Allosteric P=O-based receptors for dicarboxylic acids

Article abstract of DOI:10.1021/ol201277d

The synthesis of new P=O-disubstituted receptors with appended crown ethers and their properties as receptors for dicarboxylic acids have been studied. High affinities have been observed (oxalic and malonic acids with 4-, 5-, 6-, or 8-crown ethers). Binding of a cationic effector within the crown ether unit resulted in a positive "allosteric" effect, which has been determined to be K_rel = 7 in the best case (binding of malonic acid with Li ⁺ @ rac-3b).

Full text of DOI:10.1021/ol201277d

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3632–3635
Allosteric PdO-Based Receptors for
Dicarboxylic Acids
†
†
†
†
ꢀ
ꢀ
ꢀ
ꢀ
D. Amilan Jose, Ignasi Mon, Hector Fernandez-Perez, Eduardo C. Escudero-Adan,
J. Benet-Buchholz,† and Anton Vidal-Ferran*,†,‡
ꢁ
ICIQ, Institut Catala d’Investigacio Quımica, Avda. Paısos Catalans, 16, 43007
Tarragona, Spain, and ICREA, Institucio Catalana de Recerca i Estudis Avanc-ats,
ꢀ
´
¨
ꢀ
´
Passeig Lluıs Companys, 23, 08010 Barcelona, Spain
avidal@iciq.es
Received May 12, 2011
ABSTRACT
The synthesis of new PdO-disubstituted receptors with appended crown ethers and their properties as receptors for dicarboxylic acids have been
studied. High affinities have been observed (oxalic and malonic acids with 4-, 5-, 6-, or 8-crown ethers). Binding of a cationic effector within the crown
ether unit resulted in a positive “allosteric” effect, which has been determined to be Krel = 7 in the best case (binding of malonic acid with Liþ @ rac-3b).
Allosteric modulation is a quite common feature in
living systems and has allowed for structural and func-
tional regulation.1 The term allosterism involves the mod-
ification of the properties of the biologically active site by
the interaction of an external unit (effector) with a specific
regulating site in the biological system. This effector can
either enhance or decrease the functional properties of the
biological system. The design of artificial allosteric recep-
tors is of great significance for controlling molecular
function by external stimuli. Since Rebek’s pioneering
design of an artificial allosteric receptor,2a other systems
have been designed and studied to control catalysis and
binding by combining allosteric sites and effectors of a
diverse nature.2bꢀd,3,4
A wide variety of receptors for neutral molecules
(aromatic derivatives, nucleic bases, sugars, ureas, etc.)
and charged species (alkali metal ions, halide anions,
carboxylates, etc.) incorporating an appended crown ether
unit as the allosteric site have been reported.3 Binding
of suitable effectors not identical to the substrates
(heterotropic allostery) within the crown ether unit has
led to increased receptor affinity toward the aforemen-
tioned substrates (positive allosteric effects). Crown ethers
are certainly not the only allosteric units that have been
studied (examples on the use of bipyridine, Schiff base,
cathecol, β-diketone, calixarene, resorcinarene, boronic
acid groups, and other motifs as allosteric sites have been
reported3,4). However, with the possibility to easily vary
the crown ether size, shape, and topology together with
† ICIQ.
‡ ICREA.
(1) For example, see: (a) Perutz, M. F.; Fermi, G.; Luisi, B.; Shaanan,
B.; Liddington, R. C. Acc. Chem. Res. 1987, 20, 309. (b) Grandori, R.;
Lavoie, T. A.; Pflumm, M.; Tian, G.; Niersbach, H.; Maas, W. K.;
Fairman, R.; Carey, J. J. Mol. Biol. 1995, 254, 150. (c) Burke, J. R.;
Witmer, M. R.; Tredup, J.; Micanovic, R.; Gregor, K. R.; Lahiri, J.;
Tramposch, K. M.; Villafranca, J. J. Biochemistry 1995, 34, 15165.
(2) (a) Rebek, J., Jr.; Trend, J. E. J. Am. Chem. Soc. 1978, 100, 4315.
(b) Rebek, J., Jr.; Trend, J. E.; Wattley, R. V.; Chakravorti, S. J. Am.
Chem. Soc. 1979, 101, 4333. (c) Rebek, J., Jr. Acc. Chem. Res. 1984, 17,
258. (d) Rebek, J., Jr.; Costello, T.; Marshall, L.; Wattley, R.; Gadwood,
R. C.; Onan, K. J. Am. Chem. Soc. 1985, 107, 7481.
(4) As recent examples, see: (a) Hirata, O.; Takeuchi, M.; Shinkai, S.
