Kinetics and mechanism for oxime formation from benzoylformic acid: Electrostatic interactions in the dehydration of carbinolamines

Article abstract of DOI:10.1002/kin.20342

The evidence establishes that oxime formation from benzoylformic acid in the pH range from 0.25 to 5.5 occurs with acid-catalyzed dehydration of carbinolamines derived from the acid and its anion. The pH-rate profile shows in order of decreasing pH in two regions: (1) In the pH range from 5.5 to ～2.2 the second-order rate constants are linearly dependent on the concentration of hydronium ion and (2) from pH ～2.2 to 0.25 the rate constants deviate slightly from the line of slope = -1. This slight deviation is a consequence of the very similar values of limiting rate constants of the two forms of the substrate. Electrostatic interactions between charged carbinolamines and hydronium ions are analyzed.

Full text of DOI:10.1002/kin.20342

Kinetics and Mechanism
for Oxime Formation
from Benzoylformic Acid:
Electrostatic Interactions
in the Dehydration
of Carbinolamines
A. MALPICA, M. CALZADILLA, I. MEJIAS
Escuela de Qu´ımica, Facultad de Ciencias, Universidad Central de Venezuela, Caracas 47102, Venezuela
Received 23 August 2007; revised 28 November 2007, 27 January 2008, 20 March 2008; accepted 20 March 2008
DOI 10.1002/kin.20342
Published online in Wiley InterScience (www.interscience.wiley.com).
ABSTRACT: The evidence establishes that oxime formation from benzoylformic acid in the pH
range from 0.25 to 5.5 occurs with acid-catalyzed dehydration of carbinolamines derived from
the acid and its anion. The pH-rate profile shows in order of decreasing pH in two regions:
(1) In the pH range from 5.5 to ∼2.2 the second-order rate constants are linearly dependent on
the concentration of hydronium ion and (2) from pH ∼2.2 to 0.25 the rate constants deviate
slightly from the line of slope = −1. This slight deviation is a consequence of the very similar
values of limiting rate constants of the two forms of the substrate. Electrostatic interactions
between charged carbinolamines and hydronium ions are analyzed. ꢀ 2008 Wiley Periodicals,
C
Inc. Int J Chem Kinet 40: 554–558, 2008
Investigations of the kinetics and mechanism of
oxime formation from activated carbonyl compounds
exhibit a pH-rate profile with only one break, indicative
of a transition in the rate-determining step from un-
catalyzed carbinolamine formation to hydronium ion-
INTRODUCTION
The elegant works of Jencks and Sayer has established
the principal features of the mechanism of addition of
nitrogen nucleophiles to the carbonyl group [1,2]
catalyzed dehydration with increasing pH. The change
of rate-determining step occurs at lower pH values
when the activity of the carbonyl compounds is suf-
ficiently increased, e.g., no break is observed in the
Correspondence to: A. Malpica; e-mail: amalpica@yahoo.com.
Contract grant sponsor: Consejo de Desarrollo Cient´ıfico y
Human´ıstico de la Universidad Central de Venezuela.
2008 Wiley Periodicals, Inc.
c
ꢀ

