Carbon Kinetic Isotope Effects and the Mechanisms of Acid-Catalyzed Decarboxylation of 2,4-Dimethoxybenzoic Acid and CO2 Incorporation into 1,3-Dimethoxybenzene

Article abstract of DOI:10.1021/jacs.7b07504

The rate of decarboxylation of 2,4-dimethoxybenzoic acid (1) is accelerated in parallel to the extent that the carboxyl group acquires a second proton (1H⁺). However, the conjugate acid would resist C-C bond breaking as that would lead to formation of doubly protonated CO₂. An alternative via formation of a higher-energy protonated phenyl tautomer (2H⁺) prior to C-C bond breaking would produce protonated CO₂, an energetically inaccessible species that can be avoided by transfer of the carboxyl proton to water in the same step. Headspace sampling of CO₂ that evolves in the acid-catalyzed process and analysis by GC-IRMS gives a smaller than expected value of 1.022 for the carbon kinetic isotope (CKIE), k¹²/k¹³. While this value establishes that C-C cleavage is part of the rate-determining process, intrinsic CKIEs for decarboxylation reactions are typically greater than 1.03. Computational analysis of the C-C bond cleavage from 2H⁺ gives an intrinsic CKIE of 1.051 and suggests two partially rate-determining steps in the decarboxylation of 1: transfer of the second carboxyl proton to the adjacent phenyl carbon and C-C cleavage in which the carboxyl proton is also transferred to water. Applying the principle of microscopic reversibility to fixation of CO₂ in acidic solutions reveals the importance of proton transfers to both carbon and oxygen in the overall fixation process.

Full text of DOI:10.1021/jacs.7b07504

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Article
Carbon Kinetic Isotope Effects and the Mechanisms of
Acid Catalyzed Decarboxylation of 2,4-Dimethoxybenzoic
2
acid and CO Incorporation into 1,3-Dimethoxybenzene
Adelle A. Vandersteen, Graeme W. Howe, Barbara Sherwood Lollar, and Ronald Kluger
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 05 Oct 2017
Downloaded from http://pubs.acs.org on October 5, 2017
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Carbon Kinetic Isotope Effects and the Mechanisms of Acid Catalyzed Decarboxylation of 2,4-
Dimethoxybenzoic acid and CO Incorporation into 1,3-Dimethoxybenzene
2
§
‡
§‡
†
‡
Adelle A. Vandersteen , Graeme W. Howe , Barbara Sherwood Lollar , and Ronald Kluger*
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‡
Davenport Chemical Research Laboratories , Department of Chemistry and The Stable Isotopes
†
Laboratory , Department of Earth Sciences, University of Toronto, Toronto, Ontario M5S 3H6,
Canada
Email: r.kluger@utoronto.ca
RECEIVED DATE:
Abstract: The rate of decarboxylation of 2,4-dimethoxybenzoic acid (1) is accelerated in parallel
+
to the extent that the carboxyl group acquires a second proton (1H ). However, the conjugate acid
would resist C-C bond breaking as that would lead to formation of doubly protonated CO . An
2
+
alternative via formation of a higher energy protonated phenyl tautomer (2H ) prior to C-C bond
breaking would produce protonated CO
by transfer of the carboxyl proton to water in the same step. Headspace sampling of CO
evolves in the acid catalyzed process and analysis by GC-IRMS gives smaller than expected value
2
, an energetically inaccessible species that can be avoided
2
that
1
2
13
of 1.022 for the carbon kinetic isotope (CKIE), k /k . While this value establishes that C-C
cleavage is part of the rate-determining process, intrinsic CKIEs for decarboxylation reactions are
+
typically greater than 1.03. Computational analysis of the C-C bond cleavage from 2H gives an
intrinsic CKIE of 1.051 and suggests two partially rate-determining steps in the decarboxylation
of 1: transfer of the second carboxyl proton to the adjacent phenyl carbon and C-C cleavage in
which the carboxyl proton is also transferred to water. Applying the principle of microscopic
reversibility to fixation of CO
2
in acidic solutions reveals the importance of proton transfers to
both carbon and oxygen in the overall fixation process.
