Professor David L. Van Vranken Chemistry 201: Organic Reaction Mechanisms I Topic 17: Enols, Enamines, and Enolates .. .. .. O O + .. H - H Read: Molecular Orbitals and Organic Chemical Reactions I. Fleming; section 4.3.2 Advanced Organic Chemistry. Part A: Structure and Mechanisms, 5th Ed., Francis A. Carey and Richard J. Sundberg; sections 6.4, 6.5 Check out: Herbert Mayr, et al. “π-Nucleophilicity in Carbon−Carbon Bond-Forming Reactions” Acc. Chem. Res. 2003, 36, 66–77. Enols / Enol Ethers ■ What do you get when you mix two non-bonding lone pair MO with one pi MO? 0.618 -0.575 O HOMO H .. .. .. + O O E .. H - H MO HOMO-1 O STO-3G H HOMO-2 O H ■ HOMO is π-like, not lone pair-like. ■ End carbon has larger HOMO coefficient, but the oxygen has more negative charge. ■ THP Protection cat. TsOH H OH O O + O O O O + H ■ Ferrier rearrangement MeOH + O SnCl4 O O OR w/ MeOH - 76:14 CH Cl AcO SnCl4 2 2 AcO AcO α/β 25 °C, 30 min O O + Bhate, P.; Horton, D.; Priebe, W. Carbohydr Res. 1985, 144, 331. Tautomer Stability ■ Keto/enol tautomerism keto enol K <10-8 H O eq O EtO.. EtO O OH 10-8 O OH 10-5 H H H O O Ph -3.6 C 10 H π acceptor O 2 H O O O H-bond 10-2 RO RO H O O O O π acceptor 0.2 + H-bond ■ Enol ether tautomerization with transition metal catalysts Ir+ cat. Baudry, D.; Ephritikhine, M.; Felkin, H. 97% MeO MeO JCS, Chem. Commun. 1978, 694 THF 22 °C, 33 h Enamines ■ Imine/enamine equilibrium is unfavorable 0.620 -0.650 O HOMO H H H H Keq = 2.6 H H .. N N N N + EMO similar amounts .. H - H STO-3G (vs. keto/enol) H O HOMO-1 H Enamine formation driven by azeotropic removal of water. Common: O O H toluene N N distilled + H O 2 as azeotrope N N 120 °C K. Lammertsma JACS1994, 114, 642 ■ Enolate equivalents Br Br- N.. N H O O + 2 ■ Relative reactivity .. .. .. OH < N < O-Li Regioselective Enolate Formation ■ Thermodynamic regiocontrol isn't very good for ketones KO KO Olefins: more substituted = more stable more substituted Bu Bu 58 : 42 House, H.O.; Kramar, V. J. Org. Chem 1963, 28, 3362. KO KO Me Me 52 : 48 (±7) (±7) ■ Thermodynamic regiocontrol can be great with enamines N N Me Me F. Johnson Chem. Rev. 1968, 375. A1,3 strain (Don't worry about it until Chem 202) ■ Kinetic regiocontrol is excellent with LDA LDA O inverse addn LiO LiO Bu Bu Bu THF, -78 °C 100 : 0 Stork, G.; Kraus, G. A.; Garcia, G. A. J. Org. Chem. 1974, 39, 3959. Stereoselective Enolate Formation ■ Et3N, NaH, KOtBu: Z enolate is more stable -O O -O E Z E/Z 16:84 Excess ketone Et Et Et catalyzes E/Z isomerization JACS1980, 102, 3959. ■ LDA deprotonates through 6-membered ring chair T.S. Don’t use the symbol B: for this mechanism. more in Chem 204 - - Li R Li + R Li i : Li R + R R Pr O N O ..N R O N R O N H R H H H O N i Et Et chair Et Et Li Pr TS H R Me R. Ireland JACS 1976, 2868 ■ LDA: E enolate forms faster Inverse addn = rapid, irreversible at -78 °C Li Li Li O O O Ireland, et. al. JOC 1991, 56, 650. 