Control of the ketone to gem-diol equilibrium by host-guest interactions

Article abstract of DOI:10.1021/ol800021r

In water, N-methyl-4-(p-substituted benzoyl)pyridinium cations, BP-X, exist in equilibrium with their hydrated forms (gem-diols), whose concentrations depend on the para substituent (-X). In the presence of cucurbit[7]uril (CB[7]), the benzoyl group shows a preference for the CB[7] cavity, and the ketone to gem-diol equilibrium is shifted toward the keto form, meaning that the stabilization realized through hydrophobic interactions of the benzoyl group in the CB[7] cavity exceeds the hydrogen-bonding stabilization of the gem-diols in the aqueous environment.

Full text of DOI:10.1021/ol800021r

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1131-1134
Control of the Ketone to gem-Diol
Equilibrium by Host−Guest Interactions
Abdel Monem M. Rawashdeh,†,‡ Arumugam Thangavel,§
Chariklia Sotiriou-Leventis,*,§ and Nicholas Leventis*,§
Department of Chemistry, Yarmouk UniVersity, Irbid, 211-63, Jordan, Department of
Chemistry, Missouri UniVersity of Science and Technology,| Rolla, Missouri 65409
leVentis@mst.edu; csleVent@mst.edu
Received January 5, 2008
ABSTRACT
In water, N-methyl-4-(p-substituted benzoyl)pyridinium cations, BP-X, exist in equilibrium with their hydrated forms (gem-diols), whose
concentrations depend on the para substituent (-X). In the presence of cucurbit[7]uril (CB[7]), the benzoyl group shows a preference for the
CB[7] cavity, and the ketone to gem-diol equilibrium is shifted toward the keto form, meaning that the stabilization realized through hydrophobic
interactions of the benzoyl group in the CB[7] cavity exceeds the hydrogen-bonding stabilization of the gem-diols in the aqueous environment.
Host-guest complexes are vehicles for understanding and
using supramolecular interactions for purposeful function in
sensors, molecular machines, and switches.1 Cucurbiturils
(CB[x], 5 e x e 10), the result of a condensation reaction
between glucouril and formaldehyde, are barrel-shaped hosts
with a hydrophobic cavity whose mean internal diameter
ranges from 4.4 Å (CB[5]) to >10 Å (CB[10]).2,3 Since the
rims are formed by the negative ends of the carbonyl dipoles,
they can develop hydrogen bonding and ion-dipole interac-
tions with their environment. Consequently, some members
This property has been explored recently in conjunction with
photoisomerization and photodimerization. For instance, only
one trans-diaminostilbene dihydrochloride dication (DAS)
can be accommodated in CB[7]; irradiation leads to the cis
isomer, which is not thermally converted back to trans at
room temperature owing to stabilization by interaction of
both terminal protonated amines with the two negative rims
of CB[7].4 CB[8], however, can accommodate two molecules
of DAS leading to stereoselective photodimerization.5 Similar
results have been obtained more recently with 2:1 complexes
between trans-1,2-bis(4-pyridyl)ethylene and CB[8],6 while
CB[7] can accommodate two of the smaller 2-aminopyridine
(1) (a) Kaifer, A. E.; Gomez-Kaifer, M. Supramolecular Electrochem-
istry; Wiley-VCH Verlag GmbH: Weinheim, Germany, 1999. (b) Balzani,
V.; Credi, A.; Raymo, F. M.; Stoddart, J. F. Angew. Chem., Int. Ed. 2000,
39, 3348-3391.
(2) (a) Lagona, J.; Mukhopadhyay, P.; Chakrabarti, S.; Isaacs, L. Angew.
Chem., Int. Ed. 2005, 44, 4844-4870. (b) Lee, J. W.; Samal, S.; Selvapalam,
N.; Kim, H.-J.; Kim, K. Acc. Chem. Res. 2003, 36, 621-630. (c) Kim, K.
Chem. Soc. ReV. 2002, 31, 96-107.
of the CB[x] family are water soluble, and the cavity can
bind one or more cationic guests, depending on their size.
(3) Liu, S. L.; Zavalij, P. Y.; Isaacs, L. J. Am. Chem. Soc. 2005, 127,
16798-16799.
† Yarmouk University.
(4) Choi, S.; Park, S. H.; Ziganshina, A. Y.; Ko, Y. H.; Lee, J. W.; K.
K. Chem. Commun. 2003, 2176-2177.
(5) Jon, S. Y.; Ko, Y. H.; Park, S.-H.; Kim, H.-J.; Kim, K. Chem.
Commun. 2001, 1938-1939.
‡ Visiting faculty at the University of MissourisRolla, Summer 2007.
§ Missouri University of Science and Technology.
| Formerly, University of MissourisRolla.
10.1021/ol800021r CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/16/2008

