Acid Hydrolysis Mechanism of Acetals
SCHEME 1. Catalytic Deprotection of Acetals under Basic
Conditions Using 1
Furthermore, the protonation of encapsulated guests has been
investigated and has revealed in the effective basicity of
3
4
a
encapsulated protonated amines of up to 4.5 pK units and
has allowed for the observation and quantification of hydrogen
bond breaking followed by nitrogen inversion/rotation of
3
5
encapsulated protonated diamines. The thermodynamic sta-
bilization of protonated guests and has been further exploited
FIGURE 1. (Left) Schematic representation of 1 with only one ligand
shown for clarity. (Right) Space-filling model of 1 as viewed down
the 2-fold axis defined by the naphthalene-based ligand.
for the catalytic hydrolysis of orthoformates and acetals in
17,36,37
1
.
Herein, we expand upon our initial report of the scope
of acetal hydrolysis in 1 to include a detailed study of the
mechanism of this reaction.
with size selectivity with assemblies able to concentrate solvent
molecules inside of their interior cavities. Similarly, ꢀ-cyclo-
20
dextrin has been used to catalyze the hydrolysis of acetals at
Results and Discussion
2
1
neutral pH. Furthermore, the simple modification of cyclo-
dextrins has been explored to change the guest binding
preferences and acidity of pendant hydroxyl groups on the
Acetals are a common protecting group for ketones and
aldehydes in organic synthesis and are generally hydrolyzed by
the use of Brønsted or Lewis acid catalysts in the presence of
water. More recently, a number of mild methods for acetal
deprotection have been reported which include Lewis acids such
2
2-25
periphery of the cyclodextrins.
These functionalized cy-
clodextrins are active catalysts for the hydrolysis of encapsulated
glycosides near physiological pH. Depending on the substrate,
pH, and cyclodextrin functionalization, rate accelerations of up
to 8000 have been observed with respect to the background
3
8-42
Bi(III) or Ce(III) or reagents supported on silica.
Also of
importance is that Mark o´ and co-workers recently reported an
example of acetal deprotection under mildly basic conditions
using catalytic cerium ammonium nitrate at pH 8 in a water-
2
6
hydrolysis reaction.
Over the past decade, Raymond and co-workers have used
the strategy of self-assembly to develop tetrahedral M (M
Ga (1), Al , In , Fe , Ti , or Ge , L ) N,N′-bis(2,3-
dihydroxybenzoyl)-1,5-diaminonaphthalene) supramolecular as-
4
3
acetonitrile solution. In our initial communication of acetal
4 6
L
3
7
III
III
III
III
IV
IV
hydrolysis, we demonstrated that 1 was a viable catalyst for
the hydrolysis of acetals in basic solution under mild conditions
(pH 10, 5 mol % 1, 6 h, 87-95% conversion, 79-92% isolated
yield) (Scheme 1). With the intention of better understanding
how the catalysis in 1 occurs, we investigated the mechanism
of the process. The acetal 2,2-dimethoxypropane (2) was chosen
as an ideal substrate for mechanistic studies due to its convenient
water solubility and the solubility of both of the hydrolysis
)
27,28
semblies (Figure 1).
Although 1 is water soluble, it maintains
a hydrophobic interior cavity able to isolate encapsulated guests
2
8,29
from bulk solution.
Monocationic guests are preferentially
encapsulated in 1, but neutral hydrophobic guests are also
3
0
bound. Although isolated from bulk solution, encapsulated
guests are able to exchange into and out of 1 by dilation of the
4
4
31
products (acetone and methanol). As reported in our initial
communication, 2 is quickly hydrolyzed by 1 but the hydrolysis
3
-fold symmetric apertures of the assembly. The host assembly
1
has been used to mediate both stoichiometric and catalytic
can be inhibited by the addition of a strongly binding guest
organometallic reactions and has been used as a catalyst for
+
1
6,32,33
such as NEt
4
a
(log(K ) ) 4.55).
the sigmatropic rearrangement of enammonium cations.
Although 2 was readily hydrolyzed by the assembly, separate
resonances for the encapsulated substrate were not observed by
H NMR under the catalytic conditions, but rather the resonances
(
(
20) Ryu, E.-H.; Cho, H.; Zhao, Y. Org. Lett. 2007, 9, 5147–5150.
21) Krishnaveni, N. S.; Surendra, K.; Reddy, M. A.; Nageswar, Y. V. D.;
1
Rao, K. R. J. Org. Chem. 2003, 68, 2018–2019.
22) Bjerre, J.; Nielsen, E. H.; Bols, M. Eur. J. Org. Chem. 2008, 4, 745–
52.
corresponding to the substrate were significantly broadened. For
example, under catalytic conditions in the presence of 1, the
(
7
(
(
23) Ortega-Caballero, F.; Bols, M. Can. J. Chem. 2006, 84, 650–658.
24) Ortega-Caballero, F.; Rousseau, C.; Christensen, B.; Petersen, T. E.;
(34) Pluth, M. D.; Bergman, R. G.; Raymond, K. N. J. Am. Chem. Soc. 2007,
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2007, 46, 8587–8589.
(38) Ates, A.; Gautier, A.; Leroy, B.; Plancher, J.-M.; Quesnel, Y.; Vanherck,
J.-C.; Marko, I. E. Tetrahedron 2003, 59, 8989–8999.
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(42) Mirjalili, B. F.; Zolfigol, M. A.; Bamoniri, A. Molecules 2002, 7, 751–
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(44) The acetone product formed in the reaction is stable under the reaction
conditions and does not undergo an aldol reaction to form mesityl oxide.
Bols, M. J. Am. Chem. Soc. 2005, 127, 3238–3239.
25) Rousseau, C.; Christensen, B.; Bols, M. Eur. J. Org. Chem. 2005, 13,
734–2739.
26) Functionalized cyclodextrins have been used as catalysts for other types
(
2
(
of reaction with high rate accelerations. For example, the oxidation of substituted
4
benzyl alcohols has been accelerated by ∼6 × 10 ; see: Marinescu, L. G.; Bols,
M. Angew. Chem., Int. Ed. 2006, 45, 4590–4593.
(
27) Caulder, D. L.; Bruckner, C.; Powers, R. E.; Konig, S.; Parac, T. N.;
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(
(
1
1
7
(
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(
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(
(
J. Org. Chem. Vol. 74, No. 1, 2009 59