Kinetics and mechanism for oxime formation from methyl pyruvate

Article abstract of DOI:10.1002/poc.443

Rate and equilibrium constants for methyl pyruvate oxime formation were determined as a function of pH over the range 0-7 in aqueous solution at 30°C and ionic strength 0.5 by spectrophotometric methods. The reaction occurs with rate-determining carbinolamine dehydration over the entire range of pH investigated. Carbinolamine dehydration is not susceptible to detectable general acid-base catalysis by a carboxylic acid buffer or hydroxylamine/hydroxylammonium ion buffer. Specific acid catalysis for carbinolamine formation is dominant at pH values below 5. Above that value, a pH-independent, water-catalyzed reaction becomes apparent. The pH-independent carbinolamine dehydration is unusually important with this substrate. Copyright

Full text of DOI:10.1002/poc.443

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2002; 15: 48–51
DOI:10.1002/poc.443
Kinetics and mechanism for oxime formation from methyl
pyruvate
T. CoÂrdova, A. J. Peraza, M. Calzadilla and A. Malpica*
Escuela de QuõÂmica, Facultad de Ciencias, Universidad Central de Venezuela, Caracas, 47102, Venezuela
Received 26 February 2001; revised 2 July 2001; accepted 20 July 2001
ABSTRACT: Rate and equilibrium constants for methyl pyruvate oxime formation were determined as a function of
pH over the range 0–7 in aqueous solution at 30°C and ionic strength 0.5 by spectrophotometric methods. The
reaction occurs with rate-determining carbinolamine dehydration over the entire range of pH investigated.
Carbinolamine dehydration is not susceptible to detectable general acid–base catalysis by a carboxylic acid buffer or
hydroxylamine/hydroxylammonium ion buffer. Specific acid catalysis for carbinolamine formation is dominant at
pH values below 5. Above that value, a pH-independent, water-catalyzed reaction becomes apparent. The
pH-independent carbinolamine dehydration is unusually important with this substrate. Copyright  2001 John Wiley
& Sons, Ltd.
KEYWORDS: methyl pyruvate; oxime; kinetics; mechanism
INTRODUCTION
choice of methyl pyruvate as substrate is motivated by the
need to simulate certain aspects of pyruvic acid oxime
formation. In a previous study of pyruvic acid oxime
formation, it proved impossible to determine directly the
equilibrium constant for carbinolamine formation from
pyruvic acid (as opposed to the pyruvate anion).7 The low
values of pH required to form pyruvic acid convert
substantially all the hydroxylamine to its conjugate acid.
Consequently, accumulation of the carbinolamine from
pyruvic acid and hydroxylamine free base could not be
observed. This equilibrium constant was estimated from:
(i) the relative extents of hydration of pyruvic acid and its
anion; (ii) the equilibrium constant for addition of
hydroxylamine to pyruvate; (iii) the assumption that the
ratio of equilibrium constants for addition of water and
hydroxylamine to pyruvic acid and pyruvate is the same.7
Methyl pyruvate is expected to be a good model for
pyruvic acid.
Imine formation from moderately basic amines and
moderately reactive carbonyl compounds occurs with a
single break in the pH–rate profile over the pH range
0–7.1–3 This break reflects a transition from rate-
determining amine addition under acidic conditions to
rate-determining carbinolamine dehydration as the pH is
increased.
When the electrophilicity of the carbonyl group and
the nucleophilicity of the amine are enhanced, the rate of
carbinolamine formation is increased without a compen-
sating increase in the rate of carbinolamine dehydration.
Thus, carbinolamine dehydration becomes rate determin-
ing over this pH range and the break in the pH–rate
profile disappears.4–8
In the work reported herein, we examine the kinetics
and mechanism for addition of hydroxylamine to methyl
pyruvate. This work is motivated by the desire to provide
an additional example of mechanism and reactivity for
imine formation to test and extend the detailed mechan-
istic proposal of Jencks and Sayer.1,2 In addition, the
EXPERIMENTAL
Materials
Methyl pyruvate and hydroxylamine were obtained
commercially. Solutions of these reagents were prepared
just prior to use to minimize the possibility of decom-
position. Buffer solutions of dilute hydrochloric acid,
chloroacetic acid, acetic acid and hydroxylamine were
employed in the appropriate ranges of pH. Glass-distilled
water was used throughout. Values of pH were measured
with an Orion pH-meter model 420-A.
*Correspondence to: A. Malpica, Mr Anais Ron Calzadilla, 8824 NW
Street Suite CCS 00123, Miami, FL 33166, USA.
Contract/grant sponsor: Consejo de Desarrollo Cientı´fico y Human´ıs-
tico de la Universidad Central de Venezuela.
Copyright  2001 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2002; 15: 48–51

