthesizing regioselectively dinitro-substituted diaza con-
gener 1 from commercially available material 2 in only three steps, which would be a key building
block to develop new receptors because the conversion of the nitro substituent to several func-
tional groups is quite easy. With this strategy in mind, incorporating thiourea units as an ecient
anion-binding site8 onto the building block can create a multi-site receptor for a unique coop-
erative recognition of cationic and anionic species.9 As detailed below, this does in fact occur
upon the title receptor 3.
The synthetic procedure is shown in Scheme 1. The commercial compound 2 was reacted with
3,6,9-trioxaundecane-1,11-diyl bistosylate in the presence of K2CO3 to produce podand 4, followed
by nucleophilic reaction with MeNH2 to a€ord 5 in quantitative yield.10 Again, the Williamson
synthesis with 3,6,9-trioxaundecane-1,11-diyl bistosylate was performed to give the synthon 111 in
22% yield after column chromatography. This, via reduction (to produce 6) and the reaction with
MeNCS, converted into the desired 312 conveniently.
Scheme 1. Reagents and conditions: (i) 3,6,9-trioxaundecane-1,11-diyl bistosylate, K2CO3, dry acetone, re¯ux, quant.; (ii)
methanolic solution of MeNH2 (40% v/v), in sealed tube, 100ꢀC, quant.; (iii) 3,6,9-trioxaundecane-1,11-diyl bistosylate,
NaH, dry DMF, 80ꢀC, 22%; (iv) 10% Pd/C, H2 (2 atom), EtOH, rt; (v) MeNCS, CH2Cl2, 40ꢀC; 40% (from 1 to 3)
1H NMR dilution experiments in CD3CN on 3 and N-phenylthiourea 7 were carried out so
that almost no concentration-dependent shifts of thiourea hydrogens took place, suggesting that
the e€ect arising from interaction between the thiourea units was quite small. As a consequence,
system 3 was deduced to have a ¯exible structure in the polar solvent. Quantitative assessment of
the cooperative ion-pair binding properties was made by 1H NMR titration using CD3CN solution.
We initially tested the complexation behavior with potassium tetrakis(p-chlorophenyl)borate
(KTCPB) as a putative cation. The K+-induced spectral shifts were observed with overall chemical
shifts of the crowned moiety; in particular, the proximal proton resonances in terms of nitrogens
shifted up®eld by 0.34 ppm for N-CH3 and 0.26 ppm for N-CH2CH2-, respectively, indicating
that K+ was accommodated in the concave cavity of the crowned site. Also noted is that K+ led
the resonances of thiourea NHs to down®eld by ca. 0.1 ppm, bringing about an enhancement of the
acidity. Use of a Job plot analysis13 suggested a 1:1 stoichiometry of the complex. The association
constant was calculated as 5,600 M^1 by use of a nonlinear curve-®tting procedure and adding of
3 equiv. of K+ to 3 (2 mM) allowed for ca. 95% of K+-3 complex. Based on this ®nding, we

5221
Figure 1. (a) Titration plots of Ar-NHC(S) resonance of 3 upon addition of (PhO)2P(O)O^ in CD3CN: (*) 3+K+ (3
equiv.); (*) 3; [3]=2.0 mM at 297 K; (b) an energy-minimized complex structure [3-K+-(PhO)2P(O)O^]
investigated the cation-facilitated binding with anions. Fig. 1(a) shows the results of titration in
which the shifts of Ar-NH-C(S) resonances were monitored as a function of the incremental
amounts of (PhO)2P(O)O^ in the absence and presence of 3 equiv. of K+. Clearly, the presence of
K+ caused a much more rapid shift in the resonance than did only system 3. The analysis of the
!
binding curves led us to consider two stepwise complexations as follows: H+G
HG (K1),
!
HG+G
HGG (K2), [H0]=[H]+[HG]+[HGG], wherein [H] and [G] refer to the system 3 and
anion, respectively. A nonlinear curve-®tting procedure14 based on the complexation modes could
fully reproduce the experimental data to estimate each association constant (K1 and K2). The
values as well as the result of the case with I^ are summarized in Table 1. System 3 shows high
selectivity for an oxoanion such as (PhO)2P(O)O^, as comparing with K1ÂK2, which is suggestive
of a signi®cant binding by the thiourea units. Therefore, an ecient cooperative complexation of
K+ and (PhO)2P(O)O^ was obtained; the K1 value of the phosphate ion increased remarkably by a
factor of 19 upon the presence of K+, being 9,200 M^1. Although similar positive cooperative
binding was also observed in the case of I^, by adding the cation there was a considerable increase
in 1:1 stoichiometric recognition with (PhO)2P(O)O^ over I^, with the selectivity of 130-fold. This
was taken as indication that a certain K+-assisted organization of the receptors favored the ditopic
binding with the phosphate ion, accompanying an increase in acidity of the thiourea protons. The
binding ability toward the phosphate ion could also be accelerated with added Cs+ as a tetra-
phenylborate salt (CsTPB)15 (see Table 1). However, because of the greater ionic size of Cs+ the
e€ect was not as strong as that in the case of K+.
As a control experiment, when 8, lacking the crowned cavity, was used for the complexation
event, there was not such signi®cant cooperative binding behavior. The energy-minimized molecular
model16 (Fig. 1(b)) has implied that 3 binds simultaneously K+ and (PhO)2P(O)O^ in an induced
®t fashion where the distance between the encapsulated ions is ca. 6.3 A. The value would provide
a signi®cant electrostatic interaction. Presently, we are attempting to obtain an X-ray crystal
structure of the 3-K+-(PhO)2P(O)O^ complex to clarify such result.

5222
Table 1
Association constants (K1 and K2/M^1)a for 3 with anions in
the absence and presence of metal ions in CD3CN at 297 K
In conclusion, the results described in this paper lead us to suggest a new approach to a multi-
site receptor for cooperative ion-pair binding. Most notably, use of K+ remarkably enhanced the
binding ability of the phosphate ion at two thiourea units. This feature may be applicable to an
arti®cial catalysis enabling hydrolyzation of phosphate diesters;17 the corresponding cation-
regulated catalytic systems are possible by modifying this receptor. Of course, the synthetic
availability of the synthon 1 could allow us to develop other cooperative or allosteric systems.
Extensive e€orts are being directed toward this end.
Acknowledgements
This work is partly supported by TORAY Award in Synthetic Organic Chemistry, Japan.
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