Alcohols
Biological Activity
Nomenclature
Preparation
Reactions
Some Alcohols
CH3CH2OH
HO
OH
OH
CHCH2NH2
CHCHNHCH3
CH3
ethanol
HO
adrenaline (epinephrine)
OH
H
HOCH2CHCH2OH
glycerol
H
HO
H
cholesterol
pseudephedrine
Alcohols are Found in Many
Natural Products
HO
N CH3
O
H
HO
Morphine
most abundant of opium's alkaloids
Paralytic Shellfish Poisoning
NH2
O
O
H
HN
H
N
N
NH
N
A possible chemical warfare agent
roughly 1000 times more toxic
than saran gas or cyanide
N H
OH
The toxin blocks entry of sodium
OH required by cells to make "action potentials"
Saxitoxin (STX)
LD 50 = 2 g/kg
OH
O
O
OH
OH
HO
OH
O
H2N
OH
OH
OH
OH
HO
PALYTOXIN
LD 50 = 0.15 g/kg
OH
OH
OH
OH
OH
OH
O
HO
O
N
N
H
H
HO
OH
OH
OH
OH
OH
O
OH
OH
OH
OH
HO
OH
O
O
O
OH
HO
OH
OH
OH
OH
HO
OH
OH
OH
OH
OH
Ethanol: the Beverage
Ethanol is a central nervous system depressant
- depresses brain areas responsible for judgement
(thus the illusion of stimulation)
alcohol dehydrogenase
CH 3CH 2OH
ethanol
NAD
+
O
CH 3CH + NADH + H
acetaldehyde
LD 50 = 1.9 g/Kg
NAD
enz.
+
CH 3CO 2H + NADH + H
acetic acid
+
+
Methanol: Not a Beverage
CH3OH
methanol
ADH
NAD
+
O
+
HCH + NADH + H
formaldehyde
LD 50 = 0.07 g/Kg
Oxidation levels of
oxygen- halogen- and nitrogencontaining molecules
CH2=CH2
CH3CH3
[O]
CH3CH2OH
HC
[O]
CH
CH3CH=O
[O]
CH3CO2H
CH3CH2Cl
CH 3CHCl2
CH3CCl3
CH3CH2NH2
CH3CH=NH
CH3CN
Oxidation
Reduction
Acidity of Alcohols
• Due to the electronegativity of the O atoms,
alcohols are slightly acidic (pKa 16-18).
• The anion dervived by the deprotonation of an
alcohol is the alkoxide.
• Alcohols also react with Na (or K) as water
does to give the alkoxide (red-ox):
CH3CH2OH + Na
CH3CH2O Na + 1/2 H2
Withdrawing Groups Enhance
Acidity
CF3
CF3
CF3
C OH + NaHCO3
CF3
CF3
alcohol
CH3OH
CH3CH2OH
CF3CH2OH
(CH3)3COH
(CF3)3COH
C O Na + H2CO3
CF3
pKa
15.54
16.00
12.43
18.00
5.4
Phenols are more acidic than alcohols
Physical Properties
b.p. oC
D
sol. in H2O
CH3CH2CH3
-42
0.08
i
CH3OCH3
-25
1.3
ss
CH3CH2OH
78
1.7
vs
Intermolecular H-Bonding
 
O H
H
H
 
O H
 
O H
O
associated liquid
intermolecular H bonding
O H
H
H
O
Alcohol Nomenclature
OH
3
3-heptanol
6
2
5
5-methyl-6-hepten-2-ol OH
2
OH
1
1
3
CH3
CH3
3,3-dimethylcyclohexanol
OH
CH3
5
CH3
5,5-dimethylcyclohex-2-enol
Nomenclature
OH
OH
(E) 3-methyl-3-penten-2-ol
(S) 2-hexanol
OH
OH
trans 3-isopropylcyclopentanol
H
OH
(R) 2-butyl-1,4-butanediol
(R) 2-butylbutane-1,4-diol
Preparation of Alcohols
•
•
•
•
Reduction of ketones and aldehydes
Reduction of esters and carboxylic acids
Hydration of Alkenes
Nucleophilic addition
– Grignard reaction
– Acetylide addition
• Substitution
• Epoxide opening
NaBH4 Reduction
O
R
1) NaBH4, ethanol
R'
2) H3O
+
H
H
OH
R
R'
H 3O
H
R
O
R'
+
Some Examples
O
OH
1) NaBH 4, ether
2) H3O
O
CH
+
"
CH2OH
Two Alcohol Products Form in Lab
O
H
axial approach
NaBH4
(CH3)3C
H
O Na
(CH3)3C
trans
O Na
O
NaBH4
(CH3)3C
H
(CH3)3C
H
equatorial approach
cis
LiAlH4 Reduction
a Stronger Reducing Agent
OH
O
1) LiAlH 4, THF
2) H3O
+
LiAlH 4 will reduce:
o
ketones to 2 alcohols
o
aldehydes to 1 alcohols
o
carboxylic acids and esters to 1 alcohols
LiAlH4 is a much stronger
reducing agent
1) LiAlH 4
O
OH
+
2) H3O
+ CH3OH
O
1) NaBH4
+
2) H3O
no reaction
NaBH4 is More Selective
O
O
1) NaBH4
OH
OH
+
2) H3O
O
OH
OH
1) LiAlH 4
+
2) H3O
OH
Oxymercuration Hydration
Markovnikov
1) Hg(OAc) 2 in
THF/H2O
2) NaBH4
OH
H
Hydroboration Hydration
Anti-Markovnikov
3
1) BH3-THF
2) H2O2, NaOH
H OH
3
Base Catalyzed Ring-Opening
of Epoxides
Acid Catalyzed Ring-Opening
Aqueous and in Alcohol
Nucleophilic addition to Carbonyl
Compounds
Acetylides

