A large enhancement in the binding affinity of artificial hosts by Os(VI) chelation

Article abstract of DOI:10.1039/a906252a

Mononuclear Os(VI)-chelated macrocycles, self-assembled from OsO₄, 2,3-dimethylbut-2-ene and bispyridyl ligands, bind diamides much more strongly than the Os(VI)-free ligands (ΔΔG = -14.6 kJ mol^-1).

Full text of DOI:10.1039/a906252a

A large enhancement in the binding affinity of artificial hosts by OsVI chelation
Kyu-Sung Jeong,* Jung Wha Lee, Tae-Yoon Park and Sung-Youn Chang
Department of Chemistry, Yonsei University, Seoul 120-749, Korea. E-mail: ksjeong@alchemy.yonsei.ac.kr
Received (in Cambridge, UK) 2nd August 1999, Accepted 8th Septmber 1999
Mononuclear OsVI-chelated macrocycles, self-assembled
from OsO4, 2,3-dimethylbut-2-ene and bispyridyl ligands,
bind diamides much more strongly than the OsVI-free
ligands (DDG = 214.6 kJ mol21).
of OsO4 ( ~ 1 equiv., 0.1 M in toluene) to a 1+1 molar mixture
of the ligands 1a–c and 2,3-dimethylbut-2-ene in a CHCl3 at
room temperature. After concentration, the residues were
thoroughly washed with Et2O to afford the OsVI-complexes 2a–
c as brown solids (66–88% yield).
Self-assembly by weak noncovalent interactions has recently
attracted a great deal of attention in the area of host–guest and
supramolecular chemistry. The strategy has been effectively
used to synthesise artificial receptors in which two or more
subunits are spontaneously coordinated to a metal ion to
generate a binding cavity complementary to the targeted
substrates.1 On the other hand, metal ion chelation to one part of
a flexible host may result in the structural reorganisation of
another binding site, leading to allosteric behaviour in the
binding events.2–5 Here, we have prepared three bispyridyl
ligands 1a–c that spontaneously self-assemble into the corre-
sponding macrocyclic complexes 2a–c in the presence of alkene
and OsO4,6,7 and compared the binding affinities of 1a–c and
2a–c toward diamide guests.
As shown in Scheme 1, the bispyridyl ligands 1a–c were
prepared by dropwise addition of diamines 4a–c followed by
aminolutidine 5 to a solution of pyridine-2,6-dicarbonyl
dichloride 5 in CH2Cl2. The yields were 10–18% after repeated
chromatography. The neutral macrocyclic complexes 2a–c
were spontaneously assembled within a few minutes by addition
Elemental analysis of the products agreed well with 1+1+1
molar composition of OsO4, 2,3-dimethylbut-2-ene and the
ligand. Their IR spectra show a strong, characteristic band near
830 cm21 diagnostic of the trans ONOsNO moiety of the
octahedral dioxoosmiumVI complexes.8 In the 1H NMR spectra,
the lutidyl C–H resonances of 2a–c were shifted downfield
( ~ 0.28 ppm) relative to those for ligands 1a–c, as expected
1
upon coordination of the nitrogen to the OsVI ester. The H
NMR spectra remain constant over a wide range of concentra-
tions (0.25–10 mM) and temperatures (240 to 40 °C) in CDCl3,
indicating that no aggregation or dissociation occurs under these
1
conditions. H NMR integration also confirmed a 1+1 molar
ratio of the ligand and 2,3-dimethylbut-2-ene. The FAB-MS
analyses strongly support the formation of mononuclear
complexes 2a–c. For example, the mass spectrum of 2a shows
the molecular ion [MH+] peak at 1169.4 (intensity 1.8%, 1168.4
calc. for C56H64N8O8192Os), [M 2 O]+ at 1152.4 (intensity
3.3%), and [M 2 (O2C2(CH3)4)]+ at 1052.4 (intensity 2.4%).
The observed isotopic distribution patterns of all these peaks are
consistent with those calculated for the mononuclear macro-
cycle 2a. The complexes 2b and 2c also show the same FAB-
MS spectral behaviour as seen for complex 2a.
The binding properties of hosts 1a–c and 2a–c with diamide
1
guests 6 and 7 were revealed in CDCl3 by H NMR titration
experiments, performed by adding the guest solution
(5–10 mM) to the host stock solution (1–2 mM, 500 ml) in small
potions. The time-averaged signals for the free and bound
species were observed due to a fast exchange on the NMR time–
scale. The association constants (Ka/M21) were calculated by
non-linear least-squares fitting9 of the titration data, which
corresponded well to the expression for a 1+1 binding isotherm.
All the hosts contain two different NH protons, and both N–H
signals of the hosts were significantly downfield shifted (Dd ≥
1 ppm) when guests 6 and 7 were added, indicating significant
hydrogen bond formation. As a representative example, the two
NH signals in the OsVI complex 2a were shifted downfield from
d 8.83 and 9.22 to d 9.80 and 10.62, respectively, upon
complexation with terephthalamide 6. The titration curves,
plotting either NH chemical shift change vs. equivalents of
guest, gave essentially identical association constants within
experimental error ( < 5%), indicating that both NHs are
involved in a single binding mode.
As seen in Table 1, the association constants between Os-free
ligands 1a–c and guests 6 and 7 decrease in the order 1a > 1b
> 1c. This is expected because 1a contains conformationally
the most rigid linker, while 1c possesses the most flexible
Scheme 1 Reagents and conditions: i, EtNPri2, 0 °C to room temp.; ii,
2,3-dimethylbut-2-ene, OsO4.
Chem. Commun., 1999, 2069–2070
This journal is © The Royal Society of Chemistry 1999
2069