hydrochloride cations whose irradiation leads to stereo-
selective [4 + 4] photodimerization.7 Modulation of thermal
equilibria of the quests are also known, e.g., shifting the 4,4′-
bis(dimethylamino)diphenylcarbinol/carbocation equilibrium
toward the carbocation with CB[7].8 Here, we demonstrate
host-guest interactions between CB[7] and a family of
guests based on the N-methyl-4-(p-substituted benzoyl)-
pyridinium cation (BP-X, where X ) -OCH3, -CH3, -H, -Br,
-CHO, -NO2, and -S+(CH3)2), and we report that the ketone
to gem-diol equilibrium in water (eq 1) is controlled by the
preference of the keto form for the CB[7] cavity.
1
Figure 1. Room temperature (23 °C) H NMR of the aromatic
region of BP-H (X ) H; 16.1 mM) in D2O/0.1 M KCl before (A)
and after (B) addition of 1.25 mol equivalents of CB[7]. The upfield
shift of all protons supports the endo-orientation. The small
“impurities” in the baseline is the gem-diol form of BP-H in
equilibrium with the dominant keto form.
In aqueous solution, carbonyl compounds exist in equi-
librium with their hydrated forms (gem-diols). The concen-
tration of the latter is usually very low, but it can increase if
substitution renders the carbonyl group more susceptible to
nucleophilic addition.9 The position of this equilibrium can
be of vital importance in biological systems where reactivity
may be either associated with or stereoelectronically con-
trolled by only one of the two forms.10-13 Ideally, the
carbonyl/gem-diol equilibrium would be controlled with
supramolecular additives rather than by modifying the
substrate or the environment (e.g., by changing the pH).
All BP-Xs of this study were available from previous
work14 and were chosen as model ketones because of their
water solubility, their relation to the NAD+/NADH coenzyme
of dehydrogenases, their expected adjustable aptitude for
hydration by para substitution, and their structural similarity
to methyl viologen (N,N′-dimethyl-4,4′-bipyridinium di-
cation, MV2+),15,16 which warrants interaction with CB[7].
In this regard, it is noted that MV2+ fits well in CB[7], and
the two positive charges are stabilized by ion-dipole
interactions with the carbonyl groups of the rims.2,15,16 By
the same token, however, since BP-Xs have only one
pyridinium ring, their orientation relative to the cavity of
CB[7] was not obvious a priori: they could assume either
an exo or an endo stereochemistry as illustrated below:
1
presence of CB[7] (purchased from Aldrich), the H NMR
of BP-H (X ) H) in D2O shows an upfield shift for all
protons, consistent with the endo-BP-H@CB[7]. Identical
results were observed for all BP-X of this study. The exo
orientation is in fact observed with the corresponding
N-hexyl-4-(p-substituted benzoyl)pyridinium cations, by
analogy to that reported for hexylviologen (N,N′-dihexyl-
4,4′-bipyridinium dication; refer to the Supporting Informa-
tion).16 Clearly, the benzoyl group, despite possible H-bond-
ing interactions with the solvent through the carbonyl oxygen,
prefers to retreat into the hydrophobic cavity where it must
enjoy greater stabilization through hydrophobic interactions.
As shown in Figure 2, upon intercalation in CB[7] the longest
wavelength electronic absorption of BP-X decreases in
analogy to what has been reported for MV2+.17 The 1:1
stoichiometry of the resulting BP-X@CB[7] complexes is
supported by the presence of stable isosbestic points in the
UV-titration of BP-X with CB[7], and in the case of BP-H,
it was confirmed by a peak at m/z ) 1361.58 (expected at
m/z ) 1361.20) in the ESI mass spectrum of the BP-H/CB[7]
aqueous solution (see the Supporting Information). The
strong binding aptitude of BP-H with CB[7] is reflected in
the equilibrium constant for complex formation (Keq ) (6.2
( 2.1) × 103 M-1 by analysis of the UV titration data of
Figure 2; see the Supporting Information).18
(10) Silva, A. M.; Cachau, R. E.; Sham, H. L.; Erickson, J. W. J. Mol.
Biol. 1996, 255, 321-346.
(11) Eisses, K. Th. Bioorg. Chem. 1989, 17, 268-274.
(12) Likar, M. D.; Taylor, R. J.; Fagerness, P. E.; Hiyama, Y.; Robins,
R. H. Pharm. Res. 1993, 10, 75-79.
1
(13) Hanessian, S.; Roy, R. Tetrahedron Lett. 1981, 22, 1005-1008.
(14) Leventis, N.; Rawashdeh, A.-M. M.; Zhang, G.; Elder, I. A.;
Sotiriou-Leventis, C. J. Org. Chem. 2002, 67, 7501-7510.
(15) Kim, H.-J.; Jeon, W. S.; Ko, Y. H.; Kim, K. Proc. Natl. Acad. Sci.
U.S.A. 2002, 99, 5007-5011.
The exo versus endo orientation was elucidated by H
NMR. As shown in Figure 1 for the aromatic region, in the
(6) Maddipatla, M. V. S. N.; Kaanumalle, L. S.; Natarajan, A.; Patta-
biraman, M.; Ramamurthy, V. Langmuir 2007, 23, 7545-7554.
(7) Wang, R.; Yuan, L.; Macartney, D. H. J. Org. Chem. 2006, 71, 1237-
1239.
(16) Moon, K.; Kaifer, A. E. Org. Lett. 2004, 6, 185-188.
(17) Ong, W.; Go´mez-Kaifer, M.; Kaifer, A. E. Org. Lett. 2002, 4, 1791-
1794.
(8) Wang, R.; Macartney, D. H. Tetrahedron Lett. 2008, 49, 311-314.
(9) See for example: Greenzaid, P.; Luz, Z.; Samuel, D. J. Am. Chem.
Soc. 1967, 89, 749-756.
(18) Connors, K. A. Binding Constants, The Measurement of Molecular
Complex Stability; John Wiley and Sons, Inc.: New York, 1987; Chapter
4, p 141.
1132
Org. Lett., Vol. 10, No. 6, 2008

