Química rgânica I Ciências Farmacêuticas Bioquímica Química AFB Q I 2007/08 1
alcohols Adaptado de rganic Chemistry, 6th Edition; Wade rganic Chemistry, 6 th Edition; McMurry AFB Q I 2007/08 2
Typical reactions of alcohols Two general classes of reaction At the carbon of the C bond At the proton of the H bond AFB Q I 2007/08 3
Types of Alcohol Reactions Dehydration to alkene xidation to aldehyde, ketone Substitution to form alkyl halide Reduction to alkane Esterification Tosylation Williamson synthesis of ether => AFB Q I 2007/08 4
Summary Table AFB Q I 2007/08 5 =>
xidation States Easy for inorganic salts Cr 4 2- reduced to Cr 2 3 KMn 4 reduced to Mn 2 xidation: loss of H 2, gain of, 2, or X 2 Reduction: gain of H 2 or H-, loss of, 2, or X 2 Neither: gain or loss of H +, H 2, HX => AFB Q I 2007/08 6
xydation 1º Carbons 2º Carbons 3º Carbons AFB Q I 2007/08 7 =>
xidation of 1 Alcohols 1 alcohol to aldehyde to carboxylic acid Difficult to stop at aldehyde Use pyridinium chlorochromate (PCC) to limit the oxidation. PCC can also be used to oxidize 2 alcohols to ketones. H N H Cr 3 Cl CH 2 CH 2 CH 2 CH 2 CH 2 CH AFB Q I 2007/08 8 =>
xidation of 2 Alcohols 2 alcohol becomes a ketone Reagent is Na 2 Cr 2 7 /H 2 S 4 Active reagent probably H 2 Cr 4 Color change: orange to greenishblue H CHCH 2 Na 2 Cr 2 7 / H 2 S 4 CCH 2 => AFB Q I 2007/08 9
Mechanism of Chromic Acid xidation Alcohol forms a chromate ester followed by elimination with electron transfer to give ketone AFB Q I 2007/08 10
3 Alcohols Don t xidize Cannot lose 2 H s Basis for chromic acid test => AFB Q I 2007/08 11
ther xidation Reagents Collins reagent: Cr 2 3 in pyridine Jones reagent: chromic acid in acetone KMn 4 (strong oxidizer) Nitric acid (strong oxidizer) Cu, 300 C (industrial dehydrogenation) Swern oxidation: dimethylsulfoxide, with oxalyl chloride and hindered base, oxidizes 2 alcohols to ketones and 1 alcohols to aldehydes. => AFB Q I 2007/08 12
xidation of Primary Alcohols with K Cr (Jones) 2 2 7 K 2 Cr 2 7 K 2 Cr 2 7 R CH 2 H R C H R C H H 2 S 4 H 2 S 4 + Cr 3+ Jones xidation
xidation with Chromic xide and Pyridine H R CH R Cr 3. CH 2 Cl 2 N R C R Sarrett reaction: Primary alcohols get oxidized to aldehydes Aldehydes are not further oxidized to carboxylic acids Sarett xidation
The Swern xidation AFB Q I 2007/08 15
Mechanism of the Swern xidation AFB Q I 2007/08 16
The Tollens Reagent xidizes nly Aldehydes AFB Q I 2007/08 17
Both aldehydes and ketones can be oxidized by peroxyacid: The Baeyer Villiger oxidation AFB Q I 2007/08 18
AFB Q I 2007/08 19
Mechanism of the Baeyer Villiger xidation AFB Q I 2007/08 20
Therefore, the product of the Baeyer Villiger oxidation of cyclohexyl methyl ketone will be cyclohexyl acetate, because a secondary alkyl group is more likely to migrate than AFB a methyl group Q I 2007/08 21
Biological xidation Catalyzed by ADH, 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. AFB Q I 2007/08 22 =>
Biological xidation Reduction Reactions AFB Q I 2007/08 23
AFB Q I 2007/08 24
NAD + oxidizes ethanol by accepting a hydride ion AFB Q I 2007/08 25
NADH reduces a carbonyl compound by donating a hydride ion AFB Q I 2007/08 26
Alcohol as a Nucleophile H C R X RH is weak nucleophile R - is strong nucleophile New -C bond forms, -H bond breaks. => AFB Q I 2007/08 27
Alcohol as an Electrophile H - is not a good leaving group unless it is protonated, but most nucleophiles are strong bases which would remove H +. + C H Convert to tosylate (good leaving group) to react with strong nucleophile (base) C-Nuc bond forms, C- bond breaks => AFB Q I 2007/08 28