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ꢀ
INTRODUCTION
Decarboxylation reactions in water typically occur as electrophilic substitution processes in which
rate-determining loss of CO from a carboxylate is followed by protonation or oxidation of the
2
1
residual anion. In those cases, catalysts can promote decarboxylation by better accommodating
the electrons that are gained from the bond that is broken upon release of CO
. 2-7 An alternative
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pattern occurs in the decarboxylation of activated benzoic acids. In solutions of moderate acidity,
rates of decarboxylation depend on the concentration of the un-ionized carboxyl group.8,9 We
expect that the proton on the un-ionized carboxyl group will prevent direct formation of CO ,
2
requiring an alternative mechanism. Those reactions are likely to proceed via a transition state that
occurs after tautomerization of the aromatic carboxylic acid. The process involves loss of
aromaticity by protonation of the phenyl group adjacent to the carboxyl, leading to direct loss of
CO
neutral carboxyl group, a product would be the inaccessible conjugate acid of CO
“protonated CO ”), a species that is much too acidic to exist in solution (pK
knowledge of the mechanism of this catalytic route applies to the potentially important reaction in
which acids catalyze the fixation of CO onto benzene derivatives.
2
from the minor tautomer. If the reaction were to proceed to a transition state directly from the
, HOCO+
2
(
2
A
<-30).10,11 A detailed
2
The decarboxylation of 2,4-dimethoxybenzoic acid (1 in Scheme 1) in highly acidic solutions
conforms to the rate law for a specific-acid catalyzed process:8,12 the rate increases with acidity in
+
9,12,13
parallel with the expected extent of formation of the conjugate acid of 1 (1H in Scheme 1).
For comparison, decarboxylation of 1 under neutral conditions also avoids release of protonated
8
CO
2
but that results from a reactive tautomeric form (2 in Scheme 1). It is not obvious how
increasing acidity would accelerate the reaction based on this neutral mechanism. Yet, the
observed increase in rate with acidity indicates that increasing the extent to which 1 is converted
1
4
to its carboxyl-protonated conjugate acid is associated with lowering the energy of the rate
determining transition state. The observation also implies that the proton of the carboxyl group is
present in the transition state that produces C-C bond cleavage (Scheme 2). Still, the transition
state must not produce protonated CO2.11
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Scheme 1 – Rate-determining proton transfer converts the unreactive form of DMBA (1) to the
reactive tautomer (2) in which the C-C bond cleaves to form 1,3-dimethoxybenzene (3) and CO .
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We previously proposed potential mechanisms for acid catalyzed decarboxylation of 1 that avoid
formation of protonated CO 8
. Based on the results of computations, we concluded that the most
2
+
favorable transition state involves the combined cleavage of the C-C bond of 2H and transfer of
the carboxyl proton to water (Scheme 2).8
+
Scheme 2 – The C-C bond cleavage occurs from the ring-protonated tautomer of 1H with
simultaneous deprotonation of the carboxyl group by solvent water. This mechanism is consistent
with the observed acid catalysis and avoids the formation of protonated CO .
2
12 13
Determinations of k /k carbon kinetic isotope effects (CKIEs) for the formation of CO in
2
decarboxylation reactions also help to reveal the nature of the transition states of the acid-promoted
mechanism.15,16 Together with the transition state proposed from computations, we can use the
magnitude of the CKIE to determine if the C-C bond cleavage step is competitive with other
processes. We expect that transfer of the carboxyl proton to water can occur in the same transition
state as C-C cleavage. As a result, the energy of the transition state would be likely to be
comparable to those of a preceding proton transfer step.
We report CKIEs for the decarboxylation of 1 under conditions where (1) the neutral form (1)
converts to the very reactive zwitterion tautomer and (2) the reaction proceeds from the conjugate
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acid (1H ). We utilize head-space coupled isotope ratio mass spectral analysis of the evolved CO
We follow the isotopic composition of the CO produced over the course of the decarboxylation
reaction.17,18 The acquired data provide information that is transformed to rate constants with
2
.
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application of the Rayleigh equations. The results provide accurate values needed to deduce the
CKIEs of the reactions of interest.19
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ꢀ
RESULTS AND DISCUSSION
The CKIE for the decarboxylation of 1 at high acidity, where the reactant is present in the form of
+
its conjugate acid (1H ), is 1.022 (Table 1). In an important contrast, reactions that produce CO
2
directly from a carboxylate have values for intrinsic CKIEs that are > 1.03.16,20 The smaller value
for the acid catalyzed process most likely indicates that another step is partially rate-determining.
