Carbonyl groups as molecular valves to regulate chloride binding to squaramides

Article abstract of DOI:10.1021/ol801204s

(Chemical Equation Presented) Environment-sensitive binding of anions to synthetic receptors is important for the functional mimicry of ion channels. We describe new squaramide-based chloride ion receptors whose anion binding cavity can be opened and clos

Full text of DOI:10.1021/ol801204s

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3315-3318
Carbonyl Groups as Molecular Valves to
Regulate Chloride Binding to
Squaramides
Vijayakumar Ramalingam, Maciej E. Domaradzki, Seogjoo Jang,
and Rajeev S. Muthyala*
Department of Chemistry and Biochemistry, Queens College and the Graduate Center
of the City UniVersity of New York, Flushing, New York 11367-1597
rajeeV.muthyala@qc.cuny.edu
Received May 27, 2008
ABSTRACT
Environment-sensitive binding of anions to synthetic receptors is important for the functional mimicry of ion channels. We describe new
squaramide-based chloride ion receptors whose anion binding cavity can be opened and closed by using carbonyl groups as valves. In
nonpolar solvents, the carbonyls preclude chloride binding via intramolecular hydrogen bonding with the squaramide NHs. In polar solvents,
disruption of the intramolecular hydrogen bonds reorients the carbonyl groups and opens the anion-binding cavity.
Artificial receptors for chloride ions are increasingly sought
after as mimics of anion channels.1 In diseases such as cystic
fibrosis that are caused by mutations in chloride channels,
artificial receptors could potentially serve as surrogate
chloride transporters for rectifying defective ion transport.1b
However, in the synthetic Cl- ion receptors reported so far,2
exploit secondary diphenyl squaramides, which are known
to prefer the extended ZZ conformation,8 as the anion-
the incorporation of an environment-dependent switching/
gating mechansim has rarely been attempted.2h,3 This is rather
surprising since gating is an integral feature of all ion
channels.4 “Smart” artificial chloride ion receptors whose
binding cavities can be opened and closed in response to
changes in the environment can be useful in regulating ion
transport1 as well as in other areas including environmental
remediation5 and sensor design.6
binding scaffold.9 We reasoned that introduction of o-
carbonyl substituents capable of intramolecular hydrogen
(2) For general reviews on supramolecular chemistry of anions, see: (a)
Gale, P. A.; Garcia-Garrido, S. E.; Garric, J Chem. Soc. ReV. 2008, 37,
151–190. (b) Kang, S. O.; Begum, R. A.; Bowman-James, K. Angew. Chem.,
Int. Ed. 2006, 45, 7882–7894. (c) Katayev, E. A.; Ustynyuk, Y. A.; Sessler,
J. L. Coord. Chem. ReV. 2006, 250, 3004–3037. (d) Schmidtchen, F. P
Coord. Chem. ReV. 2006, 250, 2918–2928. For recent leading references
on chloride ion receptors, see: (e) Calderon-Kawasaki, K.; Kularatne, S.;
Li, Y. H.; Noll, B. C.; Scheidt, W. R.; Burns, D. H. J. Org. Chem. 2007,
72, 9081–9087. (f) Li, X.; Shen, B.; Yao, X.-Q.; Yang, D. J. Am. Chem.
Soc. 2007, 129, 7264–7265. (g) Piatek, P. Tetrahedron Lett. 2007, 48, 4427–
4430. (h) Winstanley, K. J.; Smith, D. K. J. Org. Chem. 2007, 72, 2803–
2815. (i) Li, Y.; Flood, A. H. Angew. Chem., Int. Ed. 2008, 47, 2649–
2652. (j) Kondo, S. I.; Fukuda, A.; Yamamura, T.; Tanaka, R.; Unno, M.
Tetrahedron Lett. 2007, 48, 7946–7949. (k) Lin, C.; Simov, V.; Drueck-
hammer, D. G. J. Org. Chem. 2007, 72, 1742–1746.
In our strategy (Scheme 1) to regulate chloride binding,
we envisioned a molecular valve approach.7 We sought to
(1) (a) Jentsch, T. J Crit. ReV. Biochem. Mol. Biol. 2008, 43, 3–36. (b)
Davis, A. P.; Sheppard, D. N.; Smith, B. D Chem. Soc. ReV. 2007, 36,
348–357. (c) Smith, B. D.; Lambert, T. N. Chem. Commun. 2003, 2261–
2268.
