Evolution of the Diels‐Alder Reaction Mechanism Since the 1930s:Woodward, Houk with Woodward, and the Influence of Computational Chemistry on Understanding Cycloadditions

The first Cope Award was presented in 1973 to R. B. Woodward and Roald Hoffmann (the only shared Cope Award). In his award lecture, Woodward described his fascination in his early teens with the Diels-Alder reaction. Beginning in the late 1930s with his B.S. and Ph.D. theses and extending throughout his career, Woodward studied the mechanism of the Diels-Alder reaction and used it extensively in his total syntheses. This article describes the evolution of Woodward's mechanistic thinking, beginning in the late 1930s and early 1940s with his proposal of a charge-transfer mechanism for the Diels-Alder reaction, eventually leading to the Woodward-Katz two-stage concerted mechanism in 1959, and then to its mechanistic solution in terms of orbital symmetry control. There was much debate in the chemical literature about the validity of Woodward's early mechanisms, especially with Michael Dewar. However, as discussed in this paper, many of Woodward's mechanistic hypotheses have turned out to be valid. Modern calculations with quantum mechanics and molecular dynamics simulations have shown that Woodward indeed had perfectly described not only the cyclopentadiene dimerization mechanism, but a new class of transition states now known as ambimodal or bis-pericyclic transition states. This mechanistic type was first discovered in 2002 by the late Pierluigi Caramella from Pavia, Italy. In recent years, the Houk group has found that ambimodal reactions are operative in the [6+4] cycloaddition that Woodward and Hoffmann predicted in 1965, and that Houk studied experimentally as a graduate student. Molecular dynamics simulations of many Diels-Alder and ambimodal cycloadditions, in solvents and in enzymes, provide a time-resolved picture of how Woodward's favorite reactions occur. Lastly, Roald Hoffmann provides a Coda in which he describes his joy in "being taken along the journey" of the cycloaddition story from Woodward's youth to today's trajectory simulations.