complex is stabilized by two cation-dipole interactions, much
like MV2+ whose Keq∼2 × 105 M-1.15-17
1
If the effect of substitution is also followed by H NMR
(no CB[7] present), we are able to see that as X- becomes
more electron withdrawing (e.g., going from -H to -NO2),
in aqueous solutions BP-X exist in equilibrium with progres-
sively increasing amounts of their gem-diol forms, whose
identity was confirmed by the 13C NMR signature resonance
of the C(OH)2 carbon at ∼94.5 ppm. The relative ratio of
the two forms, and therefore the value of each ketone h
gem-diol equilibrium constant (Kdiol), is extracted directly
from the 1H NMR spectra. Kdiol data show a good Hammett
correlation (Figure 4) with a reaction constant F ) 1.31 (
Figure 2. Room-temperature (23 °C) titration of BP-H (9.88 ×
10-5 M) in H2O/0.1 M KCl with CB[7]. (Initial pH ∼6.0; after
addition of CB[7], pH∼4.0. Results identical in phosphate buffer
at pH ) 7.0.) Inset curve: by nonlinear regression (see the
Supporting Information).
Similarly, all the other BP-Xs examined showed strong
binding aptitudes toward CB[7]. Equilibrium constants, Keq,
increase with electron-withdrawing substitution (Figure 3,
Figure 4. Substitution effect for the keto/gem-diol equilibrium in
D2O/0.1 M KCl with and without 1.0 molar equiv of CB[7]. ([BP-
X] ) 16.0 ( 0.6 mM.) Equilibrium constants, Kdiol, directly from
1H NMR data: spectra recorded 15 min and 24 h after dissolving
BP-X in D2O/0.1 M KCl were identical. Data for BP-S+(CH3)2
are not included because the t1/2 of the ketone to gem-diol equi-
librium was a few hours.
0.02, which is similar to values reported for substituted
benzaldehydes (1.71-1.75).19
The effect of CB[7] upon the keto/gem-diol equilibrium
is best illustrated with the N-methyl-4-(p-formylbenzoyl)-
pyridinium cation (BP-CHO), which in CH3CN appears as
a pure compound (Figure 5A), while in D2O consists of a
mixture of three forms (Figure 5B).20
Upon addition of increasing amounts of CB[7] (Figures
5C and 5D), the fate of the individual forms in equilibrium
can be followed separately: the dicarbonyl form, BP-CHO,
shows an evolution-pattern similar to that of BP-H in Figure
1, underscoring the preference of the benzoyl group for the
CB[7] cavity. A similar case is made for the hydrated
aldehyde: BP-CH(OH)2. However, when the gem-diol is
on the benzoyl group only small chemical shift changes are
observed with increasing the concentration of CB[7] indicat-
Figure 3. Substitution effects for the BP-X + CB[7] h BP-
X@CB[7] equilibrium in D2O/0.1 M KCl showing that as BP-X
becomes more electron deficient, its compatibility with the hydro-
phobic cavity of CB[7] increases.
F ) 0.58 ( 0.06) reflecting that as the benzoyl group
becomes more electron deficient, its ability to form H-
bonding with the aqueous environment decreases, thus
increasing its preference for the hydrophobic interior of
CB[7]. The extreme case of BP-S+(CH3)2 is noteworthy
because it shows an abnormally high affinity for CB[7] (Keq
) (3.6 ( 1.0) × 105 M-1), most probably because that
(19) Baymak, M. S.; Vercoe, K. L.; Zuman, P. J. Phys. Chem. B 2005,
109, 21928-21929.
(20) The bis gem-diol of BP-CHO is not detectable, reflecting the change
in the electronic properties of carbonyls converted to gem-diols.
Org. Lett., Vol. 10, No. 6, 2008
1133

