Self-assembly and binding properties of a metallomacrocycle having two interactive binding subcavities

Article abstract of DOI:10.1039/b306497b

A metallomacrocycle containing two topologically discrete binding subcavities is self-assembled and shows a positive homotropic cooperative binding behavior.

Full text of DOI:10.1039/b306497b

Self-assembly and binding properties of a metallomacrocycle having two
interactive binding subcavities†
Sung-Youn Chang, Myoung-Chul Um, Hyounsoo Uh, Hye-Young Jang and Kyu-Sung Jeong*
Department of Chemistry, Yonsei University, Seoul 120-749, S. Korea. E-mail: ksjeong@yonsei.ac.kr;
Fax: (+)82-2-364-7050; Tel: (+)82-2-2123-2643
Received (in Cambridge, UK) 9th June 2003, Accepted 24th June 2003
First published as an Advance Article on the web 3rd July 2003
A metallomacrocycle containing two topologically discrete
binding subcavities is self-assembled and shows a positive
homotropic cooperative binding behavior.
(Fig. 1a) in 3% (v/v) CD3CN–CDCl3. The ESI-mass experi-
ments also support the formation of 1 : 2 (1 : 9) complex. For
example, in 3% (v/v) CH3CN–CHCl3, the ESI-mass spectrum
of 1 in the presence of excess 9 ( ~ 10 equiv) showed
characteristic peaks corresponding to 1 : 2 complex; [MG2 2
A large number of the coordinate bond-mediated macrocycles
such as triangles, squares, rectangles and higher polygons have
been prepared in the last decade.1 These metallomacrocycles
have rigid cavities of single binding domain that potentially
accommodate small molecules.2 Herein we report a new class of
the metallomacrocycle 1 that folds to generate two homotropic
binding subcavities and therefore gives an opportunity to
investigate allosteric binding events.3 On the guest binding, two
identical subcavities of 1 strongly interact with each other and
show a positive homotropic cooperativity.
The ligand 8 designed here consists of three functional parts;
the pyridyl end for metal coordination, the pyridine-dicarbox-
amido corner for hydrogen bonding site, and the butadiynyl unit
for the connection. Especially, the butadiynyl unit in the middle
has been chosen to minimize possible steric congestion around
the crossing point of two ligand strands on the self-assembly of
the metallomacrocycle. Furthermore, its rigidity prevents the
formation of mononuclear macrocycles by 1 : 1 (ligand : metal)
assembly. The synthesis of 8 is outlined in Scheme 1. Reaction
4
of 8 with the metallic moiety Pd(dppp)OTf2 provided the
corresponding metallomacrocycle 1 in 95% isolated yield.
Elemental analysis was consistent with the molecular
formula of 1. The 1H NMR signal for the terminal pyridines was
downfield shifted by 0.3 ppm relative to that of free ligand 8, as
expected on the coordination of the pyridyl nitrogen to the Pd(II
)
center. Furthermore, the 1H NMR spectra of 1 were found to be
concentration-independent over a wide range of 0.5–20 mM,
suggesting that no aggregation or dissociation occurs. The mass
spectral analysis provided definitive evidence for the formation
of 1. For example, the ESI-mass spectrum of 1 in 1 : 1 CHCl3–
CH3CN showed characteristic peaks of [M 2 2OTf]2+, [M 2
3OTf]3+ and [M 2 4OTf]4+ at m/z = 1574 (100%), 1000 (65%)
and 712 (70%), respectively. The observed isotope distribution
patterns of the fragments are consistent with the calculated ones
based on the dinuclear macrocycle. The molecular weight of 1
in solution was measured by vapor pressure osmometry (VPO)5
and found to be 3650 ± 250 in the range of concentrations
between 3.6 and 13 g kg21 (sample/CH2Cl2), which is very
close to the calculated one (3448 for 1).
Scheme 1 Reagents and conditions: (a) i-Pr2NEt, CH2Cl2, 0 °C to rt (65%);
(b) PPh3, CuI, triisopropylsilylacetylene, Pd(dba)2, THF, Et3N, 60–70 °C
(85%); (c) Bu4NF, THF, H2O, 70–72 °C (85%); (d) Cu(OAc)2, pyridine,
60–65 °C (85%); (e) Pd(dppp)OTf2, CH2Cl2, rt (95%).
Despite being a monocyclic compound, 1 is designed to
possess two topologically discrete binding subcavities, like
giant porphyrinoids.6 Consequently, each subcavity can accom-
modate in a cooperative manner a guest molecule with
complementary size, shape and functionality.7
On the basis of computer modeling8 and our previous
