Chapter 15

Alcohols, Diols, and Thiols

1
 15.1. Sources of Alcohols
Methanol
Methanol is an industrial chemical.
- End uses: solvent, antifreeze, fuel.
- Principal use: preparation of formaldehyde.
- Prepared by hydrogenation of carbon monoxide.

CO + 2H2 → CH3OH

2
 Ethanol

- Ethanol is an industrial chemical.

- Most ethanol comes from fermentation.
- Synthetic ethanol is produced by hydration of ethylene.
- Synthetic ethanol is denatured (made unfit for drinking)
by adding methanol, benzene, pyridine, castor oil,
gasoline, etc.

3
 Other Alcohols

- Isopropyl alcohol is prepared by hydration of

propene.
- All alcohols with four carbons or fewer are readily
available.
- Most alcohols with five or six carbons are readily
available.

4
 Sources of alcohols

Reactions discussed in earlier chapters (Table 15.1)

¾ Hydration of alkenes.
¾ Hydroboration-oxidation of alkenes.
¾ Hydrolysis of alkyl halides.

¾ Syntheses using:
- Grignard reagents.
- Organolithium reagents.

5
 Sources of alcohols

New methods in Chapter 15

- Reduction of aldehydes and ketones.

- Reduction of carboxylic acids.

- Reduction of esters.

- Reaction of Grignard reagents with epoxides.

- Diols by hydroxylation of alkenes.

6
 15.2. Preparation of Alcohols by
Reduction of Aldehydes and Ketones

Reduction of Aldehydes Gives Primary Alcohols

R R

C O H C OH
H H

7
Example: Catalytic Hydrogenation

CH3O CH + H2

Pt, ethanol

CH3O CH2OH

(92%) 8
 Reduction of Ketones Gives Secondary Alcohols

R R

C O H C OH
R' R'

Example: Catalytic Hydrogenation

O H OH

Pt
+ H2
ethanol
(93-95%) 9
 Retrosynthetic Analysis

R R

H C OH H:– C O
H
H

R R
H C OH H:– C O

R' R'
10
 Metal Hydride Reducing Agents

H H
+ – + –
Na H B H Li H Al H

H H

Sodium Lithium
borohydride aluminum hydride

act as hydride donors

11
 Examples: Sodium Borohydride
Aldehyde
O2N O2N
O
NaBH4
CH CH2OH
methanol
(82%)
Ketone

O NaBH4 H OH

ethanol 12
(84%)
 Lithium aluminum hydride

- More reactive than sodium borohydride.

- Cannot use water, ethanol, methanol etc. as

solvents.

- Diethyl ether is most commonly used solvent.

13
 Examples: Lithium Aluminum Hydride
Aldehyde

O 1. LiAlH4
diethyl ether
CH3(CH2)5CH CH3(CH2)5CH2OH
2. H2O
(86%)
Ketone
O 1. LiAlH4 OH
diethyl ether
(C6H5)2CHCCH3 (C6H5)2CHCHCH3
2. H2O
(84%) 14
 Selectivity

O
1. LiAlH4,
Neither NaBH4 or LiAlH4
reduces isolated double bonds. diethyl ether
2. H2O

(90%)
H OH 15
 15.3. Preparation of Alcohols By Reduction
of Carboxylic Acids and Esters

¾ Reduction of carboxylic acids gives primary alcohols:

R R

C O H C OH

HO H

Lithium aluminum hydride is only

effective reducing agent.
16
Example: Reduction of a Carboxylic Acid

O 1. LiAlH4
diethyl ether
COH 2. H2O CH2OH

(78%)

17
 Reduction of Esters
Gives Primary Alcohols
¾ Lithium aluminum hydride preferred for laboratory
reductions.
¾ Sodium borohydride reduction is too slow to be
useful.
¾ Catalytic hydrogenolysis used in industry but
conditions difficult or dangerous to duplicate
in the laboratory (special catalyst, high temperature,
high pressure.

18
Example: Reduction of an Ester

COCH2CH3

1. LiAlH4
diethyl ether
2. H2O

CH2OH + CH3CH2OH

(90%) 19
15.4. Reaction of Grignard Reagents
with Epoxides

R MgX R

H2C CH2 CH2 CH2 OMgX

O H3O+

RCH2CH2OH

20
 Example

CH3(CH2)4CH2MgBr + H2C CH2

O
1. diethyl ether
2. H3O+

CH3(CH2)4CH2CH2CH2OH

(71%)

21
 15.5. Preparation of Diols

Diols are prepared by...

- Reactions used to prepare alcohols.

- Hydroxylation of alkenes.

