Chapter 11 Reactions of Alcohols. Types of Alcohol Reactions

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1 hapter 11 Reactions of Alcohols Types of Alcohol Reactions Dehydration to alkene (Discussed in hap 7) xidation to aldehyde, ketone Substitution to form alkyl halide Reduction to alkane Esterification Tosylation Williamson synthesis of ether hap 11 Alcohol Reactions Slide

2 Summary Table hap 11 Alcohol Reactions Slide 11-3 rganic Redox Easy for inorganic salts r 2-4 reduced to r 2 3 (r 3+ ) KMn 4 reduced to Mn 2 xidation: loss of 2, gain of, 2, or X 2 Reduction: gain of 2 or -, loss of, 2, or X 2 Neither: gain or loss of +, 2, X hap 11 Alcohol Reactions Slide

3 1º, 2º, 3º arbons Note: carbon is gaining oxygen Note: carbon is losing oxygen hap 11 Alcohol Reactions Slide 11-5 xidation of 2 Alcohols 2 alcohol becomes a ketone lassic reagent is Na 2 r 2 7 / 2 S 4 (hromic acid oxidn) Active reagent probably 2 r 4 olor change: orange to greenish-blue BRUTAL 2 Na 2 r 2 7 / 2 S 4 2 hap 11 Alcohol Reactions Slide

4 xidation of 1 Alcohols 1 alcohol to aldehyde to carboxylic acid using classic harsh conditions Difficult to stop at aldehyde; need more gentle conditions Use pyridinium chlorochromate (P) to limit the oxidation. Made by adding r3 to l, followed by pyridine. Stable, crystalline solid, easy to handle and use. P can also be used to oxidize 2 alcohols to ketones N r 3 l 2 2 hap 11 Alcohol Reactions Slide 11-7 P Preparation Tetrahedron Letters, No. 31, orey, E.J. and Suggs, W., 'Pyridinium hlorochromate. An Efficient Reagent for xidation of Primary and Secondary Alcohols to arbonyl ompounds', , 1975 To 184 ml of 6 M l (1.1 mol) was added 100 g (1 mol) of r3 rapidly with stirring. After 5 min. the homogeneous solution was cooled to 0o and 79.1 g (1 mol) of pyridine was carefully added over 10 min. Recooling to 0o gave a yelloworange solid which was collected on a sintered glass funnel and dried for 1 hr in vacuuo (yield g, 84%). The solid is not appreciably hygroscopic and can be stored for extended periods at room temperature without change. hap 11 Alcohol Reactions Slide

5 3 Alcohols Don t xidize annot lose 2 s (no alpha to lose!) Basis for chromic acid test hap 11 Alcohol Reactions Slide 11-9 ther xidation Reagents ollins reagent: r 3 in pyridine Jones reagent: chromic acid in acetone KMn 4 (strong oxidizer) Nitric acid (strong oxidizer) u, 300 (industrial dehydrogenation) Swern oxidation: dimethylsulfoxide (DMS), with oxalyl chloride and hindered base, oxidizes 2 alcohols to ketones and 1 alcohols to aldehydes. Moffat oxidation: DMS and dicyclohexylcarbodiimide (D); not as clean as the Swern hap 11 Alcohol Reactions Slide

6 Swern xidation: Mechanism xalyl chloride activates DMS, chlorosulfonium ion reacts with alcohol, ylide formed decomposes to carbonyl compound 3 S l l -78 o 3 3 S l - l S l R 1 R S l R 1 R 2 S 2 - Base R 1 S R 2 + S 2 R 1 R 2 3 hap 11 Alcohol Reactions Slide Biological xidation atalyzed by AD, alcohol dehydrogenase. xidizing agent is NAD +, nicotinamide adenine dinucleotide. Ethanol oxidizes to acetaldehyde, then acetic acid, a normal metabolite. Methanol oxidizes to formaldehyde, then formic acid, more toxic than methanol. Ethylene glycol oxidizes to oxalic acid, toxic. Treatment for poisoning is excess ethanol. hap 11 Alcohol Reactions Slide

7 Alcohol as a Nucleophile R X R is weak nucleophile R - is strong nucleophile New - bond forms, - bond breaks. hap 11 Alcohol Reactions Slide Alcohol as an Electrophile - is not a good leaving group unless it is protonated, but many nucleophiles are strong bases which would remove +. onvert to tosylate (good leaving group), or any other sulfonate leaving group, to react with strong nucleophile (base). δ + -Nuc bond forms, - bond breaks hap 11 Alcohol Reactions Slide

