Chapter 7 Organometallics: Group I & II Advanced Org Chem-Carey B Fall 2002 Chapter 7 Organometallics: Group I & II Grignard reagents: RMgX  Rd--d+MgX; X = I > Br > Cl preparation: Rd+-Xd- + Mgo  RMgX in ether or THF commercially available: R = Me, Et, Ph, allyl, vinyl, benzyl less reactive vinyl/aryl halides made in more basic THF activated Mg0: I2, (CH2X)2, MgX2 with Na0/K0 formation mechanism: SET from Mg0;  621 top aryl/vinyl/cyclopropyl halides: dianions;  622 top 5-ring from 5-hexenyl bromide and Mg0: radical intermediates racemization except cyclopropyl & vinly Grignards Schlenk equilibrium in solution:  623 middle monomeric or dimeric complexes with solvents:  624 Fig. 7.1 factors: concentration, solvent, types of halide & R Carey B-Chap7-5ed Chapter 7

Grignards: Mechanism of Formation Advanced Org Chem-Carey B Fall 2002 Grignards: Mechanism of Formation Carey B-Chap7-5ed Chapter 7

Organolithium Reagents (I) Advanced Org Chem-Carey B Fall 2002 Organolithium Reagents (I) Preparation: Rd+-Xd- + 2 Lio  Rd-Lid+ + LiX radical transfer: naphthalene, DTBB, LDMAN;  625 top reduction of sulfides: a-lithio ethers/sulfides;  625 middle aggregate structure in solvation:  626 Fig. 7.2 higher aggregates in hydrocarbons, lower aggregates in ethers & monomers in strong donor solvents (TMEDA, HMPA, DMPU) Deprotonation: hydrogen-metal exchange acidity of hydrogens:  627 bottom directing (chelating) groups:  629 Scheme 7.1 Carey B-Chap7-5ed Chapter 7

Organolithium Reagents: Preparation (II) Advanced Org Chem-Carey B Fall 2002 Organolithium Reagents: Preparation (II) Preparation with RLi: BuLi < s-BuLi < t-BuLi directed a-metallation: chelating donor groups:  630 top b-metallation with amides:  631 top without directing groups: BuLi & KOtBu;  631 bottom halogen-metal exchange: 2 eq. RLi;  632 top toward more stable alkenyl/aryllithiums:  633 Scheme 7.2 high degree of retention: vinyl & cyclopropyl lithiums metal-metal exchange: vinyl-SnR3;  634 top retention of chiral carbanions:  634 bottom vinyl lithium from the Shapiro reaction:  631 middle Carey B-Chap7-5ed Chapter 7

Alkylation Reactions of RLi & RMgX Advanced Org Chem-Carey B Fall 2002 Alkylation Reactions of RLi & RMgX RLi: competing with e--transfer & elimination good yields: 1o iodides with HMPA;  635 top delocalized RLi: high degree of inversion;  635 middle alkenyllithiums: retention of configuration;  635 middle allylic halides: good yields with mostly SN2’;  635 bottom 1,3-/1,4-/1,5-diiodides: 3-/4-/5-rings;  636 top R3SiX/R3SnX + R’Li  R3SiR’/R3SnR’ RMgX: less reactive than RLi;  636 bottom good with reactive E+: MeX, allyl-X, BnX, R-SO3-R’ Carey B-Chap7-5ed Chapter 7

Reactions of RMgX with Carbonyls (I) Advanced Org Chem-Carey B Fall 2002 Reactions of RMgX with Carbonyls (I) Alcohols: additions;  639 Scheme 7.3 A-E RCHO/RCOR’: single addition; 1o to 3o,  637 top RCOX (X=L): double addition; 2o to 3o alcohols,  637 mid hydride transfer: reduction with bulky substrates;  642 top more additions: in PhH/PhMe or use of RLi;  642 middle enolization with ROMgX: no addition reaction;  642 bot RCO2H with CO2:  640 Scheme 7.3 section H Carey B-Chap7-5ed Chapter 7

Reactions of RMgX with Carbonyls (II) Advanced Org Chem-Carey B Fall 2002 Reactions of RMgX with Carbonyls (II) Ketones or aldehydes:  639-640 Scheme 7.3 F-G addition to R-CN: via an imine Mg salt;  637 bottom excess R-COCl at low temp in THF:  638 top other R-CO-X producing ketones:  640 entries 16-19 aldehydes from orthoformates:  638 middle; section F aldehydes from formamides:  638 bottom Barbier reaction: in-situ formation & reaction;  644 middle Isomerization: allyl/homoallyl-MgX;  643 top no equilibrium in the 5-hexenyl system:  643 bottom Amines by addition to imines:  640 Scheme 7.3 I Carey B-Chap7-5ed Chapter 7

