290
J. N. Harvey
2 Chemical Reaction Mechanisms
Ever since the progress of chemical theories meant that the notion of ‘chemical reaction mechanism’ was a recognizable concept, it has been clear that understanding
the mechanisms of chemical reactions provides a powerful tool that can be used
to help in the development of synthetically more attractive variations. Accordingly,
many techniques have been developed to study reaction mechanisms. One of the
most powerful approaches is based on determining the reaction kinetics, while varying experimental conditions such as temperature, initial concentrations of reagents,
additives or catalysts, pressure, and perhaps also the structure of the reagents through
the modification of substituents. This enormous field of endeavor leads to most of
the modern understanding of organic and organometallic reaction mechanisms as it
is described in textbooks and used by researchers to help imagine new reactions or
reaction conditions.
A huge number of examples of the power of this technique could be given and
would take this chapter into areas that are not directly relevant. One particular family
of studies will however be mentioned, to underline just how much information can
be obtained by such techniques: the work done by the groups of Jencks [1] and
others concerning the hydrolysis of carbonyl compounds such as amides. The broad
mechanism of this reaction was established early on to involve nucleophilic attack by
water or hydroxide ion on the carbonyl carbon, leading to a tetrahedral intermediate,
which, perhaps after some adjustment of its protonation, can then collapse with loss
of the amine moiety to yield a carboxylate salt. Studying the kinetics for this reaction
under one particular set of conditions can tell you how fast the reaction proceeds, but
detailed study of the kinetics can reveal much more. For example, it is possible to
identify that a given ‘general’ acid catalyst is involved in transferring a proton to the
amide carbonyl oxygen at the rate-determining transition state (TS) of the reaction,
the extent to which this proton transfer has taken place, the fact that upon using
a different acid catalyst, the rate-determining step changes to another step in the
mechanism, and far more besides. All of this based only on kinetic studies, without
the need for any direct experimental detection of the transition states to reaction!
The name given to the field most often associated with such studies is ‘physical
organic chemistry,’ which correctly identifies that early work of this type usually
addressed organic reactions. However, essentially the same techniques can also be
applied to organometallic and inorganic chemistry. Indeed, much of our modern
understanding of organometallic reactivity comes from similar studies. One famous
example of this type of insight concerned the hydrogenation of alkenes by a rhodium
complex, which was shown to proceed not through the relatively abundant metal–alkene complex that can be detected experimentally under reaction conditions,
but instead from an isomeric and more reactive form [2].
As a student, like many people of my and preceding generations, I was taught about
reaction mechanisms largely based upon studies of this type. However, in the intervening period, theoretical and computational methods have come to adopt a greater
and greater role in examining reaction mechanisms. Theory in its various forms
J. N. Harvey
2 Chemical Reaction Mechanisms
Ever since the progress of chemical theories meant that the notion of ‘chemical reaction mechanism’ was a recognizable concept, it has been clear that understanding
the mechanisms of chemical reactions provides a powerful tool that can be used
to help in the development of synthetically more attractive variations. Accordingly,
many techniques have been developed to study reaction mechanisms. One of the
most powerful approaches is based on determining the reaction kinetics, while varying experimental conditions such as temperature, initial concentrations of reagents,
additives or catalysts, pressure, and perhaps also the structure of the reagents through
the modification of substituents. This enormous field of endeavor leads to most of
the modern understanding of organic and organometallic reaction mechanisms as it
is described in textbooks and used by researchers to help imagine new reactions or
reaction conditions.
A huge number of examples of the power of this technique could be given and
would take this chapter into areas that are not directly relevant. One particular family
of studies will however be mentioned, to underline just how much information can
be obtained by such techniques: the work done by the groups of Jencks [1] and
others concerning the hydrolysis of carbonyl compounds such as amides. The broad
mechanism of this reaction was established early on to involve nucleophilic attack by
water or hydroxide ion on the carbonyl carbon, leading to a tetrahedral intermediate,
which, perhaps after some adjustment of its protonation, can then collapse with loss
of the amine moiety to yield a carboxylate salt. Studying the kinetics for this reaction
under one particular set of conditions can tell you how fast the reaction proceeds, but
detailed study of the kinetics can reveal much more. For example, it is possible to
identify that a given ‘general’ acid catalyst is involved in transferring a proton to the
amide carbonyl oxygen at the rate-determining transition state (TS) of the reaction,
the extent to which this proton transfer has taken place, the fact that upon using
a different acid catalyst, the rate-determining step changes to another step in the
mechanism, and far more besides. All of this based only on kinetic studies, without
the need for any direct experimental detection of the transition states to reaction!
The name given to the field most often associated with such studies is ‘physical
organic chemistry,’ which correctly identifies that early work of this type usually
addressed organic reactions. However, essentially the same techniques can also be
applied to organometallic and inorganic chemistry. Indeed, much of our modern
understanding of organometallic reactivity comes from similar studies. One famous
example of this type of insight concerned the hydrogenation of alkenes by a rhodium
complex, which was shown to proceed not through the relatively abundant metal–alkene complex that can be detected experimentally under reaction conditions,
but instead from an isomeric and more reactive form [2].
As a student, like many people of my and preceding generations, I was taught about
reaction mechanisms largely based upon studies of this type. However, in the intervening period, theoretical and computational methods have come to adopt a greater
and greater role in examining reaction mechanisms. Theory in its various forms