1. Chemistry 125: Lecture 68 April 14, 2010 HIO 4 Cleavage; Alcohols Grignard, Wittig Reactions Green Chemistry Mitsunobu Reaction Acids and Acid Derivatives Preliminary This For copyright notice see final page of this file

2. Teleology Lectures 69 (4/15) Determining Bond Strength by Prof. G. B. Ellison (Cf. Lect. 37,38) Lecture 70-71 (4/18-20) 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. Vicinal Diol Cleavage by Periodic Acid (e.g. J&F Sec. 16.14b p. 807) I HIO4HIO4 H 2 SO 4 I “Ketal” I ? ? C +1 C +2 I +7 I +5

4. Periodic Acid Cleavage of Carbohydrates as a Diagnostic Tool CH 2 =O + OH HC=O CH 2 =O + HCO 2 H OH HO H2OH2O HIO 4 OH 2 CH 2 =O HIO 4 OH HIO 4 Formaldehyde (CH 2 O) arises from primary alcohols Formic acid (HCO 2 H) arises from secondary alcohols from F. E. Ziegler

5. OH CHO HIO 4 OH HIO 4 2 CH 2 =O + HCO 2 H CH 2 =O + 2 HCO 2 H HIO 4 OH O CH 2 =O + OH CO 2 H HIO 4 CH 2 =O + CO 2 RCH 2 OH CH 2 =O R 2 CHOHHCO 2 H RCH=O HCO 2 H CO 2 R 2 C=O Periodic Acid Cleavage of Carbohydrates as a Diagnostic Tool from F. E. Ziegler

6. Periodic Acid Cleavage of Carbohydrates HCO 2 H H 2 CO CH 2 OH CHO HO OH D-glucose CH 2 OH HO OH CH 2 OH HO D-mannitol H 2 CO HCO 2 H H 2 CO HCO 2 H H 2 CO CO 2 HO OH CH 2 OH O OH D-fructose Periodic Acid Cleavage of Carbohydrates as a Diagnostic Tool from F. E. Ziegler

7. Periodic Acid Cleavage of Methyl  -Glucopyranoside HO OH O OCH 3 OH O OCH 3 OHC HCO 2 H HIO 4 20°C 24 hr. H3O+H3O+ OH CHO + OHCCHO + CH 3 OH D-glyceraldehyde glyoxal Problem: What would other ring sizes have given? from F. E. Ziegler 

8. + - Alcohol (retro)Synthesis (e.g. J&F Secs. 16.13, 16.15) Hydride Reduction (e.g. J&F Sec. 16.13 p. 802, Sec. 16.18) H+H+ R-M = R-MgX, R-Li, etc. + - H+H+ H H H H LiAlH 4 NaBH 4 H-M = H-AlH 3 Li, H-BH 3 Na, etc. - - ++ also NADH simultaneous

9. Versatility of Grignard Reagents R-OHR-BrR-MgBr PBr 3 Mg nucleophile? / electrophile? Suggest high-yield syntheses incorporating carbon only from alcohols with no more than three carbons and any other reagents. (e.g. J&F problem 16.24) H 2 C=O PCC CH 2 Cl 2 H 3 C-OH n-C 3 H 7 -MgBr + n-C 2 H 5 -MgBr + H 2 C=CH 2 mCPBA NaOH  CH 3 -MgBr + ? not in an activated position

10. Versatility of Grignard Reagents Suggest high-yield syntheses incorporating carbon only from alcohols with no more than three carbons and any other reagents. (e.g. J&F problem 16.24) nucleophile? / electrophile? n-C 3 H 7 -MgBr + PCC CH 2 Cl 2 i-C 3 H 7 -MgBr + n-C 3 H 7 -MgBr + Is there a preferred order? n-C 3 H 7 -MgBr + i-C 3 H 7 -MgBr +