In highly acidic solutions, steps in which proton transfers precede C-C bond breaking would not
be kinetically significant if the reactant interconverts rapidly with the higher energy tautomer from
which C-C bond cleavage occurs. Scheme 2 presents the case where the barrier associated with k-1
would be comparable to that for k
2
, reducing the observed CKIE from its intrinsic value.
) occurs in concert with transfer of the carboxyl
Alternatively, the C-C bond-cleaving step (k
2
proton to water in a way that reduces the intrinsic CKIE. In the latter model, the lower CKIE is
consistent with a smaller difference in C-C bonding in the transition state compared to the reactant
state than in reactions without proton transfer. Since the isotope effect could reflect differences in
2
0
bonding, the measured value would be consistent with considerable C-C bond character being
present at the highest energy point on the lowest energy pathway.
Table 1. Carbon kinetic isotope effects (CKIEs) for the acid-catalyzed decarboxylation of 2,4-
dimethoxybenzoic acid. The H
o
values report the acidity of solutions based on the extent of
protonation of aniline-derived indicators according to Hammett’s acidity function.
H
0
(HClO
4
)
CKIE (±0.002)
1.022
-2.62
0.36
-
1.002
Marlier and O’Leary applied transition state analysis from CKIEs for decarboxylation reactions in
20
general: “The range of CKIEs is 1.03-1.07, where the carbon-carbon bond-making or -breaking
process is entirely rate limiting:. …Carbon isotope effects in decarboxylation reactions increase
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as the transition state becomes more product-like. ...” The value we observe for the protonated
reactant is below the range of intrinsic values cited by Marlier and O’Leary, indicating that the C-
C bond cleavage is only partially rate-determining. We also observed a significant solvent isotope
+
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effect for the reaction of 1H at high acidity. It is therefore likely that the reduced CKIE is the
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result of kinetically significant proton transfer.
+
Our computational modelling of the decarboxylation of 2H provides an intrinsic CKIE of 1.051
for the C-C bond breaking step that is accompanied by loss of proton. This is significantly larger
than the experimental value (1.022). The larger value is within the range that had been reported
2
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for decarboxylation CKIEs in general. Therefore, we conclude that the smaller CKIE results from
partially rate-limiting proton transfer in a step that forms the pre-decarboxylation intermediate.
This is consistent with the similar Gibbs free energies computed for the ring protonation and C-C
bond cleavage transition states.8
Another basis for comparison of intrinsic CKIE values for C-C bond-cleavage is the
2
1
decarboxylation of Kemp’s 5-nitro-3-carboxybenzisoxazole (Scheme 3). This is a single-step,
irreversible process where C-C cleavage is achieved with no involvement of a catalyst in the
transition state. Under a very wide range of conditions, rate constants for the decarboxylation vary
1
6
over a ten thousand-fold range. In contrast, the CKIEs vary only to a very small extent, from
1
6
1
.043 to 1.046. This provides a good estimate for the intrinsic CKIE of a process in which C-C
cleavage is considerable in the transition state and is also clearly rate determining.
Scheme 3. The decarboxylation of 5-nitro-3-carboxybenzisoxazole is irreversible and
spontaneous, with protonation remote from the site of C-C cleavage.21
As the acidity of the solution is decreased, the CKIE becomes insignificant (Table 1), while the
8
SKIE becomes more substantial. This indicates that the decarboxylation of 1 in slightly acidic
solutions involves rate-determining proton transfers prior to or in the same step that releases CO .
