Advanced Organic Chemistry

Transcription

1 D. A. Evans, G. Lalic Chem 530A Chemistry 530A Advanced Organic Chemistry Lecture notes part 8 Carbanions Organolithium and Grignard reagents Organocopper reagents

2 1. Direct metalation 2. From radical anion salts Magnesium

3 3. Metal halogen exchange Megnesium halogen exchange Angew. Chem. Int. Ed. 2003, 42, Knochel, Angew. Chem. Int. Ed. 2006, 45, Reagent: Mechanism Schlenk equilibrium Mechanism: Reaction proceeds through an ate complex

4 4. Transmetalation The effect is most likely a result of selective coordination of lithium in the transition state of the proton transfer. For a detailed analysis see: Collum, Acc. Chem. Res. 1992, 25, 448. Directed deprotonation 5. Deprotonation Directing group increases the acidity of protons in ortho position and contributes to the solvation of Lithium ion in the transition state of the proton transfer.

5 Structure of organolithium and organomagnesium compounds Organolithium compounds are rarely monomeric and aggregation state depends on the structure and stability of the reagent and the solvent (coordinating ability). Structure depends on the solvent Directing group ability

6 Stereochemical integrity Reactions of organometallic reagents Inversion barrier depends on: 1. Counterion More covalent the bond higher the barrier. 2. Solvent Less polar the solvent higher the barrier 3. Electronegativity of the substituents.

7 Organocopper reagents History Structure 1936 Gilman PhCu is insoluble, polymeric, unreactive and thermally unstable 1952 Gilman Gilman reagents, also called lithium dialkylcuprate Corey Details can vary a lot. Reactivity General scheme: heterocuprate homocuprate The alkyne serves as a non-transferable ligand. Other dummy ligands are alcoholate, thienyl, and thiolate 1981 Lipshutz The most relevant review: Nakamura, E. Chem. Rev. 2012, 112, Knochel Higher order cyanocuprates are easy to make and are sometimes more reactive from Gilman reagents. Structure is more consistant with cyano-gilman formulation Me 2 CuLi + LiCN Transmetallation from zinc reagents can be used to prepare functionalized organocopper compounds All reactions of cuprates involve transmetallation (i), oxidative addition (ii) and reductive elimination (iii). Homo and heterocuprates can be formed either stoichiometrically or catalytically. Whether the reactive reagent is homo or heterocuprate depends on the nucleophilicity of R-M. With M=Li usually homocupraes, With M=Zn heterocuprates and M=Mg depends. Copper(III) complexes have been observed experimentally. S. H. Bertz, S. Cope, M. Murphy, C. A. Ogle and B. J. Taylor, J. Am. Chem. Soc. 2007, 129, The most relevant review: Ribas. X. Chem. Sci. 2013, 4, 2301.

8 Mechanism: Nakamura, E. Chem. Rev. 2012, 112, 2339 Orbital interactions Examples Conjugate addition Mechanism Scope carbocupration substitution at sp3 Lewis acids, such as BF 3 and Me 3 SiCl, can promote conjugate addition. allylic substitution Further reaction of the enolate conjugate addition substitution at sp2

9 Enantioselective catalytic conjugate addition S N 2 Stoichiometric in copper. Works well for primary and secondary RX. Epoxide opening Feringa, Acc. Chem. Res. 2000, 33, Wallis, Perkin Trans. 1892, Proposed catalytic cycle. Regioselectivity determined by sterics. Allylic substitution - S N 2 cat. E = H + Hoveyda, J. Am. Chem. Soc. 2004, 126, Feringa, Acc. Chem. Res. 2000, 33, and orbitals of allylic electrophiles.

10 Mechanism Both products (S N 2 and S N 2 ) Nakamura, E. J. Am. Chem. Soc. 2008, 130, For S N 2 selectivity it is essential that the two R groups are different. Organocopper vs Organolithium and Grignard reagents None of the reactions described for organocopper reagents is possible for organolithium and Grignard reagents. Why? All nucleophiles and electrophiles can be divided in to soft and hard. Hard Nu have low-energy HOMO, and high charge density. Soft Nu have high-energy HOMO and low charge density Hard E have high-energy LUMO and high charge density Soft E have low-energy LUMO and low charge density Soft reagents are polarizable, have large orbitals or large orbital coefficients. Hard-hard reaction is fast because of Coulombic attraction Soft-soft reaction is fast because of the HOMO-LUMO interaction Copper is very soft and orbital intereactions are dominant Carbanions in RLi and RMgX are hard.