REVIEWS Wherefore Art Thou Copper? Structures and Reaction Mechanisms of Organocuprate Clusters in Organic Chemistry Eiichi Nakamura* and Seiji Mori Organocopper reagents provide the principles. This review will summarize example of molecular recognition and most general synthetic tools in organic first the general structural features of supramolecular chemistry, which chemistry for nucleophilic delivery of organocopper compounds and the pre- chemists have long exploited without hard carbanions to electrophilic car- vious mechanistic arguments, and then knowing it. Reasoning about the bon centers. A number of structural describe the most recent mechanistic uniqueness of the copper atom among and mechanistic studies have been pictures obtained through high-level neighboring metal elements in the reported and have led to a wide variety quantum mechanical calculations for periodic table will be presented. of mechanistic proposals, some of three typical organocuprate reactions, which might even be contradictory to carbocupration, conjugate addition, Keywords: catalysis ´ conjugate addi- others. With the recent advent of and SN2 alkylation. The unified view tions ´ copper ´ density functional physical and theoretical methodolo- on the nucleophilic reactivities of met- calculations ´ supramolecular chemis- gies, the accumulated knowledge on al organocuprate clusters thus ob- try organocopper chemistry is being put tained has indicated that organocup- together into a few major mechanistic rate chemistry represents an intricate 1. Introduction 1 R Cu X The desire to learn about the nature of elements has been R or R1 R and will remain a main concern of chemists. In this review, we R Cu will consider what properties of copper make organocopper R1 chemistry so useful in organic chemistry. O "RCu" R1 O Lying on the border between the transition metals and the [R2CuLi, RCu(X)Li, RMgX•CuY, etc.] main group elements, copper occupies a unique position in the R R1 periodic table. The key roles of copper have been widely [1] recognized in various areas including superconductivity, O O R1X biological oxygenation,[2] and organic synthesis.[3±6] The most R–R1 important utility of copper in organic chemistry is in the form of nucleophilic organocopper&i) reagents, which are used R either in a catalytic or a stoichiometric manner. Generally Scheme 1. Nucleophilic reactivities of organocopper reagents RCu. R sp2,sp3 carbon anionic centers; X, Y halogen, etc. formulated as R2CuM with a variety of metal and organic groups &M and R, respectively), metal organocuprates and related species are uniquely effective synthetic reagents for nucleophilic delivery of hard anionic nucleophiles such as reactions that can be achieved readily with organocuprate alkyl, vinyl, and aryl anions &Scheme 1). Conjugate addition,[7] reagents but not with other organometallics &Scheme 1). Half [11] carbocupration,[8] alkylation,[9] and allylation[10] represent the a century after Kharasch and Tawneys initial discovery, organocopper reagents are still the most useful synthetic [*]Prof. Dr. E. Nakamura, Dr. S. Mori reagents among transition metal organometallics.[12] The Department of Chemistry chemistry of organocopper reagents has been reviewed many The University of Tokyo times with emphasis on synthetic utility and sometimes Bunkyo-ku, Tokyo 113-0033 &Japan) [13] Fax : &81)3-5800-6889 on structural properties, but rarely on reaction mecha- E-mail: [email protected] nisms.[14] Angew. Chem. Int. Ed. 2000, 39, 3750 ± 3771 WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000 1433-7851/00/3921-3751 $ 17.50+.50/0 3751 REVIEWS E. Nakamura and S. Mori In spite of the long history and popularity of copper, there 1.1. Historical Background and Recent Progress remains the fundamental question: what properties of copper make organocopper reagents so useful? In a similar manner The initial implication of the forthcoming golden age of to Juliet on the balcony, we may say to ourselves ªO Copper, organocopper chemistry was in 1941, when Kharasch and O Copper, wherefore art thou Copper?º Information on the Tawney[11] reported the 1,4-addition reaction of a Grignard nature of reactive species in solution and their reactivities has reagent to an a,b-unsaturated ketone in the presence of a been fragmentary and incomplete. The most widely accepted small amount of a CuI salt.[24] Gilman et al. reported in 1952 ªresting stateº of the metal organocuprate&i) species in that addition of one equivalent of MeLi to a CuI salt results in solution is represented by the eight-centered dimer &R2CuLi)2 the formation of yellow precipitates, which then afford a shown in Equation &1), but there has been little consensus on colorless solution upon addition of another equivalent of MeLi &Scheme 2).[25] In 1966 Costa et al. isolated a complex between phenylcopper&i) and magnesium, as well as crystals of R Cu R ? ? a lithium diphenylcuprate&i) complex.