2
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Collectively, these kinetic isotope effects are consistent with our previous proposal and support
this unusual mechanism for catalysis of decarboxylation.8
Applying this information to deduce the detailed mechanism (Scheme 4), we propose that the C-C
bond cleavage step includes transfer of the C-H on the carboxyl attached to the protonated phenyl
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group to water (k
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) or directly to the carboxyl (k-1). In either case, it is likely that the C-protonated
phenyl group is highly energetic. Thus, transfer of the proton in the exergonic direction will have
2
2
a rate constant that is near the diffusion limit. The significant solvent isotope effect confirms that
-4
-1
proton transfer is kinetically significant. The observed rate constant at 60 °C is 2 x 10 s under
conditions where the carboxyl group of 1 is in the form of its conjugate acid. We estimate the pK
A
+
of 1H to be -3.5, based on the known values of related benzoic acids and the intramolecular
8
hydrogen-bond based stabilizing effect of the methoxy group. The estimated pK
A
of the ring-
8
6
protonated tautomer is -9. Therefore, only one part in 10 of the protonated carboxyl species will
+
be present as the C-protonated tautomer (2H ). Based on the observed rate constant and the fraction
2
-1
of species in the reactive form, k = 2 x 10 s for the decarboxylation step that proceeds directly
from the reactive tautomer, the value of k
proton transfer.
2
is less than the value for a thermodynamically favorable
Scheme 4. The pre-decarboxylation intermediate undergoes loss of a proton at a rate that is
competitive with C-C bond cleavage of the carboxyl group of the reactive tautomer (k-1 ~ k ).
2
+
We also note that the carboxyl group in 1H is likely to exist in a conformation that has the OH
synperiplanar to the carbonyl in order to be stabilized by internal H-bonding with the methoxy
1
4
oxygen as suggested by Stewart and Granger. In that array, the proton is not directly accessible
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for transfer to solvent water. This suggests the possibility that C-C bond cleavage from 2H could
occur with an intramolecular proton transfer from the carboxyl group to the methoxy group
(Scheme 5). Our results indicate that while this transition state (Figure 1) gives a CKIE (1.034)
that is in better agreement with the observed CKIE, this pathway involves a barrier that is
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‡
significantly higher in energy (ΔG = 46.4 kcal/mol) than that involving the proton transfer to a
‡
8
solvent water molecule (ΔG = 23.7 kcal/mol). From this analysis, we conclude that the reaction
proceeds by intermolecular deprotonation of the carboxyl by the solvent water as was proposed
previously.8
Scheme 5. An alternative high-energy pathway with transfer of the carboxyl proton to the adjacent
+
+
ether oxygen (via 1’H and 2’H ) rather than to solvent.
O
O
OH
C
H
2
C
H
C
H
O
k1
O
H
k2
O
H
O
H
+
+
H O
+
O C O
3
k-1
O
O
O
O
O
O
O
'H+
'H+
3
1
- H+
H+
+
O
k3
C
O
H
O
O
1
Figure 1. Calculated transition state for decarboxylation of the conjugate acid via internal transfer
of the carboxyl proton to the methoxy group. This transition state is much higher in energy (ΔG‡
‡
8
=
7
46.4 kcal/mol) than the alternative process shown in Scheme 4 (ΔG = 23.7 kcal/mol).
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An important conclusion from knowledge of the details of the mechanism of decarboxylation is
the application to the reverse process using the principle of microscopic reversibility. That process
would incorporate CO
2
into 1,3-dimethoxybenzene in acidic solutions to form 2,4-
dimethoxybenzoic acid or an isomer of that species. Our results show that deprotonation of the
carboxyl occurs ahead of C-C bond cleavage in a common step with imperfect synchronization. In
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the reverse, the substituted benzene ring undergoes addition to CO to form a C-C bond at a
2
benzene-derived carbon α to that of a methoxy group. This produces a positively charged carbon
attached to the benzene ring that is stabilized by its oxonium ion character (Scheme 6). In that
process, addition of a solvent proton to the oxygen from CO occurs to a small extent. The unstable
2
assembly is lowered in energy as the carboxyl group with its proton forms adjacent to a positive
charge on the benzene ring”: Scheme 6 is written as the microscopic reverse of Scheme 4.
Formation of the internal H-bond in 1 helps stabilize the final product from addition of CO .
2
Scheme 6. Acid catalyzed trapping of carbon dioxide
ꢀ CONCLUSIONS
The rate of decarboxylation of the neutral form of 1 increases in acidic solutions, with the acidity
+
dependence of the rate consistent with formation of a more reactive species (2H ) that is a minor
tautomer of the conjugate acid of 1. For the reaction in the dilute acid medium, the small CKIE is
consistent with formation of the reactive tautomer by proton migration being rate determining. In
more acidic solutions, the larger CKIE is consistent with C-C bond breaking being a significant
part of the rate-determining step. That step avoids the formation of protonated CO
2
as the carboxyl
proton transfers to water while the C-C bond breaks, producing CO . In addition, a proton transfer
2
step that precedes the C-C bond-breaking step is also partially rate-determining.