10.1021/ol801204s CCC: $40.75
Published on Web 07/01/2008
2008 American Chemical Society

Scheme 1
.
Proposed Molecular Valve Approach
Scheme 2. Synthesis of Secondary Squaramides
bonding with the squaramide NHs would preclude anion
binding. We anticipated further that a combined solvent-
induced disruption2h of the intramolecular hydrogen bond
and anion-induced reorientation of the carbonyls3f,10 would
facilitate binding. We wish to describe in this paper the use
of carbonyl groups as molecular valves to regulate chloride
ion binding to squaramides. The opening and closing of the
carbonyl valves is controlled by solvent-polarity dependent
intramolecular hydrogen bonding.
The key distinguishing feature of our work is that we
exploit the rigid preorganized anion-binding cavity in squara-
mides and use intramolecular hydrogen bonding to open and
close the cavity. Our approach complements that of Santac-
roce et al.,3a who used intramolecular hydrogen bonding as
a tool for preorganizing the anion-binding cavity of isoph-
thalimides.
reaction of squaric acid chloride with the appropriate
substituted aniline.11 The crude squaramides were purified
by chromatography followed by repeated recrystallization.
NMR analysis showed that the H6 doublet was consistently
the most deshielded signal in the benzoyl squaramides 1-3.
This indicated a preference for the extended ZZ conformation
with the deshielding attributable to the proximity of H6 to
the cyclobutene dione carbonyl.8a In the case of the ortho-
substituted derivatives 1 and 2, the ZZ conformation is further
reinforced by intramolecular hydrogen bonding between the
carbonyl of the ortho benzoyl groups and the squaramide
N-Hs.12 This is suggested by the following: (a) the 2 ppm
downfield shift of the N-H signal for the ortho isomers (11.4
and 11.3 ppm, respectively, for 1 and 2 in CDCl3) relative
to the meta derivative 3 (9.2 ppm in CDCl3); (b) in the 13C
NMR spectra, the benzoyl carbonyl in the ortho derivative
1 is deshielded by ∼4 ppm compared to the meta isomer 3;
and (c) in IR spectra, in CHCl3, the benzoyl carbonyl signal
of 1 and 2 appears at lower frequencies (1641 cm-1 and 1644
cm-1 respectively) than that for the meta derivative 3 (1660
cm-1).
The interactions of the o-benzoylsquaramides 1 and 2 with
chloride ions13 were dependent on solvent polarity (Figure
1). In nonpolar solvents such as toluene, methylene chloride,
and chloroform, there was no observable interaction of the
squaramides with chloride ions despite addition of a large
excess. In contrast, in polar solvents such as acetonitrile,
addition of Cl- ion led to a downfield shift of the N-H peak
along with changes14 in the aromatic region of the NMR
spectrum, suggestive of a hydrogen-bonded supramolecular
complex. The alternative possibility of covalent attachment
of the chloride to the benzoyl carbony15 was considered
Benzoyl-substituted squaramides 1-3 were chosen as the
chloride ion receptors and were synthesized (Scheme 2) by
(3) (a) Santacroce, P. V.; Davis, J. T.; Light, M. E.; Gale, P. A.; Iglesias-
Sanchez, J. C.; Prados, P.; Quesada, R. J. Am. Chem. Soc. 2007, 129, 1886–
1887. (b) Okunola, O. A.; Seganish, J. L.; Salimian, K. J.; Zavalij, P. Y.;
Davis, J. T. Tetrahedron 2007, 63, 10743–10750. (c) Tajc, S. G.; Miller,
B. L. J. Am. Chem. Soc. 2006, 128, 2532–2533. (d) Schlesinger, P. H.;
Ferdani, R.; Liu, J.; Pajewska, J.; Pajewski, R.; Saito, M.; Shabany, H.;
Gokel, G. W J. Am. Chem. Soc. 2002, 124, 1848–1849. For examples of
Cl- driven switching, see: (e) Nielsen, K. A.; Sarova, G. H.; Martin-Gomis,
L.; Fernandez-Lazaro, F.; Stein, P. C.; Sanguinet, L.; Levillain, E.; Sessler,
J. L.; Guldi, D. M.; Sastre-Santos, A.; Jeppesen, J. O. J. Am. Chem. Soc.
2008, 130, 460–462. (f) Chmielewski, M. J.; Jurczak, J Chem.sEur. J.
2006, 12, 7652–7667.
(4) Dutzler, R.; Campbell, E. B.; MacKinnon, R. Science 2003, 300,
108–112.
