AlcoholsReactions

Dr. Sapna Gupta

Types of Alcohol Reactions

• Dehydration to alkene

• Substitution to form alkyl halide

• Tosylation

• Oxidation

Alcohol Reactions 2

Dehydration Reactions

• Conc. H2SO4 produces alkene via E1.

• Carbocation is the intermediate.

• Rearrangement can also occur.

• Zaitsev product is predominant.

• Low temp, 140°C and below, favors ether (substitution – will cover in ethers)

• High temp, 180°C and above, favors alkene (elimination)

Alcohol Reactions 3

CH3CHCH3

OHH2SO4

alcohol

CH3CHCH3

OH

H

CH3CHCH3

CH2 CHCH3H2O

CH3OH

H3O+

CH3OH CH3 OH2 CH3 O

H

CH3

H2OCH3OCH3

Dehydration Contd…

• Primary Alcohols

• Secondary Alcohols

• Tertiary Alcohols

Alcohol Reactions 4

180°CCH3 CH2 OH

H2 SO4CH2 = CH2 + H2 O

140°C

Cyclohexanol Cyclohexene

OH

+ H2 OH2 SO4

CH3 COH

CH3

CH3

H2 SO4CH3 C= CH2

CH3

+ H2 O50°C

2-Methyl-2-propanol

(tert- Butyl alcohol)2-Methylpropene

(Isobutylene)

Dehydration Contd…

• Where possible, the alkene having the greater number of substituents on the double bond (the more stable alkene) is the major product (Zaitsev rule).

• Dehydration of 1o and 2o alcohols may give rearranged alkenes.

• Ease of dehydration (3° > 2° > 1°)

Alcohol Reactions 5

1-Butene

(20%)

2-Butene

(80%)

2-Butanol

+

heat

8 5 % H3 PO4

CH3 CH= CHCH3

CH3 CH2 CHCH3

CH3 CH2 CH= CH2 + H2 O

OH

1-Butene

(20%)

2-Butene

(80%)

2-Butanol

+

heat

8 5 % H3 PO4

CH3 CH= CHCH3

CH3 CH2 CHCH3

CH3 CH2 CH= CH2 + H2 O

OH

OH

H2 SO4

140 - 170°C+

3,3-Dimethyl-2-butanol

2,3-Dimethyl-2-butene

(80%)

2,3-Dimethyl-1-butene

(20%)

Dehydration - Mechanism

Protonation of alcohol followed by formation of carbocation (this is where rearrangement can occur) and finally elimination step (this is where Zaitsev’s product is formed) gives the alkene.

Alcohol Reactions 6

O

H O

H

H

O

O

H

H

H HH

+

+

rapid and

reversible

+

+

A 2° carbocation

intermediate

O

H H+ slow, rate

determining

H2 O+

rapid andreversible

O

H

H

HH

+ + O

H

+

+ H H

Dehydration – Zaitsev’s Product

• Primary alcohols give Zaitsev’s (from hydride shift) and Hoffman’s product (by regular E2 mechanism).

Alcohol Reactions 7

O-H O H

H

H O-H

H

O-H

H

++

++

1-Butanol

rapid andreversible

H

OH O-H

HH H

H O H

H

O H

H

++

++

1-Butene

E2+

O-H

HHHO-H

H

+++

1,2-shif t of ahydride ion

A 2°carbocation

H O H

H

+E1+ +

++

t rans-2-Butene ci s-2-Butene

H

H O

H

Protonation of alcohol

E2 elimination to give Hoffman’s product

Hydride shift to give a more stable carbocation

E1 elimination to give Zaitsev’sproduct

Dehydration - Rearrangement

• This is usually for secondary alcohols and can involve a hydride or methyl shift.

Alcohol Reactions 8

A 2° carbocationintermediate

A 3° carbocationintermediate

H2 O

H2 O

2,3-Dimethyl-2-butene

2,3-Dimethyl-1-butene

+ H3 O+

+ H3 O+

OH

3,3-Dimethyl-2-butanol

-H2 O

H+

+

+

A 2° carbocationintermediate

A 3° carbocationintermediate

H2 O

H2 O

2,3-Dimethyl-2-butene

2,3-Dimethyl-1-butene

+ H3 O+

+ H3 O+

OH

3,3-Dimethyl-2-butanol

-H2 O

H+

+

+

Alkyl Halides from Alcohols

• Hydroxyl groups are poor leaving groups, and as such, are often converted to alkyl halides when a good leaving group is needed

• Three general methods exist for conversion of alcohols to alkyl halides, depending on the classification of the alcohol and the halogen desired. Reagents used are: hydrogen halides, phosphorus tribromide and thionyl chloride.

Alcohol Reactions 9

Can also use PCl3 or PCl5 to get alkylhalide

Reaction with Hydrogen Halide contd..

The order of reactivity is as follows

• Hydrogen halide HI > HBr > HCl > HF

• Type of alcohol 3o > 2o > 1o < methyl

Mechanism of the Reaction of Alcohols with HX:

• SN1 mechanism for 3o, 2o, allylic and benzylic alcohol.

• These reactions are prone to carbocation rearrangements

Alcohol Reactions 10

Reaction with Hydrogen Halide contd..

