Cryptand-like porphyrinoid assembled with three dipyrrylpyridine chains: Synthesis, structure, and homotropic positive allosteric binding of carboxylic acids

Article abstract of DOI:10.1021/ja710424n

Cryptand-like porphyrinoid assembled with three 2,6-dipyrrylpyridine chains binds alcohol at each molecular crevice in the C_3h symmetric conformation through three hydrogen bondings. This receptor binds dichloroacetic acid at each crevice in th

Full text of DOI:10.1021/ja710424n

Published on Web 02/05/2008
Cryptand-like Porphyrinoid Assembled with Three Dipyrrylpyridine Chains:
Synthesis, Structure, and Homotropic Positive Allosteric Binding of
Carboxylic Acids
Jun-ichiro Setsune* and Keigo Watanabe
Department of Chemistry, Graduate School of Science, Kobe UniVersity, 1-1 Rokkodai-cho,
Nada-ku, Kobe 657-8501, Japan
Received November 19, 2007; E-mail: setsunej@kobe-u.ac.jp
Scheme 1. Synthesis of Bicyclic Hexapyrroles (3a, 3c) and
Monocyclic Tetrapyrroles (4b, 4c)
Artificial receptors showing homotropic positive allosteric effect
are drawing considerable attention in view of the exquisite reaction
control in many biological processes based on those allosteric
effects,1 but there are a limited number of successful examples.1-4
Bridging two rigid subunits composed of multibinding sites by metal
ions3 or bifunctional ligands4 is one of the more successful strategies
that takes advantage of entropy penalty in binding the first ligand.
It is even more difficult to demonstrate how positive cooperativity
is realized in binding monofunctional ligands. Herein we describe
new cryptand-like porphyrinoid assembled with three dipyrrylpy-
ridine chains for this purpose. Cryptand-like hosts can provide not
only an inside space but also three crevices toward ligands.5 The
latter binding mode which allows the incorporation of large ligands
at multiple binding sites has potential application but has not been
well explored. One such molecular design is cryptand-like calix-
pyrrole constructed by three tripyrrane chains which was used for
anion binding at a single crevice.5a Since three crevices can
influence each other through partitions or via the central cavity,
the cryptand-like structure is a promising scaffold for cooperative
ligand binding. Of great importance in our receptor is that the
π-conjugated pyrrole and pyridine are involved in the hydrogen
bondings with ligands at different crevices, which leads to strong
homotropic positive allostericity in binding carboxylic acids.
It is exceptional that cryptand-like bicyclic calixpyrrole was
formed by the conventional MacDonald-type condensation between
R-free tripyrrane and tripyrrane dialdehyde, because it usually gives
monocyclic compounds.5a The reaction of 2,6-bis(3,4-diethyl-2-
pyrryl)pyridine 1a6 and the corresponding dialdehyde 2a in 2:1
molar ratio in HCl/ethanol at reflux for 1 h afforded 48% yield of
the bicyclic hexapyrrole 3a, whereas the reaction of the benzene
analogues with a 1,3-phenylene spacer, 1b6 and 2b, gave ordinary
monocyclic tetrapyrrole 4b in 76% yield under the same reaction
conditions (Scheme 1). The monocyclic hybrid tetrapyrrole 4c was
also obtained in 30% yield, if 1a and 2b were allowed to react in
2:1 molar ratio. However, the reverse combination of dipyrrole and
dialdehyde, 1b and 2a, in 2:1 molar ratio afforded both the bicyclic
hybrid hexapyrrole 3c and the monocyclic tetrapyrrole 4c in 19
and 71% yield, respectively. Since protonation at the pyridine
nitrogen activates the dialdehyde 2a and deactivates the dipyrrole
1a for their coupling reaction, the product yields are superior in
the reactant combination of 1b and 2a to any other combination.
The hybrid tetrapyrrole 4c would be protonated both at the pyridine
nitrogen and the pyrrolenine nitrogens under strongly acidic con-
ditions. The resulting tricationic species would undergo nucleophilic
attack by 1b at the meso-like carbons to lead to 3c, while 1a is not
so reactive as to attack this trication because of the protonation of
1a itself. The nucleophilic reactivity of 1a seems sufficient toward
highly reactive monocyclic tetracation generated from the reaction
of 1a and 2a under acidic conditions, thus giving 3a.
The crystals of 3a grown from ethanol-CHCl3 showed well-
resolved 1H NMR signals due to EtOH at δ 3.60 (quartet) and 1.13
(triplet) at 20 °C in CDCl3 with EtOH/3a molar ratio of 3/1. These
EtOH signals are shifted to δ 2.6 (CH2) and 0.4 (CH3) with
broadening upon lowering the temperature to -60 °C (Supporting
Information). These facts are indicative of binding three EtOH
molecules by 3a.
X-ray crystallography of 3a‚(EtOH)3 showed C3h symmetric
structure where two pyrrole rings in one dipyrrylpyridine chain are
