On the Structural Assignments Underlying R. B. Woodward's Most Personal Data That Led to the Woodward–Hoffmann Rules: Subramania Ranganathan's Key Role and Related Research by E. J. Corey and A. G. Hortmann

In the early 1960s, as part of R. B. Woodward's isoxazole route to vitamin B₁₂, Subramania Ranganathan uncovered two coupled sets of stereospecific reactions, a thermal set and a photochemical set. These four reactions illustrated the alternating configurations that were the major data points that prompted the solution of the no-mechanism problem. Though Ranganathan's reactions played a major role, according to Woodward, in the development of the Woodward–Hoffmann rules, they were published only as part of the documentation of a lecture given by Woodward in 1966. The authors of this paper have uncovered Subramania Ranganathan's 1964 postdoctoral report and have used modern quantum chemical theory to predict the ¹H NMR spectra for Ranganathan's key compounds, providing support for the structure assignments made by Woodward and Ranganathan. A similar set of alternating, stereospecific reactions was observed by E. J. Corey and Alfred Hortmann in their 1963 total synthesis of dihydrocostunolide. We also have applied the computational process used for Ranganathan's compounds to Hortmann's compounds, now also including the calculation of coupling constants, and find computational support for Corey and Hortmann's structure assignments.     

A variational transition state theory description of periselectivity effects on cycloadditions of ketenes with cyclopentadiene

The reaction of cycloaddition of ketene and cyclopentadiene presents experimentally a competing mechanism where the branching ratio between the Woodward?CHoffmann allowed [4+2] and forbidden [2+2] cycloaddition product is 4.56?at ?20?°C, but because the minimum energy path misses the [2+2] product altogether, it has been claimed to lie beyond the scope of transition state theory. In this paper, a variational transition state theory study on this reaction is presented. It is found that the minimum energy path affording the [4+2] product travels through a potential energy plateau very close to the minimum energy path that describes the interconversion between both cycloaddition products, allowing the transfer between both and the direct formation of the forbidden [2+2] product, in this way acting as a means to circumvent the Woodward?CHooffmann rules. Within the domain of the competitive canonical unified statistical theory, a value for the branching ratio in very good agreement with experiment is computed.     

Photochemistry studied with ab initio orbital-correlation and state-correlation plots: Classic cyclobutene ring opening, and the reaction of N2 with photoexcited O2

Pericyclic reaction theory arose from ideas presented in 1965, based on orbital-energy correlation diagrams (Woodward and Hoffmann) and state-energy correlation diagrams (Longuet-Higgins and Abrahamson). Here we have used ab initio complete-active-space self-consistent field (CASSCF) calculations to generate such diagrams. First we present diagrams for the classic case of cyclobutene ring opening, to demonstrate agreement between the CASSCF results and the classic diagrams of both Woodward/Hoffmann and Longuet-Higgins/Abrahamson. Then we present diagrams for the more difficult cases of N(2) + photoexcited O(2), to produce either 2 NO or NNO + O. These N(2) + O(2) cases feature significant electron reorganization, for which elementary pencil-and-paper diagrams are less accurate. Finally, the benefits and limitations of such diagrams for predicting photochemistry are briefly discussed.     

Die tödliche Brechnuss. Strychnin – von der Isolierung zur Totalsynthese

Strychnine, one of the most poisonous alkaloids, has fascinated scientists since its first isolation in 1818. It took over 130 years until its chemical structure was unequivocally determined and another 7 years until the first total synthesis by Robert B. Woodward was finished. Nowadays scientists are still developing new strategies for the synthesis of this fascinating complex compound. Some chemical aspects and personal accounts of synthesis #17 from 2010 are given.     

Overlap repulsion and reaction barrier

A simple selection rule for the reaction energy barrier is presented which is based on the HOMO—HOMO overlap repulsion. The present rule states that the most favorable reaction orientation between the two molecules is the one with the least magnitude of the HOMO—HOMO overlap. The four-electron destabilization effect considered here bears the resemblance to the familiar nonbonding—nonbonding repulsion in the theory of stereochemistry. The results of the present scheme are consistent with those from the HOMO—LUMO interaction scheme and the Woodward—Hoffmann rule.     

