Chemistry 125: Lecture 68 April 13, 2010 HIO 4 Cleavage; Alcohols Grignard, Wittig Reactions Green Chemistry This For copyright notice see final page of this file

Rest of the Year Lectures 69 (4/15) Determining Bond Strength by Prof. G. B. Ellison (Cf. Lect. 37,38) Lecture (4/18-20) Acid Derivatives and Condensations (e.g. F&J Ch ) Lecture (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)

Vicinal Diol Cleavage by Periodic Acid (e.g. J&F Sec b p. 807) I HIO4HIO4 H 2 SO 4 I “Ketal” I C +1 C +2 I +7 I +5 ? O3O3 ? ? pinacol Wittig

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

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

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

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 

+ - Alcohol (retro)Synthesis (e.g. J&F Secs , 16.15) Hydride Reduction (e.g. J&F Sec p. 802, Sec ) 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

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

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 +

“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 Risk of Reduction no H  no reduction Preferred H  and steric hindrance (CH 3 ) 2 C=CH 2

Wittig Reaction (e.g. J&F Sec ) 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 Bu - Li Ph 3 P = CH 2 O=CR 2 Ph 3 P - CH 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

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, Frequency of Use, Volume, Safety Solvents Solvent-less reactor cleaning. Replacements for NMP, DMAc, DMF.

“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

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