Decarboxylation via addition of water to a carboxyl group: Acid catalysis of pyrrole-2-carboxylic acid

Article abstract of DOI:10.1021/ja905196n

(Chemical Equation Presented) The decarboxylation of pyrrole-2-carboxylic acid is subject to acid catalysis in strongly acidic solutions. Protonation of the pyrrole ring at C2 produces a potentially low-energy carbanion leaving group. Carbon dioxide forma

Full text of DOI:10.1021/ja905196n

Published on Web 07/31/2009
Decarboxylation via Addition of Water to a Carboxyl Group: Acid Catalysis of
Pyrrole-2-Carboxylic Acid
Scott O. C. Mundle and Ronald Kluger*
DaVenport Chemical Laboratories, Department of Chemistry, UniVersity of Toronto, Toronto, Ontario M5S 3H6,
Canada
Received June 24, 2009; E-mail: rkluger@chem.utoronto.ca
Decarboxylation, formally the conversion of a carboxyl group
to a proton and carbon dioxide, is normally a dissociative process
that leads directly to the formation of carbon dioxide and a stabilized
1
carbanion. This mechanism is unusual among carbonyl substitution
reactions, which are commonly associative processes involving
2
tetrahedral addition intermediates. Because protonated carbon
3,4
dioxide is a very high energy species, the bond-breaking process
in decarboxylation reactions occurs from the conjugate base of the
carboxylic acid. However, reversible addition of water to carboxyl
5
groups is well-known and subject to specific acid catalysis. In the
case where the leaving group would be a very weakly basic
carbanion, the resulting decarboxylation from the hydrated carboxyl
group would produce protonated carbonic acid. This is a much more
stable species than protonated carbon dioxide, which would result
Figure 1. Logarithm of the observed first-order rate constant (kobs) as a
function of the Hammett acidity function (H ) in hydrochloric acid,
0
6
from a dissociative acid-catalysis mechanism. In accord with
expectations for acid-catalyzed decarboxylation, we report observa-
tion of a reaction whose characteristics are consistent with an
associative mechanism.
perchloric acid, and sulfuric acid at 25 °C.
carboxyl group is largely suppressed under those conditions, as is
the rate of any process that would pass through that species.
The observed decarboxylation of 1 in acid suggests that proton-
ation of a ring carbon is more significant in promoting the reaction
than is ionization of the carboxyl group. Kinetic observations are
consistent with a mechanism involving at least two distinct steps:
Pyrrole is an unusually weak base that undergoes equilibrium
7
protonation on its R and ꢀ carbons rather than on nitrogen. The
neutral form of pyrrole 2-carboxylic acid (1) is subject to acid-
8
catalyzed decarboxylation in strong acids but resistant to decar-
8
boxylation in less acidic solutions (Scheme 1).
protonation of the ring and carbon-carbon bond cleavage. Dunn
8
This is in contrast to the reactivity of 2-picolinic acid, the related
derivative of pyridine, which is most reactive in solutions at pH 5,
where its zwitterionic form is at its maximum concentration; the
and Lee proposed that at low acid concentrations, protonation of
the ring at the R-carbon is rate-determining, while at higher acid
concentrations that produce significant quantities of the protonated
intermediate, C-C bond cleavage is rate-determining. Consistent
with this proposition, they observed that the C/ C kinetic isotope
effect in dilute acid is much smaller than it is in a more acidic
solution. However, those authors formulated the reaction as
proceeding through the neutral zwitterion, a process that would
require removal of the proton from the carboxyl group in acid,
which is inconsistent with the observed increase in rate with
increasing acidity.
9
,10
rate decreases in more acidic solutions.
A logical mechanism
12
13
for the decarboxylation in that case involves the usual dissociative
transition state (Scheme 2).
Scheme 1 shows that protonation of 1 at the R-carbon to give 2
activates the molecule toward decarboxylation only if the carboxyl
group is ionized. Since equilibrium protonation of the R-position
requires highly acidic solutions, the concentration of the dissociated
Scheme 1. Neutral Decarboxylation of Pyrrole-2-carboxylic Acid
