Effect of structure on reactivity in oxime formation of benzaldehydes

Article abstract of DOI:10.1002/(SICI)1099-1395(199909)12:9<708::AID-POC180>3.0.CO;2-T

Second-order rate constants for substituted benzaldehyde oxime formation increase linearly with the activity of hydrated protons over the pH range ca 2-7. Under these conditions, first-order rate constant show saturation behavior with increasing hydroxylamine concentration, establishing carbinolamine dehydration as the rate-determining step. Equilibrium constants for the formation of the neutral carbinolamine are correlated by the σ⁺ substituent constants; ρ = 1.26. Under more acidic conditions, second-order rate constants increase less rapidly than the activity of hydrated protons, indicative of a transition to pH-independent carbinolamine formation, presumably the uncatalyzed addition of amine to aldehyde. The corresponding value of ρ for this process is 1.21. This value, together with that for the equilibrium constants (see above), suggests that C-N bond formation is nearly complete in the transition state. The rate constants for acid-catalyzed carbinolamine dehydration are correlated by the σ substituent constants; ρ = -0.85. Copyright

Full text of DOI:10.1002/(SICI)1099-1395(199909)12:9<708::AID-POC180>3.0.CO;2-T

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 12, 708–712 (1999)
Effect of structure on reactivity in oxime formation of
benzaldehydes
M. Calzadilla, A. Malpica* and T. Cordova
Escuela de Quimica, Facultad de Ciencias, Universidad Central de Venezuela, Caracas, 47102, Venezuela
Received 22 December 1998; revised 29 April 1999
ABSTRACT: Second-order rate constants for substituted benzaldehyde oxime formation increase linearly with the
activity of hydrated protons over the pH range ca 2–7. Under these conditions, first-order rate constants show
saturation behavior with increasing hydroxylamine concentration, establishing carbinolamine dehydration as the rate-
‡
determining step. Equilibrium constants for the formation of the neutral carbinolamine are correlated by the s
substituent constants; ꢀ = 1.26. Under more acidic conditions, second-order rate constants increase less rapidly than
the activity of hydrated protons, indicative of a transition to pH-independent carbinolamine formation, presumably
the uncatalyzed addition of amine to aldehyde. The corresponding value of r for this process is 1.21. This value,
together with that for the equilibrium constants (see above), suggests that C—N bond formation is nearly complete in
the transition state. The rate constants for acid-catalyzed carbinolamine dehydration are correlated by the s
substituent constants; ꢀ = � 0.85. Copyright  1999 John Wiley & Sons, Ltd.
KEYWORDS: benzaldehydes; oximes; structure; reactivity
INTRODUCTION
Compared with the wealth of information about the
reactions involving aromatic aldehydes and semicarba-
zide, little work has been undertaken on the reactions
involving aromatic aldehydes and hydroxylamine. We
have begun to explore the kinetics and mechanism for the3
addition of amines to formyl-1-methylpyridinium ions
and the addition of hydroxylamine to pyridine-2-, -3- and
The reactions of carbonyl compounds with nitrogen
nucleophiles to yield imines proceed by a stepwise
mechanism involving the formation of a neutral addition
intermediate followed by its decomposition to yield the
1
,2
product. The formation of the neutral carbinolamine,
usually the rate-determining step under mildly acidic
conditions, may occur via two routes: (i) a stepwise
pathway involving addition of the amine to the carbonyl
group to form a zwitterionic intermediate followed by
protolytic reactions or (ii) a concerted pathway in which
substrate protonation and amine addition are in some
sense concerted. The stepwise pathway may reveal three
distinct steps to be limiting at different values of pH:
amine addition, protonation of the zwitterionic species or
a proton switch (through water) that generates the neutral
species directly from the zwitterion. Under more basic
conditions, the rate of carbinolamine dehydration be-
comes rate determining (Scheme 1). This complex
reaction mechanism accounts for the pH–rate profiles
for these reactions, which show as many as five separate
regions, and also for many structure–reactivity correla-
4
5
-4-carboxaldehyde and 2-quinolinecarboxaldehyde. In
these cases it was established that carbinolamine
dehydration is rate determining over the entire pH range
from ca 1 to 7, reflecting the increased reactivity for
nucleophilic addition resulting from the electron-with-
drawing power of the cationic nitrogen function. In
continuation of this work, we have now explored the
kinetics for addition of hydroxylamine to the less
activated series of 4-substituted benzaldehydes. We
initiated this study with the examination of the behavior
of oxime formation from 4-dimethylaminobenzaldehyde
6
and 4-trimethylammoniobenzaldehyde iodide. It seemed
worthwhile to extend the investigation to several
additional benzaldehydes in order to provide more
complete structure–reactivity information for this sys-
tem.
1
,2
tions. The most basic amines and/or the most activated
carbonyl compounds exhibit pH–rate profiles in which a
2
single break is found.
EXPERIMENTAL
Materials
*
Correspondence to: A. Malpica, Escuela de Quimica, Facultad de
Ciencias, Universidad Central de Venezuela, Caracas, 47102,
Venezuela.
4-Methoxybenzaldehyde, 4-nitrobenzaldehyde, 4-chloro-
Contract/grant sponsor: Consejo de Desarrollo Cientifico y Humanis-
tico de la Universidad Central de Venezuela.
benzaidehyde and benzaidehyde were obtained commer-
Copyright  1999 John Wiley & Sons, Ltd.
CCC 0894–3230/99/090708–05 $17.50

