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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
A possible chemical warfare agent
H
N
N
NH
N
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
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'
H3O
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
2) H3O
OH
+
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
Regiochemistry
Ring Opens at More Hindered Site
+
H , CH3OH
OH
O
OCH3
OH
O
CH3OH
H
OCH3
CH3OH
H
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
HO
+ MgBrOH
+
2) H3O
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 Reagents open
Epoxides
O
RCO3H
CH3MgBr
OH
MgBrO
CH3
+ enant.
H3O
+
CH3
Ring-Opening is Sterically
Controlled
CH2CH3
OH
O
CH3
1) CH3CH2MgBr
+
2) H3O
base opens epoxide at less hindered site
CH3
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
+ H2O
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
SN1: Carbocations can Rearrange
HO
Br
Br
HBr
+
cis & trans
HO
Br
Br
H-Br
+
cis & trans
H
Br
HO
- H2O
H
Br
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
O
O
H
S
Cl + SO2 + HCl
pyridine
O
Cl
O
Cl
H
N
S
+
Cl
-H
O
Cl
O
S
Cl
Dehydration of Alcohols – E1
OH
H
H2SO4 (aq) cat.
+ H2O
H
regenerated
H
O
HSO 4
or H2O
H
-H2O
H
Methide Shift is Faster than
Loss of H+
CH3
OH
CH3
CH3
CH3
CH3
H2SO4 (aq)
CH3
+
distill
major
minor
+ H2O
CH3OH
OCH3
OH
1) Br 2, h
PCC or
+
Na2Cr2O7, H
2) Mg
P/I2
or
CH3I
MgBr
1) Na
2) CH3I
+
H3O
+
O
OH
Provide a sequence of steps
OH
Br
OH
HO
2 Approaches
OH
Br
HO
OH
PCC
in CH 2Cl2
O
Br
KOH, DMSO
OH
1) CH3MgBr in ether
H
+
2) H3O
Br
Alternate Approach
OH
Br
HO
OH
ClSi(CH 3)3
pyridine
Br
1) CH3MgBr
in ether
2) H3O
OSi(CH3)3
+
KOH, DMSO
(SN2)
HO
OSi(CH3)3
PCC
in CH 2Cl2
H
OSi(CH3)3
O
Propose a Mechanism
OCH2CH3
+
H3O
Where do you protonate?
O
+ CH3CH2OH
Both approaches seem logical
H
OCH2CH3
+
H
OCH2CH3
OCH2CH3
+
H
H
OCH2CH3
H
Take the Blue Route
O
+
OCH2CH3
H3O
H
+ 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