[26] Although the or- – + Li ? Li + E+ RCuR /E R–E + RCu (1) ganocopper reagents derived from Grignard reagents are ? RCuR widely used and may be described as R2CuMgX, it is still uncertain to what extent this reflects the reality in solution. the ªreactive conformation of a true reactive speciesº. To make matters worse, the structures of the final copper- containing products are generally unknown. Those exploring RLi RLi the frontiers of organocopper chemistry in industry and CuI RCu + LiI R2CuLi + LiI academia have desperately required a better mechanistic organocopper reagent organocuprate reagent understanding. Two sources of mechanistic information have surfaced in 2 RMgY CuX R2CuMgY•MgXY the past several years, new analytical and theoretical methods. Scheme 2. Preparation of organocopper reagents. As recently demonstrated by Nakamura, Morokuma, and co- workers, theoretical analysis of the reactions of large lithium organocuprate clusters with realistic electrophiles has become The organic chemistry of organocuprates started its rapid possible with explicit consideration of solvent molecules and development in 1966, when House et al. showed that the bulk solvent polarity.[15±23] In this review, the current status of reactive species of conjugate addition is the lithium dior- understanding of organocuprate mechanisms will be summar- ganocuprate&i) called the ªGilman reagentº.[27] Foundations ized by focusing on lithium dialkylcuprate&i) clusters in the for subsequent vigorous synthetic development were laid by context of the following topics: &1) structures of the clusters in Corey and Posner,[28] and other important initial develop- crystals, in solution, and as studied by theoretical methods, ments, such as substitution reactions on sp2 carbons or in an &2) conventional mechanistic schemes for organocuprate re- allylic system[10, 29±31] and the carbocupration of acetylene[32] actions, and &3) reaction pathways of large lithium dialkylcu- were reported before the mid 1970s. prate&i) clusters as analyzed through a combination of The nature of the Gilman reagent now needs some careful theoretical and experimental data. We will suggest an answer definition. While numerous reports &in particular, old ones) to part of the question ªWherefore art thou copper?º describe the Gilman reagent as R2CuLi, a vast majority of Eiichi Nakamura received his PhD in Chemistry from Tokyo Institute of Technology in 1978. Following postdoctoral study in the Department of Chemistry at Columbia University, he joined the faculty of his alma mater in 1980 and was promoted to the rank of full professor in 1993. In 1995, he moved to the Department of Chemistry of the University of Tokyo. His interest in the dynamism of action of organic molecules forms the basis for his research activities which range through organic synthesis, chemical theory, and biology. Seiji Mori was born in 1968 in Tokyo. He studied at the Tokyo E. Nakamura S. Mori Institute of Technology, and was awarded his BSc in 1993 and MSc in 1995. In 1998, he recieved his PhD degree at the University of Tokyo under the guidance of Professor Eiichi Nakamura. He became a fellow of Japan Society for the Promotion of Science in 1997, worked at Emory University in USA, and is currently an assistant professor at Ibaraki University in Japan. His research interests center on the theoretical studies of organic and organometallic reactions. 3752 Angew. Chem. Int. Ed. 2000, 39, 3750 ± 3771 Organocopper Chemistry REVIEWS them actually used an LiX cluster R2CuLi ´ LiX, prepared by Bu OP(O)(OEt)2 an in situ reaction between RLi and CuX &X Br, I, or CN, without Me3SiCl sometimes with a ligand such as Me S and PR ). Although 2 3 1.0 equiv BuTi(O-iPr)4Li R CuLi and R CuLi ´ LiX may show largely the same reac- + 5 mol% CuI•2LiCl 2 2 O (2) tivities, Lipshutz et al.[33] showed by analyses of reactivities OSiMe3 and spectroscopic properties that they are indeed different Me3SiCl species. Even a small difference of solvent may affect the composition of the reagent and hence the reactivities. Due to Bu such complexity, it is now customary to show all ingredients [64] upon describing a reagent &for example, R CuLi ´ LiI ´ Me S/ catalyst, and a chiral ligand [Eq. &3)]. Magnesium-based 2 2 reagents have found use in quantitative fivefold arylation of BF3 ´Et2O in THF/hexane). Shortly after the opening of the ªLewis acid ageº with the discovery of the Mukaiyama aldol reaction in 1973,[34] O Et2Zn O Cu(OTf)2 (2 %) Yamamoto and Marayamas reports on the ªRCu ´ BF3º (3) reagent[35] introduced the new concept of Lewis acid assis- ligand (4 %) [36] tance in organocopper chemistry. Although the identity of C7H8, 3 h, -30°C [37] 94 % RCu ´ BF3 is still elusive, the BF3 activation was applied to >98%ee numerous synthetic works, as illustrated in Scheme 3 by a diastereoselective addition of a homoenolate species in a total synthesis.[38] Since the initial discovery by Nakamura and Kuwajima in O CH3 [39] ligand = PN 1984, Me3SiCl has become a standard reagent for accel- O CH3 eration of conjugate addition.