KINETICS AND MECHANISM FOR OXIME FORMATION FROM BENZOYLFORMIC ACID
555
pH-rate profile in the pH range from ∼1 to 5 when
oximes are formed from the very activated 2-, 3-,
and 4-formyl-1-methylpyridinium ions [3]. The jus-
tification of this behavior was basically attributed to
two factors: (1) very activated substrates for addition
and (2) difficulty of the acid-catalyzed dehydration
of the carbinolamines owing to an unfavorable elec-
trostatic situation. In other cases, the presence of a
break in the pH-rate profile has nothing to do with
a transition in the rate-determining step, it only indi-
cates a protonation of the substrate, e.g., oxime for-
mation from 2-, 3-, 4- pyridinecarboxaldehydes, 2-
quinolinecarboxaldehyde, and pyruvic acid [4–6], in
which the reactions are complicated by the protonic
equilibria of the substrates; therefore, the breaks occur
at pH values near their pKa values.
for accumulation of carbinolamine intermediate using
exp
corr
obs
k
= kobs (1 + Kadd[NH2OH]fb). In the pH range of
∼4 to ∼5.5, the progress of the reaction was followed
by the initial rate method because the rate of the pro-
cess was very slow as described in our previous paper
[8].
RESULTS AND DISCUSSION
Second-order rate constants for benzoylformic acid
oxime formation were determined as a function of hy-
droxylamine concentration over the pH range ∼0.25 to
∼5.5, in aqueous solution and ionic strength 0.5 (KCl).
At pH ∼5.5 and sufficiently high hydroxylamine con-
centration, the first-order rate constants increase less
rapidly than the concentration of the hydroxylamine.
This conduct agrees with that observed previously for
related reactions [9]. Since the pKa value of the sub-
strate is reported to be 1.39 [10], far removed from pH
5.5, this behavior strongly suggests that the carbino-
lamine formed from addition of hydroxylamine to the
deprotonated acid accumulates and that dehydration of
this species is a rate-limiting step. In general, accu-
mulation of carbinolamines is not observed at low pH,
because high hydronium ion concentration converts
substantially all the hydroxylamine free base to its con-
jugate acid and it is not surprising therefore that at low
pH, at which unionized benzoylformic acid is the prin-
cipal reacting species, no accumulation of intermediate
was observed. Nevertheless, we propose that the dehy-
dration of carbinolamine formed from the acid form
of the substrate is also the rate-determining step. This
proposal is based on the similarity of the Kadd1k1 value
here obtained and the corresponding value found in
oxime formation from methyl benzoylformate [7], for
which accumulation of carbinolamine was observed.
In Fig. 1 logarithms of second-order rate constants
(kobs/[NH2OH]fb) are plotted against pH. The pH pro-
file shows one break at a pH value of ∼1.5, which is
near to the pKa reported for benzoylformic acid [10].
In the pH range from 5.5 to ∼2.2, the rate constants are
linearly dependent on hydronium ion concentration, in
the pH range from ∼2.2 to 0.25 the rate constants de-
viate from observed behavior at higher pH. These facts
are interpreted in terms of the mechanism outlined in
Scheme 1 wherein we propose that carbinolamine de-
hydration is considered to be the sole rate-limiting step.
Carbinolamine dehydration occurs via “T1” and “T2.”
The rate law for the mechanism is
In previous works, we studied the formation of
oxime from methyl benzoylformate and benzoylformic
anion, to (1) model the behavior of the benzoylformic
acid [7] and (2) evaluate the equilibrium constant of
addition and the specific acid-catalyzed dehydration of
the anionic carbinolamine [8].
EXPERIMENTAL
Materials
Hydroxylamine hydrochloride, hydrochloric, benzoyl-
formic, acetic, and formic acids and potassium chlo-
ride were obtained commercially. Solutions of these
reagents were prepared just prior to use to minimize
the possibility of decomposition. Buffer solutions from
hydrochloric, formic, and acetic acids were employed
according to the pH investigated. Glass-distilled water
was used throughout. Benzoylformic acid oxime was
prepared and characterized in a previous paper [8].
Kinetic Measurement
UV spectra of benzoylformic acid oxime obtained at
pH from about 0.25 to 5.5 indicate quantitative kinetic
yields. All rate measurements were determined as pre-
viously described [8]. Rate constants were measured
in water at 30◦C and ionic strength 0.5 (KCl) under
pseudo-first-order conditions. The pH was maintained
constant through the use of buffers with hydrochloric,
formic, and acetic acids. Values of pH were measured
with radiometer pH meters. Oxime formation was fol-
lowed by observing the appearance of the product at
253 nm (pH ∼0.25 to ∼4). Second-order rate constants,
kobs/[NH2OH]fb, were obtained from slopes of plots
of the first-order rate constants against the concentra-
tion of hydroxylamine free base and were corrected
k
obs/[NH2OH]fb = Kadd1k1[H+]/(1 + Kdiss/[H+])
+ k2Kadd2[H+]/(1 + [H+]/Kdiss
)
(1)
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556
MALPICA, CALZADILLA, AND MEJIAS
5
4
3
2
1
0
0
1
2
3
4
5
6
−1
−2
pH
Figure 1 Logarithms of second-order rate constants for oxime formation from benzoylformic acid plotted as a function of pH.
: Experimental points. The solid line was calculated based on the rate law in Eq. (1) and the rate and equilibrium constants
ꢀ
in Table I. Dashed line (slope = −1) was calculated assuming rate-determining dehydration of the carbinolamine derived from
anion of the benzoylformic acid only.
where the terms Kadd1 and Kadd2 are the equilibrium of
addition constants for carbinolamines formed from the
acid and its anion, respectively; k1 and k2 represent rate
constants for specific acid-catalyzed reaction for neu-
tral and anionic carbinolamines, respectively; and Kdiss
is the equilibrium constant for acid dissociation [10].
The superior solid line in Fig. 1 is a theoretical
line based on Eq. (1) and values of rate and equilib-
rium constants experimentally determined and on the
reported values of Kdiss and Kadd2. All constants are
summarized in Table I.
The experimental values of second-order rate con-
stants used in Fig. 1 are corrected for the extent of
carbinolamine accumulation using
corr
obs
k
= koexbps (1 + Kadd2[NH2OH]fb)
Scheme 1
International Journal of Chemical Kinetics DOI 10.1002/kin