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EXPERIMENTAL SECTION
The decarboxylation reactions were carried out in 125 mL septum-capped bottles. Solutions of
perchloric acid (50 mL) were added to the vessel and the headspace was purged with helium to
remove atmospheric CO . The reactant, 2,4-dimethoxybenzoic acid (1, 0.1 mL), was dissolved in
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degassed dimethyl sulfoxide (0.5 mL) and injected directly into the vessel to initiate the reaction.
The reaction vessels were maintained at 60°C by immersion in a thermostatic circulating water
bath and cooled to 0 °C prior to analysis at the designated reaction time points. The headspace
was sampled by use of a pressure-lock analytical syringe with a side-port taper needle. The
reaction progress was approximated by reaction time and by comparison with the peak area
obtained from mass intensity scans on an isotope-ration mass spectrometer coupled to a gas
chromatograph and combustion oven (GC-IRMS). Measurements of materials from complete-
conversion of the reactants were taken after 24-96 hrs, based on the half-life of the reaction. The
reaction sequence was repeated without substrate as a control experiment and CO was not
2
12
13
detected in the headspace. The magnitudes of k /k kinetic isotope effects (CKIE) were
calculated based on the equation developed by Bothner-By and Bigeleisen23 for monitoring
kinetic isotope effects in decarboxylation reactions: 23 The term f refers to the fraction of the total
conversion reaction that has occurred.
1
2
13
k /k = log (1 - f)/log [1 - f(N /Nx0)]
x
1
2
13
k and k are the observed first-order rate coefficients for reaction of the isotopic materials. R
13 12
and R
0
in the original equation are replaced with N and Nx0, the C/ C concentration ratios
x
13
12
as determined and reported from the IRMS, converted into abundances: N
x
= C O
2
/C O at
2
13
12
f=f and Nx0 = C O
2
/C O at f= 1.
2
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Data collected to obtain the CKIE for decarboxylation of 1 are summarized in Table 2 including
the resulting isotope effects.
12
13
Table 2. k /k
kinetic isotope effects for the acid-catalyzed decarboxylation of
2
,4-dimethoxybenzoicacid
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
1
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9
0
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9
0
[
HClO
4
], wt %
f
Nx
Nx
0
CKIE
4
2%
0.13
0.010498
0.010498
0.010497
0.010500
0.010712
0.010712
0.010712
0.010712
Av.
1.0213
1.0212
1.0225
0
.13
0.25
.25
0
1.0221
1.022 ±0.002
10%
0.13
0.010693
0.010692
0.010694
0.010693
0.010710
0.010710
0.010710
0.010710
Av.
1.0018
1.0019
1.0018
0
0
0
.13
.25
.25
1.0019
1.002 ±0.002
Optimal geometries and the associated vibrational frequencies were calculated with M06-2X/6-
+
+
24
311 G(2d,2p) as implemented in Gaussian 09. All calculations included two explicitly modelled
water molecules and considered the bulk solvent implicitly with the SMD model. The calculated
+
25,26
value for the intrinsic CKIE for the decarboxylation of 2H was obtained using ISOEFF 07.
ꢀ
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Full citation for ref 24; coordinates and thermodynamics of optimized structures
ꢀ
AUTHOR INFORMATION
Corresponding Author
r.kluger@utoronto.ca
*
Author Contributions
§G.W.H. and A.A.V. contributed equally.
1
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ꢀ
ACKNOWLEDGEMENTS
We thank NSERC Canada for support through the Discovery Grant program (#A9918) and for a
postgraduate fellowship to GWH. Our computational studies were made possible by the facilities
of the Shared Hierarchical Academic Research Computing Network (SHARCNET) and
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Compute/Calcu
l Canada. Scott Mundle and Georges Lacrampe-Couloume provided expert
guidance in the use and data analysis of the GC-IRMS system in the Department of Earth Sciences.
ꢀ
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0
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Where the loss of CO
2
is acid catalyzed, the carbon isotope effect is significant but reduced. The reverse is
acid catalyzed trapping of CO
2
with partially rate-determining carboxyl bond formation.
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