Acceleration of acetal hydrolysis by remote alkoxy groups: Evidence for electrostatic effects on the formation of oxocarbenium ions

Article abstract of DOI:10.1002/anie.201410043

In contrast to observations with carbohydrates, experiments with 4-alkoxy-substituted acetals indicate that an alkoxy group can accelerate acetal hydrolysis by up to 20-fold compared to substrates without an alkoxy group. The acceleration of ionization in more flexible acetals can be up to 200-fold when compensated for inductive effects.

Full text of DOI:10.1002/anie.201410043

Angewandte
Chemie
DOI: 10.1002/anie.201410043
Carbohydrates
Acceleration of Acetal Hydrolysis by Remote Alkoxy Groups:
Evidence for Electrostatic Effects on the Formation of Oxocarbenium
Ions**
Angie Garcia, Douglas A. L. Otte, Walter A. Salamant, Jillian R. Sanzone, and K. A. Woerpel*
Abstract: In contrast to observations with carbohydrates,
experiments with 4-alkoxy-substituted acetals indicate that an
alkoxy group can accelerate acetal hydrolysis by up to 20-fold
compared to substrates without an alkoxy group. The accel-
eration of ionization in more flexible acetals can be up to 200-
fold when compensated for inductive effects.
where the alkoxy group was replaced with a substituent which
is not electron withdrawing (for example, 3; Figure 1).
[
7,13,14]
Herein we provide evidence that the electrostatic stabi-
lization conferred by an alkoxy group four carbon atoms away
from an acetal group, the arrangement found in the pyrano-
sides 1 and 2, can overcome inductive effects and accelerate
acetal hydrolysis if the system is more conformationally
flexible than carbohydrates are. Flexibility likely allows the
alkoxy group to approach the acetal functional group during
substitution to provide up to a 20-fold increase in the rate of
acetal hydrolysis compared to substrates that do not have an
alkoxy group. When rates are compensated for inductive
destabilization of the transition state for hydrolysis, through-
space electrostatic stabilization of the developing charge can
accelerate hydrolysis by up to 200-fold.
S
tudies of the relative reactivities of glycosyl donors, often
[
1,2]
determined by measuring the kinetics of acetal hydrolysis,
provide critical information used for designing iterative
[
3]
oligosaccharide synthesis. These experiments reveal that
the relative rates of substitution reactions of carbohydrate-
derived acetals
[3–6]
depend upon the stereochemical config-
urations of substituents. For example, the methyl acetal of
galactose (2) hydrolyzed five times faster than the glucose-
derived acetal 1, which differs only in the stereochemical
To evaluate the difference in reactivity exerted by a 4-
alkoxy group based upon its position in space, a series of 4-
alkoxy-substituted acetals resembling 4 [Eq. (1)] were syn-
[
1,7–10]
configuration at C4 (Figure 1).
This difference in rate has
been attributed to favorable electronic interactions between
the electron-rich oxygen atom at C4 and the developing
positive charge at C1 in the transition state for hydroly-
[
7,11,12]
sis.
This stabilizing electrostatic effect, however, does
not compensate for the electron-withdrawing influence of the
oxygen atom at C4: inductive destabilization by the hydroxy
group slows hydrolysis by 4–30 times compared to reactions
thesized and their rates of acetal hydrolysis were measured.
These compounds were designed so the ability of the alkoxy
group to approach the acetal carbon atom could be varied
systematically. The two key functional groups were arrayed
around a ring, just as for the carbohydrate systems (Figure 1),
[
15]
Figure 1. Relative rates of hydrolysis of a-methyl pyranosides (2.0m
HCl, 748C).
so entropic effects
would be similar for all substrates.
[7]
Protection of the alkoxy group as the benzyl ether was chosen
because the fate of the benzyl group could reveal the
structures of reactive intermediates. The hydrolysis reactions
[
16]
follow the reaction conditions depicted in Equation (1).
[*] Dr. A. Garcia, D. A. L. Otte, J. R. Sanzone, Prof. K. A. Woerpel
The relative rates of acid-catalyzed hydrolysis are sum-
marized in Figure 2, listed in order of increasing rate. Relative
rates were normalized to the rate of hydrolysis of the alkyl
acetal 8. This simple acetal should be sterically equivalent to
the other b-substituted acetals because the two-carbon side-
chains of the acetals 4, 6, and 10–12 should adopt conforma-
Department of Chemistry, New York University
100 Washington Square East, New York, NY 10003 (USA)
E-mail: kwoerpel@nyu.edu
Dr. W. A. Salamant
Bridgestone Americas Center for Research and Technology
1659 S Main St., Akron, OH 44301 (USA)
[
**] This research was supported by the National Institutes of Health,
National Institute of General Medical Sciences (GM-61066). We
thank Lisa Barker for her intellectual contributions and Dr. Chin Lin
for assistance with NMR spectroscopy and mass spectrometric
data. D.A.L.O. was supported by a Margaret Strauss Kramer
Fellowship from the NYU Department of Chemistry.
tions where the acetal groups are oriented away from the
[17,18]
alkoxy groups.
Comparison of the rates of ionization of
the a-branched acetal 9 and b-branched acetal 8 indicates that
steric effects play only a minor role in the hydrolysis of acetals
[19]
in this series.
The acetal models illustrated in Figure 2 share trends in
reactivity with their carbohydrate relatives. The presence of
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410043.
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Figure 4. Structural requirements for acceleration of acetal hydrolysis
by an alkoxy group.
protonated acetal group during hydrolysis (14; Figure 4), the
ring would need to adopt an orientation resembling a strained
[
26]
bicyclic structure
with substituents in disfavored axial
[
27]
orientations. These energetic penalties and the inductive