KINETICS AND MECHANISM FOR OXIME FORMATION FROM BENZOYLFORMIC ACID
557
Table I Summary of rate and equilibrium constants
for benzoylformic acid oxime formation in aqueous
solution at 30◦C and ionic strength 0.5a
benzoylformate is a good model for benzoylformic
acid in terms of reactivity toward amines, owing to
structural similarity of carbinolamines and hydrates.
Likewise, it is logical to suppose that the ester is also
a good model in terms of reactivity toward water. If
the value of Khyd = 0.078 [12] for methyl ester is
k2 (M−1 s−1
Kadd2 (M−1 b
Kadd1k1 (M−2 s−1
Kd∗iss (M−1 b
Kdiss (M−1 c
)
5.32 × 103 102
)
1.12 10−2
)
3.5 × 103 1.8 × 102
5.50 × 10−4
exp
corr
obs
)
)
used in k = kobs (1 + Khyd) to evaluate the cor-
4.07 × 10−2
rected hydration constant of the keto form, kocbosrr results
are substantially equal to those of koexbps . Therefore, the
anion must be still less hydrated.
We have interpreted the negative break observed
at low pH as a result of ionization of the substrate
and not as a change of the rate-determining step. Our
argument is that decreasing the pH, the unionized
carbinolamine increases its concentration and it de-
hydrates more slowly than the anionic carbinolamine.
This is supported by the finding that the dehydration
rate constant k2 of carbinolamine formed from the an-
a All constants are defined in Scheme 1.
b From [8].
c From [10].
Rearrangement of Eq. (1) to
(1 + Kdiss/[H+])[kobs/[NH2OH]fb
− k2Kadd2[H+]/(1 + [H+]/Kdiss)] = Kadd1k1[H+]
(2)
ion is 5.32 × 103 M−1
s
−1, whereas k1 for the acid is
34.62 M−1 s−1 (taking as a model the methyl ester of
benzoylformic acid) [7]. This fact strongly suggests
that the presence of a negative charge near the reaction
center of the carbinolamine formed by benzoylformic
anion exerts a strong positive influence on the velocity
of acid-catalyzed dehydration as a result of a favorable
electrostatic attraction to the oxonium ion. This indi-
cates that in spite of the presence of neutral carbino-
lamine (pKa∗ = 3.26) [8], within the 2.5–5.5 pH range
it does not form oxime.
K
addk1 was evaluated from the ordinal intercept (pH 0)
of a plot log of the left term of Eq. (2) versus pH.
The obtained value (3.5 × 103 M−2 s−1) is very similar
to the value 2.7 × 103 M−2 s−1 reported for the same
constant in oxime formation from methyl benzoylfor-
mate [7]. This finding suggests that the methyl group
apparently serves as a reasonable model for a proton in
terms of the reactivity toward amines. This argument is
reinforced by comparison of σm values of COOH and
COOMe groups (σCOOH = 0.35 and σCOOMe = 0.32)
[11]. Within the pH range ∼2.2 to ∼5.5, Fig. 1 shows
a linear dependence of the process on pH, indicatiing
that Eq. (1) simplifies to
Electrostatic Interactions in the
Dehydration of Charged Carbinolamines
Catalyzed by Acid
k
obs/[amine]fb = Kadd2k2[H+]
In this pH range, the slope of the line = −1 repre-
sents oxime formation from only benzoylformic anion.
Since Kadd2 was previously determined [8], we used the
above equation to establish the value of k2, which re-
sulted in a value similar to the one previously reported
[8].
In Scheme 1, the rate constants were not corrected
by general acid catalysis because in our previous work
it was found that such constants are independent of
buffer concentration and the reaction is subject only to
specific acid catalysis [8].
The conversion of hydrates of the acid and its an-
ion to the reactive keto forms is not included, and in
Table I the rate and equilibrium constants represent
the behavior of mixtures hydrate–keto forms. To our
knowledge values of hydration constants have not been
reported, nevertheless, such constants must be very
small, as judged by the following argument: methyl
In early studies carried out in our laboratory [3,4],
we realized the importance of electrostatic interac-
tions between charged carbinolamines and the hy-
dronium ion for the dehydration processes. Thus,
in the acid-catalyzed dehydration of the carbino-
lamine derived from hydroxylamine and 2-formyl-1-
methylpyridinium ions the value of the rate constant is
4.11 M−1 s−1 [3]. To our knowledge, this is the lowest
value reported in the literature. Therefore, the positive
charge near the center of the reaction has a negative
influence on the process of the dehydration catalyzed
by acid due to the repulsion of charges of the same
sign in the transition state. This argument is reinforced
by the fact that oxime formation from the conjugate
acid of 2-pyridincarboxaldehyde avoids the proxim-
ity of positive charges going through a reaction path-
way that involves the neutral carbinolamine [4]. Oth-
erwise the expulsion of water as a leaving group from
International Journal of Chemical Kinetics DOI 10.1002/kin

