Noncovalent tailoring of the binding pocket of self-assembled cages by remote bulky ancillary groups

Article abstract of DOI:10.1021/ja311373f

The binding properties of a self-assembled coordination cage were subtly tuned by ancillary groups on the metal corners of the cage. Since the bulky mesityl groups of the ligand hang over the cage cavity, the effective cavity volume is reduced. Due to the tighter guest packing inside the shrunken cavity, smaller guests were efficiently bound and guest motion was restricted even at high temperatures.

Full text of DOI:10.1021/ja311373f

Communication
pubs.acs.org/JACS
Noncovalent Tailoring of the Binding Pocket of Self-Assembled
Cages by Remote Bulky Ancillary Groups
Yu Fang, Takashi Murase, Sota Sato, and Makoto Fujita*
Department of Applied Chemistry, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656,
Japan
S
* Supporting Information
with AgNO3 and identified by NMR, MS, and X-ray analyses
ABSTRACT: The binding properties of a self-assembled
(see Figures S1−S5 in the Supporting Information). Complex-
coordination cage were subtly tuned by ancillary groups on
the metal corners of the cage. Since the bulky mesityl
groups of the ligand hang over the cage cavity, the effective
cavity volume is reduced. Due to the tighter guest packing
inside the shrunken cavity, smaller guests were efficiently
bound and guest motion was restricted even at high
temperatures.
ation of 2 (20 mg, 31 μmol) with 2,4,6-tri(4-pyridyl)-1,3,5-
triazine (3; 6.3 mg, 20 μmol) in H2O/CH3CN (4:1, 4.0 mL) at
60 °C for 1 h gave cage 1a as a single product as confirmed by
1H NMR spectroscopy (Figures 2b−d) and ESI-MS (Figure
he elaborate substrate specificity in the binding pocket of
T
enzymes is often governed by the subtle variation in
amino acid residues that exist, not at the interior, but at the
exterior of the pocket.1 Two similar serine proteases, trypsin
and chymotrypsin, have, for example, almost identical binding
pockets but exhibit distinctly different substrate specificity2
because of the difference in their surface loops that do not
touch the substrates.3 The role-separation of recognition and its
regulation is nature’s clever approach for specific guest binding,
where the specificity can be finely tuned without changing the
binding pocket structure itself. We report here that the binding
properties of synthetic coordination cages 1 (Figure 1) can be
Figure 2. (a) Self-assembly of cage 1a from bulky Pd(II) complex 2
1
and triazine panel ligand 3. (b−d) H NMR spectra (500 MHz, 300
K) of (b) Pd(II) complex 2 (in CD3CN), (c) triazine ligand 3 (in
CDCl3), and (d) cage 1a (in D2O). TMS (CDCl3 solution) in a
capillary served as an external standard (δ = 0 ppm) in D2O.
S24). Notably, the pyridyl protons (PyHα and PyHβ) of
triazine panel 3 shifted upfield (Figures 2c,d) in contrast to the
common downfield shifts characteristic to pyridyl coordination
to Pd(II) in the formation of cages 1b−d (Figure S17). The
unusual upfield shift is explained by the shielding effect of the
mesityl groups of the Mes-phen ligand that hang over the
pyridyl groups of the cage. The signals of the mesityl aromatic
protons (Hd) were also shifted upfield (Δδ = −0.28 ppm) due
to the shielding by the pyridyl group (Figures 2b,d). These
observations indicate a significant through-space interaction
between the mesityl and the pyridyl groups in cage 1a. After
Figure 1. Self-assembled coordination cages 1.
easily tailored by modifying the remote ancillary group on the
component metal ions.4 Since a variety of cis-chelating ligands
can be employed as ancillary groups,5 our approach provides
the most efficient and straightforward way to subtly control the
binding properties of the cages.
A bulky ancillary ligand, 2,9-dimesityl-1,10-phenanthroline
(Mes-phen),6 is employed to noncovalently control the binding
of encapsulated guests. The bulky cis-protected Pd(II) complex,
Pd(Mes-phen)(NO3)2 (2), was prepared in high yield by
treating PdCl2 with Mes-phen followed by counterion exchange
Received: November 20, 2012
Published: December 27, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
anion exchange from NO3− to PF6 , ESI-MS clearly confirmed
with adamantane in water.12 To our surprise, cage 1a could no
longer encapsulate adamantane in its cavity because of the
shrunken cavity. In contrast, tetraphenylmethane (4a) is too
small to be efficiently encapsulated in the large cavities of 1b−d
but was efficiently bound by 1a to give the inclusion complex
1a·4a in 56% yield.
−
the M6L4 composition of the cage with a molecular weight of
6126.75 Da.
−
The structure of cage 1a (PF6 salt) was unambiguously
determined by a synchrotron X-ray diffraction study (Figure 3).
A series of rigid tetrahedral guests 4a−d (362−394 Å3) were
also examined as probe molecules (Table 1). The inclusion
Table 1. Guest-Binding Specificity of Cages 1 for
a
Tetrahedral Guests 4
a
Figure 3. X-ray crystal structure of cage 1a (PF6− salt). For clarity, H-
atoms, PF6− counteranions, and solvent molecules have been omitted.
C, gray; N, blue; Pd, yellow; mesityl group, orange. The coordination
environment of the Pd(II) center is highlighted on the right with
