(t, J=7.0, 3H) (d, J=7.0, 3H) (pentet, J=7.0, 2H)

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Melvin York
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1 δ= 2.61 (d, J=7.0, 3) δ= 2.61 (t, J=7.0, 3) δ= 2.61 (sextet, J=7.0, 1) δ= 2.61 (pentet, J=7.0, 2) δ= (m, 5) 73 hapter 15: Alcohols, Diols, and Thiols 15.1: Sources of Alcohols (Table 15.1, p. 616) ydration of alkenes (hapter 6) 1. Acid-catalyzed hydration (hapter 6.6) 2. xymercuration (p ) 3. ydroboration (hapter 6.8) ydrolysis of alkyl halides (hapter 8.1) nucleophilic substitution Reaction of Grignard or organolithium reagents with ketones, aldehydes, and esters. (hapter 14.5) Reduction of aldehydes, ketones, esters, and carboxylic acids (hapters ) Reaction of epoxides with Grignard Reagents (hapter 15.4) Diols from the dihydroxylation of alkenes (hapter 15.5) 74 37

2 15.2: Preparation of Alcohols by Reduction of Aldehydes and Ketones - add the equivalent of 2 across the π-bond of the carbonyl to yield an alcohol R R' [] R R' aldehyde (R or R = ) 1 alcohol ketone (R and R ) 2 alcohol atalytic hydrogenation is not typically used for the reduction of ketones or aldehydes to alcohols. Metal hydride reagents: equivalent to : (hydride) sodium borohydride lithium aluminium hydride (ab 4 ) (LiAl 4 ) a B Li Al electronegativity B Al target disconnection precursors R 2 ab 4 R 2 ab 4 reduces aldehydes to primary alcohols 2 ab ab 4 reduces ketones to secondary alcohols ab ketones 2 alcohols ab 4 does not react with esters or carboxylic acids ab

3 Lithium Aluminium ydride (LiAl 4, LA) - much more reactive than ab 4. Incompatible with protic solvents (alcohols, 2 ). LiAl 4 (in ether) reduces aldehydes, carboxylic acids, and esters to 1 alcohols and ketones to 2 alcohols. 1) LiAl 4, ether 2) 3 ketones 2 alcohols aldehydes 1) LiAl 4, ether 2) 3 1 alcohols : Preparation of Alcohols By Reduction of arboxylic Acids (and Esters) - LiAl 4 (but not ab 4 or catalytic hydrogenation). Esters 2 3 1) LiAl 4, ether 1) LiAl 4, ether 2) 3 2) 3 1 alcohols arboxylic acids 15.4: Preparation of Alcohols From Epoxides - the threemembered ring of an epoxide is strained. Epoxides undergo ringopening reaction with nucleophiles (Grignard reagents, organolithium reagents, and cuprates). ether, BrMg- 3 then 3 S

4 target disconnection precursors MgBr Br Mg(0) MgBr TF then : Preparation of Diols - Vicinal diols have hydroxyl groups on adjacent carbons (1,2-diols, vic-diols, glycols) Dihydroxylation: formal addition of - across the π-bond of an alkene to give a 1,2-diol. This is an overall oxidation. s 4 (catalytic) ( 3 ) 3 - ( 3 ) 3 s osmate ester intermediate : Reactions of Alcohols: A Review and a Preview Table 15.2, p.623 onversion to alkyl halides (hapter 4) 1. Reaction with hydrogen halides (hapter 4.7) 2. Reaction with thionyl chloride (hapter 4.12) 3. Reaction with phosphorous trihalides (hapter 4.12 Acid-catalyzed dehydration to alkenes (hapter 5.9) onversion to p-toluenesulfonate esters (hapter 8.11) onversion to ethers (hapter 15.7) onversion to esters (hapter 15.8) xidation to carbonyl compounds (hapter 15.9) leavage of vicinal diols to ketones and aldehydes (hapter 15.11) 80 40

5 15.7: onversion of Alcohols to Ethers - Symmetrical ethers can be prepared by treating the corresponding alcohol with a strong acid S Limitations: ether must be symmetrical works best for 1 alcohols : Esterification - Fischer esterification: acid-catalyzed reaction between a carboxylic acid and alcohol to afford an ester. The reverse reaction is the hydrolysis of an ester -R 2 Mechanism (hapters 18 and 19) R1 R2 Dean-Stark Trap 82 41

6 Ester formation via the reaction of an acid chloride or acid anhydride with an alcohol (nucleophilic acyl substitution) l -R 2 R 2 l acid chloride R1 acid anhydride -R 2 R1 R 2 R1 Mechanism (hapters 19) 83 Esters of Inorganic Acids carboxylic acid -R 2 alcohol nitric acid -R S sulfuric acid -R P phosphoric acid -R R 2 esters R nitrate ester S R sulfate ester P R phosphate ester nitroglycerin 3 S 3 dimethylsulfate S sulfogalactosamine 2 2 phosphotyrosine 2 2 P phosphoserine P P Phosphodiester of DA 84 P 42

