Chapter 15: Alcohols, Diols, and Thiols 15.1: Sources of Alcohols (Table 15.1, P

C10H14 127.0

31.2 128.2 125.7 41.7 21.8 12.3 147.6

δ= 2.61 δ= 2.61 (d, J=7.0, 3H) (t, J=7.0, 3H)

δ= 2.61 δ= 2.61 (pentet, (sextet, J=7.0, 2H) J=7.0, 1H)

δ= 7.4-7.1 (m, 5H)

Chapter 15: Alcohols, Diols, and Thiols 15.1: Sources of Alcohols (Table 15.1, p. 616)

Hydration of alkenes (Chapter 6) 1. Acid-catalyzed hydration (Chapter 6.6) 2. Oxymercuration (p. 258-9) 3. Hydroboration (Chapter 6.8)

Hydrolysis of alkyl halides (Chapter 8.1) nucleophilic substitution

Reaction of Grignard or organolithium reagents with ketones, aldehydes, and esters. (Chapter 14.5)

Reduction of aldehydes, ketones, esters, and carboxylic acids (Chapters 15.2 - 15.3)

Reaction of epoxides with Grignard Reagents (Chapter 15.4)

Diols from the dihydroxylation of alkenes (Chapter 15.5) 74

37 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 electronegativity 2.0 2.1 1.5 2.1 75

target disconnection precursors

R1 R1 R2 C OH C O + NaBH4 H 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 76

38 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

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, organolithium reagents, and cuprates).

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

39 target disconnection precursors OH MgBr O +

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 79

15.6: Reactions of Alcohols: A Review and a Preview Table 15.2, p.623

Conversion to alkyl halides (Chapter 4) 1. Reaction with hydrogen halides (Chapter 4.7) 2. Reaction with thionyl chloride (Chapter 4.12) 3. Reaction with phosphorous trihalides (Chapter 4.12

Acid-catalyzed dehydration to alkenes (Chapter 5.9)

Conversion to p-toluenesulfonate esters (Chapter 8.11)

Conversion to ethers (Chapter 15.7)

Conversion to esters (Chapter 15.8)

Oxidation to carbonyl compounds (Chapter 15.9)

Cleavage of vicinal diols to ketones and aldehydes (Chapter 15.11) 80

40 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 81

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 18 and 19)

Dean-Stark Trap

41 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 19)

Esters of Inorganic Acids 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 ONO 2 N H O N O2NO ONO2 H2N H O N H N N O HO2C C C O P O N N O nitroglycerin O H H O O O H N H O O O O H3CO S OCH3 phosphotyrosine H P O O O O H N N P O O N dimethylsulfate N H N H2N H O O N N O O O HO OSO HO2C C C O P O 3 O H H O HO O O

H2N Phosphodiester OH phosphoserine 84 6-sulfogalactosamine of DNA

42 15.9: 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

Potassium permanganate (KMnO4) and chromic acid + (Na2Cr2O7, H3O ) oxidize secondary alcohols to ketones, and primary alcohols to carboxylic acids. 85

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 86

43 15.10: Biological Oxidation of Alcohols (please read) Ethanol metabolism:

alcohol aldehyde O O dehydrogenase dehydrogenase C C CH3CH2OH H C H 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

15.11: 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

44 15.12: 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

Oxidation States of organosulfur compounds 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 Oxidation of thiols to sulfonic acids [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 Oxidation of thioethers – O– O [O] [O] +2 R S R' R S R' R S R' 90 O– Thioether Sulfoxide Sulfone

45 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

15.13 Spectroscoic Analysis of Alcohols and Thiols: Infrared (IR): Characteristic O–H stretching absorption at 3300 to 3600 cm-1 Sharp absorption near 3600 cm-1 except if H-bonded: then broad absorption 3300 to 3400 cm-1 range Strong C–O stretching absorption near 1050 cm-1

H O

% T T % O-H

C-O

92 cm-1

46 1H NMR: protons attached to the carbon bearing the hydroxyl group are deshielded by the electron-withdrawing nature of the oxygen, δ 3.3 to 4.7

H3C H H δ= 0.9, H3C C C C OH d, 6H H H H δ= 1.5, q, 2H

δ= 3.65, δ= 1.7, t, 2H δ= 2.25, m, 1H br s, 1H

61.2 22.6 41.7 24.7

CDCl3

O-H C-O 93

Usually spin-spin coupling is not observed between the O–H proton and neighboring protons on carbon due to exchange reaction

H A C O H C O H + H A H H

The chemical shift of the -OH proton occurs over a large range (2.0 - 5.5 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.

47 13C NMR: The oxygen of an alcohol will deshield the carbon it is attached to. The chemical shift range is 50-80 ppm

δ 14 δ 19 δ 35 δ 62

CH3 — CH2 — CH2 — CH2 — OH

OH HO OH H H 145.2 H C C C H DMSO-d6 H H H (solvent) δ= 63.5 δ= 25

13C: 138.6 129.4 128.4 126.3 68.8 45.8 22.7

13C: 145.2 128.8 127.8 126.5 76.3 32.3 10.6