relative amount of BP-CHO increases at the expense of both
hydrated forms. After addition of 1.25 mol equivalent of
CB[7] into the aqueous solution of BP-CHO, the 1H NMR
spectrum (Figure 5D) looks similar to that in CD3CN (Figure
5A), while the relative ratios of the three forms BP-CHO/
gem-diol/hydrated aldehyde change from 1.0:0.26:0.20 to 1.0:
0.06:<0.01 after addition of one equivalent of CB[7].22 The
new keto h gem-diol equilibrium constants after addition
of CB[7], still show a good Hammett correlation (Figure
4). The new line runs almost parallel to (F ) 1.41 ( 0.18),
but below the one representing the keto/gem-diol equilibrium
before the addition of CB[7] reflecting similar stereoelec-
tronic factors but much lower equilibrium concentrations of
gem-diols. Clearly, the stabilization realized by H-bonding
of the gem-diols in water is still less than the stabilization
realized through hydrophobic interactions of the benzoyl
groups in the interior of the cavity.23 It is noteworthy that in
systems where the benzoylpyridinium group assumes the exo-
configuration (the case of N-hexyl-4-benzoylpyridinium
cations), the keto to gem-diol equilibrium is affected less by
the presence of CB[7] (see the Supporting Information).
The results described herewith have been possible because
all BP-X@CB[7] complexes seem to include strong hydro-
phobic interactions with the CB[7] cavity and are oriented
endo in water. Our results viewed together with those
reported in recent and current literature suggest that the
broader scope of exerting control on potentially useful
homogeneous reactions of the guest via host-guest interac-
tions should be explored further.2,4-7 Finally, BP-X@CB[7]
having one redox center, the benzoyl group, inside the cavity
invites further studies of the electron transfer through the
cage wall.
Figure 5. 1H NMR data of BP-CHO in CD3CN (A) and in D2O/
0.1 M KCl without CB[7] (B), with 0.75 molar equiv CB[7] (C),
and 1.25 molar equiv of CB[7] (D). Peak assignment by COSY
2D NMR and simulation; blue and red color coding to match
structures on top.
ing that this form is oriented mostly outside the cavity.
Starting with similar geometries (the carbonyl or the gem-
diol groups inside the cavity), PM3-optimized structures of
BP-NO2@CB[7] and of the corresponding gem-diol support
that the gem-diol of the benzoyl group prefers to stay outside
the cavity, where presumably it can be further stabilized by
hydrogen bonding with the aqueous environment.21
Acknowledgment. We thank the University of Missouri
Research Board for financial support.
Supporting Information Available: Data analysis and
1
data tables; H NMR spectra (in D2O) of (a) N-hexyl-4-
benzoylpyridinium, (b) N-methyl-4-(p-nitrobenzoyl)pyridin-
ium, and (c) N-hexyl-4-(p-nitrobenzoyl)pyridinium tetra-
fluoroborate with/without CB[7]; ESI mass spectral data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL800021R
(22) It is emphasized that in the presence of CB[7] the concentration of
BP-CH(OH)2 is extremely small; hence, the point for BP-CHO in the
Hammett plot of Figure 3 falls in line with the rest of the substituents.
(23) Apparently, CB[7] can intercalate even neutral aromatic ketones.24
Equilibrium constant data in the presence of K+ are about 1 order of
magnitude less than the values plotted in Figure 3, probably reflecting the
lack of positive charge.
The most significant observation in Figure 5, however, is
that upon addition of increasing amounts of CB[7], the
(21) DFT-optimized structures (by the B3LYP/6-31G* method) were
used as inputs of the PM3 optimizations for all three: CB[7], BP-NO2,
and the gem-diol of the latter.
(24) Mezzina, E.; Cruciani, F.; Pedulli, G. F.; Lucarini, M. Chem. Eur.
J. 2007, 13, 7223-7233.
1134
Org. Lett., Vol. 10, No. 6, 2008