• Primary and methyl alcohols undergo substitution by an SN2 mechanism

Alcohol Reactions 11

• Reaction with HCl• Add ZnCl2, which bonds strongly with -OH,

to promote the reaction.• The chloride product is insoluble.• Lucas test: ZnCl2 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.

• Limitation: Carbocation intermediate may rearrange.

Reaction with PCl5 and SOCl2

• Good yields with 1° and 2° alcohols

• PCl3 for alkyl chloride (but SOCl2 better)

• PBr3 for alkyl bromide

• Mechanism is SN2 – no rearrangement

• P and I2 for alkyl iodide (PI3 not stable)

Alcohol Reactions 12

Tosylates and Mesylates• The hydroxyl group of an alcohol can be converted to a good leaving group by

conversion to a sulfonate ester.

• Sulfonyl chlorides are used to convert alcohols to sulfonate esters

• Base is added to react with the HCl generated

Alcohol Reactions 13

Tosylates and Mesylates contd..

• A sulfonate ion (a weak base) is an excellent leaving group

• If the alcohol hydroxyl group is at a stereo center then the overall reaction with the nucleophile proceeds with inversion of configuration (SN2). The second step to form a sulfonate ester proceeds with retention of configuration.

Alcohol Reactions 14

Stereochemistry of Tosylates

• The SN2 reaction of an alcohol via an alkyl halide proceeds with twoinversions, giving product with same arrangement as starting alcohol

• The SN2 reaction of an alcohol via a tosylate, produces inversion at the chirality center

Alcohol Reactions 15

SN2 Reactions of Tosylates

Alcohol Reactions 16

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 LiAlH4 produces alkane

Oxidation of Alcohols

Alcohol Reactions 17

Oxidation of Alcohols contd..

Oxidation of Primary Alcohols to Aldehydes

• A primary alcohol can be oxidized to an aldehyde or a carboxylic acid. The oxidation is difficult to stop at the aldehyde stage and usually proceeds to the carboxylic acid

• A reagent which stops the oxidation at the aldehyde stage is pyridiniumchlorochromate (PCC)

Alcohol Reactions 18

Oxidation of Alcohols contd…

Oxidation of Primary Alcohols to Carboxylic Acids

• Potassium permanganate (KMnO4) is a typical reagent used for oxidation of a primary alcohol to a carboxylic acid. (a brown precipitate of MnO2

indicates that oxidation has taken place)

Oxidation of Secondary Alcohols to Ketones

• Oxidation of a secondary alcohol stops at the ketone (e.g. chromic acid (H2CrO4) and Jones reagent (CrO3 in acetone))

Alcohol Reactions 19

Oxidation of Alcohols contd…

• 3° Alcohols Don’t Oxidize• Cannot lose 2 H’s

• Basis for chromic acid test

Alcohol Reactions 20

Summary of Oxidation of Alcohols

Substrate Product Reagent

1o Alcohol Aldehyde PCC,chromic acid

1o Alcohol Acid KMnO4

2o Alcohol Ketone PCC, chromic acid

3o Alcohol Don’t get oxidized NR

Oxidation of Glycols

• Glycols (vicinal alcohols) can be cleaved by periodic acid, HIO4 to give carbonyls – aldehydes or ketones.

Alcohol Reactions 21

A cyclic periodate

+C

C

OH

OH

IO

OOC

CO

OO

O

IOH OH + H2OOC

C O

I

O

OH

O

C O

C O

O

O

I OH+OC

C O

I

O

OH

O

C O

C O

O

O

I OH+

OH

OH

+ HIO4 CHO

CHO+ HIO3

cis- 1,2-Cyclo-

hexanediol

HexanedialPeriodicacid

Iodicacid

Other Oxidizing Agents and Biological Oxidation

• Other Oxidizing Agents• Collins reagent: Cr2O3 in pyridine

• Jones reagent: chromic acid in acetone

• KMnO4 (strong oxidizer)

• Nitric acid (strong oxidizer)

• CuO, 300°C (industrial dehydrogenation)

• Biological Oxidation • Catalyzed by ADH, alcohol dehydrogenase.

• Oxidizing 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.

Alcohol Reactions 22

Esterification

Alcohol + Carboxylic Acid Carboxylic Ester + Water

base acid salt water

• Acid is needed to catalyze the reaction.

• The reaction is similar to acid base reaction.

CH3OH + CH3COOH CH3COOCH3 + H2O

For example: what alcohol and acid is required to make CH3CH2COOC6H5?

Cleave between the carbonyl

and “O” group.

Add HO-H to the appropriate fragment to form

the acid and alcohol. (OH goes to carbonyl to form acid)

Alcohol Reactions 23

H+

O

OC6H5

O

OC6H5

O

OH

HOC6H

5

Alcohol Analysis

• A Chemical Test for Primary and Secondary Alcohols• Chromium oxide in acid has a clear orange color which changes to greenish

opaque if an oxidizable alcohol is present

Alcohol Reactions 24

Key Concepts

• Dehydration of alcohols (Zaitsev’s product and rearrangement)

• Synthesis of alkyl halides from alcohols (stereochemistry)

• Mesylates and tosylates (stereochemistry)

• Oxidation of alcohols

• Esterification

• Analysis of alcohols

Alcohol Reactions 25