Table 1 Association constants (Ka/M21) of ligands 1a–c and Os complexes
2a–c with diamide guests 6 and 7 in CDCl3 at 25 ± 1 °C
Os
DDG°/
Guest Ligand Ka/M21 a complex Ka/M21 a
kJ mol21 b
6
6
6
7
7
7
a
1a
1b
1c
1a
1b
1c
2800
580
80
210
95
2a
2b
2c
2a
2b
2c
1.7 3 104
1.9 3 104
2.9 3 104
1.6 3 104
2.9 3 104
6.1 3 103
24.5
28.6
214.6
210.7
214.2
213.2
30
Titrations were duplicated and errors in Ka are within 10% for Ka < 1
3 104 M21 and within 30% for Ka > 1 3 104 M21
complex) 2 DG°(ligand).
. DDG° = DG°(Os
b
linker. More important a trend in the association constants is
that Os complexes 2a–c bind the guests 6 and 7 much more
strongly than the corresponding Os-free ligands 1a–c. The
difference in the binding energy is up to DDG° = 214.6 kJ
mol21, depending on the linker group; the more flexible the
linker is, the greater the difference observed. The large
enhancements of the association constants in the OsVI com-
plexes are possibly attributed to the following two factors. One
is the conformational preorganization of the hosts 2a–c as a
consequence of OsVI chelation, which greatly reduces the
conformational entropy loss upon association of the host and
guest. Another contributing factor may be the increased
hydrogen-bonding donor ability of the lutidyl N–H protons as a
result of OsVI chelation to the terminal nitrogens.
Fig. 1 1H NMR spectra of (a) host 2a (3 mM), (b) host 2a (3 mM) + guest
6 (3 mM), and (c) guest 6 (3 mM) in CDCl3 at 25 °C.
1
which induce an anisotropic shielding environment in the H
NMR spectrum.
In conclusion, we have shown the self-assembly of cleft-like
bispyridyl hosts into the corresponding macrocycles by OsVI
ester chelation, which significantly increases the binding
affinity toward guests. Further studies are underway to develop
optically active hosts for the chiral recognition of peptide
derivatives.
This work was financially supported in part by Yonsei
University and the Korea Science and Engineering Foundation
(96-0501-04-01-03).
Notes and references
1 For reviews, see: B. Linton and A. D. Hamilton, Chem. Rev., 1997, 97,
1669; M. Fujita, Chem. Soc. Rev., 1998, 417; P. J. Stang, Chem. Eur. J.,
1998, 4, 19; D. L. Caulder and K. N. Raymond, J. Chem. Soc., Dalton
Trans., 1999, 1185; also, see for self-assembling receptors via hydrogen
bonds: J. Rebek, Jr., Acc. Chem. Res., 1999, 32, 278.
2 H.-J. Schneider and D. Ruf, Angew. Chem., Int. Ed. Engl., 1990, 29,
1159.
3 Y. Kobuke and Y. Satoh, J. Am. Chem. Soc., 1992, 114, 789.
4 M. Inouye, T. Konishi and K. Isagawa, J. Am. Chem. Soc., 1993, 115,
8091.
The ligand 1a and its OsVI complex 2a strongly bind diamide
guest 6, while they bind only slightly the monoamide analogue,
N,N-diethylbenzamide 8 (Ka ≤ 15 M21 in CDCl3, observed
Ddmax ≤ 0.15 ppm). The Job plots10 showed a 1+1 stoichio-
metry between the host 1a or 2a and the diamide guest 6. These
observations clearly indicate that two hydrogen-bonding sites in
the hosts must simultaneously participate in the complexation,
as shown in the proposed structure of the complex 2a·6.
Additional evidence for the complex structure was obtained
from 1H NMR spectroscopy (Fig. 1). When 2a and 6 are mixed
in a 1+1 molar ratio, the NH signals of the host 2a are largely
downfield shifted (Dd ≥ 1 ppm), and more importantly, the aryl
C–H signal of the guest 6 is significantly upfield shifted (Dd
~ 1.5 ppm). The latter strongly suggests that the guest 6 is
located inside the cavity surrounded by the host aryl walls,
5 M. Yamamoto, M. Takeuchi and S. Shinkai, Tetrahedron Lett., 1998,
39, 1189.
6 For the preparation of binuclear macrocyclic boxes using this self-
assembling motif, see: K.-S. Jeong, Y. L. Cho, J. U. Song, H.-Y. Chang
and M.-G. Choi, J. Am. Chem. Soc., 1998, 120, 10983.
7 For covalently-bonded macrocycles with amide groups, see: C. A.
Hunter and L. D. Sarson, Angew. Chem., Int. Ed. Engl., 1994, 33,
2313.
8 M. Schröder, Chem. Rev., 1980, 80, 187.
9 R. S. Macomber, J. Chem. Educ., 1992, 69, 375.
10 K. A. Connors, Binding Constants, Wiley, New York, 1987, p. 24.
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Chem. Commun., 1999, 2069–2070