Chem. Commun. 2005, 3805. (b) Meyer, M.; Fremond, L.; Espinosa, E.;
Brandes, S.; Yves Vollmer, G.; Guilard, R. New J. Chem. 2005, 29, 1121.
(c) Sessler, J. L.; Tomat, E.; Lynch, V. M. J. Am. Chem. Soc. 2006, 128,
4184. (d) Setsune, J.-i.; Watanabe, K. J. Am. Chem. Soc. 2008, 130, 2404.
(e) Zahn, S.; Reckien, W.; Kirchner, B.; Staats, H.; Matthey, J.; Luetzen,
A. Chem.;Eur. J. 2009, 15, 2572. (f) Ercolani, G.; Schiaffino, L. Angew.
Chem., Int. Ed. 2011, 50, 1762.
(3) (a) Nabeshima, T. Coord. Chem. Rev. 1996, 148, 151.
(b) Takeuchi, M.; Ikeda, M.; Sugasaki, A.; Shinkai, S. Acc. Chem.
Res. 2001, 34, 865. (c) Kovbasyuk, L.; Kraemer, R. Chem. Rev. 2004,
104, 3161. (d) Kubo, Y.; Ishii, Y. J. Nanosci. Nanotechnol. 2006, 6, 1489.
r
10.1021/ol201277d
Published on Web 06/13/2011
2011 American Chemical Society

Scheme 1. Synthesis and X-ray Structures of rac-3aꢀe
well established synthetic strategies for their preparation,
they have become popular artificial allosteric sites. Most
surprisingly, allosteric receptors for dicarboxylic acids are
scarce in the literature,5 and this work details our initial
efforts in the design, preparation, and binding studies of
PdO-based receptors rac-3aꢀe for the recognition of
dicarboxylic acids with a crown ether mediated allosteric
modulation mechanism (Scheme 1). It was envisaged that
binding of cationic species (allosteric effectors) within the
crown ether moiety via ionꢀdipole interactions would
induce conformational changes to the [1,10-biphenyl]-
2,20-diylbis(diphenylphosphine oxide) unit resulting in
modified binding properties toward the dicarboxylic
acids.6 Molecular recognition of both mono- and dicar-
boxylic acids is of considerable interest because of their
important roles in biology. Over the past few years, a
variety of receptors containing different functional groups
have been reported for selective binding of carboxylic
acids.6 However, to the best of our knowledge, no reports
on PdO-based receptors have been made for selective
dicarboxylic acid recognition.
New receptors rac-3aꢀe were straightforwardly synthe-
sized from easily available compound rac-17 by reaction
with the corresponding bistosylated polyethylene oxide
derivative 28 and an excess of Cs2CO3 (10 equiv) in
DMF at 60 °C for 24 h. Compounds rac-3aꢀe were
isolated as white solids in 42ꢀ65% yield (Scheme 1) and
characterized by standard analytical methods (NMR and
HRMS). X-ray analysis9 confirmed the proposed structures.
Binding properties of PdO-based crown receptors rac-
3bꢀe with different dicarboxylic acids were studied with
several spectroscopic techniques. Changes in the UV spec-
tra of rac-3bꢀe were observed after the addition of in-
creasing amounts of the acid solutions to solutions of rac-
3bꢀe in DCM/MeOH (99.5/0.5 v/v): the absorption band
at 300 nm experienced a 5 nm bathochromic shift upon
binding, and association constants between rac-3bꢀe with
(7) (a) Schmid, R.; Foricher, J.; Cereghetti, M.; Schoenholzer, P.
Helv. Chim. Acta 1991, 74, 370. (b) Qiu, L. Q.; Qi, J. Y.; Ji, J. X.; Zhou,
Z. Y.; Yeung, C. H.; Choi, M. C. K.; Chan, A. S. C. Acta Crystallogr.,
Sect. C: Cryst. Struct. Commun. 2003, C59, o33.
(8) Compounds 2bꢀd are commercially available, and 2e was pre-
pared as reported in the literature: Zhu, X.-Z.; Chen, C.-F. J. Am. Chem.
Soc. 2005, 127, 13158. Compound 2a was synthesized following the
same synthetic strategy than for 2e.
(9) Crystals of compounds rac-3aꢀe and the complex between rac-3c
and oxalic acid were obtained by slow evaporation of their solutions in
organic solvents at rt. Supplementary crystallographic data for this
paper (CCDC 791802ꢀ791806 and 823794) can also be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing data_r-
equest@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallo-
graphic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax:
þ44 1223 336033.
