Preface for Volumes 1-3

This three-volume book originates from a widely cited 2008 review with the same title, Lewis Base Catalysis in Organic Synthesis, coauthored by Denmark and Beutner. Given the interest generated by that article, as well as the explosion of related topics in the literature, a more comprehensive treatment was desired by Wiley-VCH. Scott Denmark declined taking on the current project as sole editor due to extensive prior commitments, but did agree to serve as coeditor in planning the project and determining scientific content. In addition, he edited Chapter 1, authored several of the later chapters, and wrote the Introduction that traces definitions of catalysis from Ostwald to the current era and presents an updated, broadly inclusive definition that is used in the current volumes.

After extensive discussion by both coeditors during the planning stages, the decision was made to emphasize mechanistic aspects of Lewis base catalysis where possible, and to provide broad coverage of the most important preparative advances with sufficient commentary and explanation to facilitate graduate instruction as well as to stimulate new research initiatives. Another important objective was to remind the current generation of the remarkable insight and contributions of G.N. Lewis. He was the first to recognize the possibility of catalysis by electron pair donors, and did so two decades before independent attempts to classify this family of reactions resulted in the alternative terminology "nucleophilic catalysis." For historical as well as heuristic and conceptual reasons, it is better and more correct to regard this chemistry as Lewis base catalysis.

All of the examples of Lewis base catalysis in these volumes feature activation by a key bonding event between a substrate acceptor orbital (classified as n*, p*, or s* in chapter headings) and two electrons from a donor orbital in the Lewis base catalyst, but this donor-acceptor interaction is only the appetizer. The main course consists of the stages that follow the Lewis base activation step, and the menu of mechanistic options can be incredibly rich. The options can be very simple, as in halide catalysis (Chapter 1) where a single activation stage by the halide Lewis base is usually followed by a single product-forming stage. However, such mechanistic simplicity is the exception. More often, the mechanisms are deceptively simple, multifaceted, and amazingly subtle. Even that familiar undergraduate-level example of Lewis base catalysis, the venerable benzoin condensation, can be challenging for students who must confront multiple conceptual layers (reversible nucleophilic addition of cyanide; acid-base concepts; carbanion delocalization; leaving group ability) and decipher several steps following the activation stage. It is worth recalling that an earlier mechanism for the benzoin condensation proposed the dimerization of "PhC(OH)" (yes, the hydroxyl carbene tautomer of benzaldehyde!) to the intermediate enediol PhC(OH)=C(OH)Ph (Bredig, 1904). This suggestion was perfectly logical, concise, and plausible at the time, but lasted only until the alternatives were considered and the mechanism was studied. Perhaps a similar fate awaits other plausible mechanisms, a phrase that appears often in these volumes.

By now, many of the fundamental principles underlying Lewis base catalysis have indeed been studied, and several of the most extensively investigated topics are featured in Volume 1. Chapter 1 begins with a historical account tracing key highlights in the development of catalysis, including important contributions by Berzelius, Liebig, Ostwald, and other major figures of nineteenth century chemistry. This chapter also mentions milestones in Lewis base catalysis from 1834 to 1970, and briefly comments on a few more recent developments that await detailed investigation.

Lewis was the first to recognize the electronic features that define Lewis base catalysis (Introduction and Chapter 2). An overview of his profound insight is presented in Chapter 2, which traces the evolution of Lewis's landmark formulation of the electronic theory of structure and bonding to a clear assertion that his (Lewis's) bases possess every property ascribed to Brønsted bases, including their ability to act as catalysts. The Lewis concepts benefited greatly from refinement and popularization by Mulliken and Jensen, who helped to develop the unifying conceptual basis, a classification scheme of reaction types according to relevant orbital interactions, and a generally applicable terminology that serves as the organizational framework for these volumes.