22
 Example: reduction of a dialdehyde

O O
H2 (100 atm)
HCCH2CHCH2CH
Ni, 125°C
CH3

HOCH2CH2CHCH2CH2OH

CH3
3-Methyl-1,5-pentanediol
(81-83%) 23
 Hydroxylation of Alkenes
Gives Vicinal Diols

¾ Vicinal diols have hydroxyl groups on

adjacent carbons.
¾ Ethylene glycol (HOCH2CH2OH) is most
familiar example.

24
 Osmium Tetraoxide is Key Reagent

syn addition of —OH groups to each carbon

of double bond

C C
C C
HO OH
C C
OsO4 Oxidizing
O O agent
Os
O O 25
 Example

CH3(CH2)7CH CH2

(CH3)3COOH
OsO4 (cat)
tert-Butyl alcohol
HO–

CH3(CH2)7CHCH2OH

OH
(73%) 26
 Example

(CH3)3COOH
H
H OsO4 (cat)

tert-Butyl alcohol H
H
HO– HO
OH

(62%)

27
 15.7. Conversion of Alcohols to Ethers

RCH2O CH2R

H OH

H+
RCH2O CH2R + H OH
About this rxn:
- Acid-catalyzed.
- Referred to as a "condensation”.
- Equilibrium; most favorable for primary alcohols. 28
 Example

2CH3CH2CH2CH2OH

H2SO4, 130°C

CH3CH2CH2CH2OCH2CH2CH2CH3

(60%)

29
Mechanism of Formation of Diethyl Ether

Step 1:
••
CH3CH2O •• H OSO2OH
H

H
+ –
CH3CH2O •• + OSO2OH
H 30
 Mechanism of Formation of Diethyl Ether

Step 2:

H H
CH3CH2
CH3CH2 +O •• + •• O ••
+
H CH3CH2O •• H
••
CH3CH2O •• H

31
Mechanism of Formation of Diethyl Ether

Step 3:

CH3CH2 CH3CH2
+
CH3CH2O •• CH3CH2O •• +
••
H
– •• ••
•• OSO2OH H OSO2OH
•• ••

32
 Intramolecular Analog

HOCH2CH2CH2CH2CH2OH

H2SO4 130°

Reaction normally works well

only for 5- and 6-membered
O rings.

(76%)
33
 Intramolecular Analog

HOCH2CH2CH2CH2CH2OH

via:
H2SO4 130°

H
•• O
•• O•• +

O H
H
(76%)
34
 15.8. Esterification

O O
H+
ROH + R'COH R'COR + H2O

About this rxn:

- A condensation reaction.
- Called Fischer esterification.
- Acid catalyzed.
- Reversible.
35
 Example of Fischer Esterification
O

COH + CH3OH

0.1 mol 0.6 mol (i.e. excess)

H2SO4

COCH3 + H2O

70% yield based on benzoic acid 36

 Reaction of Alcohols with Acyl Chlorides

O O

ROH + R'CCl R'COR + HCl

About this rxn:

- High yields.
- Not reversible when carried out in presence
of pyridine.
37
 Example
CH3CH2 O

OH + O2N CCl

CH3
pyridine

CH3CH2 O

OC NO2

CH3
(63%) 38
Reaction of Alcohols with Acid Anhydrides

O O O O

ROH + R'COCR' R'COR + R'COH

analogous to reaction with acyl chlorides

39
 Example
O O

C6H5CH2CH2OH + F3CCOCCF3

pyridine

C6H5CH2CH2OCCF3

(83%) 40
 15.9. Esters of Inorganic Acids

ROH + HOEWG ROEWG + H2O

EWG is an electron-withdrawing group

+ –
HONO2 (HO)2SO2 (HO)3P O

CH3OH + HONO2 CH3ONO2 + H2O

(66-80%)
41
 15.10. Oxidation of Alcohols

Primary alcohols
O O

RCH2OH RCH RCOH

Secondary alcohols

OH O from H2O

RCHR' RCR'

42
Typical Oxidizing Agents
Aqueous solution
Mn(VII) Cr(VI)
KMnO4 H2CrO4
H2Cr2O7

43
 Aqueous Cr(VI)

H
FCH2CH2CH2CH2OH
OH

K2Cr2O7 H2SO4,
H2O H2SO4,
Na2Cr2O7
H2O
O

FCH2CH2CH2COH O

(74%) (85%)
44
 Nonaqueous Sources of Cr(VI)

All are used in CH2Cl2:

- Pyridinium dichromate (PDC)
(C5H5NH+)2 Cr2O72–
- Pyridinium chlorochromate (PCC)
C5H5NH+ ClCrO3–

45
Example: Oxidation of a
primary alcohol with PCC ClCrO3–
(pyridinium chlorochromate)
+N

O
PCC
CH3(CH2)5CH2OH CH3(CH2)5CH
CH2Cl2
(78%)

