PART
KINETICS OF
IV
FOBMJfflONS OF OXIMES OF ACETOPHENONE AND
SUBSTITUTED ACETOPHENONES
CHAPTER
8
A BRIEF ACCOUNT OF THE MECHANISM AND KINETICS OF FORMATION
OF OXIMES AND RELATED SCHIFF BASES.
152
Synthetic organic chemists take great interest in
reactions of the carbonyl group or the group that is
greatly influenced by the former.
Inspite of the fact
that very many chemical reactions in organic as well as
in biochemistry involve this particular grouping, not
much attention is paid to understand the mechanistic
aspects.
The mechanism of formation of condensation
compounds with nitrogen bases such as hydroxylamine
hydrazine, semicarbazide etc. are studied in some detail
in recent years.
The mechanism with all the nitrogen
bases appear to be similar.
Apparent observed differences
between different reagents or different carbonyl compounds
are usually resolved into differences in the rates of
several steps or in the position of equilibrium of one
or all of the steps.
The basic mechanism of the condensation reactions
of the carbonyl compounds with nitrogen bases containing
two dissociable protons is a two step addition-elimination
mechanism.
In the first step the nitrogen base adds to
the carbonyl compound to give a carbinolamine intermediate.
15o
This is followed by the elimination of water to form the
C=N bond in the second step.
0 + H2NR
>'0H
jsMj
x MR
= NR + H20
...
8.1.1
The first step is pronedto a very weak specific
acid catalysis 144 ’ 145 . The second step is aminable to
both general 74 ’ 146 and specific acid catalysis. The
following facts are important in the azomethine formation
reactions.
1.
The nitrogen bases are good nucleophiles and hence
require no prior ionisation.
2.
The intermediate addition compound is not isolable
and generally never accumulates innthe reaction
medium to a measurable extent.
3.
The condensations are all acid catalysed eventhough
oxime formation has been shown to be catalysed by
hydroxide ion too.
154
4,
The rates of condensation passes through a maximum
with changing acidity.
5.
The rate is found in general proportional to the
concentration of the nitrogen base at low concentration
of it while it is independent of the same at high
concentration.
Addition of hydroxylamine and semicarbazide to
neutral solutions of carbonyl compounds give a rapid
decrease in typical ultraviolet and infra-red carbonyl
absorption followed by a slow increase in the oxime or
74
semicarbazone absorption .
The role of the acid in these
reactions is attributed to the catalysis of the slow
dehydration step rather than the fecilitation of the
addition step through conversion of the carbonyl compound
into its conjugate acid.
The addition equilibrium is
rapidly established relative to the dehydration step.
Hence the overall rate of condensation at constant pH
dependent on the product of the equilibrium concentration
of the carbinolamine and the specific rate coefficient
for dehydration.
At low concentrations of the nitrogen
base the overall rate is second order at constant pH. ,
At high reagent concentration, the overall rate approaches
first order since most of the carbonyl compound is, present
as carbinolamine intermediate.
Hammett ascribed the maximum
in the pH-rate profile to the opposing effects of (a) the
general acid catalysis of the addition reaction and
(b) the decrease in the concentration of the free nitrogen
base by its conversion into the conjugate acid.
Jencks
on the other hand attributed the rate maximum to a change
in the rate determining step from acid catalysed dehydration
of the carbinolamine intermediate on the basic side of the
maximum to rate limiting addition of the free base on the
acid side of the maximum.
This transition of the rate
determining step can also take place by structural changes
of the substrate.
The decrease in rate with increasing
acid concentration is generally attributed to the decrease
in the concentration of the reactive nucleophile.
Thus
in acid solutions the rate is governed by a steady state
concentration of the intermediate.
At acidities where
the carbinolamine base is dehydrated rapidly as it forms,
the addition step becomes rate determining.
For aldehydes the dehydration takes place rapidly
in acidic solution and hence addition of tydroxylamine
becomes rate determining.
For ketones on the other hand
the dehydration is rapid even at higher pHs.
Hence the
addition of hydroxylamine becomes rate determining even at
higher pHs.
and Eabern
Similar conclusion was arrived at by Dickinson
147
in their studies on oxime formation of
benzophenone at pH 5.
Noyce, Bottini and Smith148 and
Santeree aid co-workers14^ suggested that rate of addition
of the base is slower and the rate of dehydration is
faster for ketones than for aldehydes.
The dehydration of the carbinolamine intermediate
is subjected to both specific and general acid catalysis.
However the addition of hydroxylamine shows slight specific
acid catalysis.
Addition of semicarbazide, a weaker base,
is subject to both specific and general acid catalysis.
Lapworth
15D
recognised that the oxime formation is
a two step mechanism and the electron pair of the attacking
reagent (hydroxylamine) must be free in order to m^ke the
reaction occur.