The next two chapters focus on the thermodynamic and kinetic aspects of Lewis base catalysis, respectively. Chapter 3 presents the classical methods that have been used to quantify Lewis basicity of the most important Lewis bases, and defines the concepts of Lewis Affinity and Basicity. Extensive discussion and tables compare Lewis bases using representative affinity parameters, including those for various cations (proton, methyl, lithium) and neutral Lewis acids (BF3, iodine, 4-fluorophenol). Similarly, Chapter 4 quantifies the corresponding kinetic component (nucleophilicity) using the Mayr Scale, introduces the related concepts of electrofugality and nucleofugality, and provides examples of how these concepts are used by synthetic chemists.

The selection of topics for the subsequent chapters of Volume 1 was made according to several criteria: (i) extensive in-depth mechanistic study, (ii) preparative importance, and (iii) mechanistic diversity following attack by the Lewis base. The first of these chapters (Chapter 5) takes on acyl transfer catalysis by pyridine derivatives, a topic that has been studied in sufficient depth to develop a mechanism that is well understood and widely accepted. Perhaps the same can now be said for much of Chapter 6, involving the mechanism for proline-catalyzed carbonyl activation in enantioselective synthesis, but this is complex, broadly applicable chemistry and the evaluation of models for enantioselection often depends on computational methods that are still undergoing refinement. Similar concerns regarding computations arise in reactions where complexity is associated with the timing and nature of proton transfer events, or with the role of various additives. Those scenarios have long confounded attempts to fully understand the mechanism of the Morita-Baylis-Hillman reaction, a topic that is summarized in Chapter 7. Progress has been made using sophisticated mechanistic tools based on kinetics, mass spectroscopy, computation, and acid-base relationships, but developing a generally applicable mechanism has proven to be difficult.

Some of the mechanistically most intriguing examples of Lewis base catalysis are featured in Chapters 8-11 of Volume 1. These chapters describe reactions that begin with a bonding interaction between the Lewis base and the s* or n* (unoccupied p) orbitals of the electrophile, reactions that proceed with astonishing mechanistic diversification, even in the relatively simple context of Lewis base activation of silicon nucleophiles (Chapter 8). One take-home message is that only by extensive mechanistic investigation of each substrate category is it possible to classify the reactive intermediates as carbon-bound siliconates or as free carbanions. This conclusion would not surprise authors from an earlier era when physical organic chemistry was the central focus of organic chemistry, and it is underscored by the content of Chapters 9-11. Massive mechanistic study and correlation of enantioselectivity data were required to reveal details of how a chiral Lewis base induces the catalytic formation of cationic silicon electrophiles in aldol and related reactions (Chapter 9), or how Noyori's bifunctional Lewis base catalyst converts dimeric organozinc reagents into intermediates having both Lewis base and Lewis acid character (Chapter 10). In the case of Chapter 11, the combination of kinetic isotope effects, computation, and correlation of extensive enantioselectivity data are shown to confirm Corey's insightful dual activation mechanism for borane reduction of ketones catalyzed by oxazaborolidines, catalytically active intermediates that rely on a single B-N subunit in the key role of both Lewis base and Lewis acid. An unexpected bonus from these studies is the entertaining conclusion that those who favored a boat-like six-center transition state were right, but those who preferred a chair-like transition state were also right. The two transition state geometries are similar in terms of free energy, and both predict the same major enantiomer.

In some cases, the topics selected for Volume 1 were so large that most of the applications and preparative chemistry were split into separate chapters and placed in Volume 2 or Volume 3. Several of the Volume 2 and 3 chapters, such as the N-heterocyclic carbene (NHC) chemistry of Chapter 27, could easily have worked as chapters in Volume 1. Indeed, most of the Volume 2 and 3 chapters contain substantial mechanistic discussion, but the primary consideration is the preparative chemistry and, in particular, the enantioselectivity. No simple generalizations can prepare the reader for the exceptional scope of applications that are covered in Volumes 2 and 3, but some examples will be mentioned below due to their historical, preparative, or mechanistic...