Reviews S. E. Denmark and G. L. Beutner DOI: 10.1002/anie.200604943 Reaction Mechanisms Lewis Base Catalysis in Organic Synthesis Scott E. Denmark* and Gregory L. Beutner Keywords: catalysis · donor–acceptor interactions · electrophilic · nucleophilic stereoselectivity Angewandte Chemie 1560 www.angewandte.org 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2008, 47, 1560 – 1638 Angewandte Lewis Base Catalysis Chemie The legacy of Gilbert Newton Lewis (1875–1946) pervades the From the Contents lexicon of chemical bonding and reactivity. The power of his concept of donor–acceptor bonding is evident in the eponymous 1. Introduction 1561 foundations of electron-pair acceptors (Lewis acids) and donors 2. Defining Lewis Base Catalysis 1563 (Lewis bases). Lewis recognized that acids are not restricted to those substances that contain hydrogen (Brønsted acids), and 3. Lewis Acid–Base Interactions 1563 helped overthrow the “modern cult of the proton”. His discovery ushered in the use of Lewis acids as reagents and catalysts for 4. Scope of the Review 1568 organic reactions. However, in recent years, the recognition that 5. Examples of Lewis Base Catalysis: Lewis bases can also serve in this capacity has grown enormously. The n–p* Interaction 1569 Most importantly, it has become increasingly apparent that the behavior of Lewis bases as agents for promoting chemical reac- 6. The n–s* Interaction: Lewis Base Catalysis with Polarized and Ionized tions is not merely as an electronic complement of the cognate Intermediates 1585 Lewis acids: in fact Lewis bases are capable of enhancing both the electrophilic and nucleophilic character of molecules to which 7. Lewis Base Catalysis Beyond Silicon: they are bound. This diversity of behavior leads to a remarkable Novel Reactivity 1609 versatility for the catalysis of reactions by Lewis bases. 8. Bifunctional Catalysis: Engineering Stereocartography[354] 1612 1. Introduction 9. Carbenes: Lewis Base Catalysis with Dual Activation 1622 The modern theory of acid–base interactions, pioneered by G. N. Lewis at the beginning of the 20th century, has 10. Lewis Base Catalysis: Quo Vadis? 1625 become one of the most widely accepted, unifying theories of chemical structure and reactivity.[1] In the place of earlier definitions based on complex ideas about the properties of specific species, such as the proton, electrolytes, and solvent implication of a decreased reactivity of the acid and the base interactions, the Lewis definitions provide a simpler, yet all (that is, neutralization). For example, the trimethylphos- encompassing, picture founded on the sharing of electrons.[2] phane–borane complex (1) possesses little of the character- Lewis envisioned all bonding phenomena as interactions istic chemical reactivity of either of the parent components between electron-rich and electron-poor species. Simply put, (Scheme 1).[5] a Lewis acid is an electron-pair acceptor and a Lewis base is However, just as notable exceptions to Lewis assump- an electron-pair donor.[3] tions about the octet rule exist, so do exceptions about this Inherent to Lewiss definition of the acid–base interaction concept of acid–base interactions as stabilizing phenomena is the need to satisfy the octet rule and the underlying that lead to reduced reactivity.[6] A brief survey of the assumption that this interaction is stabilizing, because in its literature reveals numerous examples where stable, acid–base most stable state an atom should have eight valence electrons. adducts show enhanced reactivity. For example, strongly The clear predictive powers of this simple statement, often Lewis basic solvents and additives have found important one of the first concepts taught to students of chemistry, has applications as promoters of a variety of diverse chemical an impact not only on our understanding of structure, but also processes.[7] In the chemistry of alkyllithium reagents and of reactivity.[4] lithiated amide bases, additives such as N,N,N’,N’-tetrame- To a first approximation, if the formation of an acid–base thylethylenediamine (TMEDA) and hexamethylphosphoric adduct is favorable, that is, the donor and acceptor atoms have triamide (HMPA) exert a strong influence on the reactivity completed their octets through formation of a dative bond and selectivity [Eq. (1) in Scheme 2].[8] In the case of strong that leads to greater thermodynamic stability, there is an reducing agents such as samarium diiodide, the addition of either HMPA or N,N-dimethylpropylene urea (DMPU)[7a] leads to a higher oxidation potential and enhanced reactivity [Eq. (2) in Scheme 2].