EFFECT OF STRUCTURE ON REACTIVITY IN OXIME FORMATION OF BENZALDEHYDES
709
Scheme 1
cially and were purified by distillation or crystallization.
Hydroxylamine hydrochloride was obtained commer-
cially and purified by crystallization from ethanol.
Solutions of these reagents were prepared just prior to
use to minimize the possibility of decomposition.
Distilled water was used throughout.
amine free base and were not corrected for the action of
buffers. which show a small general acid catalysis.
Equilibrium constants
The equilibrium constants for the formation of the
addition intermediate from hydroxylamine and the
substituted benzaidehydes were determined spectropho-
tometrically in 0.125 M phosphate–hydrogenphosphate
buffer at 30°C and ionic strength 0.5 (KCI) by measuring
the initial decrease in carbonyl absorption after the
addition of four or more different concentrations of
Kinetic measurements
All rate measurements were carried out spectrophotome-
trically employing a Zeiss PMQ II spectrophotometer
equipped with thermostated cell holders and PI-2
photometer indicator. Rate constants were measured in
water, at 30°C and ionic strength 0.5 (KCI), under
pseudo-first-order conditions. The pH was maintained
constant through use of buffers. Values of pH were
measured with Radiometer pH-meters. First-order rate
constants were obtained from plots of the difference
between optical density at infinite time and optical
density against time. The reactions with benzaldehyde, 4-
methoxybenzaldehyde and 4-nitrobenzaldehyde were
followed by observing the appearance of product at
hydroxylamine. These equilibrium constants, K , which
ad
are the average of ca 20 determinations, were obtained
from the negative abcissa intercept of a plot of 1/D A°eq
against 1/[NH OH]: (a) benzaldehyde, pH 8.07, ꢁ =
2
�
1
� 2
240 nm, [NH OH] = 1 Â 10 –7.05 Â 10 M; (b) 4-
2
methoxybenzaldehyde, pH = 8.01, ꢁ = 290 nm, [NH OH]
2
�
1
� 1
= 1.5 Â 10 –2.85 Â 10 M; (c) 4-chlorobenzaldehyde,
�
1
pH = 8.05, ꢁ = 260 nm, [NH OH] = 1 Â 10 –3.4
2
�
2
 10 M. Spectrophotometric determination of K
ad
for 4-nitrobenzaidehyde is subject to a relatively
large error because the measurements were hampered
by the fact that the absorbance changes were very
small; therefore, Kad in this case was determined
kinetically; the method used is described in the Results
265, 360 and 310 nm, respectively. First-order rate
constants, kobs, were measured at low concentrations of
hydroxylamine, conditions at which carbinolamines do
not accumulate. Second-order rate constants, kobs
/
[
NH OH] , were obtained from slopes of plots of first-
and Discussion Section. The values of K for 4-
trimethylammoniobenzaldehyde iodide and 4-nitroben-
2
fb
ad
6
order rate constants against the concentration of the
Copyright  1999 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 12, 708–712 (1999)