7 15.9: xidation of Alcohols oxidation [] reduction [] R 2 [] R 2 2 alcohols ketone [] 1 alcohols aldehyde carboxylic acids [] Potassium permanganate (KMn 4 ) and chromic acid (a 2 r 2 7, 3 ) oxidize secondary alcohols to ketones, and primary alcohols to carboxylic acids. 85 xidation of primary alcohols to aldehydes Pyridinium Dichromate (PD) a 2 r 2 7 l pyridine Pyridinium hlorochromate (P) 2- r r 3 6M l pyridine lr 3 - P and PD are soluble in anhydrous organic solvent such as 2 l 2. The oxidation of primary alcohols with P or PD in anhydrous 2 l 2 stops at the aldehyde. 2 2 r 2 7 3, acetone P 2 l 2 arboxylic Acid 1 alcohol Aldehyde 86 43

8 15.10: Biological xidation of Alcohols (please read) Ethanol metabolism: 3 2 alcohol dehydrogenase 3 icotinamide Adenine Dinucleotide (AD) aldehyde dehydrogenase ethanol acetaldehyde acetic acid 3 2 P P 2 2 P P 2 R reduced form R= AD, AD R= P 3 2- ADP, ADP R oxidized form Vitamin B 3, nicotinic acid, niacin : xidative leavage of Vicinal Diols xidative leavage of 1,2-diols to aldehydes and ketones with sodium periodate (ai 4 ) or periodic acid (I 4 ) R2 R 4 R 3 ai 4 TF, 2 R 2 R 3 R 4 I R 3 R2 R 4 periodate ester intermediate 3 ai 4 2, acetone

9 15.12: Thiols Thiols (mercaptans) are sulfur analogues of alcohols. Thiols have a pk a ~ 10 and are stronger acids than alcohols. RS- RS - (pk a ~10) (pk a ~15.7) RS and S are weakly basic and strong nucleophiles. Thiolates react with 1 and 2 alkyl halides to yield sulfides (S 2) S a, TF _ 3 2 -S a Br S S _ S a TF Br S 2 S xidation States of organosulfur compounds Thiols can be oxidized to disulfides R-S S glutathione thiols 2 [] [] -2e -, -2 2e -, 2 xidation of thiols to sulfonic acids R S [] R S [] 3 2 R-S-S-R disulfide 2 R S S S [] R S Thiol sulfenic acid sulfinic acid sulfonic acid xidation of thioethers R S R' [] R S R' [] 2 R S R' Thioether Sulfoxide Sulfone 90 45

Bioactivation and detoxication of benzo[a]pyrene diol epoxide: P450 2 benzo[a]pyrene P450 2 DA 2 glutathione transferase G-S DA SG 3 2 S glutathione 2 91 15.

10 Bioactivation and detoxication of benzo[a]pyrene diol epoxide: P450 2 benzo[a]pyrene P450 2 DA 2 glutathione transferase G-S DA SG 3 2 S glutathione Spectroscoic Analysis of Alcohols and Thiols: Infrared (IR): haracteristic stretching absorption at 3300 to 3600 cm -1 Sharp absorption near 3600 cm -1 except if -bonded: then broad absorption 3300 to 3400 cm -1 range Strong stretching absorption near 1050 cm -1 % T - - cm

11 1 MR: protons attached to the carbon bearing the hydroxyl group are deshielded by the electron-withdrawing nature of the oxygen, δ 3.3 to δ= 1.5, q, 2 δ= 0.9, d, 6 δ= 3.65, t, 2 δ= 2.25, br s, 1 δ= 1.7, m, Dl Usually spin-spin coupling is not observed between the proton and neighboring protons on carbon due to exchange reaction A A The chemical shift of the - proton occurs over a large range ( ppm). It chemical shift is dependent upon the sample concentration and temperature. This proton is often observed as a broad singlet (br s). Exchangable protons are often not to be observed at all

12 13 MR: The oxygen of an alcohol will deshield the carbon it is attached to. The chemical shift range is ppm δ 14 δ 19 δ 35 δ δ= 63.5 δ= DMS-d 6 (solvent) : :

But in organic terms: Oxidation: loss of H 2 ; addition of O or O 2 ; addition of X 2 (halogens).

But in organic terms: Oxidation: loss of H 2 ; addition of O or O 2 ; addition of X 2 (halogens). Reactions of Alcohols Alcohols are versatile organic compounds since they undergo a wide variety of transformations the majority of which are either oxidation or reduction type reactions. Normally: Oxidation