(5) (a) Takeuchi, M.; Imada, T.; Shinkai, S. Angew. Chem., Int. Ed.
1998, 37, 2096. (b) Ikeda, T.; Hirata, O.; Takeuchi, M.; Shinkai, S. J. Am.
Chem. Soc. 2006, 128, 16008.
(6) See the following reviews and references cited therein: (a) Rebek,
J., Jr. Mol. Struct. Energ. 1988, 10, 219. (b) Chen, H.; Weiner, W. S.
Hamilton, A. D. Curr. Opin. Chem. Biol. 1997, 1, 458. (c) Fitzmaurice, R. J.;
Kyne, G. M.; Douheret, D.; Kilburn, J. D. J. Chem. Soc., Perkin Trans. 1
2002, 841. (d) Korendovych, I. V.; Roesner, R. A.; Rybak-Akimova, E. V.
Adv. Inorg. Chem. 2007, 59, 109.
Org. Lett., Vol. 13, No. 14, 2011
3633

oxalic and malonic acids could in this way be determined
(see Table 1).10 Other dicarboxylic acids with a longer
spacer between the carboxylic groups (i.e., succinic, glu-
taric, and adipic acids) induced very small changes in the
absorption spectra, which led us to conclude that weak
binding was taking place in these cases. Binding studies
consistently revealed that the binding affinity of the re-
ceptor decreased upon increasing the spacer chain length
of the dicarboxylic acid, thus the selectivity order being
HOOCꢀCOOH > HOOCꢀCH2ꢀCOOH > HOOCꢀ
(CH2)2ꢀCOOH . HOOCꢀ(CH2)n>2ꢀCOOH (Table 1).
It is worth mentioning that the ring size of the crown ether
in the receptors does not seem to influence the affinity of
the PdO binding groups toward oxalic and malonic acids.
leading to a well-defined linear complex with an overall
1:1 stoichiometry).9,11
Table 1. Association Constants of Receptors rac-3bꢀe with
Dicarboxylic Acids
Figure 1. X-ray structure of rac-3c with oxalic acid (arrows
indicate binding groups for further oxalic acid molecules).
binding constants (Mꢀ1 a,b
)
entry
receptor
oxalic acid
malonic acid
1
2
3
4
rac-3b
rac-3c
rac-3d
rac-3e
6.7 ꢁ 103
4.9 ꢁ 103
6.2 ꢁ 103
7.4 ꢁ 103
4.5 ꢁ 103 c
4.4 ꢁ 103
4.6 ꢁ 103
5.0 ꢁ 103
The next step in the investigation of our allosteric
receptors consisted of the study of the complexation of
several potential allosteric “effectors” within the crown
ether cavity (SI Table 1 in the Supporting Information).
Crown ethers are well-known to form complexes with
positively charged species.12 Association of rac-3aꢀe with
potential crown ether binders was studied with fluores-
cence emission spectroscopy: the emission band was par-
tially quenched and red-shifted (ca. 5ꢀ7 nm) upon
addition of a solution of crown ether binders to solutions
of receptors rac-3aꢀe. Association constants (see SI Table
1) were calculated from the titration data by nonlinear
curve fitting assuming a 1:113 binding model. Our binding
studies revealed that crown ether containing receptors rac-
3aꢀe did not show a pronounced selectivity for any of the
different cationic species that were analyzed (Liþ, Naþ,
Kþ, Ca2þ, Ba2þ, and NH4þ), K-values at 25 °C in DCM/
MeOH (99.5/0.5 v/v) being around 104 Mꢀ1 in almost
every case.14 However, and as expected from the ring size,
the receptor incorporating the smallest ring (rac-3b)
showed a small preference for Liþ over Naþ. Receptor
rac-3c presented a slightly higher binding affinity for Naþ
and Kþ over Liþ; rac-3d had a small preference for Ba2þ
whereas rac-3a and rac-3e had a preference for Ca2þ. All
a Measured in DCM/MeOH (99.5/0.5 v/v) at 25 °C with UVꢀvis
absorption spectroscopy. b Average value of at least two measurements.
