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)

15.2: Preparation of Alcohols by Reduction of Aldehydes and Ketones

- add the equivalent of H 2 across the  -bond of the carbonyl to yield an alcohol O R C R' [H] O

H

R R' C

H

aldehyde (R or R ´ = H)  ketone (R and R ´ ≠ H)  1 ° 2 ° alcohol alcohol 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 (NaBH 4 ) (LiAlH 4 ) Na + H H B H H Li + H H Al H H electronegativity B H 2.0 2.1

Al H 1.5 2.1

R 2 R 1 C OH H synthons R 1 C OH R 2 + H: = NaBH 4 reduces aldehydes to primary alcohols O H

H

O 2 N NaB

H

4 H O 2 N O

H H

OCH 2 CH 3 precursors R 1 C O R 2 + NaBH 4 NaBH 4 reduces ketones to secondary alcohols O NaB

H

4

H

O

H H

OCH 2 CH 3 ketones 2° alcohols NaBH 4 does not react with esters or carboxylic acids O NaB

H

4 H 3 CH 2 CO

H

OCH 2 CH 3 H 3 CH 2 CO O O

H

O

H

Lithium Aluminium Hydride (LiAlH 4 , LAH) - much more reactive than NaBH 4 . Incompatible with protic solvents (alcohols, H 2 O).

LiAlH 4 to 1 ° (in ether) reduces aldehydes, carboxylic acids, and esters alcohols and ketones to 2 ° alcohols.

O ketones 1) LiAl

H

4 , ether 2)

H 3

O +

H

O

H

2° alcohols O H 1) LiAl

H

4 , ether 2)

H 3

O + aldehydes H

H

O

H

1° alcohols

15.3: Preparation of Alcohols By Reduction of Carboxylic Acids and Esters

- LiAlH 4 (but not NaBH 4 or catalytic hydrogenation).

O

H H

O OCH 2 CH 3 1) LiAl

H

4 , ether 2)

H 3

O + O

H

1) LiAl

H

4 , ether 2)

H 3

O + OH 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).

H H O C C H H + BrMg -CH 3 ether, then H 3 O + S N 2 H O CH 2 CH 2 CH 3

disconnection OH synthons + H 2 C CH 2 OH = precursors MgBr + O Br Mg(0) THF MgBr O then H 3 O + OH

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  -bond of an alkene to give a 1,2-diol. This is an overall oxidation. OsO 4 (catalytic) (H 3 C) 3 C-OOH (H 3 C) 3 COH H OH H OH H H O O O Os O osmate ester intermediate

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)

15.7: Conversion of Alcohols to Ethers

- Symmetrical ethers can be prepared by treating the corresponding alcohol with a strong acid. H 3 CH 2 C-O H + HO -CH 2 CH 3 H 2 SO 4 H 3 CH 2 C-O-CH 2 CH 3 + H 2 O Limitations: ether must be symmetrical works best for 1 ° alcohols

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 R 1 O C

OH

+

H

O-R 2 H + R 1 O C OR 2 +

HOH

Mechanism (Chapters 19 and 20) Dean-Stark Trap

Ester formation via the reaction of an acid chloride or acid anhydride with an alcohol (nucleophilic acyl substitution) O R 1 C

Cl acid chloride

+

H

O-R 2 R 1 O C OR 2 +

H Cl

R 1 O C O

O

C R 1

acid anhydride

+

H

O-R 2 Mechanism (Chapters 20) O R 1 C OR 2 + R 1 O C

O H

15.9: Esters of Inorganic Acids

(please read) R 1 O C

OH carboxylic acid

+

H

O-R 2

alcohol

O N O

OH nitric acid

+

H

O-R HO O S O

OH sulfuric acid

+

H

O-R HO O P OH

OH phosphoric acid

+

H

O-R R 1 O C OR 2 +

esters HOH

O 2 NO ONO 2 ONO 2

nitroglycerin

H 3 CO O S O OCH 3

dimethylsulfate

O O N

OR nitrate ester

HO 2 H 2 N H C C C H H +

HOH

O O P O O

phosphotyrosine

HO 2 H 2 N H C C C O H H O P O O HO O S O

OR sulfate ester

O O O P O O +

HOH

O HO O P OH

OR phosphate ester

+

HOH

N H N H O N N O H N H N H N N O O O O H N H N O P O O N N H O N N N O O O O

phosphoserine Phosphodiester of DNA

15.10: Oxidation of Alcohols

oxidation [O]