O

H
O

C
CH3
CH3CH2C

CH3
CH3
CH3CH2C
C
CH3
C
C
H3O
+
OH
CH3
CH3CH2C
C
C
CH3
Organometallic Chemistry
Grignard Reaction
CH3
Br + Mg
"CH3 MgBr "
excellent nucleophile
very strong base
 
CH3 MgBr
Grignard Reagent
Grignard Reagents React With
Ketones to form tertiary alcohols
O
CH3
1) CH3MgBr in ether
2) H3O
HO
+ MgBrOH
+
o
a 3 alcohol
H3O
MgBrO
CH3
CH3
+
Grignard Reagents React With
Aldehydes to form secondary alcohols
O

 
MgBr
in ether
1)
H
OH
+
2) H3O
H
Grignard Reagents React With
Formaldehyde to form primary
alcohols
CH2CH2O MgBr
CH2CH2OH
H3O
+
O

C 
H
H
formaldehyde
CH2 MgBr
CH2Br
Mg, ether, 
Grignard Reagents react (twice) with
Esters to form 3o Alcohols
O
OH
C
C CH
3
CH3
OCH3
1) 2 CH3MgBr
2) H3O
+
CH3
O
C OCH
3
CH3
2nd eq.
1) CH3MgBr
+
2) H3O
O
C
CH3
ketone
(more reactive than ester)
Grignard Summary
H
H
R
MgX
+
+
C
O
H3O workup
R
H formaldehyde
R
MgX
R'
+
O
R'
H3O workup
R
H aldehyde
R
MgX
R'
+
C
R''
ketone
C
OH
H
R'
+
O
OH
H
+
C
C
H3O workup
R
C
R''
OH
Grignard Summary
R
O
H3O workup
R'
MgX +
epoxide
R''
R
R'
2 R
MgX
+
OH
+
R'
+
C
O
RO ester
H3O workup
R
C
OH
R + ROH
Grignard Reagents are
exceptionally strong bases
H2O
CH3OH
CH3CH2CH2MgBr +
CH3CO2H
HC
CH
CH3NH2
CH3CH2CH3
Synthesis
OH
?
Retrosynthetic Analysis
OH
?
Br
MgBr
4-Step Synthesis
OH
1) HCHO
+
2) H3O
Br 2, h
Br
Mg in ether
MgBr
Synthesize Using Only 1,2, or
3-Carbon Reagents
OH
HC
CH
Retrosynthesis
+
OH
O 
MgBr
HC
Mg
Br
CH
HBr
CH3X
CH3X
reduce
Reactions of Alcohols
Oxidation
R-X, Ether, and Ester Preparation
Protection of Alcohols
Synthesis
The Logic of Mechanisms
Alcohols are Synthetically
Versatile
Oxidation - Reduction
Oxidation of 2o Alcohols with
Cr(VI)
Mechanism
Na2Cr2O7 + H2O + 2 H2SO4
O
OH
+
HO
o
2 alcohol
O
Cr
OCrO3H
OH
O
Chromic Acid (Cr VI)
CrO3H
H
2 H2CrO 4 + 2 NaHSO4
+ H 2O
Chromate ester
O
OH2
+ H3O + HCrO3
ketone
(Cr IV)
Oxidation of 1o Alcohols
PCC oxidizes 1o Alcohols to
Aldehydes
CrO3Cl
N
PCC
H
pyridinium chlorochromate
Oxidation of 1o Alcohols to
Aldehydes: PCC
Oxidation Summary
CH2CO2H
Na2Cr2O7
H2SO4
CH2CH2OH
NH
CrO3Cl
OO
DMSO, ClCCCl
(CH3CH2)3N, in CH 2Cl2
CH2CHO
CH2CHO
Reduction Summary
CH2CO2H
1) LiAlH 4
2) H3O
+
CH2CH2OH 1) NaBH
4
2) H3O
CH2CHO
+
or
H2, Raney Ni
CH2CHO
Conversion of Alcohol into a
Leaving Group
• Form Tosylate (p-TsCl, pyridine)
• Use strong acid (H3O+)
• Convert to Alkyl Halide (HX, SOCl2, PBr3)
Formation of
p-Toluenesulfonate Esters
Best to use p-TsCl with
pyridine
CH3
OH
CH3
O
CH3
+ ClS