46
Example: Oxidation of a
primary alcohol with PDC
(pryidinium dichromate)

(CH3)3C CH2OH

PDC CH2Cl2

(CH3)3C CH
(94%) 47
Mechanism H •• H
O
••
O
H H
C HOCrOH C O

OH O O CrOH

O
involves formation
and elimination of a
chromate ester

C O
48
15.11. Biological Oxidation of Alcohols

Enzyme-catalyzed
+
CH3CH2OH + NAD (a coenzyme)

alcohol
dehydrogenase

CH3CH O + NAD H + H+
49
 Figure 15.3. Structure of NAD+

_ _
O OO O
H
O P P O
O O O
N NH2
HO
+ C
N OH
HO N HO
O

NH2

nicotinamide adenine dinucleotide (oxidized form)

50
 Enzyme-catalyzed
H O

CNH2
CH3CH2OH + + H+
+
N

R
H H O
O
CNH2
CH3CH
••
N
51
R
 15.12. Cleavage of Vicinal Diols by
Periodic Acid

HIO4
C C C O + O C

HO OH

52
Cleavage of Vicinal Diols by Periodic Acid

CH3

CH CCH3

HO OH

HIO4
O O

CH + CH3CCH3

(83%) 53
Cyclic Diols are Cleaved

OH O O
HIO4
HCCH2CH2CH2CH
OH

54
 15.13. Preparation of Thiols
Nomenclature of Thiols

1) Analogous to alcohols, but suffix is -thiol rather

than –ol.
2) Final -e of alkane name is retained, not dropped
as with alcohols.

CH3CHCH2CH2SH

CH3
3-Methyl-1-butanethiol
55
 Properties of Thiols

1. Low molecular weight thiols have foul odors.

2. Hydrogen bonding is much weaker in thiols than
in alcohols.
3. Thiols are stronger acids than alcohols.
4. Thiols are more easily oxidized than alcohols;
oxidation takes place at sulfur.

56
Thiols are less polar than alcohols

Methanol Methanethiol
bp: 65°C bp: 6°C
57
 Thiols are stronger acids than alcohols

Thiols have pKas of about 10; can be deprotonated in

aqueous base.

•• – •• •• – ••
RS H + •• OH RS •• + H OH
•• •• •• ••
stronger acid weaker acid
(pKa = 10) (pKa = 15.7)

58
RS– and HS– are weakly basic and good nucleophiles

H Cl C6H5S H
C6H5SNa
(75%)
SN2

KSH
Br SH
SN2
(67%)

59
 Oxidation of thiols take place at sulfur
•• •• ••
RS H RS SR
•• •• ••
thiol (reduced) disulfide (oxidized)

- Thiol-disulfide redox pair is important in biochemistry.

- Other oxidative processes place 1, 2, or 3 oxygen
atoms on sulfur.

60
 Oxidation of thiols take place at sulfur
•• •• ••
RS H RS SR
•• •• ••
thiol disulfide

•• – •• –
•• O •• •• O ••
•• + 2+
RS OH RS OH RS OH
•• ••
•• O ••
•• –
sulfenic acid sulfinic acid sulfonic acid
61
 Example: sulfide-disulfide redox pair

SH O
HSCH2CH2CH(CH2)4COH

O2, FeCl3

S S O
(CH2)4COH α-Lipoic acid (78%)

62
15.14. Spectroscopic Analysis of Alcohols

Infrared Spectroscopy

O—H stretching: 3200-3650 cm–1 (broad)

C—O stretching: 1025-1200 cm–1 (broad)

63
Figure 15.4: Infrared Spectrum of Cyclohexanol

OH

C— H
O—H C—O

3500 3000 2500 2000 1500 1000 500

Wave number, cm-1
64
 1H NMR
¾ Chemical shift of O—H proton is variable; depends
on temperature and concentration
¾ O—H proton can be identified by adding D2O; signal
for O—H disappears (converted to O—D)

H C O H
δ 3.3-4 ppm δ 0.5-5 ppm

65
Figure 15.5 (page 607)

CH2CH2OH

10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

Chemical shift (δ, ppm) 66

 13C NMR
Chemical shift of C—OH is d 60-75 ppm C—O is about
35-50 ppm less shielded than C—H.

CH3CH2CH2CH3 CH3CH2CH2CH2OH

δ 13 ppm δ 61.4 ppm

67
 UV-VIS
¾ Unless there are other chromophores in the
molecule, alcohols are transparent above about 200
nm; λmax for methanol, for example, is 177 nm.

68
 Mass Spectrometry of Alcohols
••
- Molecular ion peak is usually R CH2 OH
••
small.

- A peak corresponding to loss

of H2O from the molecular ion •+
R CH2 OH
(M - 18) is usually present. ••

- Peak corresponding to loss of

an alkyl group to give an +
R• CH2 OH
oxygen-stabilized carbocation is ••
usually prominent.
69