Chapter 15: Alcohols, Diols, and Thiols 15.1: Sources of Alcohols (please read) Hydration of alkenes (Chapter 6) 1. Acid catalyzed hydration 2. Oxymercuration 3. Hydroboration Hydrolysis of alkyl halides (Chapter 8) nucleophilic substitution Reaction of Grignard or organolithium reagents with ketones, aldehydes, and esters. (Chapter 14)

Reduction of alehydes, ketones, esters, and carboxylic acids (Chapter 15.2 - 15.3) Reaction of epoxides with Grignard Reagents (Chapter 15.4)

Diols from the dihydroxylation of alkenes (Chapter 15.5)320

15.2: Preparation of Alcohols by Reduction of Aldehydes and Ketones - add the equivalent of H2 across the π-bond of the carbonyl to yield an alcohol

H O [H] O aldehyde (R or R´= H) → 1° alcohol C C ketone (R and R´≠ H) → 2° alcohol R H R R' R'

Catalytic hydrogenation is not typically used for the reduction of ketones or aldehydes to alcohols. Metal hydride reagents: equivalent to H:– (hydride) sodium borohydride lithium aluminium hydride

(NaBH4) (LiAlH4) H H Na+ H B H Li+ H Al H H H

B H Al H 321 electronegativity 2.0 2.1 1.5 2.1

1 synthons precursors R1 R1 R1 + H: R2 C OH C OH = C O + NaBH4 H R2 R2

NaBH4 reduces aldehydes to primary alcohols O H H NaBH O2N 4 O N H 2 OH HOCH2CH3

NaBH4 reduces ketones to secondary alcohols H OH O NaBH4

HOCH2CH3 ketones 2° alcohols

NaBH4 does not react with esters or carboxylic acids O HO H

NaBH4 H CH CO H3CH2CO 3 2 HOCH2CH3 O O 322

Lithium Aluminium Hydride (LiAlH4, LAH) - much more reactive than NaBH4. Incompatible with protic solvents (alcohols, H2O).

LiAlH4 (in ether) reduces aldehydes, carboxylic acids, and esters to 1° alcohols and ketones to 2° alcohols.

H OH O 1) LiAlH4, ether

+ 2) H3O ketones 2° alcohols

O H H 1) LiAlH4, ether H OH + 2) H3O aldehydes 1° alcohols

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2 15.3: Preparation of Alcohols By Reduction of Carboxylic

Acids and Esters - LiAlH4 (but not NaBH4 or catalytic hydrogenation).

O H H O 1) LiAlH , ether 4 OH 1) LiAlH4, ether OCH2CH3 OH + + 2) H3O 2) H3O

Esters 1° alcohols Carboxylic acids 15.4: Preparation of Alcohols From Epoxides - the three- membered ring of an epoxide is strained. Epoxides undergo ring- opening reaction with nucleophiles (Grignard reagents, organo- lithium reagents, and cuprates).

ether, O then H O+ C C + 3 H H BrMg-CH3 HO CH2CH2 CH3 H H SN2

324

disconnection synthons precursors OH MgBr O + + H2C CH2OH =

O OH Br Mg(0) MgBr then THF + H3O

15.5: Preparation of Diols - Vicinal diols have hydroxyl groups on adjacent carbons (1,2-diols, vic-diols, glycols) Dihydroxylation: formal addition of HO-OH across the π-bond of an alkene to give a 1,2-diol. This is an overall oxidation.

OsO (catalytic) H H 4 OH (H3C)3C-OOH O O Os (H C) COH 3 3 OH O O H H

osmate ester intermediate 325

3 15.6: Reactions of Alcohols: A Review and a Preview Conversion to alkyl halides (Chapter 4) 1. Reaction with hydrogen halides 2. Reaction with thionyl chloride 3. Reaction with phosphorous trihalides Acid-catalyzed dehydration to alkenes (Chapter 5) Conversion to p-toluenesulfonate esters (Chapter 8

Conversion to ethers (Chapter 15.7) Conversion to esters (Chapter 15.8) Esters of inorganic acids (Chapter 15.9) Oxidation to carbonyl compounds (Chapter 15.10) Cleavage of vicinal diols to ketones and aldehydes (Chapter 15.12) 326

15.7: Conversion of Alcohols to Ethers - Symmetrical ethers can be prepared by treating the corresponding alcohol with a strong acid.