11. “Versatility” of Grignard Reagent 1) CH 3 MgBr O OH CH 3 95% 2) H + / H 2 O MgBr OH t-Bu 0% 1) t-BuMgBr 2) H + / H 2 O O 1) t-BuCH 2 MgBr 2) H + / H 2 O O OH CH 2 -t-Bu 4% O MgBr HH H OH 65% H - reduction H-CH 2 -t-Bu HH H-t-Bu + ketone 35% H+H+ + enolate  ketone 90% from Roberts & Caserio (1965) Cf. 2 t-Bu  t-Bu-H + no H  avoid steric hindrance HH :-( +

12. “Versatility” of Grignard Reagent Risk of Reduction no H  no reduction Preferred H  and steric hindrance (CH 3 ) 2 C=CH 2

13. Wittig Reaction (e.g. J&F Sec. 16.17) Ph 3 P=O (100 kcal/mole) vs. (CH 3 ) 3 N - O (70 kcal/mole) Ph 3 P: CH 3 - Br pK a ~30 Ph 3 P - CH 3 Br - + Ph 3 P - CH 2 + - Bu - Li Ph 3 P = CH 2 O=CR 2 Ph 3 P - CH 2 + - O - CR 2 Ph 3 P - CH 2 O - CR 2 Ph 3 P=O H 2 C=CR 2 Replaces O= directly with H 2 C= + CH 3 MgBr H+H+ minor major

14. Pharmaceuticals generate 50% of its chemical waste. 13 Processes That Need Improving AstraZeneca, GSK, Lilly, Pfizer, Merck, Schering-Plough (5 votes / company / area) 14 New Processes Desired “Key green chemistry research areas - a perspective from pharmaceutical manufacturers” Green Chemistry, 2007, 9, 411-420 Frequency of Use, Volume, Safety Solvents Solvent-less reactor cleaning. Replacements for NMP, DMAc, DMF.

15. “Lithium aluminum hydride, having a molecular weight of 38 and four hydrides per molecule, has the highest hydride density and is frequently used, even though it cogenerates an inorganic by-product which is difficult to separate from the product…slow filtration and product loss through occclusion or adsorption are typical problems…” 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 “…the use of stoichiometric high-valent metals (Mn, Os, Cr) have virtually been eliminated from pharmaceutical processes…” Votes

16. 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

17. 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 C 61% yield >99% inversion great leaving group pK a = 13 (enolate nucleophile) HO COOH C epimers? -CO 2 C C Oyo Mitsunobu (1934-2003) H AcO (R) H HO (R) - OH OH H (S) Mitsunobu Inversion Allows correcting a synthetic “mistake”! O. Mitsunobu Synthesis (1981)

18. 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) H+H+ (reduced DEAD) Eliminating H 2 O (18 m.wt.) generates 450 m.wt. of by-products. “atom inefficient” but separable only by chromatography! unless hooked to polymer beads Three Nucleophiles “tuned” just right H OR 2

19. Acidity of RCO 2 H (p. 836) Making RCO 2 H by Oxidation and Reduction (sec. 17.6)

20. RCOO-H to RCOO-R’ (p. 848) Activating RCO 2 H (sec. 17.7b,d,e) making OH a leaving group

21. GREEN H Milstein et al., J.A.C.S. 127, 10840 (2005) H O-CH 2 -R H H H O-C-R H Catalytic Formation of Ester + H 2 Another oxidation involving removal of an H from RCHO and one from another RCH 2 OH, plus C-O coupling, completes 2 R-CH 2 -OH  R-CO 2 -CH 2 R + 2H 2 with no other activation! H H H H H 3

22. Milstein et al., J.A.C.S. 127, 10840 (2005) Catalytic Formation of Ester + H 2 Thermochemistry of 2 EtOH  AcOEt + 2 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! K 3/2 RmT  10 -1/2 17.4  10 -9 need p H 2 > 10 -9 atm

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

24. Oil of Bitter Almonds Benzoic Acid O2O2

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

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

27. End of Lecture 68 April 13, 2011 Copyright © J. M. McBride 2010. 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

28. Biological Oxidation NAD +, NADH revisited (sec. 16.18)