tilted to the same side of the central pyridine plane with a N-C-
C-N torsion angle of 35.6°.7 As a consequence, two pyrrole NH
bonds in one chain and the pyridine nitrogen lone pair orbital in
the next chain are pointing to one focal point. This structural feature
promotes binding of an ethanol molecule in each crevice of 3a
through three hydrogen bondings (Figure 1). Ethanol OH proton
(HO1) is bonded to the pyridine nitrogen (N2) with 2.864 Å O1-
N2 distance, and the ethanol oxygen (O1) is bonded to two pyrrole
NH protons (HN1) belonging to the next dipyrrylpyridine chain with
3.093 Å N1-O1 distance. These hydrogen-bonded protons were
found in the difference Fourier map in the X-ray analysis, and
structural refinement was performed. They lie close to the N-to-O
lines with N1-HN1
-O1 and O1-HO1-N2 angles of 164.2 and
170.2°, respectively, and with N1-HN1 and O1-HO1 distances of
0.84 and 0.83 Å, respectively. The bond angles around O1 shows
ideal tetrahedral geometry: 106.5° (C13-O1-HO1), 108.1° (C13-
O1-HN1), 113.3° (HN1-O1-HO1), and 107.2° (HN1-O1-HN1).
UV-vis titration of 3a (8.92 µM) in CH2Cl2 with CF3CO2H
(TFA) showed two straight lines that intersect at the [TFA]/[3a]
ratio near 3, which is the case known as the mole ratio method to
determine stoichiometry using very strongly binding ligands. Yellow
coloration as a 416 nm band develops with tailing up to 550 nm is
indicative of protonation at the pyridine nitrogen. A binding
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10.1021/ja710424n CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Mechanism for Positive Allosteric Binding of
Carboxylic Acids with 3a
belonging to the third crevice more basic. Binding two ligands to
3a strengthens both the pyridine basicity and pyrrole acidity in the
remaining free crevice to further enhance binding the third ligand.
This polarization of the π-conjugated chains and the reorganization
in D3 symmetric conformation rationalize the remarkable positive
cooperativity in binding carboxylic acids.
Figure 1. Ortep drawing (50% thermal ellipsoids) of 3a‚(EtOH)3 viewed
along the C3 axis; pyrrole-â ethyl groups are omitted for clarity (left). Partial
structure (side view) showing only one crevice with a EtOH ligand: N1-
HN1, 0.84; HN1-O1, 2.27; O1-HO1, 0.83; HO1-N2, 2.05 Å (right).
Dipyrrylpyridines are known as molecular cleft receptors used
for binding enolates.8 The present work points out that fabrication
with three units of dipyrrylpyridine into the cryptand-like structure
gives rise to the new molecular crevice receptor with the positive
cooperativity in binding carboxylic acids. It is also remarkable that
the dual binding mode, C3h or D3 type, of this receptor can responds
to structurally different ligands. Further study of molecular recogni-
tion using these crevice receptors is now going on in our laboratory.
Acknowledgment. This work was supported by Grant-in-Aid
for Scientific Research (No.16350023 and No.18550058) from the
Ministry of Education, Culture, Sports, Science and Technology,
Japan. The author is also grateful to the CREST program (the Japan
Science and Technology Agent) and the VBL project (Kobe
University).
Figure 2. Binding isotherms based on the UV-vis titration of 3a ([3a] )
8.92 µM) with dichloroacetic acid (DCA) at 420 nm (filled square) and
trifluoroacetic acid (TFA) at 416 nm (circle) in CH2Cl2 at 293 K. (Inset)
Hill plot for the binding of DCA to 3a. Y ) ∆abs/∆abs(max).
isotherm for Cl2CHCO2H (DCA) showed a sigmoidal response
characteristic of positive cooperativity between three binding sites
(Figure 2). Cooperativity was estimated by the Hill coefficient (n
) 2.7 ( 0.2) and the association constant (log K ) 13.6 ( 1.8) on
the basis of the Hill plot (log(Y/1 - Y) ) n log [DCA] + log K).
Supporting Information Available: Synthetic procedures and
characterization data for all compounds, including VT-NMR spectra
1
of 3a‚(EtOH)3, details of UV-vis and H NMR binding studies, and
X-ray crystallographic data of 3a‚(EtOH)3 and 3a‚(DCA)3. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
In the H NMR titration of 3a‚(EtOH)3 (7.1 mM) in CDCl3 with
TFA at -50 °C, a singlet at δ 10.9 (6H) due to the pyrrole-NH of
3a‚(EtOH)3 decreased in intensity with increasing two singlets at
δ 11.6 (6H) and 11.9 (3H) due to the pyrrole-NH and pyridinium-
NH, respectively, of 3a‚(TFA)3. No other porphyrinoid species such
as 3a‚(TFA) and 3a‚(TFA)2 was detected during titration, and 3a‚
(EtOH)3 was completely replaced by 3a‚(TFA)3 at 3 molar equiv
of TFA (Supporting Information). These UV-vis and H NMR
titrations clearly indicate that the strong positive allosteric effect
is operating in binding carboxylic acids to 3a.
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