Mitsunobu Reaction Acids and Acid Derivatives Chemistry 125: Lecture 70 April 18, 2011 Green Chemistry Mitsunobu Reaction Acids and Acid Derivatives This For copyright notice see final page of this file

Rest of the Year Lecture 71 (4/20) Lecture 72-73 (4/22,25) Acid Derivatives and Condensations (e.g. F&J Ch. 18-19) Lecture 72-73 (4/22,25) Carbohydrates - Fischer's Glucose Proof (e.g. F&J Ch. 22) Lecture 74 (4/27) Synthesis of an Unnatural Product (Review) (Anti-Aromatic Cyclobutadiene in a Clamshell) Lecture 75 (4/29) Synthesis of a Natural Product (Review) (Woodward's Synthesis of Cortisone)

Like Nature New Processes Desired Votes Aromatic cross-coupling (avoiding haloaromatics) 6 Aldehyde or ketone + NH3 & reduction to chiral amine 4 Asymmetric hydrogenation of olefins/enamines/imines 4 + NH3 + NADH H H+ glutamic acid Greener fluorination methods 4 Like Nature Nitrogen chemistry avoiding azides (N3), H2NNH2, etc. 3 Asymmetric hydramination 2 Greener electrophilic nitrogen (not ArSO2N3, NO+) 2 Asymmetric addition of HCN 2

Current Processes That Need Improving Votes Amide formation avoiding poor atom-economy reagents 6 OH activation for nucleophilic substitution 5 Reduction of amides without hydride reagents 4 Oxidation/Epoxidation (without chlorinated solvents) 4 Safer and more environmental Mitsunobu reactions 3 Friedel-Crafts reaction on unactivated systems 2 Nitrations 2

Mitsunobu Reaction Oyo Mitsunobu Ph3P O R Nu- Very general for (1934-2003) Mitsunobu Reaction Ph3P O R Nu- Very general for acidic Nu-H (pKa < 15) e.g. R-CO2- (RO)2PO2- (RCO)2N- N3- “active methylene compounds” Ph3P O R Nu great leaving group O. Mitsunobu Synthesis (1981)

Mitsunobu Reaction Oyo Mitsunobu mild painful C epimers? (1934-2003) PhP: 1 “DEAD” 2 mild COOH pKa = 13 2 CO2 painful HO C C epimers? H HO COOH “active methylene” compound 61% yield >99% inversion 29 O. Mitsunobu Synthesis (1981)

O. Mitsunobu Synthesis (1981) Oyo Mitsunobu (1934-2003) Mitsunobu Reaction OH H (S) H AcO (R) H HO (R) Mitsunobu Inversion Ph3P DEAD AcOH -OH Allows correcting a synthetic “mistake”! O. Mitsunobu Synthesis (1981)

Mitsunobu Mechanism HOR2 Ph3P H OR Ph3P O R Nu- Ph3P O R Nu Three Nucleophiles “tuned” just right O. Mitsunobu Synthesis (1981) Mitsunobu Mechanism Diethylazodicarboxylate (DEAD) -3 Ph3P H OR need an oxidizing agent pKa < 15 Nu- Ph3P O R Ph3P O R Nu great leaving group -1 OR2 if X- attacks P+, it comes off again HOR2 but complete separation requires chromatography! H H+ + unless hooked to polymer beads Eliminating H2O (18 mol.wt.) generates 450 mol.wt. of by-products. “atom inefficient” (reduced DEAD) irreversible

Green Oxidation of Aldehydes and Alcohols

Benzoic Acid O2 Oil of Bitter Almonds

Air Oxidation of Benzaldehyde Cf. sec. 18.12a

Catalytic Formation of Ester + H2 O-C-R H O-C-R H H H H H + Reminiscent of closely balanced NAD+ NADH Another oxidation involving analogous removal of H2 from RCH(OH)2 plus some kind of C-O coupling, completes 2 R-CH2-OH  R-CO2-CH2R + 2 H2 + with no other activation! but Ru-H won’t quite reach. GREEN Milstein et al., J.A.C.S. 127, 10840 (2005)

Catalytic Formation of Ester + H2 Thermochemistry of 2 EtOH  AcOEt + 2 H2 Hf HOEt -66.1±0.5 x 2 -132.2±1.0 AcOEt -114.8±0.2 H2 0 Hrxn 17.4 endothermic! but forming 3 molecules from 2 is favored by entropy especially at low pH2 Milstein et al., J.A.C.S. 127, 10840 (2005)

Also Amines Imines, Amides, etc. Milstein et al., Angew IEE 2008, 8661 Angew. Chem. IEE. 17, 8661 (2008)

Acids and Acid Derivatives This

Acidity of RCO2H (e.g. J&F p. 836) Additivity pKa 4.8 4.5 4.1 2.8 4.8 2.9 1.3 0.7 1.9 1.6 0.6 “Inductive Effect” -0.3

Acidity of RCO2H (Rablen, JACS 2000) Resonance / Inductive Numerology From this viewpoint only ~20% of the special acidity of the carboxylic acid is due to resonance! Resonance Oind × 2 DpKa = 16 – 5 = 11 localized charge means better solvation Resonance Oind DHH2O = 4/3 * 11 = 15 + 34.1 = 3 Oind Resonance = 4.8 Oind = 11.4 Resonance Oind × 3 +39 (calc) Resonance × 2 Oind × 2 -13.2 (calc)

Making RCO2H by Oxidation and Reduction (e.g. J&F Sec. 17.6)

R-Li & LiAlH4 (e.g. J&F Sec. 17.7f) stop at C=O?

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