8 Formation of Tosylate Ester l S N S S p-toluenesulfonyl chloride Tsl, tosyl chloride RTs, a tosylate ester an use any sulfonyl chloride (RS 2 l) hap 11 Alcohol Reactions Slide S N 2 Reactions of Tosylates Sulfonate leaving groups are kick-butt leaving groups. All S N 2 reactions are available With hydroxide produces alcohol With cyanide produces nitrile With halide ion produces alkyl halide With alkoxide ion produces ether With ammonia produces amine salt With LiAl 4 produces alkane hap 11 Alcohol Reactions Slide

9 Summary of Tosylate Reactions hap 11 Alcohol Reactions Slide Reduction of Alcohols Dehydrate with conc. 2 S 4, then add 2 2 S Pt alcohol alkene alkane Tosylate, then reduce with LiAl 4 alcohol Tsl Ts tosylate LiAl 4 2 alkane hap 11 Alcohol Reactions Slide

10 Reaction with Br - of alcohol is protonated is good leaving group Br - good nucleophile 3 and 2 alcohols react with Br - via S N 1; can get rearrangement! 1 alcohols react via S N Br - R R R Br => hap 11 Alcohol Reactions Slide Reaction with l hloride is a weaker nucleophile than bromide. Add Znl 2, which bonds strongly with -, to promote the reaction. The chloride product is insoluble (solution turns cloudy). Lucas test: Znl 2 in conc. l 1 alcohols react slowly or not at all. 2 alcohols react in 1-5 minutes. 3 alcohols react in less than 1 minute. hap 11 Alcohol Reactions Slide

11 Limitations of X Reactions I does not react Poor yields of 1 and 2 chlorides May get alkene instead of alkyl halide (good probability!) arbocation intermediate may rearrange. hap 11 Alcohol Reactions Slide Reactions with Phosphorus alides Good yields with 1 and 2 alcohols Pl 3 for alkyl chloride (but Sl 2 better) PBr 3 for alkyl bromide P and I 2 for alkyl iodide (PI 3 not stable) hap 11 Alcohol Reactions Slide

12 Mechanism with PBr 3 P bonds to - as Br - leaves Br - attacks backside (S N 2) PBr 2 leaves Note similarity to Swern! hap 11 Alcohol Reactions Slide Reaction with Thionyl hloride Produces alkyl chloride, S 2, l S bonds to -, l - leaves l - abstracts + from - bond breaks as l - transferred to hap 11 Alcohol Reactions Slide

13 Dehydration Reactions onc. 2 S 4 produces alkene arbocation intermediate Zaitsev product Bimolecular dehydration produces ether Low temp, 140 and below, favors ether igh temp, 180 and above, favors alkene hap 11 Alcohol Reactions Slide Dehydration Mechanisms alcohol 2 S hap 11 Alcohol Reactions Slide

14 Energy Diagram, E1 hap 11 Alcohol Reactions Slide Unique Reactions of Diols Pinacol rearrangement Periodic acid (I 4 ) cleavage hap 11 Alcohol Reactions Slide

15 Pinacol Rearrangement Pinacol: 2,3-dimethyl-2,3-butanediol Dehydration with sulfuric acid Nothing special! Rearrangements lead to more stable intermediates! + pinacolone hap 11 Alcohol Reactions Slide => Periodic leavage of Glycols Same products formed as from ozonolysis of the corresponding alkene. I 4 + s ( ) 2 S 3 hap 11 Alcohol Reactions Slide

16 Esterification Fischer: alcohol + carboxylic acid Tosylate esters Sulfate esters Nitrate esters Phosphate esters hap 11 Alcohol Reactions Slide Fischer Esterification Acid + Alcohol yields Ester + Water Sulfuric acid is a catalyst. Each step is reversible hap 11 Alcohol Reactions Slide

17 Tosylate Esters Alcohol + p-toluenesulfonic acid, Ts Acid chloride is actually used, Tsl 2 + S 2 S => + hap 11 Alcohol Reactions Slide Sulfate Esters Alcohol + Sulfuric Acid S S S S 2 => hap 11 Alcohol Reactions Slide

18 Nitrate Esters N N 2 => hap 11 Alcohol Reactions Slide Phosphate Esters => hap 11 Alcohol Reactions Slide

19 Phosphate Esters in DNA 2 P base 2 P base 2 P base 2 P base => hap 11 Alcohol Reactions Slide Alkoxide Ions R + Na (or Na) yields sodium alkoxide R alkyl halide yields ether (Williamson ether synthesis) Br 2 2 => hap 11 Alcohol Reactions Slide

20 End of hapter 11 omework: 41, 42, 48, 52, 53, 55, 58, 62, 63 hap 11 Alcohol Reactions Slide