Computational Chemistry

This skepticism was engendered by the difficulties and ambiguities in studying very
transient intermediates, and the impossibility (at the time at least) of observing
transition states.

9.1.2.1 The Diels–Alder Reaction. A One- or Two-Step Dance?

This is one of the most important reactions in all of organic synthesis, as it unites
two moieties in a predictable stereochemical relationship, with the concomitant
formation of two carbon–carbon bonds (Fig.9.5)[ 37 ]. The reaction has been used
in the synthesis of complex natural products, for example in an efficient synthesis of
the antihypertensive drug reserpine [ 38 ]. Such a reaction seems to be well worth
studying.
The Diels–Alder reaction and related pericyclic reactions, which can be treated
qualitatively by the Woodward–Hoffmann rules (Section 4.3.5), have been
reviewed in the context of computational chemistry [ 39 ]. The reaction is clearly
nonionic, and the main controversy was whether it proceeds in a concerted fashion
as indicated in Fig.9.5or through a diradical, in which one bond has formed and
two unpaired electrons have yet to form the other bond. A subtler question was
whether the reaction, if concerted, was synchronous or asynchronous: whether both
new bonds were formed to the same extent as reaction proceeded, or whether the
formation of one ran ahead of the formation of the other. Using the CASSCF
method (Section 5.4.3), Li and Houk [ 40 ] concluded that the butadiene–ethene
reaction is concerted and synchronous, and chided Dewar and Jie [ 41 ] for stub-
bornly adhering to the diradical (biradical) mechanism.

MeO 2 C

H O

O

H

O

O

H

H

* *

*

MeO 2 C

Fig. 9.5The prototypical Diels–Alder reaction is that between 1,3-butadiene and ethene, to form
cyclohexene. The Diels–Alder reaction has been used in the synthesis of complex natural products;
above, methyl 2,4-pentadienoate reacts with 1,4-benzoquinone to form an intermediate in the
synthesis of the drug reserpine. In a one-pot reaction two carbon–carbon bonds are made and three
chiral centers (*) are created with the correct relative orientations (i.e. essentially one diastereomer
is formed)

9.1 From the Literature 567