space-filling depiction in the background.
Conditions: cage 1 and guest (10 equiv) in D2O (1.0 mM) at 80 °C
for 4 h unless otherwise noted. Excess guest was removed by filtration
before NMR measurements. van der Waals volumes calculated from
structures optimized using SPARTAN’10 with MP2 using both a 6-
31G* and a larger 6-311+G** basis set. NMR yields.
b
c
A block-shaped single crystal of 1a (PF6− salt) was obtained by
slow diffusion of ethanol into the acetonitrile solution at 15 °C
for 2 d. The crystal structure shows that the two mesityl
substituents in the Mes-phen ligand hang over the two
remaining coordination sites on the Pd(II) center, narrowing
the coordination bite angle.7 At the same time, the mesityl
groups interact through space with the pyridyl groups of the
triazine-cored ligand 3 of the cage at a distance of ∼3.5 Å. Due
to the steric demand of the mesityl groups, the pyridine rings of
3 are tilted by 9.4° on average with respect to the triazine core.
Most importantly, the Pd(II) ions display a distorted square
planar geometry and the average N−Pd−N bite angle defined
by the two 4-pyridyl nitrogen atoms on every Pd(II) ion is
83.3° and significantly deviates from the ideal 90° angle.
We calculated the cavity volumes of cages 1a, 1c, and 1d
using the VOIDOO program8 based on their crystal
structures.9,10 The cavity volumes occupied by a large sphere
probe with a radius of 3.36 Å were measured and are visualized
in Figure 4. While cages 1c and 1d have similar void volumes
yields are quite sensitive to subtle changes in both the host and
guest structures. The highest inclusion yield was obtained for
1a·4b, but the yields fall significantly with increasing cavity
volume (1a ≪ 1d < 1b ≈ 1c). The 2D NOESY NMR spectrum
of inclusion complex 1a·4b (Figure S34) indicated that 4b is
located at the cavity center with the four phenyl groups at the
cavity portals. Interestingly, with guests 4c and 4d, which are
slightly larger than 4b, the inclusion yields decreased (43% and
38%, respectively).
Guest mobility largely depends on the cavity volumes of
hosts 1. Two molecules of diketone 5 are quantitatively
encapsulated by cages 1a and 1b to form an orthogonally
associated, S4 symmetric dimer (5)2 in the cavity.13 In both
1
cases, 12 sharp signals are observed in the H NMR spectrum
for triazine ligand 3 at 300 K because of the symmetry
reduction of the host from Td to S4 (Figures 5a,c).13 With
increasing temperature, the host signals of 1b·(5)2 gradually
broaden, indicating the dissociation of the (5)2 dimer (Figure
5d). In contrast, those of 1a·(5)2 remain sharp even at elevated
temperatures (Figure 5b). This observation indicates that dimer
(5)2 fits more snuggly and is confined in the shrunken cavity of
cage 1a even at high temperature.
In summary, we prepared self-assembled cage 1a with Mes-
phen ancillary ligands on the Pd(II) centers, where the cavity-
forming ligand and the ancillary ligand cooperatively but
independently play important roles: the former forms an
efficient recognition pocket, and the latter tunes the recognition
ability. Though not involved in the structural components of
the cavity, the bulky mesityl groups hang over the cavity,
reducing the effective volume and controlling the guest binding
and motion. Since replacement of the ancillary ligands is
straightforward, the unique functions of cages 1 can be rapidly
elaborated using the present strategy.
Figure 4. The central void volumes (green mesh) in cages 1a, 1c, and
1d. Probe radius = 3.36 Å.
(482 and 462 Å3, respectively), cage 1a shows a much smaller
volume (380 Å3).11 Thus, the cavity of cage 1a is considerably
reduced by the smaller N−Pd−N bite angles and the deformed
ligand 3 with tilted pyridine moieties.
The guest-binding properties of cage 1a were compared with
those of cages 1b−d, which form 1:4 host−guest complexes
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Journal of the American Chemical Society
Communication
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the Supporting Information. Although the cavity volume of cage 1b
could not be calculated due to the poor crystal data, the volume is
expected to be almost the same as that of cage 1c.
(11) The estimated central void volumes are much smaller than the
actual open cavity volumes containing the portal regions.
Figure 5. VT-1H NMR spectra (500 MHz, D2O) of (a,b) inclusion
complex 1a·(5)2 and (c,d) inclusion complex 1b·(5)2.
(12) Kusukawa, T.; Fujita, M. Angew. Chem., Int. Ed. 1998, 37, 3142.
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, physical properties, and crystallo-
graphic data (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
mfujita@appchem.t.u-tokyo.ac.jp
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by a Grant-in-Aid for Specially
promoted Research (24000009) and for Young Scientists (B)
(23750057). The experiments of synchrotron X-ray crystallog-
raphy were performed at the BL41XU and BL38B1 beamlines
in the SPring-8 with the approval of the Japan Synchrotron
Radiation Research Institute (JASRI) (Proposal Nos.
2012A0042 and 2012A0039).
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