MECHANISM OF OXIME FORMATION FROM METHYL PYRUVATE
49
Kinetic measurements
The rate constants for the reaction were measured by
injecting a small amount (typically 50 ml) of a 3 Â 10À3
M
stock solution of the substrate in dioxane into 3 ml of
buffered solutions of hydroxylamine. A Zeiss PMQ II
spectrophotometer equipped with a thermostatic cell
compartment was used for measurements, which were
conducted at 240 nm, 30°C and ionic strength of 0.5
(KCl), under pseudo first-order conditions. The extent of
the reaction was monitored by the increase in absorbance,
which accompanies oxime formation. Excellent pseudo
first-order kinetics were observed from plots of loga-
rithms of A? À At against time (where A? and At denote
the absorbances at infinite time and time t). Second-order
rate constants, the ratio between pseudo first-order rate
constant kobs and the concentration of hydroxylamine free
base (amine)fb, were obtained from plots of kobs against
(amine)fb. At constant pH, the doubling, tripling,
quadrupling and eventually octupling of the concentra-
tion of the buffer used had no appreciable effect on the
observed rate constants. Consequently, the only detect-
able catalytic component in the buffer used was that
arising from the hydronium ion. At values of pH greater
than 4.0 the intercepts of plots of kobs versus buffer
concentration show the existence of a reaction catalyzed
by water (ko).
Figure 1. First-order rate constants for methyl pyruvate
oxime formation plotted as a function of the concentration
of hydroxylamine free base. The rate constants were
measured at 30°C, ionic strength0.5, pH 5.0 maintained
with0.1 M acetate buffer. The solid line was calculated
based on the equation: kobs ˆ Kexpꢁamine† ‰k ꢁH † ‡ koŠ=
‡
‡
fb
H
add
exp
add
1 ‡ K ꢁamine†
fb
rapidly than the concentration of the amine and
eventually level off and become independent of this
variable. A typical example of this behavior is provided
in Fig. 1. This conduct agrees with that observed
previously for related reactions9,10 and strongly suggests
that carbinolamine formed from the addition of the amine
to the keto ester accumulates and that the dehydration of
this species is the rate-determining step. A plot of first-
order rate constants (measured under saturation condi-
tions) against the concentration of hydroxylamine buffer
at different pH values shows that at constant pH the rate
constants are independent of the buffer concentration.
The same behavior is observed with the different buffers
used here. This suggests that the a value for the
dehydration step of carbinolamine should be close to
unity and, therefore, difficult to observe. A plot of the
intercepts of the parallel lines obtained using hydro-
xylamine buffers against the concentration of hydronium
ion yields a line (r = 0.9972) whose slope provides the
rate constant kH for the specific acid-catalyzed compo-
nent and an intercept that provides the rate constant ko for
a water-catalyzed process.
Equilibrium-constant measurements
The equilibrium constant Kadd for addition of hydro-
xylamine to methyl pyruvate was determined by
monitoring the disappearance of the chromophore of
the substrate at 330 nm and pH 6.75. Injecting 50 ml from
a 12.6 mM solution of the substrate in dioxane into
3 ml of aqueous solutions containing hydroxylamine
(1.08 Â 10À2 to 6.76 Â 10À4 M) led to a rapid drop in
absorbance consistent with the formation of carbinola-
mine. This initial drop in absorbance was followed by a
slower increase attributed to oxime formation. An
average of five determinations of DAeq (absorbance of
the product at equilibrium) was calculated from experi-
ments at different hydroxylamine concentrations. The
equilibrium constant was obtained from the negative
intercept of a plot of 1/DAeq versus 1/(amine)fb. A value
exp
of K ˆ 713 MÀ1was obtained.
add
RESULTS AND DISCUSSION
First-order rate constants for methyl pyruvate oxime
formation were determined as a function of amine
concentration over the pH range ꢀ0 to 6.75 at 30°C, in
aqueous solution, ionic strength 0.5. At pH values greater
than 4.0 and sufficiently high amine concentration, first-
order rate constants were observed to increase less
Scheme 1
Copyright  2001 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2002; 15: 48–51