3-pentanone Ireland, et al. JACS 1978, 98, 2868 small big i-Pr2N–Li Et EtO Ph Heathcock, et. al. JOC 1980, 45, 1066. slight excess THF, -78 °C E/Z ~ 70:30 Z/E 94 : 6 E/Z <2 : >98 (Caution! C.I.P. assignments are confusing!) Enolate Formation with LDA ■ Recall: Li enolates = 99% dimer, but monomer alkylates faster ■ LDA is a dimer in THF… but reacts via the monomer rate ∝ [LDA]1/2 Dave Collum JACS 2000, 2452. Collum, D. B. Acc. Chem. Res. 1993, 26, 227. ■ THF + HMPA generates E ester enolates Li SiMe ester O 3 Ireland, et. al. JOC 1991, 56, 650. N Me Si Li THF, 23% HMPA EtO Also Fataftah, et al. JACS 1980, 102, 3959. 3 -78 °C E/Z >90 : <10 HMPA disrupts Ireland T.S. Note: LDA is still a dimer in HMPA! Enolate Formation by Metalation ■ n-BuLi has a half-life of 107 minutes in THF at 20 °C! Stanetty, P.; Mihovilovic, M. D. J. Org. Chem. 1997, 62, 1514. ■ Lithiated THF fragments to give acetaldehyde enolate O n-BuLi OLi 25 °C -LiR O O+ Li Li Honeycutt, S. C. J. Organomet. Chem. 1971, 29, 1. ■ Acetaldehyde enolate can't be made efficiently by deprotonation. Instead, you make it from THF. O LDA OLi aldol Regiochemical Reactions of Enolates: C vs. O - Li O-alkylation :O O+ OTs OEt - R big + + R small δ K+ δ small δ .. big - I δ :O: - O C-alkylation OEt ■ C vs. O alkylation C alkylation O alkylation Et K+ O - O Et-X O O O O OEt HMPA OEt OEt Et X = OTs: 11 : 88 X = I: 71 : 13 O C-alkylation : O-alkylation I > Br > Cl > P > OTs Kurts, A. L., et. al. Tetrahedron 1971, 27, 4777. O OMe OMe C-alkylation : O-alkylation Li+ > Na+ > K+ > Cs+ > Et4N+ Gompper, R.; Vogt, H.-H. Chem. Ber. 1981, 114, 2866. ■ Importance of the reagent neg. charge is big here Hard Electrophiles: nO-Li Me3SiCl, Ac2O Li .. • Big δ+ O O • High LUMO (σO-Li) Softer Electrophiles: R-X, RCHO • Small δ+ πC=C MO is big here • Low LUMO Regiochemical Reactions of Enolates: C vs. O ■ C acylation O O O O OMe :OLi O O O MeO Cl NC OMe OMe MeO CN Mander's reagent Mander, L. N.; Sethi, S. P. TL 1983, 24,5425. ■ Lithium aldol via 6-membered transition state - - Li Li H - O Li + O O O + O O O Li Chem 204 tBu O+ Ph Ph tBu Ph R Zimmerman-Traxler transition state Mayr Tables and Equation: Addition of Electrophiles to C=C pi bonds log k20 °C = sN (N + E) E = electrophilicity parameter N = nucleophilicity parameter sN = nucleophile-specific sensitivity parameter (N and SN are solvent dependent) Using the Mayr Tables ■ Relative reactivity again (Mayr tables, etc) Me F - Si Li CH OEt OSiMe OSiMe NR O Me O 3 < ~ 3 < 3 < 2 < Me < OMe x104 x104 x10 ■ Mukaiyama aldol: Lewis acid catalysis (predictable from Mayr rule of thumb) N = 6 E < -14 Mayr Rule of thumb: SiMe O OSiMe3 NO RXN 3 O PhCHO O w/o BF If E+N > -5 R Ph 3 cat. BF Plausible rates at r. t . R Ph 3 F3B + Me3Si BF3 - O +O O - E = -1.5 Ph R Ph Me Si 3 M(OTf)n Me3Si + O O O OSiMe3 Me SiOTf OSiMe3 O 3 is the active R Ph R Ph R Ph catalyst T. Keith Hollis, B. Bosnich JACS 1995,117, 4570. ■ Nucleophilic catalysis (like Hosomi rxn) ■ Enol boronates = L.A. + nuc. :F- R R SiMe - n-Bu N+ 3 PhCHO BR2 B 4 O + O O- O O+ n-Bu4N F- O :O R R Ph R Ph R Ph Me - F Si : Me O Me O R Ph.