Reactions of RLi with Carbonyls Advanced Org Chem-Carey B Fall 2002 Reactions of RLi with Carbonyls Similar reactivity to RMgX:  646-7 Scheme 7.4 A-E a,b-Enones: 1,2- vs 1,4-addition;  644 bottom highly reactive RLi vs catalytic amount of HMPA (Cu+1) Ketones from RCO2H:  645 top & entries 11-13 better yields with TMSCl: reduced carbinols;  645 middle unsymmetrical ketones with CO2: tandem;  645 middle acid chlorides/anhydrides:  647 entries 14 & 15 from amides: Weinreb amides;  645 bottom Carey B-Chap7-5ed Chapter 7

Addition of RLi: Synthesis of Ketones Advanced Org Chem-Carey B Fall 2002 Addition of RLi: Synthesis of Ketones Carey B-Chap7-5ed Chapter 7

Addition to Carbonyls: Stereochemistry Advanced Org Chem-Carey B Fall 2002 Addition to Carbonyls: Stereochemistry Steric bias: equatorial approach;  648 middle increased selectivity with added salts: LiClO4 Acyclic carbonyls: Cram’s rule;  648 bottom chelation control: a-alkoxylketones/aldehydes;  649 mid Enantioselective addition:  649 bottom Mg salt of TADDOL: chiral additive (stoichiometric) lower ee for saturated alkyl ketones Carey B-Chap7-5ed Chapter 7

Chelation Control in Addition to Carbonyls Advanced Org Chem-Carey B Fall 2002 Chelation Control in Addition to Carbonyls Carey B-Chap7-5ed Chapter 7

Organozinc Compounds: R2Zn & RZnX Advanced Org Chem-Carey B Fall 2002 Organozinc Compounds: R2Zn & RZnX Less e--positive Zn: less nucleophilic than RMgX/RLi Preparation: ZnX2 + 2 RLi/RMgX  R2Zn one-pot process: sonication of [RX + Mg0 + ZnCl2] RX + activated Zn0 (Rieke method) or Zn-Cu:  650 bottom metal-halogen exchange: functionalized R;  651 middle efficient catalysis by MnBr2, CuCl or Ni(acac)2:  651 bottom zinc-boron exchange: R2Zn-BR’3;  652 top & middle stereoselective synthesis: retention;  652 middle addition to alkynes by catalysts: alkenylzinc;  652 bottom Carey B-Chap7-5ed Chapter 7

Reactions of Organozinc Compounds Advanced Org Chem-Carey B Fall 2002 Reactions of Organozinc Compounds Addition to carbonyls: less effective with ketones activation with MgX2: catalysis with Ti(i-OPr)4 or TMSCl promoted addition with TMSCl:  653 top addition to acyl chlorides:  657 top enantioselective addition to aldehydes:  656 middle chelation control by chiral amino alcohols:  653 bottom Reformatsky reaction:  657 bottom &  660 Scheme 7.5 ‘zincates’: more reactive; [Li]/[Mg],  659 bottom olefination of ketone/ester: alkene/enol ether;  661 middle Lombardo’s reagent: Zn, CH2Br2 & TiCl4 :  661 middle Carey B-Chap7-5ed Chapter 7

Organocadmium Compounds Advanced Org Chem-Carey B Fall 2002 Organocadmium Compounds Preparation: CdX2 + 2 RLi/RMgX  R2Cd RX + activated Cd0 (Rieke method) from CdX2:  661 bot Less e--positive Cd: similar reactivity to [Zn] synthesis of ketones from acyl chlorides:  662 top toxic cadmium compounds!! Carey B-Chap7-5ed Chapter 7

Organomercury Compounds Advanced Org Chem-Carey B Fall 2002 Organomercury Compounds Preparation: HgX2 + 2 RLi/RMgX  R2Hg oxymercuration: functionalized R;  294-8 boron-Hg exchange: 1o alkyl groups;  662 bottom alkenylmercury: from hydroboration of alkynes;  662 bottom Weakly nucleophilic: reactive E+;  663 top no reactions with aldehydes/ketones reactions of alkenylmercuries with acid chlorides addition activated by Lewis acids to alkenes:  663 middle Carey B-Chap7-5ed Chapter 7

Organoindium Compounds Advanced Org Chem-Carey B Fall 2002 Organoindium Compounds Easier to be oxidized than Mg: efficient e- donors allylic halide + aldehydes + In0:  663 bottom cyclic TS: In(I);  664 top reactions possible in aqueous solution:  664 middle reactions with functionalized substrates:  664 middle chelated TS with a-donor substituents Carey B-Chap7-5ed Chapter 7

Organocerium Reagents Advanced Org Chem-Carey B Fall 2002 Organocerium Reagents Preparation: CeCl3 + RLi/RMgX  RCeCl2 + LiCl efficient addition to carbonyls with acidic a-protons/sterically hindered ketones: anhydrous CeCl3 required;  665 mid retention of strong nucleophilicity & reduced basicity catalytic CeCl3 (5-10 mol%): better yields;  665 bottom efficient addition to carboxylates: 2 CeCl3;  666 top addition to amides: ketones;  666 middle excellent reactivity for nitriles & imines:  666 middle Carey B-Chap7-5ed Chapter 7