Carbon Nucleophiles : Organometallics of Li, Mg etc. 1. Cyanide :Well known 1 carbon unit 2. Acetylides :pKa = 25 Requires polar solvent to solubilize CN - LiCN – THF NaCN – DMSO KCN – need 18-C-6

3. Grignard Reagent : R-MgX a. preparation Additives : mechanical force, I 2, MeI, BrCH 2 CH 2 Br to activate the surface of heterogeneous reaction. Reactive Mg ( Rieke Mg) : prepared from MgX 2 + K --- black Mg powder Reactivity of Halides : RI > RBr > RCl radical intermediates through electron transfer Loses stereochemistry !! b. structure Solvent dependent, sometimes temp. dependent

3. Grignard Reagent : R-MgX c. reaction Usually not so good reaction except for MeI or BnI With CuI or LiCuCl 4 cat. Reaction works Self condensation is called Wurtz coupling – problem during Grignard formation

3. Grignard Reagent : R-MgX c. reaction Reduction of ketones Very low e.e.

4. Alkyl lithium a. generation Usually contains Na(0.02%) Accelerates reaction Cl : ppt. Br : soluble I : cannot form Except MeI, ArI ii) Metal-Halogen exchange rxn.Sometimes faster than acid-base reaction

4. Alkyl lithium a. generation iii) Transmetallation – gives clean generation Too reactive to form by other ways Too slow to form by other ways iv) Metal-Hydrogen Exchange

a. generation iv) Metal-Hydrogen Exchange – directed metallation O- inductive effect through chelation

b. structure Tetramer in Solid state In solution : monomer to hexamer depending on solvents, salts, additives Reactivity : less aggregate, more reactive c. reactions Similar reactivity to Grignard for RX, carbonyls, nitriles Often times act as base rather than nucleophile Unusual reaction JACS 1989, 111, 765 Cf.

c. reactions Quenching excess R’Li is important ! via Weinreb amide

Asymmetric synthesis Felkin-Anh Model : Chem. Rev (’99) Chelation control

Asymmetric synthesis A.I. Myers, Het. 295 (’89) JOC, 766 (’93) CC, 988 (’82)

5. Organozinc (R 2 Zn) : d 10, low reactivity: less nucleophilic, less basic a. generation b. reactions Reformatsky reaction more selective high functional group tolerance Synthesis, 571(’89)

b. reactions stereoselective addition to carbonyl with chiral activator functional group tolerability in the reagent

Asymmetric reaction Noyori : ACIE 1991, 30,49 Model of catalyst – not real Works well with aryl aldehydes With alkyl aldehydes e.e. are not high

Asymmetric amplification : nonlinear effect Dimeric form of Cataylists are usually Responsible for the effect

Asymmetric amplification : nonlinear effect – mechanisms proposed Dimeric form of Cataylists are usually responsible for the effect Noyori, Kitamura, JACS, 9800 (’98)Blackmond, JACS, (’01)

Asymmetric auto catalyst : origin of chirality in nature (?) Nature 1995, 378, 767 JACS 1998,120, ACIE 2000, 39, 1510

Homework Chapter 7 : 1, 4, 5, 6, 8, 14 Due : May, 18