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

(Loudon) Alcohol Oxidation (sec ) Stopping at Aldehyde (p ) Vicinal Diol Cleavage by IO 4 - (sec b) 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

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

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

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 CH 3 OH) or (1 step from CH 3 OH)

“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 :-( +

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

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

Biological Oxidation NAD +, NADH revisited (sec )

“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…” 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, 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…”

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