1. Chemistry 125: Lecture 67 April 12, 2010 Oxidizing/Reducing Alcohols Grignard Reactions Green Chemistry Preliminary more coming This For copyright notice see final page of this file

2. (Loudon) Alcohol Oxidation (sec. 16.14) Stopping at Aldehyde (p. 805-6) Vicinal Diol Cleavage by IO 4 - (sec. 16.14b) Pyridinium Chlorochromate (Cl-CrO 2 O - ) “In practice the chromium byproduct deposits with pyridine as a sticky black tar, which can complicate matters.” (Wikipedia) no water; no diol; no overoxidation

3. 0:49-11:35 Good Practice to Fill in Reagents

4. Alcohol (retro)Synthesis (secs. 16.13, 16.15) Hydride Reduction (sec. 16.13 p. 802)

5. O “Versatility” of Grignard Reagent R-OHR-BrR-MgBr PBr 3 Mg O CH 2 O CH O C Is there a preferred order? O C nucleophilic carbon? from alkene (3 steps from EtOH) or (1 step from MeOH)

6. “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 :-( +

7. “Versatility” of Grignard Reagent from Roberts & Caserio (1965) Risk of Reduction H  and steric hindrance

8. Wittig Reaction (sec. 16.17) Ph 3 P is good at taking up O to form strong Ph 3 P=O bond.

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

10. Pharmaceuticals generate 50% of its chemical waste. Table 1 Reactions companies use now but would strongly prefer better reagents Amide formation avoiding poor atom economy reagents 6 votes OH activation for nucleophilic substitution 5 votes Reduction of amides without hydride reagents 4 votes Oxidation/Epoxidation methods without the use of chlorinated solvents 4 votes Safer and more environmentally friendly Mitsunobu reactions 3 votes Friedel-Crafts reaction on unactivated systems 2 votes Nitrations 2 votes “Key green chemistry research areas - a perspective from pharmaceutical manufacturers” Green Chemistry, 2007, 9, 411-420 Pharmaceuticals generate 50% of its chemical waste. Research Area Number of roundtable companies voting for this research area as a priority area “…the use of stoichiometric high-valent metals (Mn, Os, Cr) have virtually been eliminated from pharmaceutical processes…” “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…”

11. Mitsunobu Reaction Mitsunobu Synthesis (1981) Nu - Ph 3 P O R Ph 3 P O R Nu 61% yield >99% inversion great leaving group Ph 3 P H OR -3 pK a = 13 need oxidizing agent Diethylazodicarboxylate (DEAD) H+H+ - OR 2 (enolate nucleophile) ? (reduced DEAD) Eliminating H 2 O (18 mw) generates 450 mw of by-products. “atom inefficient”

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

13. RCOO-H to RCOO-R’ (p. 848) Activating RCO 2 H (sec. 17.7b,d,e)

14. Catalytic Formation of Ester + H 2

15. End of Lecture 67 April 12, 2010 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