O
p-toluenesulfonyl chloride
OS
N
pyridine reacts with
HCl as it forms
O
O
N
H
Cl
CH3
Reactions of Tosylates:
Reduction, Substitution, Elimination
CH3
OH
CH3
O
+ ClS
O
CH3
O
OS
pyr:
CH3
O
1) LiAl H4
KI
NaOCH3
CH3
CH3
CH3
I
H
+ LiOTs
Alcohols to Alkyl Halides
OH
HX (HCl or HBr)
X
rapid S N1
+ HOH
o
3 alcohol
OH
o
2 alcohol
HX
moderate S N1
X
+ HOH
Lucas Test
CH3
ZnCl 2
12M HCl
CH3COH
CH3
CH3CCl forms in seconds
CH3 + HOZnCl 2
CH3
CH3
CH3C
CH3
OZnCl2
CH3 H
CH3C
CH3
Cl
Qualitative test for Alcohol
Characterization
primary
OH
>10 minutes
(if at all)
OH
ZnCl 2, HCl
secondary
OH
tertiary
Cl
<5 minutes
Cl
1-2 seconds
Cl
Other Simple Qualitative Tests
Alkenes
Br
Br 2
reddish-brown
OH
colorless
Br
O
Alcohols
Na2Cr2O7
OH
H2SO4
orange
Cr(VI)
green
Cr(IV)
CO2H
1o and 2o Alcohols: best to use
SOCl2, PBr3, or P/I2
All are SN2 Reactions
SOCl2
pyridine
OH
PBr 3
P, I2
(in situ prep.
of PI3)
Cl
Br
I
Thionyl chloride mechanism
in Pyridine – SN2, Inversion
O
Cl
S
Cl
SOCl2
OH
Cl + SO2 + HCl
pyridine
O
O
O
H
S
Cl
O
Cl
H
N
S
+
Cl
-H
O
Cl
O
S
Cl
Dehydration of Alcohols – E1
OH
H
H2SO4 (aq) cat.
+ H 2O
H
regenerated
H
O
HSO 4
or H2O
H
-H2O
H
Propose a Mechanism
OCH2CH3
+
H3O
Where do you protonate?
O
+ CH3CH2OH
Both approaches seem logical
H
H
OCH2CH3
+
OCH2CH3
OCH2CH3
H
+
H
OCH2CH3
H
Take the Blue Route
OCH2CH3
H3O
H
O
+
+ CH3CH2OH
+
OCH2CH3
H2O
H
H
O
OH2
O
H
CH2CH3
HOCH2CH3
H
Problem Set:
Road Map Problem
Br
A
MgBr
B
O
1) CH3CH2CH
+
2) H3O
C
Na2Cr2O7
H2SO4
D
1) CH3MgBr
+
2) H3O
E
Ethers
Dimerization of Alcohols:
Symmetrical Ethers
Dehydration
o
2 CH3CH2CH2OH
H2SO4, 125-140 C
CH3CH2CH2OCH2CH2CH3
+ H2O
Mechanism
Dehydration, Acid-Catalyzed
o
H2SO4, 125-140 C
2 CH3CH2CH2OH
CH3CH2CH2OCH2CH2CH3
+ H2O
H
CH3CH2CH2-OH
CH3CH2CH2OH
loss of H 2O
CH3CH2CH2OCH2CH2CH3
H2O
H
Williamson Ether Synthesis
Preparation of Unsymmetrical Ethers
Mechanism, SN2
Na O
OH
Na, THF
+
I
o
1 alkyl halide
SN2
O
Alkoxides are strong bases so there is competition with E2 reactions. Bulky
alkoxides reacting with primary alkyl halides favor Williamson ether
synthesis(SN2).
How would you prepare the following ethers starting from an alcohol and an alkyl
halide?
O
O
O
Alkene Oxides, Oxiranes or Epoxides
O
CH2=CH2
ethylene
[O]
CH2
CH2
ethylene oxide
oxirane
1,2-epoxyethane
Epoxides are Extremely Reactive
Cleavage of Unsymmetrical
Ethers
H
Br
HBr
O
OH
Br
+
HBr
H
O
Br
SN2
Br
Size 1, Pairwork
8.28 b,d
8.29 a,d
8.33 e,f
8.44 a-e
8.45
8.47
8.51
8.57
8.61
8.64