It has been known that the oxime and
semicarbazone formations exhibit bell shaped pH-rate curves.
Bartlett
151
and Hammett
152
suggested that these oxime
formations give bell shaped pH-rate curve depending on the
ionisation constants of the catalyst and the attacking
187
nitrogen base.
Jencks
74
reported that the decrease in
rate with decreasing pH is due to the transition of the
rate limiting step to the attack of the free -N- base
on the carbonyl compound from the dehydration step but
is not due to general acid catalysis.
The rate limiting
of the. oxime and semicarbazone formation at neutral pH
is reported to be the acid catalysed dehydration of the
carbinolamine addition compound. Olander15^ suggested
that hydroxylammonium ion reacts with acetope to form an
addition intermediate and that only the free base form
of the intermediate can lose water to form oxime.
However
e •
kinetically such a mechanism is unequivocally ruled out
because it is not reasonable chemically. Barrett and
Lapworth^54 and Jencks74 reported that the rates of oxime
.and semicarbazone
formations in alkaline solutions increase
with the concentration of hydroxide ion.
Kadunce
155
Haas and
have shown that ring opening can be at least
partly rate determining in the reactions of sugars with
hydroxylamine or semicarbazide.
Rate of oxime formation
for farious carbonyl compounds have been determined by
-| -| /r
Fitzpatrick et al.
at different temperatures.
Under
the experimental conditions used, the reactions were all
156
irreversible and followed second order kinetics.
Craft 157
reported the rates of oxime formation of the isomeric
158
ketones. Zuman and Manousek
studied polarographically
the kinetics of the formation of pyridoxal oxime in the
pH range 3 to 12.
They reported that the three forms
of pyridoxal namely, the protonised form, the neutral
molecule and the anionic form undergo reaction with the
unprotonised of the hydroxylamine.
The antecedant acid-base
equilibrium is found to be major factor in influencing the
pH dependence of the rate.
hydroxylamines
The rate of addition of
to ketones and theiro(,-deuterated homologues
were measured by Geneste et al.
and the attack of the
free nucleophile on the carbonyl group of the ketone is
found to be the rate determining step. Further they
report ed^O that the Hammett’s reaction constant f for
oxime formation is 0.32 and this value is consistant with
the assumption that a reactant like transition state is
involved in the mechanism.
Based on the rates of proton
transfer reaction, it was concluded by Jencks and Cordes 76
that general acid catalysed reactions of the semicarbazone
formation involves concerted semicarbazide attack and
proton transfer to the carbonyl group.
Gilesx
, Marablex
ISO
studied the temperature coefficient of semicarbazone
formation of some substituted acetophenones. Takeno
and his co-workers'*"^ reported a linear free energyrelation between the logarithm of the rates of semicarba­
zone formation and Taft substituent constants.
164
Balaiah et al.
found that the rate determining step
is the attack by the nucleophile on the carbonyl carbon
in the reaction of semicarbazide with a number of para
and meta substituted acetophenones.
They also reported 165
that the effect of ortho substituents can be traced to
the ortho steric effects described by Taft equation.
Yukawa and Tsuno
1
f\f\
have proposed an emperical equation
to measure the sensitivity of the carbonyl reactions
to resonance effects. Block-Chaude 167 observed that the
rate and equilibrium constants of the reactions involving
the attack at the carbonyl group are higher for o-hydroxy
and D-methoxy substituted carbonyl compounds than the
para substituted compounds.
Lamaty et al.
1 Aft
' found that
in ketone oximation reactions the addition of hydroxylamine
to give the hydroxylamine alcohol was rate determining at
0.01 M acid.
While at concentration less than 0.01 M this
was not the only limiting step.
They further reported that
16C
in neutral and acid solution, the proton transfer is
concerted and the transition state is close to the
starting material.
From the differential temperature
time curves obtained during the addition reaction of
hydroxylamine to cyclohexanone in aqueous solutions.
DeOliva et al.
y observed that the addition step is
not rate determining when the base is in excess.
It is
however observed by them that the addition step is
rate determining if the pH of the medium is less than
0.4.
on the
Studies made by Lamaty 17 A on the effect of structure
roximation reactions of ketone in neutral and acid
solutions show that similar effects operate in the acid
catalysed and pH independent path ways.
The results were
consistent with a reactant like transition state.
Igberink and Van Heerden171 studied the oxime
formation and hydrolytic reactions of cyclohexanone in
the pH range 1-7.
The mechanism proposed by Jencks in
the formation studies of oximes of ketone was confirmed.
The carbinolamine intermediate formed in the first step
of the reaction is found to be ratio of 1:1 to ketone and
hydroxylamine.