H2SO4 H3CH2C-OH + HO-CH2CH3 H3CH2C-O-CH2CH3 + H2O

Limitations: ether must be symmetrical works best for 1° alcohols 327

4 15.8: 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 O H+ O + HOH C + HO-R C R1 OH 2 R1 OR2

Mechanism (Chapters 19 and 20)

Dean-Stark Trap

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Ester formation via the reaction of an acid chloride or acid anhydride with an alcohol (nucleophilic acyl substitution)

O O + HCl C + HO-R C R1 Cl 2 R1 OR2 acid chloride

O O O O + C + C C C HO-R2 R OR R1 O R1 1 2 R1 OH acid anhydride Mechanism (Chapters 20)

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5 15.9: Esters of Inorganic Acids (please read)

O O O O O N HO S OH + HO-R HO P OH + HO-R C + HO-R2 + HO-R R1 OH OH O OH carboxylic alcohol nitric sulfuric phosphoric acid acid acid acid

O O O O C + N OR + HOH HO S OR + HOH HO P OR + HOH R1 OR2 HOH O O OH esters nitrate sulfate phosphate ester ester ester

H N H O N

H2N H O N H N N O N N O ONO2 HO2C C C O P O O O O H N O2NO ONO2 H H O H O O nitroglycerin O H P phosphotyrosine O O O H N N P O O N H N N O N N O O H2N H O O O H3CO S OCH3 HO2C C C O P O O O H H O O Phosphodiester dimethylsulfate 330 phosphoserine of DNA

15.10: Oxidation of Alcohols oxidation [O] OH O H reduction [H]

H OH [O] O C C R1 R2 R1 R2 2° alcohols ketone

H H [O] O [O] O C C C R1 OH R1 H R1 OH 1° alcohols aldehyde carboxylic acids

+ KMnO4 and chromic acid (Na2Cr2O7, H3O ) oxidize secondary alcohols to ketones, and primary alcohols to carboxylic acids.

331

6 Oxidation of primary alcohols to aldehydes Pyridinium Dichromate (PDC) 2- Cr O Na2Cr2O7 + HCl + pyridine N 2 5 H 2 Pyridinium Chlorochromate (PCC) - ClCrO CrO3 + 6M HCl + pyridine N 3 H PCC and PDC are soluble in anhydrous organic solvent such as CH2Cl2. The oxidation of primary alcohols with PCC or PDC in anhydrous CH2Cl2 stops at the aldehyde.

H2Cr2O7 PCC CO H H O+, CHO 2 3 OH CH2Cl2 acetone

Carboxylic Acid 1° alcohol Aldehyde 332

15.11: Biological Oxidation of Alcohols (please read) Ethanol metabolism:

alcohol aldehyde O O dehydrogenase dehydrogenase C CH3CH2OH H C H C 3 H3C OH ethanol acetaldehyde acetic acid

Nicotinamide Adenine Dinucleotide (NAD)

H H O O H2N N H2N N O O O O

N N O O P O P O O N NH2 N N O O P O P O O N NH2 N OH OH N OH OH

O OH HO OH O OH HO OH R reduced form R oxidized form R= H NADH, NAD+ 2- + R= PO3 NADPH, NADP

CO2H Vitamin B3, nicotinic acid, niacin N

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7 15.12: Oxidative Cleavage of Vicinal Diols Oxidative Cleavage of 1,2-diols to aldehydes and ketones with sodium periodate (NaIO4) or periodic acid (HIO4)

R1 R3 HO OH NaIO4 O + O R1 R3 THF, H O R2 R4 R2 R4 2

OH O O I O O periodate ester

R1 R3 intermediate R2 R4

CH3 OH NaIO4 O CH3 OH H2O, acetone H H O

334

15.13: Thiols Thiols (mercaptans) are sulfur analogues of alcohols.

Thiols have a pKa ~ 10 and are stronger acids than alcohols.

RS-H + HO– RS– + H-OH

(pKa ~10) (pKa ~15.7)

RS– and HS – are weakly basic and strong nucleophiles.

Thiolates react with 1° and 2° alkyl halides to yield sulfides (SN2).

NaH, THF _ Br + CH3CH2-SH CH3CH2-S Na CH3CH2-S-CH2CH2CH2CH3 SN2

_ + + THF HS Na Br-CH2CH2CH2CH3 HS-CH2CH2CH2CH3 SN2

335

8 Thiols can be oxidized to disulfides

[O] 2 R-SH R-S-S-R [H] thiols disulfide

O C O 2 H N O C O - + H3N N CO2 2 H -2e , -2H H 2 N O H3N N CO2 S H O +2e-, +2H+ SH S O glutathione H O C N NH 2 N 3 H O CO2

[O] [O] O [O] O 2 R SH R S OH R S OH R S OH O Thiol sulfenic acid sulfinic acid sulfonic acid

336

Bioactivation and detoxication of benzo[a]pyrene diol epoxide:

P450 H2O

O2 HO O OH benzo[a]pyrene OH NH2 HO N N O P450 N N DNA HO NH HO OH N N

N N glutathione G-S transferase DNA

O C O SG 2 H HO N H3N N CO2 H O HO SH OH glutathione

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