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 -bond of
the carbonyl to yield an alcohol
O
R
C
O
[H]
R
R'
R'
C
H
H
aldehyde (R or R´= H)  1° alcohol
ketone (R and R´≠ H)  2° 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
(NaBH4)
(LiAlH4)
Na+
electronegativity
H
H B H
H
B H
2.0 2.1
Li+
H
H Al H
H
Al H
1.5 2.1
321
synthons
R1
R2 C
R1
C OH
R2
OH
H
precursors
R1
+
H:
=
C O
+
NaBH4
R2
NaBH4 reduces aldehydes to primary alcohols
O
O2N
H
NaBH4
H H
O2N
OH
HOCH2CH3
NaBH4 reduces ketones to secondary alcohols
O
NaBH4
H OH
HOCH2CH3
ketones
2° alcohols
NaBH4 does not react with esters or carboxylic acids
HO H
O
NaBH4
H3CH2CO
HOCH2CH3
O
H3CH2CO
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.
O
1) LiAlH4, ether
H OH
2) H3O+
ketones
2° alcohols
O
H
1) LiAlH4, ether
2)
aldehydes
H3O+
H H
OH
1° alcohols
323
15.3: Preparation of Alcohols By Reduction of Carboxylic
Acids and Esters - LiAlH4 (but not NaBH4 or catalytic
hydrogenation).
O
H H
OCH2CH3
1) LiAlH4, ether
2)
OH
H3O+
1) LiAlH4, ether
OH
2) H3O+
1° alcohols
Esters
O
Carboxylic acids
15.4: Preparation of Alcohols From Epoxides - the threemembered ring of an epoxide is strained. Epoxides undergo ringopening reaction with nucleophiles (Grignard reagents, organolithium reagents, and cuprates).
O
H C C H
H
H
+
BrMg-CH3
ether,
then H3O+
SN2
HO CH2 CH2 CH3
324
precursors
synthons
disconnection
MgBr
OH
+
Br
H2C CH2OH
MgBr
Mg(0)
=
O
+
O
OH
then
H3O+
THF
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.
OsO4 (catalytic)
(H3C)3C-OOH
H
(H3C)3COH
H
OH
OH
H
O O
Os
O O
H
osmate ester
intermediate
325
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.
H3CH2C-OH + HO-CH2CH3
H2SO4
H3CH2C-O-CH2CH3 + H2O
Limitations: ether must be symmetrical
works best for 1° alcohols
327
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
R1
O
C
H+
OH
+
HO-R2
R1
O
C
+
OR2
HOH
Mechanism (Chapters 19 and 20)
Dean-Stark
Trap
328
Ester formation via the reaction of an acid chloride or acid
anhydride with an alcohol (nucleophilic acyl substitution)
R1
O
C
Cl
+
HO-R2
R1
O
C
+
HCl
+
O
C
OR2
acid chloride
R1
O
C
O
O
C
+
R1
HO-R2
R1
O
C
OR2
R1
OH
acid anhydride
Mechanism (Chapters 20)
329
15.9: Esters of Inorganic Acids (please read)
R1
O
C
+
OH
carboxylic
acid
R1
O
C
OR2 +
O
HO-R2
N
OH
alcohol
nitric
acid
HOH
esters
O
HO S OH
O
O
+
O
N OR
O
HO-R
+
O
HO P OH
OH
HO-R
O
HO S OR
O
HOH
nitrate
ester
+
O
HO P OR
OH
HOH
sulfate
ester
O2NO
ONO2
ONO2
O
O P O
O
O
HOH
N
H N
O
H N
N
N
N
O
+
phosphate
ester
H
N H
H2 N H
HO2C C C
H H
HO-R
phosphoric
acid
sulfuric
acid
+
+
O
O
N
O
H
O
nitroglycerin
phosphotyrosine
O
O
O
H
H N
P
N
P
O
O
H3CO S OCH3
O
dimethylsulfate
H2N H
O
HO2C C C O P O
H H
O
phosphoserine
N H
O
N
N
O
O
N
N
O
O
O
O
Phosphodiester
330
of DNA
O
O
15.10: Oxidation of Alcohols
oxidation [O]
OH
O
H
reduction [H]
H OH
C
R1
R2
[O]
R1
2° alcohols
H H
C
R1
OH
1° alcohols
O
C
R2
ketone
[O]
R1
O
C
[O]
H
aldehyde
R1
O
C
OH
carboxylic acids
KMnO4 and chromic acid (Na2Cr2O7, H3O+) oxidize secondary
alcohols to ketones, and primary alcohols to carboxylic acids.
331
Oxidation of primary alcohols to aldehydes
Pyridinium Dichromate (PDC)
Na2Cr2O7 + HCl + pyridine
N
H
2Cr2O5
2
Pyridinium Chlorochromate (PCC)
-
CrO3 + 6M HCl + pyridine
N
H
ClCrO3
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
CO2H
H3O+,
acetone
Carboxylic Acid
PCC
OH
1¡ alcohol
CH2Cl2
CHO
Aldehyde
332
15.11: Biological Oxidation of Alcohols (please read)
Ethanol metabolism:
CH3CH2OH
alcohol
dehydrogenase
aldehyde
dehydrogenase
O
C
H3C
O
H
H3 C
acetaldehyde
ethanol
C
OH
acetic acid
Nicotinamide Adenine Dinucleotide (NAD)
H
H2N
N
O
N
N
O
O
N
P
OH
O
R
OH
H
O
O
O
P
O
O
N
NH2
H2N
O
N
O
N
N
O
O
N
OH
HO
OH
O
OH
OH
R
reduced form
P
O
O
P
O
O
N
OH
HO
OH
oxidized form
R= H NADH, NAD+
R= PO32- NADPH, NADP+
CO2H
Vitamin B3, nicotinic acid, niacin
N
333
NH2
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)
HO
R3
R1
R2
NaIO4
R1
THF, H2O
R2
OH
R4
OH
O
O
I
O
O
R1
R2
CH3
OH
OH
H
R3
R4
O
+
O
R4
periodate ester
intermediate
O
NaIO4
H2O, acetone
R3
CH3
H
O
334
15.13: Thiols
Thiols (mercaptans) are sulfur analogues of alcohols.
Thiols have a pKa ~ 10 and are stronger acids than alcohols.
HO–
RS-H +
(pKa ~10)
RS–
+
H-OH
(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
CH3CH2-SH
_
CH3CH2-S
Br
Na+
SN2
HS
_
Na+
+
Br-CH2CH2CH2CH3
THF
SN2
CH3CH2-S-CH2CH2CH2CH3
HS-CH2CH2CH2CH3
335
Thiols can be oxidized to disulfides
[O]
R-S-S-R
2 R-SH
[H]
disulfide
thiols
O2C
2
O2C
H
N
H3N
O
O
N
H
SH
-2e-, -2H+
O
H
N
H3N
N
H
O
CO2
S
+2e-, +2H+
S
glutathione
O2C
H
N
O
[O]
R SH
Thiol
[O]
R S OH
sulfenic acid
CO2
O
R S OH
sulfinic acid
[O]
O
N
H
NH3
CO2
O
2
R S OH
O
sulfonic acid
336
Bioactivation and detoxication of benzo[a]pyrene diol epoxide:
P450
H2O
O2
HO
O
OH
benzo[a]pyrene
OH
NH2
N
O
P450
N
DNA
HO
N
N
HO
NH
HO
N
OH
glutathione
transferase
SG
HO
N
DNA
G-S
N
N
O2C
H
N
H3N
O
HO
OH
O
N
H
SH
CO2
glutathione
337