1. Chemistry 125: Lecture 70 April 18, 2011 Green Chemistry Mitsunobu Reaction Acids and Acid Derivatives Decarboxylation (Ch. 17) and Acyl Compounds (Ch. 18) Preliminary This For copyright notice see final page of this file

2. Rest of the Year Lecture 71 (4/20) 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)

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

4. Current Processes That Need Improving 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 Votes

5. Very general for acidic Nu-H (pK a < 15) e.g. R-CO 2 - (RO) 2 PO 2 - (RCO) 2 N - N 3 - “active methylene compounds” Mitsunobu Reaction Nu - Ph 3 P O R Ph 3 P O R Nu great leaving group Oyo Mitsunobu (1934-2003) O. Mitsunobu Synthesis (1981)

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

7. Mitsunobu Reaction Oyo Mitsunobu (1934-2003) H AcO (R) H HO (R) - OH OH H (S) Allows correcting a synthetic “mistake”! O. Mitsunobu Synthesis (1981) Mitsunobu Inversion Ph 3 P DEAD AcOH

8. Mitsunobu Mechanism O. Mitsunobu Synthesis (1981) Nu - Ph 3 P O R Ph 3 P O R Nu great leaving group Ph 3 P H OR -3 need an oxidizing agent Diethylazodicarboxylate (DEAD) (reduced DEAD) Eliminating H 2 O (18 mol.wt.) generates 450 mol.wt. of by-products. “atom inefficient” but complete separation requires chromatography! unless hooked to polymer beads Three Nucleophiles “tuned” just right OR 2 H + H+H+ H OR 2 pK a < 15 if X - attacks P +, it comes off again irreversible

9. Green Oxidation of Aldehydes and Alcohols

10. Oil of Bitter Almonds Benzoic Acid O2O2

11. Air Oxidation of Benzaldehyde Cf. sec. 18.12a

12. but Ru - H won’t quite reach. + Reminiscent of closely balanced NAD + NADH GREEN H Milstein et al., J.A.C.S. 127, 10840 (2005) H H H O-C-RO-C-R H Catalytic Formation of Ester + H 2 Another oxidation involving removal of an H 2 from RCH(OH) 2 and one from another RCH 2 OH, plus C-O coupling, completes 2 R-CH 2 -OH  R-CO 2 -CH 2 R + 3 H 2 with no other activation! H H H H H + H O-C-RO-C-R H H H H H H

13. Milstein et al., J.A.C.S. 127, 10840 (2005) Catalytic Formation of Ester + H 2 Thermochemistry of 2 EtOH  AcOEt + 3 H 2 HfHf HOEt -66.1±0.5 x 2 -132.2±1.0 AcOEt -114.8±0.2 H 2 0  H rxn 17.4 endothermic! but forming 4 molecules from 3 is favored by entropy especially at low p H 2

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

15. Acids and Acid Derivatives This

16. Acidity of RCO 2 H (e.g. J&F p. 836) pK a 4.8 4.5 4.1 2.8 4.8 2.9 1.3 0.7 -0.3 1.9 1.6 0.6 “Inductive Effect” Additivity

17. Acidity of RCO 2 H (Rablen, JACS 2000) Resonance O ind × 2 O ind + 34.1 = 3 O ind O ind = 11.4Resonance = 4.8 Resonance O ind × 3 +39 (calc) Resonance O ind × 2 -13.2 (calc) Resonance / Inductive Numerology From this viewpoint only ~20% of the special acidity of the carboxylic acid is due to resonance!  pK a = 16 – 5 = 11  H H2O = 4/3 * 11 = 15 localized charge means better solvation

18. Making RCO 2 H by Oxidation and Reduction (sec. 17.6)

19. R-Li & LiAlH 4 (sec. 17.7f) stop at C=O?

20. Decarboxylation (e.g. J&F 17.7g) malonic acid  acid (concerted) OH 2 HO OH C O H O -CO 2 enol

21. R Kolbe Electrolysis -e--e- fast at 4K ! R R-RR-R R = CH 3 (Kolbe 1848) R = (~50% 1973) Decarboxylation (e.g. J&F 17.7g) or CO 2 as leaving group from XCO 2 - or RCO 2 (e.g. J&F pp. 859-861) H 2 O + carbonic acid NH 3 + carbamic acid