Standard deviations (expressedin % with respect to the binding constant
value) were 17% (average value for all measurements indicated in the
table). c This binding constant was also measured by 31P NMR, and its
value was found to be 2.8 ꢁ 103 Mꢀ1. The binding constant determined
by NMR agrees reasonably well with that measured by UVꢀvis spectro-
scopy. However, the magnitude of the binding contants (ca. 103 Mꢀ1
)
forced us to use dilute solutions of rac-3b during the NMR titration
(ca. 10ꢀ3 M), with the correspondingly long acquisition times and
experiment duration. For the sake of convenience, UVꢀvis instead of
NMR spectroscopy was used in all other cases for determining the
association constants.
The interaction between the COOH and the PdO
groups could be confirmed both in solution and in the
solid state (see Figure 1). 31P NMR analysis showed a
broadening and a downfield shift of the PdO signal upon
addition of oxalic or malonic acids (2.8 and 2.6 ppm,
respectively),11 thus confirming the interaction between the
PdO and COOH groups in solution and also allowing
the measurement of the binding constant with this technique
(see footnote c in Table 1).11 Crystals of the complex between
rac-3c and oxalic acid suitable for X-ray analysis could be
grown and its crystal structure investigated. In the solid state,
the substrate molecules have formed hydrogen bonds between
the PdO and COOH groups (see dashed lines in Figure 1;
(12) For example, see: (a) Cram, D. J. Angew. Chem., Int. Ed. Engl.
1988, 100, 1009. (b) Pedersen, C. J. Angew. Chem., Int. Ed. Engl. 1988,
100, 1021.
˚
˚
(13) Job plots of rac-3c with all positively charged species tested
revealed a 1:1 stoichiometry of the complex (see Supporting Information
for details).
dP=OꢀHOOC = 2.580 A and dP=OꢀHOOC= 1.70 A),
(14) A preference in the coordination of monovalent (Liþ and NH4
)
þ
and divalent cations (Ba2þ) towards the crown-ether moiety instead of
the PdO group has been observed. Whilst association constants between
(10) UVꢀvisible titration data were analyzed using multivariate
factor analysis and considering a binding model with two colored
stoichiometric states of the crown-ethers: unbound and 1:1 complex.
SPECFIT software (Version 3.0; Spectra Software Associates) was used:
the aforementioned cationic species aþnd rac-3aꢀe lie around 104 Mꢀ1
,
binding constants between Liþ, NH4 , and Ba2þ with [1,10-biphenyl]-
2,20-diylbis(diphenylphosphine oxide) (compound analogue to rac-3 but
without the crown-ether moiety) were found to be 2 to 3 orders of
magnitude lower (6.7 ꢁ 101, 1.0 ꢁ 102, and 2.6 ꢁ 102 Mꢀ1, respectively)
in DCM/MeOH (99.5/0.5 v/v) at 25 °C.
€
(a) Gampp, H.; Maeder, M.; Meyer, C. J.; Zuberbuhler, A. D. Talanta
€
1985, 32, 95. (b) Gampp, H.; Maeder, M.; Meyer, C. J.; Zuberbuhler,
A. D. Talanta 1986, 33, 943. See Supporting Information for details.
(11) See Supporting Information for details.
3634
Org. Lett., Vol. 13, No. 14, 2011

þ
receptors bound NH4 with similar affinities (entry 7, SI
Table 1).
Table 2. Allosteric Effects on Binding of rac-3bꢀe with Dicar-
We have also investigated the binding behavior between
rac-3c and Ba2þ by isothermal calorimetry (ITC).11,15 The
binding constant determined by ITC had the same order of
magnitude as that measured by fluorescence (K = 2 ꢁ
104 Mꢀ1 by ITC in DCM/MeOH (98/2 v/v) and K = 3 ꢁ
104 Mꢀ1 by fluorescence in DCM/MeOH (99.5/0.5 v/v) at
25 °C).11 A 1:1 ratio between Ba2þ and rac-3c was deduced
from the ITC data. ΔH and ΔS values (7.5 kcal/mol,
44.4 cal/mol/K, 298 K in DCM/MeOH (98/2 v/v)) were
also extracted from the titration data and revealed that
complexation is an entropically driven process.