[9] In transition-metal catalysis, the use [*] Prof. Dr. S. E. Denmark, Dr. G. L. Beutner Roger Adams Laboratory University of Illinois at Urbana-Champaign 600 South Mathews Avenue, Urbana, IL 61801 (USA) Scheme 1. The octet rule and the Lewis acid–base adduct BH3·PMe3 Fax : (+1)217-333-3984 (1). E-mail: [email protected] Angew. Chem. Int. Ed. 2008, 47, 1560 – 1638 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1561 Reviews S. E. Denmark and G. L. Beutner surprising at first glance, since both modes of activation rely on the formation of Lewis acid–base adducts. The difference becomes clear by recognizing that Lewis acid activation only leads to net transfer of electron density away from the substrate, whereas Lewis base activation leads to net transfer of electron density toward the substrate. This most funda- mental difference between the modes of activation has important consequences in the way in which electron density is distributed in the adducts (see Sections 3.1.1 and 3.1.2). Although Lewis base activation is quite common (although at times, however, unrecognized as such), it is less widely employed, especially when compared to Lewis acids in organic synthesis.[16] Beyond the extensive use of Lewis basic co-catalysts as ligands in transition-metal catalysis, the use of nonmetallic, Lewis base catalysis remains a less thoroughly explored phenomenon. Reasons for this imbalance include the lack of target Lewis acidic sites in common organic molecules and the limited number of opportunities for valence expansion at carbon centers. However, opportunities to apply this intriguing concept do exist, and a number of novel and distinct catalytic processes have been developed. One of the main goals of this Review is to provide a conceptual framework that allows a clear formulation of what “Lewis base catalysis” exactly constitutes. As it differs significantly from Lewis acid catalysis, a firm grounding in the fundamental concepts of structure and bonding and the Scheme 2. Influence of Lewis bases on reactivity patterns. Tf = nature of the dative interactions is needed. These, in turn, will trifluoromethanesulfonyl, dba = trans,trans-dibenzylideneacetone. explain the origins of the electronic perturbations that lead to the disparate manifestations of Lewis base catalysis. The Review is organized as follows. We begin by provid- of Lewis basic phosphanes[10] and other ligands[11] provides a ing a concise definition of the concept and origins of Lewis method for tuning the reactivity and stereoselectivity in, for base catalysis (in the light of current theories on acid–base example, cross-coupling reactions [Eq. (3) in Scheme 2],[12] interactions) and an organizational framework which will aid and countless other transformations.[13] Finally, the addition of in the development and identification of new examples. A dialkylzinc reagents to aldehydes is greatly accelerated by the discussion of the properties of Lewis bases themselves as well addition of a coordinating bis(sulfonamide) ligand derived as a fundamental mechanism of activation for this class of from cyclohexane-1,2-diamine 2 [Eq. (4) in Scheme 2].[14] catalysts will then be presented. We also intend to provide a As illustrated in the preceding examples, activation by a thorough review of the current literature to highlight Lewis base can enhance the chemical reactivity in a number established Lewis base catalyzed processes as well as to of ways—from increasing nucleophilicity or electrophilicity to draw attention to less well-known or even, unrecognized modulation of electrochemical properties. When compared to examples. It is hoped that this Review will not only aid in the the influence of Lewis acids,[15] Lewis bases are seen to effect a understanding of this concept but also inspire discussions much more diverse array of reactivity patterns. This may seem about new and unprecedented opportunities for catalysis. Scott E. Denmark was born in Lynbrook, Gregory L. Beutner was born in Malden, New York in 1953. He obtainedhis Massachusetts in 1976. He graduated in D.Sc.Tech. (under the direction of Albert 1998 with a BS in chemistry from Tufts Eschenmoser) from the ETH Zürich in University, where he workedwith Prof. 1980. He then began his career at the Arthur Utz andwith Prof. Marc d’Alarcao. University of Illinois, where he was promoted He completed his PhD studies under the to associate professor in 1986, to full profes- supervision of Prof. Scott Denmark at the sor in 1987, andsince 1991 he has been the University of Illinois in May 2004. Between ReynoldC. Fuson Professor of Chemistry. May 2004 andAugust 2006 he was an NIH His research interests include the invention postdoctoral research associate at the Cal- of new reactions, organoelement chemistry, ifornia Institute of Technology working with andstereocontrol in carbon–carbon cou- Prof. Robert Grubbs. He is currently pling. He is currently on the Boardof Editors employedat the Merck Process Research of Organic Syntheses andas of 2008 is the PresidentandEditor-in-Chief of andDevelopment Laboratories in Rahway, Organic Reactions. He was Associate Editor of Organic Letters and is Co- NJ. editor of Topics in Stereochemistry. 1562 www.angewandte.org 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2008, 47, 1560 – 1638 Angewandte Lewis Base Catalysis Chemie 2. Defining Lewis Base Catalysis catalyst) on an electron-pair acceptor (as the substrate or a reagent).