tively charged guests.18,21 Previously, cucurbit[6]uril (CB6)
has been employed to catalyze 1,3-dipolar cycloaddition
reactions between alkynes and alkyl azides,22-24 while
cucubit[7]uril (CB7) and cucubit[8]uril have been employed
to catalyze different types of photocycloaddition reac-
tions.25-28 However, although it is known that complexation
by cucurbit[n]urils can shift the pKa value of included guests
and thereby promote their protonation, the possibility of
catalyzing or promoting reactions of acid-labile substrates
has been invoked in only a single case.14 Herein, we find
that cucurbit[n]urils indeed catalyze the hydrolysis of amides,
carbamates, and oximes in acidic aqueous solution or, conversely,
allow their hydrolysis under significantly milder conditions.
Our general design principle (see Abstract graphic) is such
that we employ acid-labile substrates with anchoring groups
that are known to bind strongly to the macrocycle, thereby
positioning the reactive groups in the proximity of the cation-
receptor sites of the host. This induces guest protonation and
catalyzes the hydrolysis. Specifically, we use CB6 and CB7,
which bind cations at their upper and lower carbonyl rim, and
compounds 1-3 as substrates with acid-labile amide, carbamate,
or oxime functionalities. With respect to the anchoring group,
compounds 1 and 2 possess a cadaverine (1,5-diaminopentane)
residue known to particularly strongly bind to CB6,29 and 3
offers a benzyl anchor for preferential binding with CB7.21
protonation of the carbonyl oxygen in a pre-equilibrium, which
makes it susceptible to the rate-determining nucleophilic attack
of water. Subsequently, a proton transfer to the nitrogen occurs
followed by the cleavage of the intermediate to the amine and
carboxylic acid.30,31 A theoretical study suggests that the
nucleophilic attack and the protonation of the nitrogen occur
simultaneously, assisted by a second water molecule that
accepts a proton from the nucleophile and donates one to
the nitrogen.32 Regardless of the protonation site, the
resulting positive charge of the protonated amide functional-
ity should be positioned near the carbonyl portal of the
macrocycle and experience a Coulombic stabilization.
Compound 1 has a cadaverine moiety that is known to bind
very strongly with CB6.18,29 The larger phenyl moiety also
present in 1 has a 3 orders of magnitude lower affinity to
enter the CB6 cavity.18 Upfield shifts of the aliphatic protons
and downfield shifts of the aromatic protons in the 1H NMR
spectrum of 1 (Figure 1) confirmed the selective inclusion
of the cadaverine moiety experimentally. The larger CB7
macrocycle also binds cadaverine strongly (1.4 × 107 M-1)33
but has a sizable affinity for phenyl rings as well (e.g., 2 ×
106 M-1 for p-aminoaniline and 8 × 106 M-1 for p-
methylaniline).21 Accordingly, compound 1 showed large
upfield (-0.45 ppm) shifts for the cadaverine protons, as
well as slight upfield shifts (-0.05 ppm) and signal broaden-
ing of the aromatic protons (Figure 1). This can be interpreted
as a preferential binding of CB7 to the cadaverine moiety
with occasional population of a structure in which the phenyl
ring is temporarily included.
1
The hydrolysis of 1 was followed by H NMR at two
different pD values at 60 °C in a saturated solution of CB6 as
well as in solutions with 1 and 2 equiv of CB7. The concentra-
tions of both reactants and products at different times (up to 2
weeks) were determined from the H-1 and H-5 resonance
integrals of 1 along with the R-amino protons of cadaverine
(see Supporting Information). The reaction followed first-order
kinetics at low conversion (10-30%)34 for both hosts, and the
rate constants (Table 1) were calculated accordingly by linear
regression analysis of plots of the logarithmic rates against time.
While the results nicely confirmed our conjecture that
cucurbit[n]urils accelerate the rate of amide hydrolysis, the
absolute magnitude of the effect was much smaller than
expected. On the basis of previous observations, pKa shifts
between 2 and 4.5 units should correspond, under the ideal
assumption that the reaction rate is unimolecular with respect
to the protonated form (as expected for a specific acid
catalysis),35 to an acceleration factor of 100 to 30 000. We
speculated that the protonation of the cucurbituril macrocycles
(pKa(CB6) ) 3.02 and pKa(CB7) ) 2.20)36,37 under the harsh
As a classical challenge,30 we have first tackled amide
hydrolysis by using substrate 1. This reaction proceeds via
(21) Liu, S.; Ruspic, C.; Mukhopadhyay, P.; Chakrabarti, S.; Zavalij,
P. Y.; Isaacs, L. J. Am. Chem. Soc. 2005, 127, 15959–15967
(22) Mock, W. L.; Irra, T. A.; Wepsiec, J. P.; Manimaran, T. L. J. Org.
Chem. 1983, 48, 3619–3620
(23) Mock, W. L.; Irra, T. A.; Wepsiec, J. P.; Adhya, M. J. Org. Chem.
1989, 54, 5302–5308
(24) Krasia, T. C.; Steinke, J. H. G. Chem. Commun. 2002, 22–23
(25) Jon, S. Y.; Ko, Y. H.; Park, S. H.; Kim, H.-J.; Kim, K. Chem.
Commun. 2001, 1938–1939
(26) Maddipatla, M. V. S. N.; Kaanumalle, L. S.; Natarajan, A.;
Pattabiraman, M.; Ramamurthy, V. Langmuir 2007, 23, 7545–7554
(27) Pattabiraman, M.; Natarajan, A.; Kaanumalle, L. S.; Ramamurthy,
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(32) Zahn, D. Eur. J. Org. Chem. 2004, 4020–4023.
(33) Hennig, A.; Bakirci, H.; Nau, W. M. Nat. Methods 2007, 4, 629–
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632.
(34) The product of the reaction (cadaverine) is doubly positively charged
under the reaction conditions and was therefore expected to bind more
strongly to cucurbiturils than the singly positively charged reactants 1 and
2. Deviations from first order kinetics were therefore expected at high
conversion.
.
(28) Wang, R.; Yuan, L.; Macartney, D. H. J. Org. Chem. 2006, 71,
1237–1239
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(29) Mock, W. L.; Shih, N. Y. J. Org. Chem. 1983, 48, 3618–3619.
(30) O’Connor, C. Q. ReV. Chem. Soc. 1970, 24, 553–564.
(35) Laidler, K. J. Pure Appl. Chem. 1996, 68, 149–192
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