After studying the binding affinities of several cationic
species toward the different crown ether moieties, we
turned our attention to the effect of Liþ and Naþ as
allosteric effectors in the recognition of oxalic and malonic
acids by receptors rac-3bꢀe. The results obtained are
summarized in Table 2. It is noteworthy to mention that
binding constant values10 of dicarboxylic acids increased
as compared to the receptor with unbound “allosteric”
effectors. For example, malonic acid to Liþ @ rac-3b
(K = 3.3 ꢁ 104 Mꢀ1; entry 1 in Table 2) is approximately
seven times more tightly bound than to rac-3b (K = 4.5 ꢁ
103 Mꢀ1; entry 1 in Table 1). Similar effects were observed
in the interaction between Naþ @ rac-3b and oxalic acid
(entry 2 in Table 2).
boxylic Acids
binding constants (M )
ꢀ1 a,b and Krel
c
entry
receptor
oxalic acid
malonic acid
1
2
3
4
5
6
7
8
3b-Liþ
3b-Naþ
3c-Liþ
3c-Naþ
3d-Liþ
3d-Naþ
3e-Liþ
3e-Naþ
1.1 ꢁ 104; 1.7
4.3 ꢁ 104; 6.5
1.8 ꢁ 104; 3.7
1.6 ꢁ 104; 3.3
1.0 ꢁ 104; 1.7
2.0 ꢁ 104; 3.3
3.9 ꢁ 104; 5.3
1.4 ꢁ 104; 1.9
3.3 ꢁ 104; 7.4d
1.3 ꢁ 104; 2.9
1.3 ꢁ 104; 2.9
1.4 ꢁ 104; 3.1
1.4 ꢁ 104; 3.1
8.5 ꢁ 103; 1.9
8.2 ꢁ 103; 1.6
7.7 ꢁ 103; 1.5
a Measured in DCM/MeOH (99.5/0.5 v/v) at 25 °C. b Average value
of at least two measurements. Standard deviations (expressed in % with
respect to the binding constant value) were 16% (average value for all
measurements indicated in the table). c Binding constant quotient with
and without allosteric effector calculated from UVꢀvis absorption
titrations. d This binding constant was also measured by 31P NMR, to
confirm the Krel values obtained by UVꢀvis. However, the magnitude of
the binding contants (ca. 104 Mꢀ1) forced us to use dilute solutions of
rac-3b during the NMR titration (ca. 10ꢀ4 M). No K-value could be
extracted with this technique, as very broad and weak 31P NMR signals
were observed.
receptors for dicarboxylic acids have been evaluated, and
high affinities have been observed (oxalic and malonic
acids with 4-, 5-, 6-, or 8-crown ethers). Binding of cationic
effectors within the crown ether unit resulted in a positive
“allosteric” effect, which has been determined to be Krel = 7
in the best case (binding of malonic acid with Liþ @ rac-3b).
Work is in progress to develop asymmetric catalysts
based on receptors rac-3aꢀe with an allosteric regulation
mechanism.
The complex formation of dicarboxylic acids withcation
1
bound crown ethers was also confirmed by H NMR
experiments (see SI Figure 38 in the Supporting Infor-
mation): Addition of increasing amounts of malonic acid
to the solution of Liþ @ rac-3b resulted in the appearance
of a pseudotriplet at 3.35 ppm (2H) due to the malonic
methylene unit. This signal multiplicity can be justified by
transformation of the two magnetically equivalent protons
of the unbound malonic CH2-unit into a pair of diaster-
eotopic nuclei due to the close proximity of the malonic
acid to the stereogenic axis of rac-3b.11 Despite many
attempts, it has not been possible to grow crystals suitable
for X-ray analysis of any of the complexes indicated in
Table 2. We hypothesize that the changes in the torsion
angle between the central phenylene rings16 produced by
the inclusion of the effectors into the crown ether strength-
en binding in the aforementioned examples.
Acknowledgment. We thank MICINN (Grant CTQ-
2008-00950/BQU), DURSI (Grant 2009GR623), Consoli-
der Ingenio 2010 (Grant CSD2006-0003), and ICIQ Foun-
dation for financial support. A.J. gratefully acknowledges
the “Marie Curie Incoming Program” and H.F.-P. the
“Programa Torres y Quevedo” for financial support.
Supporting Information Available. Experimental de-
tails, characterization data, and NMR spectra for 1ꢀ3,
crystallographic data for 3 and details on binding studies.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have described an efficient synthesis
of new PdO-disubstituted biphenyl derivatives with
appended crown ethers rac-3aꢀe. Their properties as
(15) Binding studies of other positively charged species were not
possible by ITC, since heat evolved due to dilution was much higher than
the heat involved in the binding process.
(16) (a) Benniston, A. C.; Li, P.; Sams, C. Tetrahedron Lett. 2003, 44,
3947. (b) Benniston, A. C.; Harriman, A.; Patel, P. V.; Sams, C. A. Eur.
J. Org. Chem. 2005, 4680.
Org. Lett., Vol. 13, No. 14, 2011
3635