22. Decarboxylation (e.g. J&F 17.7g) or CO 2 as leaving group from XCO 2 - or RCO 2 (e.g. J&F pp. 859-861) RCO 2 Ag Br 2 RBr + AgBr + CO 2 “Hunsdiecker Reaction” RCO 2 H Ag 2 O R - Br R CO 2 Br 2

23. Decarboxylation (e.g. J&F 17.7g) or CO 2 as leaving group from XCO 2 - or RCO 2 (e.g. J&F pp. 859-861) RCO 2 Ag Br 2 RBr + AgBr + CO 2 “Hunsdiecker Reaction” RCO 2 H Ag 2 O ? 1833-1887 Tony award 1954 (Kismet) Alexander Porfiryevich Borodin A. Sdobnikov

24. Spectroscopy of Acid Derivatives (e.g. J&F pp. 888-889)

25. 1681 CH 3 C O NH 2 CH 3 -C=O(X) strong & independent 1727 CH 3 C O H 1715 CH 3 C O CH 3 CH 3 C O OCH 3 17461806 CH 3 C O Cl + - + - + - n N  * C=O n O  * C-Cl n O  * C-OMe :: : C=O weakened by resonance C=O strengthened by resonance

26. acyclic anhydride in phaseout of phase % Transmission %T

27. out of phase cyclic imide in phase

28. A/D Substitution via Tetrahedral Intermediate pp. 890 (Fig. 18.22) 886 (Fig 18.17)

29. Going All the Way to C-OH pp. 891, 898-9, 903 (C-NH 2 )

30. Stopping Part Way to Preserve C=O pp. 892-893 (Fig. 18.22) 900 (Fig 18.38)

31. Acidic / Basic Hydrolysis of RCN pp. 904-905 C-OH O

32. Acidic Hydrolysis of RCN

33. Basic Hydrolysis of RCN

34. Acyl Derivatives from Ketene sec. 18.11, p. 907 H 2 C=C=O Nu:

35. Remember PhCHO + O 2 Baeyer-Villiger Reaction (insert O) pp. 907-909 H - migration R - migration

36. Migration from Acyl Carbon L R X C O + R inserts X between R and C=O

37. Beckmann Rearrangement (insert N) pp. 909-911 inserts in anti bond

38. Beckmann Rearrangement (insert N) pp. 909-911 R - migration in cation

39. elongates acid by one carbon Arndt-Eistert Reaction (insert C) pp. 915-917 Wolff Rearrangement R - migration

40.  Acidity Tables 19.1 (p. 933), 19.2 (p. 943), 19.3 (p. 958) pK a ~ 18 H

41. complete formation of enolate not just a little at equilibrium LDA hindered strong base (pK a = 36) (p. 944) pK a ~ 25 K ~ 10 11 (slow attack on C=O, none on enolate)

42. Acid & Base  H/D Exchange via enol and enolate (sec. 19.2a)

43. Racemization via enol and enolate (sec. 19.3)

44.  -Halogenation ketones/aldehydes (19.4a) ++ Iodoform with base

45.  -Halogenation carboxylic acids (19.4b) Hell-Volhard-Zelinsky

46. End of Lecture 70 April 18, 2011 Copyright © J. M. McBride 2011. Some rights reserved. Except for cited third-party materials, and those used by visiting speakers, all content is licensed under a Creative Commons License (Attribution-NonCommercial-ShareAlike 3.0).Creative Commons License (Attribution-NonCommercial-ShareAlike 3.0) Use of this content constitutes your acceptance of the noted license and the terms and conditions of use. Materials from Wikimedia Commons are denoted by the symbol. Third party materials may be subject to additional intellectual property notices, information, or restrictions. The following attribution may be used when reusing material that is not identified as third-party content: J. M. McBride, Chem 125. License: Creative Commons BY-NC-SA 3.0

47. Chemistry 125: Lecture 70 April 19, 2010 Acyl Compounds (Ch. 18)  -H Reactivity (Ch. 19) This For copyright notice see final page of this file

48. OH RC O Fischer Esterification (sec. 17.7a) H + H + + RO H + Tetrahedral Intermediate (A/D, not pentavalent transition state) substitution at C OR starts with addition