Perspectives on Computational Organic Chemistry

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Introduction
In the 1950s, physical organic chemistry had two principal
parts, the determination of reaction mechanisms and the effect
of structure on reactivity. A number of tools had been developed
for the study of reaction mechanisms: reaction kinetics, substituent
effects, isotope effects, and stereochemistry. In those
early days, I, too, was active in developing such tools. One of
my most notable achievements related to secondary deuterium
isotope effects.1 I was also interested in optical activity derived
from hydrogen-deuterium asymmetry and prepared a number
of compounds whose optical activity resulted from H-D
asymmetry.2 These compounds were useful for examining the
stereochemistry of reactions at primary centers.
Substituent effects often were confined to benzene derivatives
and made use of Hammett-like Fσ relationships. When the original
version of the sigma of a substituent effect did not give satisfactory
results, new definitions were proposed giving rise to a whole
panoply of substituent constants: σ0, σ+, σ-, σΙ, etc.3 I was involved
in many of these varied activities that constituted the physical
organic chemistry of that era.
Disproportionation of Alkylbenzenes. The study of reactions
of carbocations, then known as “carbonium ions”, was popular
at midcentury, and my group was active in various aspects of
this chemistry. An example of one of these applications relates
to the disproportionation reaction of alkylbenzenes, a reaction
of some importance in petroleum chemistry. Not long after the
discovery of the Friedel-Crafts alkylation reaction, Anschu¨tz
and Immendorff4 found that aluminum chloride converts ethylbenzene
to benzene and a mixture of diethylbenzenes. When
the reaction was applied to n-propylbenzene, the product still
had n-propyl groups with no rearrangement to isopropyl.5 This
observation shows that free alkyl cations are not involved, since
rearrangement of n-propyl cations to isopropyl is facile. Mc-
Caulay and Lien found that neopentylbenzene is inert under
conditions where ethylbenzene reacts readily; since this reactivity
order is characteristic of SN2 reactions, they proposed a
corresponding mechanism for disproportionation6 (Figure 1).
FIGURE 1. SN2 displacement mechanism for disproportionation.
 Copyright 2009 by the American Chemical Society
VOLUME 74, NUMBER 12 June 19, 2009
10.1021/jo900497s CCC: $40.75  2009 American Chemical Society J. Org. Chem. 2009, 74, 4433–4446 4433
Published on Web 06/12/2009
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Published on June 12, 2009 on http://pubs.acs.org | doi: 10.1021/jo900497s
We thought to test this mechanism using the classic method
of Hughes et al.,7 who showed in the reaction of optically active
2-iodooctane with radioactive iodide ion that the rate of
racemization was twice the rate of radioiodine exchange; thus,
each act of displacement went with inversion of configuration.
Eliel had prepared optically active (ethyl-1-d)benzene earlier.8
Consequently, we could apply the same principle to optically
active (ethyl-1-d)benzene labeled in the ring with 14C (Figure
2).
The experiment was carried out by my first female graduate
student, Liane Reif (now Reif-Lehrer).9 She found, to our
surprise, that the rate of racemization was equal to the rate of
radioexchange. The results of two runs are shown in Figure 3.
Mass spectroscopy of the isolated kinetic samples showed
progressive scrambling to ethylbenzene and (ethyl-1,1-
d2)benzene at a rate somewhat less than that of exchange or
racemization. These observations led to a new mechanism shown
in Figure 4.
The sequence starts with a trace amount of phenethyl cation
from styrene impurity or a small amount of oxidation. Alkylation/
dealkylation of benzene is rapid and results in loss of
radiolabel and optical activity. The rate-determining step is
hydride transfer from ethylbenzene to phenethyl cation. This
type of process was shown earlier to occur readily between
carbonium ions and hydrocarbons.10 Only transfer of deuterium
results in scrambling and is expected to involve a significant
primary isotope effect; hence, the scrambling process is slower
than racemization or radioexchange. This mechanism has since
become accepted for such trans-alkylation processes with
primary alkyl groups. The mechanism requires that 1,1-
diphenylalkanes rapidly dealkylate under the reaction conditions.
This corollary was proved later when we showed that 1,1-dip-
tolylethane is completely converted to ethylbenzene and
toluene within seconds on treatment with GaBr3-HBr under
comparable reaction conditions.11 This mechanism example is
also notable for its use of deuterium in several roles: as a label,
for kinetic isotope effects, and for optical activity from H-D
asymmetry.
Early Theory. Molecular orbital theory at midcentury was
primarily Hu¨ckel theory (HMO). The theory is limited to
π-electronic systems, but despite this limitation and the gross
approximations in the theory it had a number of successful
applications in its day. These early results were summarized in
my book, Molecular Orbital Theory for Organic Chemists,
published in 1961.12 In order to determine how well HMO
theory could model organic reactions, my group and several
others studied the reactivities of several π-electronic systems
that could provide reasonable tests. A typical example was our
study of the exchange reaction of ArCH2D with lithium
cyclohexylamide in cyclohexylamine, in which the Ar groups
are polycyclic aromatic rings.13,14 The transition state for the
reaction has a high degree of carbanionic character.15 The
π-system model that could be calculated by HMO theory was
that of an arene going to an arylmethyl anion. For π-energies
given in the usual HMO form, Eπ ) nR + m, this energy
difference is 2R + Δm. The results we found are summarized
in Figure 5.