´
50
T. CORDOVA ET AL.
Table 1. Summary of equilibrium and rate constants of
methyl pyruvate oxime formation measured in aqueous
solution at 30°C, and ionic strength0.5
À1
Kaedxdp (M
)
713.00a
À1
kH (M sÀ1
)
200.00b
ko (sÀ1
)
2.3 Â 10À4b
À1
Kadd (M
)
2700.00a
a
Standard deviation of Kaedxdp was about 5%.
In most cases the data agree within 3%.
b
‡
‡
general bases [kf = ko ‡ kH
‡
(H ) ‡ kB(B )].† Both cata-
lytic constants are significant and their contribution to kf
depends on the pH and buffer concentration. Therefore,
hydration is important over the entire pH range
investigated. Thus the hydrate is included in the
Figure 2. Logarithms of second-order rate constants for
oxime formation from methyl pyruvate plotted as a function
of pH. Measurements were made at 30°C and ionic strength
0.5. The solid line is a theoretical line based on Eqn. 21) and
values in Table 1
formulation of the reaction mechanism and the addition
exp
constant K is corrected for hydration.
add
In Fig. 2, logarithms of second-order rate constants
[kobs/(amine)fb] for methyl pyruvate oxime formation are
plotted as a function of pH. The second-order rate
constants decrease linearly with the concentration of the
hydrated proton down to a value of pH ꢀ4.0. Above this
limiting pH value the logarithm of the second-order rate
constants deviates from linearity with pH. These devia-
tions are more pronounced as the pH increases.
Table 1 is a summary of the rate and equilibrium
constants for methyl pyruvate oxime formation. The solid
line in Fig. 2 is a theoretical line based in Eqn. (1) and
values in Table 1. The agreement of theory with
experimental data is satisfying.
This behavior is interpreted in terms of the mechanism
outlined in Scheme 1, in which it is proposed that
carbinolamine dehydration is the sole rate-determining
step over the entire range of pH investigated.
The rate law for the mechanism outlined in Scheme 1
is:
k
obs=ꢁamine† ˆ Kexp‰kHꢁH † ‡ koŠ
ꢁ1†
ꢁ2†
ꢁ3†
‡
fb
add
At low pH Eqn. (1) becomes:
obs=ꢁamine† ˆ KexpkHꢁH †
‡
k
fb
add
Values of Kadd and kH reported for pyruvic acid oxime
À1
formaÀti1on are respectively 3.5 Â 103 M
and 2.43 Â
The limiting value of Eqn. (1) at high pH is:
102 M
s
À1.7 A comparison with the same constants
k
obs=ꢁamine† ˆ Kexpko
reported here forÀm1 ethyl pyruvate oxime formation,
fb
add
À1
Kadd = 2.7 Â 103 M and kH = 2 Â 102 M
s
À1, demon-
Scheme 1 includes the conversion of the hydrate of
methyl pyruvate to the reactive unhydrated form. There-
fore, the equilibrium constant for addition of hydro-
xylamine to the keto ester is corrected for the hydration of
the substrate:
strate that methyl pyruvate is a good model for pyruvic
acid.
To our knowledge, there are no studies that relate the
values of pH in which catalysis by water is important to
the carbinolamine structure. Generally, the pH-indepen-
dent route of carbinolamine dehydration is usually
unimportant, compared with the specific acid-catalyzed
pathway, and it is ordinarily observed at values of pH
close to 8. Carbinolamine formed from methyl pyruvate
and hydroxylamine has a carbomethoxy group bonded
directly to the carbonyl moiety. The strong electron-
withdrawing inductive effect of this group decreases the
carbinolamine oxygen basicity, making hydronium ion
Kadd ˆ Kexpꢁ1 ‡ KH†
KH ˆ 2:8 (see Ref. 11)
add
The equilibrium constant for addition of hydroxylamine
to methyl pyruvate was monitored by the disappearance
of the chromophore of the unhydrated keto ester at pH
6.75. Injecting a small amount of a solution of the
substrate in dioxane into aqueous solutions of hydro-
xylamine led to a rapid drop in absorbance followed by
a slower increase in absorbance attributed to oxime
formation (see Experimental section). According to
Pocker and coworkers,11,12 the hydration of methyl
pyruvate is catalyzed by water, hydronium ions and
catalysis difficult. This is reflected in the low value of kH
À1
reported here (kH = 2 Â 102 M
(kH = 5.75 Â 104 M
s
À1) compared with
the same processÀu1sing pyruvate anion as substrate
s
À1).7 Therefore, the presence of
the carbomethoxy group increases the relative impor-
tance of spontaneous dehydration; the percent of
contribution of ko from pH 5.0 to 6.75 in this study
varies from 10 to 87%. Further investigations of imine
† Pocker et al. report several values of kf over a temperature range of 0–
25.6°C, pH 4.6 and m = 0.1. A simple Arrhenius plot from their data
allowed us to obtain kf = 0.15 sÀ1 at 30°C.
Copyright  2001 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2002; 15: 48–51

MECHANISM OF OXIME FORMATION FROM METHYL PYRUVATE
51
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Acknowledgements
We are indebted to Professor Eugene H. Cordes for
helpful comments concerning aspects of this work. This
work was supported in part by the Consejo de Desarrollo
Cient´ıfico y Human´ıstico de la Universidad Central de
Venezuela.
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Copyright  2001 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2002; 15: 48–51