Imines & Enamines Oxidation/Reduction & Electron Transfer Chemistry 125: Lecture 66 April 6, 2011 Carbonyl Chemistry: Imines & Enamines Oxidation/Reduction & Electron Transfer This For copyright notice see final page of this file

? Ketone to Imine -OH Iminium Imine Ion Allylic : R H H R H Oxime R + Oxime ? : : Overlap Iminium Ion Imine Unfavorable Equilibrium Constant 2,4-DNP (dinitrophenylhydrazone) (e.g. J&F Sec. 16.11)

makes steroidal ketones Ketone to Imine makes steroidal ketones soluble in water (cortisone) + Cl- Girard’s Reagent as cationic imines (hydrazones)

n-* Transitions of Organic “Chromophores” Imine Holds Retinaldehyde to the Protein Opsin Ketone to Imine n-* Transitions of Organic “Chromophores” * mix approaches energy of 2p orbital + - + - + - : n-* Oscillating electric field wags electrons up and down by mixing n with *. C X : With sufficient “conjugation” the * LUMO energy shifts close enough to n that the transition is at visible wavelength. R e.g. the retinaldehyde imine of rhodopsin, which is the visual pigment in our eyes.

Imine in Synthesis of Alanine (1854) by Adolph Strecker (1822-1871) CN- + NH4Cl + K+CN- + HCl + OH2 D OH2 + + H+ Often cited in discussing the “Origin of Life” Note: RCN gives RCOOH alanine 50-60% yield

An Imine in the Amino Acid Synthesis Catalyzed by L-Glutamate Dehydrogenase a-ketoglutaric acid + + NH3 + NAD H H- H+ H + glutamic acid Not an “essential” amino acid for mammals

Not an “essential” amino acid Transamination a-ketoglutaric acid Alanine Not an “essential” amino acid H H glutamic acid H

C What functional group does this hemiaminal remind you of? Ketal DNA chain What functional group does this hemiaminal remind you of? Ketal N NH2 O C H C O H O H OR Protecting Group for Sugar sugar base

a-Substitution via Enamine (Stork Enamine Acylation) + - R + OH H2O + O R R H R Cl Iminium Ion Enamine b-diketone + 85-90% yield by distilling H2O 65-70% for R = C5H11 (nucleophilic carbon) H2O with permission F. E. Ziegler O can’t lose H+ from N to give imine R but can lose this a-H+ - (Stork Enamine Alkylation) H+ - 55% for R = PhCH2 Gilbert Stork (Columbia Univ.)

(nucleophilic carbon) Enamine Lore (Stork Enamine Acylation) + - R O (acidic) Requires 2 moles of Enamine! + H + H+ H R R or add Et3N: to soak up H+ Enamine b-diketone 65-70% for R = C5H11 (nucleophilic carbon) (also Basic!)

(Stork Enamine Alkylation) Enamine Lore (Stork Enamine Alkylation) + 71% yield Actually: O - H + - enolate

Oxidation/Reduction as e- Transfer Grignard Reagent (like CH3- sec. 16.13) * CH3-Br CH3-Br CH3-Mg Br + Mg CH3 Br “reduction” Mg + Mg Nobel Prize (1912) * (CH3)2C=O Mg (CH3)2C O (CH3)2C OH “Pinacol” “reduction” H2O ~50% Mg+2 (CH3)2C O (CH3)2C=O H+ “Pinacolone” (CH3)3C C CH3 O

Oxidation/Reduction as Bookkeeping Arbitrarily assign shared electron pairs to the more electronegative element

Oxidation/Reduction as Bookkeeping (for purposes of reagent selection) Need a “reducing agent” (CH3)3C C CH3 O (CH3)3C C CH3 OH H -3 -3 ? -3 -3 C C “reduction” +2

Oxidation/Reduction as Bookkeeping (for purposes of reagent selection) Need a “reducing agent” (CH3)3C C CH3 O (CH3)3C C CH3 OH H ? C C “reduction” +2 +1 +1 +6 +1 +1 +3 -2 -1 -1 -1 -4 +1 -1 -2 1 -1 -1 Li+AlH4- H2O CrO3 NaH KCl K Oxidizing: RS-SR Br-Br CH4 H-Cl Reducing: Br Not all reducing agents would work satisfactorily, but it is usually futile to try a reagent from the wrong redox class. -2 -1 Br-Br Certainly reduces O2, and Fe2O3 at great heat; Br2 in free-radical halogenation; but not generally reactive. CH4 H2C CH2 +4 H OH HOCrO2- is a stable ion -2 -3 -1 RS-SR LiAlH4 (oxidizes RS-H H-SR to RS-SR) But photosynthesis changes H2O into O2 and “H-” (NAD+  NADH) H2C CH2 CrO3 NaH K H-Cl Neither: KCl H2O RSH

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