Mechanism and Kinetics in Homogeneous Catalysis …
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has always played a considerable role in developing our mechanistic understanding.
And the use of quantum chemistry for modeling molecular electronic structure and
exploring reactive potential energy surfaces is a practice with an already long track
record that predates both of the experimental studies mentioned above. However, the
balance between experiment and computation has firmly tipped toward the latter in
recent years.
The move toward computation as a source of mechanistic information is this
author’s view partly due to a relative drop in prestige for experimental studies, especially when set against the difficulty of such studies. Given the enormous progress
that physical organic chemistry made in understanding reactivity, more and more
reactions, even ‘new’ synthetic procedures, can now be understood at least qualitatively by analogy to well-understood previous reactions. Also, the remaining relatively poorly understood reactions are nowadays, more often than not, much more
challenging to investigate, due to the involvement of complex reaction conditions or
of unstable reagents, or due to the unavailability or complexity of suitable analytical
methods to assess reaction progress on the timescale of reaction. This does not mean
that high-quality experimental studies of mechanism have ceased to be carried out.
To again take just one example, concerning a reaction my group has been interested
in, the Suzuki–Miyaura cross-coupling reaction, considerable insight has been provided in the last years by exquisite studies of two key steps, boronic ester activation
[3] and transmetallation [4, 5]. However, the proportion of mechanistic studies using
experimental methods has dropped considerably. Indeed, the work just cited [3, 5]
includes significant contributions from computation also.
Accompanying the drop in the reward:risk ratio for experimental studies, there has
been a huge rise in the applicability and power of computational methods. This can
in turn be traced to improvements in computer hardware, to new and more accurate
approximate theoretical methods, and to more efficient computer implementations
of existing methods. Combined, these changes have led to an enormous change in
the relative cost of computational studies in recent years. In the past, studies typically addressed model compounds in which most substituents in the experimentally
studied compounds were removed, solvent and counterion effects were ignored, and
very approximate techniques such as Hartree–Fock were applied. Nowadays, most
synthetically relevant transformations are of a size such that the whole system containing reactant molecules, catalyst, and key solvent molecules contains less than
a few hundred atoms and can be directly studied using methods such as density
functional theory using relatively modest commodity computing resources.
One further reason that can be suggested for the rise in computational methods
concerns the way in which different methods convey their results. Most experimental
techniques provide indirect information concerning structure, energy, and bonding of
key intermediates and TSs. In order to convert such insights into concepts that can be
used to assist reaction design, synthetic chemists need to invest considerable effort,
perhaps through the means of constructing three-dimensional molecular ‘models’
of the system of interest. In contrast, computational methods provide at least the
illusion of direct access to these properties, with modern graphical rendering methods
seeming to allow the researchers to immerse themselves into the atomistic-level realm
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has always played a considerable role in developing our mechanistic understanding.
And the use of quantum chemistry for modeling molecular electronic structure and
exploring reactive potential energy surfaces is a practice with an already long track
record that predates both of the experimental studies mentioned above. However, the
balance between experiment and computation has firmly tipped toward the latter in
recent years.
The move toward computation as a source of mechanistic information is this
author’s view partly due to a relative drop in prestige for experimental studies, especially when set against the difficulty of such studies. Given the enormous progress
that physical organic chemistry made in understanding reactivity, more and more
reactions, even ‘new’ synthetic procedures, can now be understood at least qualitatively by analogy to well-understood previous reactions. Also, the remaining relatively poorly understood reactions are nowadays, more often than not, much more
challenging to investigate, due to the involvement of complex reaction conditions or
of unstable reagents, or due to the unavailability or complexity of suitable analytical
methods to assess reaction progress on the timescale of reaction. This does not mean
that high-quality experimental studies of mechanism have ceased to be carried out.
To again take just one example, concerning a reaction my group has been interested
in, the Suzuki–Miyaura cross-coupling reaction, considerable insight has been provided in the last years by exquisite studies of two key steps, boronic ester activation
[3] and transmetallation [4, 5]. However, the proportion of mechanistic studies using
experimental methods has dropped considerably. Indeed, the work just cited [3, 5]
includes significant contributions from computation also.
Accompanying the drop in the reward:risk ratio for experimental studies, there has
been a huge rise in the applicability and power of computational methods. This can
in turn be traced to improvements in computer hardware, to new and more accurate
approximate theoretical methods, and to more efficient computer implementations
of existing methods. Combined, these changes have led to an enormous change in
the relative cost of computational studies in recent years. In the past, studies typically addressed model compounds in which most substituents in the experimentally
studied compounds were removed, solvent and counterion effects were ignored, and
very approximate techniques such as Hartree–Fock were applied. Nowadays, most
synthetically relevant transformations are of a size such that the whole system containing reactant molecules, catalyst, and key solvent molecules contains less than
a few hundred atoms and can be directly studied using methods such as density
functional theory using relatively modest commodity computing resources.
One further reason that can be suggested for the rise in computational methods
concerns the way in which different methods convey their results. Most experimental
techniques provide indirect information concerning structure, energy, and bonding of
key intermediates and TSs. In order to convert such insights into concepts that can be
used to assist reaction design, synthetic chemists need to invest considerable effort,
perhaps through the means of constructing three-dimensional molecular ‘models’
of the system of interest. In contrast, computational methods provide at least the
illusion of direct access to these properties, with modern graphical rendering methods
seeming to allow the researchers to immerse themselves into the atomistic-level realm