7
10
M. CALZADILLA, A. MALPICA AND T. CORDOVA
Figure 1. Logarithms of second-order rate constants for 4-methoxy (~), unsubstituted (*), and 4-nitrobenzaldehyde (&) oxime
formation plotted as a function of pH. Rate constants were measured at 30° and ionic strength 0.50. The points are
experimental; the curves are theoretical ones based on eq. 1 and the data in Table 1
zaldehyde were corrected for hydration of these alde-
hydes:
that carbinolamines formed from the addition of hydro-
xylamine to the aldehydes accumulate and that the
dehydration of these species is the rate-determining step
from pH ca 3 to 7 at least. In Fig. 1, logarithms of second-
order rate constants, Kobs/[NH OH] , for three of the
Kadcor ˆ K ꢀ1 ‡ ‰hydrateŠ=‰aldehydeŠ†
ad
2
fb
7
8
where the ratios [hydrate]/[aldehyde] are 0.11 and 0.25,
studied reactions are plotted as a function of pH. For each
benzaldehyde studied, the logarithm of the second-order
rate constant increases linearly with increasing concentra-
tion of the hydrate proton down to values of pH in the
range 2–3. This is a behavior expected for rate-determin-
respectively.
RESULTS AND DISCUSSION
9,10
ing carbinolamine dehydration.
Below pH 2–3, the rate
First-order rate constants for the formation of substituted
benzaldehyde oximes were determined as a function of
hydroxylamine concentration over the pH range ca 1–7 at
constant–pH plots deviate from linearity. The deviation is
most marked for the reaction with 4-methoxybenzalde-
hyde and least evident for that with 4-nitrobenzaldehyde.
This represents a negative deviation from the rate expected
on the basis of behavior observed at higher values of pH
and must represent a transition in rate-determining step to
carbinolamine formation. As noted above, for pH >2–3,
carbinolamine dehydration must be rate determining. The
rate constant for this process is given by Kad kdeh, where
Kad is the equilibrium constant for neutral carbinolamine
30°C in aqueous solution and ionic strength 0.5. At pH
>3, first-order rate constants were observed to increase
less rapidly than the concentration of hydroxylamine free
base; at sufficiently high concentrations of this nucleo-
phile, the rate constants became independent of this
variable. This behavior accords with that observed
9,10
previously on several occasions
and strongly suggests
Copyright  1999 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 12, 708–712 (1999)