OH H

reduction [H]

R 1 H C OH R 2 [O] O R 1 C R 2 2 ° alcohols ketone O R 1 H C H OH [O] R 1 O C H [O] R 1 O C OH 1 ° alcohols aldehyde carboxylic acids KMnO 4 and chromic acid (Na 2 Cr 2 O 7 , H 3 O + ) oxidize secondary alcohols to ketones, and primary alcohols to carboxylic acids.

Oxidation of primary alcohols to aldehydes

Pyridinium Dichromate

(

PDC

) Na 2 Cr 2 O 7 + HCl + pyridine N H 2 Cr 2 O 5 2-

Pyridinium Chlorochromate

(

PCC

) CrO 3 + 6M HCl + pyridine N H ClCrO 3 PCC and PDC are soluble in

anhydrous

organic solvent such as CH 2 Cl 2 . The oxidation of primary alcohols with PCC or PDC in anhydrous CH 2 Cl 2 stops at the aldehyde.

CO 2 H H 2 Cr 2 O 7 H 3 O + , acetone

Carboxylic Acid

OH PCC CH 2 Cl 2

1° alcohol

CHO

Aldehyde

15.11: Biological Oxidation of Alcohols

(please read) Ethanol metabolism: CH 3 CH 2 OH alcohol dehydrogenase

ethanol

O H 3 C C H

acetaldehyde

aldehyde dehydrogenase H 3 C O C OH

acetic acid

Nicotinamide Adenine Dinucleotide (NAD) H 2 N N N N N O R O OH O O P OH O O P OH O HO reduced form O N H H O NH 2 H 2 N N N N N OH O R

R= H NADH, NAD + R= PO 3 2 NADPH, NADP +

O OH O O P OH O O P OH O HO oxidized form O N OH CO 2 H Vitamin B 3 , nicotinic acid, niacin N O NH 2

15.12: Oxidative Cleavage of Vicinal Diols

Oxidative Cleavage of 1,2-diols to aldehydes and ketones with sodium periodate (NaIO 4 ) or periodic acid (HIO 4 ) HO R 1 R 2 OH R 4 R 3 NaIO 4 THF, H 2 O R 1 O O OH O I O R 2 R 4 R 3 R 1 O + O R 2 R 3 R 4 periodate ester intermediate CH 3 OH H OH NaIO 4 H 2 O, acetone H O O CH 3

15.13: Thiols

Thiols (mercaptans) are sulfur analogues of alcohols.

Thiols have a p

K

a ~ 10 and are stronger acids than alcohols.

RS-H (p

K

a ~10) + HO – RS – + H-OH (p

K

a ~15.7) RS – and HS – are weakly basic and strong nucleophiles.

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

CH 3 CH 2 -SH NaH, THF _ CH 3 CH 2 -S Na + Br CH 3 CH 2 -S CH 2 CH 2 CH 2 CH 3 _ HS Na + + Br CH 2 CH 2 CH 2 CH 3 S N 2 THF S N 2 HS CH 2 CH 2 CH 2 CH 3

Thiols can be oxidized to disulfides [O] 2 R-SH [H]

thiols

R-S-S-R

disulfide

2 O 2 C H 3 N O H N N H O

SH glutathione

CO 2 -2e , -2H + +2e , +2H + O 2 C H 3 N O 2 O C H N H N

S

O O

S

N H N H CO O 2 NH 3 CO 2 R SH [O] R S OH [O] R O S OH [O] R O S 2 OH O

Thiol sulfenic acid sulfinic acid sulfonic acid

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

P450 O 2 P450 O HO OH glutathione transferase

G

-S O N N DNA NH 2 N N H 2 O HO OH OH HO HO N N DNA NH N N HO HO S

G

OH O 2 C H 3 N O O H N

SH

N H glutathione CO 2