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

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

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

 NH 4 Cl + K + CN - Imine in Synthesis of Alanine (1854) by Adolph Strecker ( ) alanine + CN -  HCl + OH 2  OH 2 + H+H % yield Often cited in discussing the “Origin of Life” Note: RCN gives RCOOH

 -ketoglutaric acid  NH 3 + NAD H An Imine in the Amino Acid Synthesis Catalyzed by L-Glutamate Dehydrogenase + + H-H- H Not an “essential” amino acid for mammals H+H+ glutamic acid

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

H C C C C C O O O N NH2NH2 O N C C C C H H H H O What functional group does this hemiaminal remind you of? OROR Ketal C C C DNA chain sugar base Protecting Group for Sugar

 -Substitution via Enamine + Iminium Ion can’t lose H + from N to give imine Enamine (nucleophilic carbon) O +  -diketone but can lose this  H + (Stork Enamine Acylation) Gilbert Stork (Columbia Univ.) O + (Stork Enamine Alkylation) - - H+H+ with permission F. E. Ziegler + - R R R 65-70% for R = C 5 H 11 55% for R = PhCH 2 R Cl R OH H 85-90% yield by distilling H 2 O H2OH2O H2OH2O

Enamine Enamine Lore (nucleophilic carbon)  -diketone (Stork Enamine Acylation) + - R + R 65-70% for R = C 5 H 11 H + H R (acidic) H+H+ O Requires 2 moles of Enamine! or add Et 3 N: to soak up H + (also Basic!)

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

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

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

(CH 3 ) 3 C C CH 3 OH H 0 Oxidation/Reduction as Bookkeeping (for purposes of reagent selection) (CH 3 ) 3 C C CH 3 O “reduction” +2 C C Need a “reducing agent” ?

Oxidation/Reduction as Bookkeeping (for purposes of reagent selection) (CH 3 ) 3 C C CH 3 O “reduction” (CH 3 ) 3 C C CH 3 OH H +2 C C 0 Need a “reducing agent” Oxidizing:Reducing : Neither : H-Cl +1 H-Cl Br-Br 0 0 CH CH 4 Li + AlH LiAlH 4 NaH +1 NaH K 0 K KCl +1 KCl RS-SR RS-SR CrO CrO 3 ? HOCrO 2 - is a stable ion +4 Not all reducing agents would work satisfactorily, but it is usually futile to try a reagent from the wrong redox class. H 2 C CH 2 Br -2 (oxidizes RS-H H-SR to RS-SR) Certainly reduces O 2, and Fe 2 O 3 at great heat; Br 2 in free-radical halogenation; but not generally reactive H2OH2O H2OH2O But photosynthesis changes H 2 O into O 2 and “H - ” (NAD +  NADH) RSH H 2 C CH 2 H OH -2 -3

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