Formation of Tosylate Ester C H Cl S N H C S C S p-toluenesulfonyl chloride TsCl, tosyl chloride RTs, a tosylate ester => AFB Q I 2007/08 29
S N 2 Reactions of Tosylates 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 LiAlH 4 produces alkane => AFB Q I 2007/08 30
Summary of Tosylate Reactions => AFB Q I 2007/08 31
Reduction of Alcohols Dehydrate with conc. H 2 S 4, then add H 2 Tosylate, then reduce with LiAlH 4 H H 2 S 4 H 2 CH CH 2 CH CH 2 Pt alcohol alkene alkane H CH alcohol TsCl Ts CH tosylate LiAlH 4 CH 2 alkane => AFB Q I 2007/08 32
Reaction with HBr -H of alcohol is protonated -H 2+ is good leaving group 3 and 2 alcohols react with Br - via S N 1 1 alcohols react via S N 2 H 3 + H Br - R H R H R Br => AFB Q I 2007/08 33
Reaction with HCl Chloride is a weaker nucleophile than bromide. Add ZnCl 2, which bonds strongly with -H, to promote the reaction. The chloride product is insoluble. Lucas test: ZnCl 2 in conc. HCl 1 alcohols react slowly or not at all. 2 alcohols react in 1-5 minutes. 3 alcohols react in less than 1 minute. => AFB Q I 2007/08 34
Limitations of HX Reactions HI does not react Poor yields of 1 and 2 chlorides May get alkene instead of alkyl halide Carbocation intermediate may rearrange. => AFB Q I 2007/08 35
Alcohols to halides Reactions with Phosphorus Halides Good yields with 1 and 2 alcohols PCl 3 for alkyl chloride (but SCl 2 better) PBr 3 for alkyl bromide P and I 2 for alkyl iodide (PI 3 not stable) => AFB Q I 2007/08 36
Mechanism with PBr 3 P bonds to -H as Br - leaves Br - attacks backside (S N 2) HPBr 2 leaves AFB Q I 2007/08 37
Reaction with Thionyl Chloride Produces alkyl chloride, S 2, HCl S bonds to -H, Cl - leaves Cl - abstracts H + from H C- bond breaks as Cl - transferred to C AFB Q I 2007/08 38
Dehydration Reactions Conc. H 2 S 4 produces alkene Carbocation intermediate Saytzeff product Bimolecular dehydration produces ether Low temp, 140 C and below, favors ether High temp, 180 C and above, favors alkene AFB Q I 2007/08 39
Dehydration Mechanisms H CH alcohol H 2 S 4 H H CH CH H 2 H 3 + H H 2 H CH 2 CH H H 2 => AFB Q I 2007/08 40
Energy Diagram, E1 AFB Q I 2007/08 41 =>
Unique Reactions of Diols Pinacol rearrangement Periodic acid cleavage AFB Q I 2007/08 42
Pinacol Rearrangement C H H + C C C H H H H C H C C H C C H C C H C C C pinacolone AFB Q I 2007/08 43
Periodic Cleavage of Glycols H C H C HI 4 C H H + C s 4 H 2 2 3 ( ) 2 S H C C H 3 C AFB Q I 2007/08 44
Esterification Fischer: alcohol + carboxylic acid Tosylate esters Sulfate esters Nitrate esters Phosphate esters => AFB Q I 2007/08 45
Fischer Esterification Acid + Alcohol yields Ester + Water Sulfuric acid is a catalyst. Each step is reversible. C H + H CH 2 CH 2 CH H + C CH 2 CH 2 CH + HH => AFB Q I 2007/08 46
Tosylate Esters Alcohol +p-toluenesulfonic acid, TsH Acid chloride is actually used, TsCl CH 2 H + H S CH 2 S => + HH AFB Q I 2007/08 47
Sulfate Esters Alcohol + Sulfuric Acid H S H + H + H CH 2 H S CH 2 CH 2 H + H S CH 2 H + CH 2 S CH 2 => AFB Q I 2007/08 48
Nitrate Esters N H + H CH 2 H + N CH 2 CH 2 CH 2 H H + 3 H N 2 CH 2 CH 2 N 2 N 2 CH 2 H CH 2 N 2 glycerine nitroglycerine => AFB Q I 2007/08 49
Phosphate Esters H P H H P H H P H H H P H => AFB Q I 2007/08 50
Phosphate Esters in DNA CH 2 H H P base H CH 2 H H P base H CH 2 base H H H P CH 2 base H H H AFB Q I 2007/08 51 P =>
Alkoxide Ions RH + Na (or NaH) yields sodium alkoxide R - + 1 alkyl halide yields ether (Williamson ether synthesis) CH 2 CH + CH 2 Br CH 2 CH 2 CH CH 2 => AFB Q I 2007/08 52