Should the Woodward–Hoffmann Rules be Applied to Mechanochemical Reactions?

Since decades, pericyclic reactions have been well‐understood by means of the Woodward–Hoffmann rules and their classification as thermally or photochemically “allowed” or “forbidden”. Recently, stunning results on such reactions subject to mechanochemical activation by external forces instead of heat or light have revealed reaction pathways at sufficiently large forces, which are not expected from the Woodward–Hoffmann rules. This led to the much reiterated idea that the “Woodward–Hoffmann rules are broken in mechanochemistry”. Here, by studying ring‐opening of cyclopropane, we show that the electronic structure underlying the dis‐ and conrotatory pathways, which are greatly distorted upon applying forces to an extent that eventually the “thermally forbidden” process becomes “mechanochemically allowed”, does not change along both pathways. It is rather the mechanical work that lowers the activation barrier of the thermally forbidden conrotatory process relative to the disrotatory one at large forces.     

R. B. Woodward: A Larger‐than‐Life Chemistry Rock Star

To mark the 100th birthday of R. B. Woodward (April 10, 1917–July 8, 1979), a discussion and analysis of Woodward's persona is given. The fundamental theme is that “Woodward experienced his own exceptionality,” as described by Albert Eschenmoser, Woodward's partner in the vitamin B₁₂ project. Woodward's rock star personality is explored and discussed as one of his legacies in addition to his scientific achievements. Woodward presented himself to his students, colleagues, and fellow chemists with an aura of nobility and romanticism.     

Why Woodward and Hoffmann? And Why 1965?**

Previous publications in this series on the history of the development of the Woodward–Hoffmann rules revealed why Woodward and Hoffmann were prime candidates to solve the pericyclic no-mechanism problem. This publication explains why it was the collaborative team of R. B. Woodward and Roald Hoffmann who did solve this mechanistic problem in a series of five communications in the Journal of the American Chemical Society in 1965. That is, the reasons why Woodward and Hoffmann were the perfect team, and why their individual capabilities, experiences, and qualities provided the perfect synergy are described. In part, this was the right time and the right place for them both, but the synergies were fundamental, intrinsic and idiosyncratic as a collaborative pair. Their orbital symmetry rules provided the mechanism of all concerted pericyclic reactions including electrocyclizations, cycloadditions, and sigmatropic rearrangements. Why it was 1965 and not earlier is also discussed.     

R. B. Woodward's Letters: Revealing,Elegant and Commanding

A collection of excerpts from letters written by R. B. Woodward to his friends, colleagues, young students and others is presented. These excerpts are representative of Woodward 's lengthy correspondence and illustrate many aspects of his personality and philosophies of life.     

The Woodward Research Institute,Robert Burns Woodward (1917–1979) and Chemistry behind the Glass Door

Certainly a highlight in the career of Nobel Laureate Professor Robert Burns Woodward (1917–1979) was the foundation of the Woodward Research Institute (WRI) at Ciba AG in Basel, Switzerland, in 1963. Woodward's remarkable accomplishments in the development of organic chemistry altered not only our concepts of molecular structure, but also our comprehension of physico‐chemical properties. In his legacy, Woodward devised innovative strategies for natural product syntheses based on brilliant rationale of their properties and an uncanny sense of Nature. The chemistry community benefited not only at Harvard but especially in Basel and Zürich from Woodward's inspiring lectures and the opportunity to learn from the chemistry Meister. This article highlights parts of the chemistry and some personalities that contributed to forefront investigations at the Woodward Research Institute which began at the former Novartis legacy company, Ciba AG, Basel.     