destabilization of the alkoxy group
[13,20]
must outweigh any
benefit the alkoxy group can confer on hydrolysis. The
hydrolysis of this compound provides a point of comparison
for the hydrolysis of the other alkoxy-substituted acetals. By
using the rate of hydrolysis of the constrained acetal 6 to
control for inductive effects, it can be estimated that electro-
static effects imparted by an alkoxy group can accelerate
Figure 2. Relative rates of hydrolysis of acetals by DCl in [D ]acetone/
D O (4:1), listed in order of increasing rate.
2
6
[
28]
an alkoxy group in the acetals cis- and trans-7 decreased the
rate compared to that of branched acetal 9 because an alkoxy
group would inductively destabilize positively charged inter-
hydrolysis by up to 200-fold.
The relatively slow ionization of the cyclopentane-derived
acetal 4 suggests the origin of the accelerating influence of an
alkoxy group on the hydrolysis in acetals. Two types of
interactions of an alkoxy group during hydrolysis can be
envisioned (illustrated in Scheme 1 for 4). At one limit, a new
[13,20]
mediates.
The relative reactivity of the acetals cis- and
trans-7 is also reminiscent of the carbohydrate systems: the
slower-reacting acetal cis-7 positions the alkoxy group at C4
further from the acetal carbon atom (Figure 3), much as the
Figure 3. Chair conformations of the acetals cis- and trans-7 illustrating
the distances between the alkoxy groups and the acetal carbon atoms.
Scheme 1. Interaction of an alkoxy group during hydrolysis: a) Forma-
tion of a new covalent bond in the transition state. b) Electrostatic
stabilization in the transition state.
[
21]
slower-reacting glucose isomer does (Figure 1). The small
difference between the rates of the stereoisomers likely
reflects the fact that the alkoxy group in trans-7 is far enough
away to exert little stabilization of the transition state for
covalent bond would form between the alkoxy group and the
acetal carbon atom in the transition state for hydrolysis
(pathway a, Scheme 1), as occurs in neighboring-group par-
[
22,23]
hydrolysis.
[
24]
[29]
In contrast to the results exemplified in Figure 1, an
alkoxy group positioned at C4 can accelerate hydrolysis of an
acetal. Whereas the cyclopentane-derived acetal 4 is less
reactive than the alkyl acetal 8, the larger cycloalkyl-
containing acetals 10–12 reacted up to 20 times faster
ticipation during solvolytic displacement reactions. Alter-
natively, the alkoxy group might only approach the acetal
carbon atom in the transition state (pathway b, Scheme 1)
without forming a new covalent bond (as suggested for the
influence of acyl groups on the hydrolysis of 2-acyloxy-
[24]
(
Figure 2). This trend is consistent with the idea that
substituted acetals ). If formation of an intermediate
[
25]
a larger, more flexible ring
allows the alkoxy group to
oxonium ion such as 16 were required, ionization of 4 would
[
26,30]
approach the acetal carbon atom more closely in the
form a strained trans-bicyclo[3.3.0]octane ring system.
In
[
1]
transition state for ionization without incurring additional
contrast, ionization of the cyclohexane-derived acetal 10
strain (13; Figure 4). As observed for galactosides compared
would form a much less strained oxonium ion (by about
[
7]
À1 [26,30]
to glucosides (Figure 1), the closer the alkoxy group can
10 kcalmol
). Consequently, 10 should hydrolyze much
[11,12]
approach the acetal carbon atom,
occurred.
the faster hydrolysis
faster than 4. The difference in rate is only 20-fold, however,
which is small considering the large difference in strain.
Electrostatic stabilization of the oxocarbenium ion 17
which forms upon hydrolysis is consistent with the relative
The slow hydrolysis of the tetrahydropyran-derived acetal
reinforces the importance of flexibility on the rates of
6
[
11,12]
hydrolysis of a 4-alkoxy-substituted acetal. If there were any
interaction of the oxygen atom of the ring of acetal with the
rates (Scheme 1, pathway b).
Electrostatic stabilization
would require the alkoxy group to be close to the acetal
2
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[
11,12]
carbon atom,
but the carbon–oxygen bond distances
Received: October 13, 2014
Revised: November 25, 2014
Published online: && &&, &&&&
[
31]
would be much longer than they would be for an oxonium
[
32]
ion. As a result, the relative rates of hydrolysis should not
track the ring strain closely because a new ring would not be
fully formed.
Other observations also suggest that oxonium ion inter-
mediates are not involved in acetal hydrolysis. In none of the
hydrolyses were products consistent with loss of a benzyl
group observed, as might be expected if an oxonium ion had
formed. In contrast, solvolysis of the 4-alkoxy-substituted
tosylate 18 reveals that the model ring systems can form
oxonium ions if required for solvolysis (Scheme 2). The
Keywords: carbocations · carbohydrates · electrostatic effects ·
.
hydrolysis · kinetics
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Angew. Chem. Int. Ed. 2015, 54, 1 – 5
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3
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Carbohydrates
A. Garcia, D. A. L. Otte, W. A. Salamant,
J. R. Sanzone,
K. A. Woerpel*
&&& — &&&
Making an approach: In contrast to
observations with carbohydrates, alkoxy
groups can accelerate acetal hydrolysis
even though they are inductively electron
withdrawing. The alkoxy group must be
able to approach the acetal carbon atom
without developing too much strain. The
data are most consistent with the alkoxy
group stabilizing the developing positive
charge by electrostatic stabilization, not
formation of a new covalent bond.
Acceleration of Acetal Hydrolysis by
Remote Alkoxy Groups: Evidence for
Electrostatic Effects on the Formation of
Oxocarbenium Ions
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