558
MALPICA, CALZADILLA, AND MEJIAS
2-formyl-1-methylpyridinium ion would require the
formation of a dicationic species in the transition
state. Furthermore, the acid-catalyzed dehydration
of carbinolamines derived from pyruvate and ben-
zoylformate anions and hydroxylamine has quite
high rate constants: 5.75 × 104 M−1 s−1 [7] and
BIBLIOGRAPHY
1. Rosenberg, S.; Silver, S. M.; Sayer, S. J. M.; Jencks, W.
P. J Am Chem Soc 1974, 96, 7986–7998.
2. Sayer, J. M.; Pinsky, B.; Schonbroum, A.; Washtien, W.
J Am Chem Soc 1974, 96, 7998–8009.
3. Sojo, P.; Viloria, F.; Malave, L.; Possamai, R.;
Calzadilla, M.; Baumrucker, J.; Malpica, A.; Moscovici,
R.; Do Amaral, L. J Am Chem Soc 1976, 98, 4519–
4525.
5.32 × 103 M−1
s
−1, respectively. Thus, the attraction
of opposite charges contributes to enhance the rate
constants. Therefore, the proximity of a cationic or
anionic center to the site of reaction must be a very
important factor in the acid-catalyzed dehydration of
carbinolamines.
4. Malpica, A.; Calzadilla, M.; Baumrucker, J.; Jime´nez,
J.; Lo´pez, L.; Escobar, G.; Montes, C. J Org Chem 1994,
59, 3398–3401.
These studies have been carried out in water solu-
tion and probably reflect an attenuation of electrostatic
interactions due to solvatation effects. Therefore, it
is quite probable that working with solvents of low
dielectric constants, the electrostatic interactions will
increase in magnitude, thus simulating reactions cat-
alyzed by enzymes. In the words of Perutz, “the non-
polar interior of enzymes provides the living cell with
the equivalent of organic solvent used by the chemists”
[13]. In the near future, we would like to establish
the importance of electrostatic interactions between
charged carbinolamines and hydronium ions with sol-
vents of low dielectric constants. It would be also of
interest to analyze electrostatic interactions between
charged carbinolamines and hydroxyl anions.
5. Malpica, A.; Calzadilla, M.; Cordova, T. J Phys Org
Chem 2000, 13, 162–166.
6. Calzadilla, M.; Malpica, A.; D´ıaz, P. M. Int J Chem
Kinet 1996, 28, 687–691.
7. Malpica, A.; Calzadilla, M. J Phys Org Chem 2005, 18,
945–949.
8. Calzadilla, M.; Malpica, A.; Mej´ıas, I. J Phys Org Chem
2007, 20, 631–635.
9. Jencks, W. P. Prog Org Chem 1964, 2, 63–128.
10. Sawaki, Y.; Ogata, Y. J Am Chem Soc 1981, 103, 6460–
6465.
11. Wells, P. R. In Linear Free Energy Relationships; Aca-
demic Press: New York, 1968; Ch. 2.
12. Malpica, A. Calzadilla, M. J Phys Org Chem 2003, 16,
1–4.
13. Perutz, M. F. Proc Roy Soc B 1967, 167, 448.
International Journal of Chemical Kinetics DOI 10.1002/kin