Spin-Free理论与Woodward-Hoffmann规则——丁二烯体系电环合反应的研究

用Spin-Free理论,对丁二烯体系电环合反应进行了研究,得到了基态和各激发态的位能面,解释了加热和加光反应机理和选择定则,对其中的单态和三态光化反应作了初步探讨并求出了有关的活化能。     

The Woodward-Doering/Rabe-Kindler total synthesis of quinine: setting the record straight

In 1918, Paul Rabe and Karl Kindler reported the three-step conversion of d-quinotoxine into quinine. In 1944 Robert B. Woodward and William von Eggers Doering reported the total synthesis of homomeroquinene and d-quinotoxine from 7-hydroxyisoquinoline. Based on the transformations by Rabe and Kindler, Woodward and Doering asserted the "Total Synthesis of Quinine" (the title of their 1944 and 1945 papers). In 2000 and 2001, Gilbert Stork concluded that the claim by Woodward and Doering is a "myth" because they had synthesized only homomeroquinene and d-quinotoxine; no synthetic quinine had been made in Cambridge. In fact, Rabe and Kindler never published the experimental details of their conversion of d-quinotoxine into quinine. This Review presents the results of a detailed examination of the synthesis of cinchona alkaloids, and previously unpublished material combined with unpublished material and numerous interviews give insight into the lives of the personalities in this nearly 100-year saga.     

Orbital symmetry,orbital stability,and orbital pairing rules for organic reactions in the ground state

A generalization of the Hartree–Fock molecular orbital (MO) theory for treating diradical intermediates was explained pictorially by drawing molecular orbitals of diradical species such as ring-opened trimethylene. The generalized MO theory applied to elucidate electronic mechanisms of concerted, ionic, radical, and ion-radical reactions of organic reactants in the ground state. Generalized MO computations revealed the most essential characteristics of these reactions and mutal relationships between the worlds of Woodward–Hoffmann and Hughes–Ingold. Generalized MO studies supported our orbital symmetry, stability and pairing rules for concerted, ionic and radical reactions in the ground state, respectively. An extension of MO treatments to excited states reactions was briefly pointed out in relation to the density and spin correlation functions by the multireference CI wave functions.     

Activation hardness and cycloadditions of even linear polyenes

Modes of thermal and photochemical cycloaddition of even linear polyenes are examined using the simple concept of activation hardness. The results are in agreement with the well-known Woodward–Hoffman rules. [R.B. Woodward and R. Hoffmann, The Conservation of Orbital Symmetry (Academic Press, New York, 1989)]. © 1994 John Wiley & Sons, Inc.     

Conservation of Orbital Symmetry can be Circumvented in Mechanically Induced Reactions

In first‐principles molecular dynamics simulations of the mechanically induced ring‐opening of substituted benzocyclobutene we observe both con‐ and disrotatory ring‐opening reactions. We show that this finding does not contradict the fundamental principle that the orbitals develop continuously in time. However, it constitutes an exception from the principle of the conservation of orbital symmetry and thus is indeed an exception from the Woodward–Hoffmann rules. In contrast, the ring‐opening of unsubstituted cyclobutene proceeds in a conrotatory fashion. This shows that the breaking of the Woodward–Hoffmann rules is significantly facilitated by the substituents.     

Ring Cleavage of N-Alkylisothiazolilm Salts by Complex Metal Hydrides. Synthesis of β-Enaminothioketones

N-Alkylisothiazolium salts undergo ring cleavage when treated with complex metal hydrides to give β-enami-nothioketones in high yields.

The isothiazole nucleus is remarkably stable to chemical attack by reducing agents.¹ In fact, little work has been published on reactions involving reductive cleavage of the isothiazole ring. Thus, other azole systems as isoxazole are readily cleaved by catalytic hydrogenolysis whereas the isothiazole nucleus, in the same conditions, remains unchanged.² However there are instances in which ring cleavage occurs. For example, cleavage of isothiazole during lithiation at the 5-position gives a small proportion of a β-mercaptoenone resulting from the cleavage of the N-S bond.^3,4 Isothiazoles are reductively desulfu-rized by Raney nickel and this method has been used by Woodward in a remarkable synthesis of colchicine.⁵     

The bromination product of santonic acid in wet chloroform

The bromination product of santonic acid in wet chloroform is found to be a dibromide closely related to the tribromosantonin characterized by Woodward, Levine and Yates.     

A Synthesis of Prostaglandins: Strategy and Reality

The prostaglandin synthesis developed in the Woodward Research Institute at Basel serves to provide an unusual look behind the scenes. A candid account is presented of the sometimes tortuous chronological sequence of ideas and experiments during work on a challenging synthesis.