studies,9 N,N,NA,NA-tetramethylterephthalamide (9) was chosen
as the guest molecule. Job’s plots10 confirmed 1 : 2 (1 : 9)
stoichiometry of the complex, showing the maximal complex
formation at ~ 0.33 mol fraction of the metallomacrocycle 1
† Electronic supplementary information (ESI) available: synthesis, ESI-
mass data, binding studies, concentration-dependent 1H NMR spectra,
modeling structure and VPO experiments of 1. See http://www.rsc.org/
suppdata/cc/b3/b306497b/
Fig. 1 (a) Job’s plot between metallomacrocycle 1 (NH1) and guest 9. (b) 1H
NMR titration plots: Chemical shift changes (3) of NH1 and NH2 in 1 on
the gradual increase of 9 in 3% CD3CN–CDCl3. Solid lines are theoretical
ones generated by HOSTEST program.12
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2OTf]2+, [MG2 2 3OTf]3+ and [MG2 2 4OTf]4+ at m/z = 1794
units in the other subcavity to form stronger hydrogen bonds
with the second 9.
In conclusion, the metallomacrocycle having two interactive
binding sites has been prepared for the first time by the
coordination-mediated self-assembly. The macrocycle shows
high homotropic cooperativity and is considered to be a new
type of artificial homotropic allosteric model.
(7%), 1146 (25%) and 823 (32%), respectively.11
1
To determine the binding affinities, the H NMR titration
experiments were performed in 3% (v/v) CD3CN–CDCl3 at 23
± 1 °C, and time-averaged resonances for the free and the
complexed species were observed under the titration conditions.
As the guest 9 was added, two NH signals of 1 were gradually
downfield shifted from 9.44 and 9.31 ppm to 10.35 and 10.22
ppm (Fig. 1b), indicative of hydrogen bond formation. In
contrast, the chemical shift changes were negligible (Dd < 0.1
ppm) when a monoamide, N,N-dimethylbenzamide, was added
under the same conditions. It is also worthwhile noting that the
aryl signal of the bound 9 was considerably upfield-shifted (Dd
> 1.0 ppm) relative to that of the free 9. These observations are
consistent with the proposed structure of the complex shown in
Scheme 2, where 9 is diagonally located inside the binding
subcavities by the formation of four hydrogen bonds.
The titration curves were slightly sigmoid in the initial stage
and analyzed with the HOSTEST program12 of a 1 : 2 (host :
guest) binding isotherm (Fig. 1b). Both titration curves from
NH1 and NH2 gave identical association constants within
experimental error ( < 5%), indicating that two NH’s are
participated in the same binding event. The macroscopic
association constants of K1 ( = [MG1]/[1][9]) and K2 ( =
[MG2]/[MG1][9]) were found to be 180 ± 5 M21 and 450 ± 20
M21, respectively.13 Considering the relationship of K2 = 1/4
K1 for noncooperative binding,10 the magnitude of the associa-
tion constants obtained here reflects a high positive cooper-
ativity between two binding sites. Hill plots10 also support the
positive cooperative bindings. The Hill coefficient h was
determined to be approximately 1.8 for this system. One
plausible explanation for this positive cooperativity is that the
first 9 binding to one subcavity possibly optimizes the distance
between two diagonally positioned pyridinedicarboxamide
This work was financially supported by the Korea Science
and Engineering Foundation (R02-2002-000-00115-0).
Notes and references
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2 (a) Some selected examples of binding studies using metallomacro-
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8 MacroModel program with MM3* force field was used. For details, see
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11 The identical ESI-mass spectrum was obtained in 50% CH3CN–CHCl3
(See ESI†).
12 C. S. Wilcox and N. M. Glagovich, HOSTEST, v5.60, Department of
Chemistry, The University of Pittsburgh, Pittsburgh, PA, 1997.
Analyses of titration data with EQNMR gave essentially identical
results; M. J. Hynes, J. Chem. Soc., Dalton Trans., 1993, 311. We thank
Prof. Wilcox and Prof. Hynes for allowing generously us to use their
programs.
13 The titration experiments were duplicated. The reported association
constants are averages of four values obtained with both NH’s.
Scheme 2
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