EFFECT OF STRUCTURE ON REACTIVITY IN OXIME FORMATION OF BENZALDEHYDES
711
Table 1. Summary of rate and equilibrium constants for substituted benzaidehyde oxime
a
formation at 30°C and ionic strength 0.5
�
1
� 1
� 1
� 1
� 1
Substituent
Kad (l mol
)
k2 (l mol min
)
kdeh (l mol min
)
b
7
5
4
4
4
-NO
-N (Me)3
-Cl
Unsubstituted
-OMe
152.5
1.43 Â 10
8.3 Â 10
2
‡
c
b
6
6
87.2
6.75 Â 10
1.27 Â 10
d
6e
6e
24
2.31 Â 10
3.33 Â 10
f
6
6g
17.6
1.8
1.58 Â 10
5.07 Â 10
5
7
4
4
4.66 Â 10
1.05 Â 10
c
4
7
-N(Me)2
0.15
1.06 Â 10
2.26 Â 10
a
b
c
d
e
f
All constants are defined in Scheme 1.
Corrected for hydration (see Experimental section).
Ref. 6.
� 1
11
Lit. Kad = 23.5 l mol at 25°C and ionic strength 0.38.
Ref. 11.
� 1
12
Lit Kad = 11.3 l mol at 25°C and ionic strength 0.3.
Lit. kdeh = 7 Â 10 l mol min at 25°C and ionic strength 0.3.
g
6
� 1
� 1
12
formation, K = [T°]/[Ald] [NH OH]. Since the data in
Table 1 are 4–13 times greater than those previously
determined for the addition of semicarbazide to the same
ad
2
the linear regions of Fig. 1 yield K k , values of kdeh
ad deh
14
could be directly calculated from the spectrophotometri-
substrates. The modest differences indicate that equili-
brium constants for the addition of amines to the carbonyl
group are not strongly dependent on the basicity of the
cally determined values of K , except for 4-nitrobenzal-
ad
dehyde. In this case kdeh was obtained directly at saturating
‡
15
concentrations of hydroxylamine at pH 7, kobs = kdeh [H ].
amine, in accord with a previous finding. The values of
With the value of kdeh now in hand, the value of Kad for
this substrate was calculated. All the values of K and k
Kad for neutral carbinolamine formation in this work are
in excellent accord with s substituent constants; the
‡
ad
deh
are collected in Table 1 and are in excellent accord with
those for 4-chlorobenzaldehyde and benzaldehyde
determined previously.
derived value of r is 1.26 (r = 0.99). When values of s
substituent constants are used, the derived value of r is
1.18, and the s–r plot shows a negative deviation for the
reaction with 4-dimethyaminobenzaldehyde and 4-meth-
oxybenzaldehyde. This downward deflection has been
11
12,13
The reaction between 4-nitrobenzaldehyde and semi-
2
carbazide shows a pH–rate profile with an initial break at
16
pH near 5.5 attributed to a transition of the rate-
determining step from carbinolamine dehydration to
noted previously by Wolfenden and Jencks in semi-
carbazone formation from substituted benzaldehydes,
when the reaction of 4-hydroxybenzaldehyde is included
in the s–r correlations. This is attributed to the resonance
effect of stabilization of the carbonyl group exerted by
electron-donating 4-substituents, such as 4-hydroxy, 4-
Æ
conversion of the zwitterionic intermediate (T ) to the
neutral species (T°) via a proton switch, k in Scheme 1.
4
Under more acidic conditions a second break is observed
and uncatalyzed amine addition becomes rate limiting, k2
in Scheme 1. Hydroxylamine is considerably more basic
than semicarbazide; this will tend to stabilize the
10
methoxy and 4-dialkylamino groups. The rate constants
for the uncatalyzed attack of hydroxylamine on the
benzaldehydes, k2 in Scheme 1, are satisfactorily
Æ
zwitterionic intermediate, T , increasing the rate of the
Æ
‡
proton switch relative to the decomposition of T to the
correlated also by the s substituent constants; the
reactants. Consequently, it appears most reasonable to
ascribe the pH-independent reaction for oxime formation
from benzaldehydes observed under acidic conditions to
uncatalyzed attack, not the proton switch step. This
corresponds to a possibility raised earlier. Therefore, the
rate law for substituted benzaldehyde oxime formation is
derived value of r is 1.21 (r = 0.97). This value is equal to
that for the formation of the neutral carbinolamine,
within experimental error. Since the value of r for
Æ
0
conversion of T to T is expected to be near zero, this
strongly suggests that the transition state for addition of
2
Æ
the amine to the carbonyl group resembles T . That is,
the transition state is late and involves extensive C—N
bond formation between nucleophile and substrate. This
conclusion is consistent with measurements of kinetic
alpha deuterium isotope effects for carbonyl addition
reactions, which have also been interpreted to suggest
‡
‡
kobs=‰NH OHŠ ˆ K k k ‰H Š=ꢀK k ‰H Š
2
fb
ad
2
deh
ad deh
‡
k †
ꢀ1†
2
The values of k obtained from the slopes of double
17
2
late transition states.
reciprocal plots:
The rate constants for acid-catalyzed carbinolamine
dehydration, kdeh in Scheme 1, show a satisfactory linear
logarithmic correlation with Hammett’s substituent
constants, s, with a r value of � 0.85 (r = 0.97). This
value is smaller than that previously measured for the
‡
1
=kobs ˆ 1=‰NH OHŠ ꢀ1=k ‡ 1=K k ‰H Š†
2
fb
2
ad deh
at acid pH are also included in Table 1. Values of Kad in
Copyright  1999 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 12, 708–712 (1999)

7
12
M. CALZADILLA, A. MALPICA AND T. CORDOVA
reaction of benzaldehyde semicarbazone formation,
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1
4
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1
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4
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5
1
1
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6
7
8
1
8
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n
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1
1
1
1
(
Acknowledgements
(
This work was supported in part by the Consejo de
Desarrollo Cientifico y Humanistico de la Universidad
Central de Venezuela.
4
Copyright  1999 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 12, 708–712 (1999)