(5) (a) Capitan-Vallvey, L. F.; Guerrero, E. A.; Merelo, C. B.; Ramos,
M. D. F. Anal. Bioanal. Chem. 2004, 380, 563–569. (b) Gardner, J. S.;
Peterson, Q. P.; Walker, J. O.; Jensen, B. D.; Adhikary, B.; Harrison, R. G.;
Lamb, J. D. J. Membr. Sci. 2006, 277, 165–176.
(6) (a) Bai, Y.; Zhang, B.-G.; Xu, J.; Duan, C.-Y.; Dang, D.-B.; Liu,
D.-J.; Meng, Q.-J New J. Chem. 2005, 29, 777–779. (b) dos Santos,
C. M. G.; McCabe, T.; Gunnlaugsson, T. Tetrahedron Lett. 2007, 48, 3135–
3139.
(11) Ehrhardt, H.; Huenig, S.; Puetter, H. Chem. Ber. 1977, 110, 2506–
2523.
(7) (a) Nguyen, T. D.; Tseng, H.-R.; Celestre, P. C.; Flood, A. H.; Liu,
Y.; Stoddart, J. F.; Zink, J. I Proc. Natl Acad. Sci. U.S.A. 2005, 102, 10029–
10034. (b) Nguyen, T. D.; Liu, Y.; Saha, S.; Leung, K. C. F.; Stoddart,
J. F.; Zink, J. I. J. Am. Chem. Soc. 2007, 129, 626–634. (c) Kocer, A.;
Walko, M.; Meijberg, W.; Feringa, B. L. Science 2005, 309, 755–758.
(8) (a) Muthyala, R. S.; Subramaniam, G.; Todaro, L. Org. Lett. 2004,
6, 4663–4665. (b) Fu, N.; Allen, A. D.; Kobayashi, S.; Tidwell, T. T.;
Vukovic, S.; Arumugam, S.; Popik, V. V.; Mishima, M. J. Org. Chem.
2007, 72, 1951–1956.
(12) For examples of intramolecular hydrogen bonding in squaramides,
see: (a) Davis, A. P.; Draper, S. M.; Dunne, G.; Ashton, P Chem.Commun.
1999, 226, 5–2266. (b) Prohens, R.; Rotger, M. C.; Pina, M. N.; Deya,
P. M.; Morey, J.; Ballester, P; Costa, A Tetrahedron Lett. 2001, 42, 4933–
4936. (c) Rotger, M. C.; Pina, M. N.; Frontera, A.; Martorell, G.; Ballester,
P.; Deya, P. M.; Costa, A. J. Org. Chem. 2004, 69, 2302–2308.
(13) The addition of Br- or I- to 1 (or 2) did not lead to any solvent-
-
polarity dependent NMR spectral shifts. For F-, CH3CO2-, and H2PO4
there were no spectral changes in CHCl3 but in CH3CN, a 77 nm
bathochromic shift in the UV-vis spectra was identical to that generated
by the addition of OH- indicating deprotonation of the squaramide (see
the Supporting Information).
(9) (a) Rotger, C.; Soberats, B.; Quinonero, D.; Frontera, A.; Ballester,
P.; Benet-Buchholz, J.; Deya, P. M.; Costa, A Eur. J. Org. Chem. 2008,
11, 1864–1868, and references therein. (b) Ambrosi, G.; Formica, M.; Fusi,
V.; Giorgi, L.; Guerri, A.; Micheloni, M.; Paoli, P.; Pontellini, R.; Rossi, P
Chem.sEur. J. 2007, 13, 702–712. (c) Garau, C.; Quinonero, D.; Frontera,
A.; Costa, A.; Ballester, P.; Deya, P. M. Chem. Phys. Lett. 2003, 370, 7–
13.
(14) Similar spectral shifts were observed in solvent mixtures such as
9:1 (v/v) CD3CN/DMSO-d6 or CD3CN/CDCl3 (9:1) but not in neat DMSO-
d6 or pyridine-d5. Compounds 1 and 2 were insoluble in methanol-d4.
(15) The resulting tetrahedral intermediate would be stabilized by
intramolecular hydrogen bonding: Kim, Y. K.; Lee, Y.-H.; Lee, H.-Y.; Kim,
M. K.; Cha, G. S.; Ahn, K. H Org. Lett. 2003, 5, 4003–4006.
(10) Kim Sung, K.; Bok Ju, H.; Bartsch Richard, A.; Lee Jin, Y.; Kim
Jong, S. Org. Lett. 2005, 7, 4839–4842
.