We determined the rate of decarboxylation of 1 in aqueous
hydrochloric, perchloric, and sulfuric acid solutions by following
the decrease in absorbance at 262 nm. A plot of the logarithm
of the observed first-order rate coefficient versus the Hammett
1
1,12
acidity function (H
also determined at H
3.0). Rather than a decrease in rate with increasing acidity, as
0
) is shown in Figure 1.
The rate was
0
) -7.4 in perchloric acid (log kobs
≈
-
8
predicted by Dunn and Lee for a mechanism involving
suppression by the acid of formation of the zwitterion at very
high acidity, we found an increase in the rate, indicating the
involvement of a different mechanism. The data in Figure 1 show
that the rate does not depend on the identity of the acid but
Scheme 2. Decarboxylation of 2-Picolinic Acid
0
only on the resulting H . It is conceivable that at high acidity,
the expected decrease in rate from the unfavorable removal of
the proton on the carboxylic acid could be compensated by the
1
1674 9 J. AM. CHEM. SOC. 2009, 131, 11674–11675
10.1021/ja905196n CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Mechanism of Decarboxylation via Addition of Water to
the Carboxyl Group of Pyrrole-2-carboxylic Acid
The rate law associated with Scheme 3 and the steady-state
assumption give the dependence of the observed first-order rate
constant on acidity and water activity (eq 1):
k k [HA][H O]
1
2
2
V ) kobs[1] )
[1]
(1)
-
k [A ] + k
2
-1
At high acidity, the increase in the observed rate constant with
additional acid is countered by the decrease in the activity of water,
1
1
leading to the plateau in Figure 1.
Biochemical catalysis of the reaction of 1 has been observed.
1
5
Omura et al. reported pyrrole 2-carboxylate decarboxylase-
carboxylase, an enzyme whose activity depends on the presence
of exogenous carboxylic acids. While the mechanism they formu-
lated involves deprotonation of the pyrrole nitrogen, the evidence
is more easily understood in terms of formation of a carbocation ꢀ
to the carboxylate, leading to dissociative loss of carbon dioxide.
However, such a process is inherently slow unless there is a way
to stabilize the requisite zwitterionic intermediate. It also does not
provide a clear rationale for the readily observed carboxylation.
On the other hand, an associative mechanism can be subject to
acid catalysis, and the reaction of carbonic acid rather than carbon
dioxide is mechanistically reasonable.
high concentration of the counterion acting as a Brønsted base
in the transition state for decarboxylation. However, it is clear
that variation of the medium’s conjugate base has no effect on
the rate, and the reaction is limited by the decreasing availability
of water at high acidity.
These results clearly rule out the involvement of the zwitte-
rionic intermediate 3 and related transition states in the acid-
catalyzed reaction. Direct formation of the zwitterion by
simultaneous loss of the proton from the carboxylic acid and
gain of a proton on the R-carbon of the ring does not require an
external source of protons. This would not be subject to acid
catalysis, as in the mechanism for decarboxylation of 2-picolinic
Thus, we conclude that while dissociative formation of carbon
dioxide is a well-established driving force in chemical reactions,
direct formation of carbonic acid via an associative mechanism may
be competitive in acidic solutions involving good leaving groups.
This alternative pathway presents an opportunity for the existence
of multiple modes of catalysis according to the reaction conditions.
1
0
acid (Scheme 2). A mechanism in which the ring nitrogen of
the already protonated reactant accepts an additional proton
would have a prohibitively high energy, as the initially proto-
nated ring is cationic at nitrogen.
Acknowledgment. We thank the Natural Sciences and Engi-
neering Research Council of Canada for support. We thank Peter
Guthrie (University of Western Ontario) for helpful discussions.
A mechanism that is consistent with the observed kinetic
patterns involves addition of water to the carboxyl group
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3
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JA905196N
J. AM. CHEM. SOC. 9 VOL. 131, NO. 33, 2009 11675