3316
Org. Lett., Vol. 10, No. 15, 2008

Figure 1
.
NMR spectra of the o-benzoylsquaramide 1 (2 × 10-3
M) in (a) CDCl3, (b) CDCl3 with 1 equiv of tetrabutyl ammonium
chloride (TBACl), (c) CD3CN, and (d) CD3CN with 1 equiv of
TBACl.
Figure 2
.
Interactions of m-benzoylsquaramide 3 (2.5 × 10-5 M)
with TBACl in (A) CHCl3 and (B) CH3CN. The binding isotherms
are shown in the insets.
unlikely since all carbonyl signals are intact in the 13C NMR
spectra even after addition of excess chloride. Aggregation
of the squaramides16 was also excluded since identical
chloride-induced spectral shifts were observed over a con-
centration range of 0.5 to 5 mM.
allowed us to use absorption spectroscopy for determining
the binding constants for 3. The Ka values for the meta isomer
were independent of solvent polarity and were considerably
larger than the ortho isomers 1 and 2, presumably due to
steric hindrance in the latter.
Job plots17 confirmed 1:1 stoichiometry for the chloride
complexes. The binding constants for compounds 1 and 2
were determined18 by NMR spectroscopy; no apparent
chloride-induced changes were seen in the absorption spectra
in either CHCl3 or CH3CN. The Ka for the ortho benzoyl
derivative 1 (Table 1) was comparable to the catechol
derivatives2h as well as some of the isophthalimides3a
The observation that Cl- binding to the o-squaramides
occurs only in CD3CN led us to examine the NMR spectra
of the uncomplexed squaramides in different solvents. We
found that for the ortho derivatives the N-H signal shifted
upfield with increasing solvent polarity. For instance, for
squaramide 1, the N-H signal is shifted upfield (relative to
CDCl3) by ∼1 ppm in CD3CN and by 1.5 ppm in DMSO.
In contrast, there was no clear trend for the meta isomer:
the N-H peak was shifted upfield in CD3CN but was
deshielded in DMSO. The trend mentioned above for the
ortho squaramides is likely due to disruption of the intramo-
lecular hydrogen bond in polar competitive solvents such as
CH3CN. In fact, similar acetonitrile-induced upfield shifts
of the NH peaks, observed in carbamoyl squaramides, have
also been attributed to disruption of N·H · · · OdC
hydrogen bonds.12a,19 In the 13C NMR spectrum of squara-
mide 1, an upfield shift of the benzoyl carbonyl signal by
∼0.9 ppm in CH3CN, relative to CHCl3, is also consistent
with disruption (or weakening) of the intramolecular hydro-
Table 1. Chloride Ion Association Constants (Ka) of
Squaramides 1-3
compd
solvent
Ka (M-1
)
1
1
2
2
3
3
CHCl3
CH3CN
CHCl3
CH3CN
CHCl3
CH3CN
84 ( 8a
517 ( 34a
(7.8 ( 1.4) × 105
b
b
(4.1 ( 0.6) × 105
a The Ka values were determined by NMR. b The Ka values were
determined by UV-vis spectroscopy. In each case, the reported Ka values
are the average of three independent measurements.
(16) Aggregation of the uncomplexed squaramides was examined
separately but was considered unlikely since in the NMR spectra of 1 and
2 only minor changes (∆δ < 0.01) were observed over a 10-fold (0.5-5
mM) variation in concentration in both CDCl3 and CD3CN. For 3, a linear
relationship between absorbance and concentration (20-2 µM) excluded
aggregation.
reported recently. Interestingly, introduction of a chloro
substituent led to a 5-fold increase in the binding affinity
for squaramide 2 (Figure 2).
In contrast to the ortho isomers, a chloride-induced
bathochromic shift of ∼10 nm (in both CHCl3 and CH3CN)
Org. Lett., Vol. 10, No. 15, 2008
(17) Job, P. Compt. Rend. 1925, 180, 928–930.
(18) Although significant changes were observed in both the NH and
the aromatic regions of the NMR spectra, tracking of the latter signals was
difficult due to peak overlap.
3317

gen bond in the former solvent. The chemical shift of benzoyl
carbonyl of the meta isomer, 3, is unaffected by changes in
solvent polarity. Therefore, based on our spectral data and
literature precedence, we infer that in squaramides 1 and 2,
disruption20 of intramolecular hydrogen bonding in CD3CN
facilitates chloride binding while in the nonpolar CHCl3,
anion binding is precluded due to a strong preference for
the intramolecularly hydrogen bonded form.
To address the issue of whether disruption of intramo-
lecular hydrogen bonding alone was important or whether
carbonyl group reorientation was also required, we prepared
the fluorenone squaramide 4.
lecular hydrogen bonding is disrupted (the N-H · · · OdC
distance increases to 2.84 Å) and the carbonyl groups pivot
out of plane with each pointing in opposite directions and
nearly perpendicular to the cyclobutene dione ring. This
pivoting of the carbonyls is presumably triggered by
unfavorable ion dipole interactions between the carbonyl of
the ortho benzoyl group and the incoming chloride ion.24
Thus, the carbonyl groups indeed function as “valves” to
open and close the anion-binding cavity of squaramides-
.(Figure 3).
The N-H signal for 4 in CHCl3 was found to be
significantly upfield (10.4 ppm) relative to 1 and 2 (11.2 and
11.3 ppm, respectively) as well as the constrained an-
thraquinone squaramide 5 (12.6 ppm). This suggests a
considerably weakened21 intramolecular hydrogen bond in
the fluorenone squaramide 4 relative to 1, 2, and 5. However,
despite the weakened intramolecular hydrogen bonding, no
chloride-induced spectral changes in CHCl3 were detected
for 4, thereby underscoring the requirement for carbonyl
reorientation. Attempts to further confirm the necessity of
carbonyl reorientation in CH3CN were not successful,
however, due to the insolubility of 4 in that solvent.
Nevertheless, gas-phase DFT calculations supported the
idea of a conformational change. In the uncomplexed form,
the intramolecularly hydrogen-bonded conformer is preferred
with each o-benzoyl carbonyl group coplanar with the nearest
squaramide NH. The N-H · · · OdC distance was
calculated to be 1.76 Å, while the hydrogen bond angle was
found to be 140°.22 In the chloride complex,23 the intramo-
Figure 3. DFT (B3LYP/6-31+G**)-minimized structures of (A)
uncomplexed squaramide 1 and (B) the chloride complex.
In summary, we have developed a unique class of
squaramides whose binding to chloride can be “gated” by
using carbonyl groups as environment-responsive molecular
valves. The binding of Cl- in polar medium and its release
in a nonpolar environment establishes a new paradigm in
the design of synthetic anion channel mimics. Future studies
will focus on examining the generality of the molecular valve
approach in other ortho substituted squaramides as well as
the design of new chloride receptors that are functional in
aqueous medium.
Acknowledgment. We thank Dr. Clifford Soll of the
CUNY Mass Spectrometry Facility at Hunter College for
the HRMS data and acknowledge the Department of
Chemistry, Queens College, for partial funding.
(19) For acetonitrile-induced weakening of the intramolecular hydrogen
bond in ortho-substituted anilines, see: Denisov, G. S.; Kuzina, L. A J.
Mol. Struct. 1992, 271, 9–18.
Supporting Information Available: Experimental details,
compound characterization data, Job plots, and Cartesian
coordinates of squaramide 1 and the chloride complex. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Numerous attempts to record IR spectra of 1 and 2 in CH3CN, as
additional evidence for hydrogen bond disruption, were not fruitful. Due
to low solubility of the squaramides, concentrated solutions (> 5 mM) in
CH3CN could not be prepared.
(21) Structural constraints enforce an increase in the hydrogen bond
distance in 4 relative to 5: Baumstark, A. L.; Graham, S. S.; Boykin, D. W
Tetrahedron Lett. 1990, 31, 957–960.
OL801204S
(22) Taylor, R.; Kennard, O.; Versichel, W. J. Am. Chem. Soc. 1983,
105, 5761–5766.
(24) Unfavorable nonbonded interactions between Cl- and the carbonyl
dipoles are likely to be severe since the distance between the oxygen atoms
of the two benzoyl carbonyls in compound 1 (3.57 Å) is about the same as
the ionic radius of Cl- (3.31 Å); see: Paula, S.; Volkov, A. G.; Deamer, D.
W Biophys. J. 1998, 74, 319–327.
(23) The computed N · · · Cl distance of 3.1 Å is close to that
determined experimentally in other chloride complexes. See, for example:
Sessler, J. L.; An., D.; Cho, W.-S.; Lynch, V.; Marquez, M Chem. Commun.
2005, 540–542.
3318
Org. Lett., Vol. 10, No. 15, 2008