Reactions of Alcohols

Reactions of Alcohols
Oxidation
R-X, Ether, and Ester Preparation
Protection of Alcohols
Synthesis
The Logic of Mechanisms
Alcohols are Synthetically

Versatile
Oxidation levels of
oxygen- halogen- and nitrogencontaining molecules
CH2=CH2
CH3CH3
[O]
CH3CH2OH
HC
[O]
CH
CH3CH=O
[O]
CH3CO2H
CH3CH2Cl
CH3CHCl2
CH3CCl3
CH3CH2NH2
CH3CH=NH
CH3CN
Oxidation
Reduction
Oxidation - Reduction
Oxidation of 2 Alcohols with

Cr(VI)
o
Mechanism
Na2Cr2O7 + H2O + 2 H2SO4
O
OH
+
HO
2 alcohol
Cr
OCrO3H
OH
O
Chromic Acid (Cr VI)
CrO3H
2 H2CrO4 + 2 NaHSO4
+ H2O
Chromate ester
O
OH2
+ H3O + HCrO3
ketone
(Cr IV)
Oxidation of 1 Alcohols
o
PCC oxidizes 1 Alcohols to

Aldehydes
o
CrO3Cl
N
PCC
H
pyridinium chlorochromate
Oxidation of 1 Alcohols to
Aldehydes: PCC
o
Oxidation Summary
CH2CO2H
Na2Cr2O7
H2SO4
CH2CH2OH
NH
CrO3Cl
OO
DMSO, ClCCCl
(CH3CH2)3N, in CH2Cl2
CH2CHO
CH2CHO
Reduction Summary
CH2CO2H
1) LiAlH4
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
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) LiAlH4
KI
NaOCH3
CH3
CH3
CH3
I
H
+ LiOTs
Alcohols to Alkyl Halides

OH
HX (HCl or HBr)
rapid SN1
+ HOH
3 alcohol
OH
HX
moderate SN1
2 alcohol
+ HOH
SN1: Carbocations can Rearrange

HO
Br
Br
HBr
+
cis & trans
HO
Br
Br
H-Br
+
cis & trans
Br
HO
- H2O
Br
Lucas Test
CH3
ZnCl2
12M HCl
CH3COH
CH3
CH3CCl forms in seconds

CH3 + HOZnCl2
CH3
CH3
CH3C
CH3
OZnCl2
CH3 H
CH3C
CH3
Cl
Qualitative test for Alcohol

Characterization
primary
OH
secondary
OH
tertiary
OH
>10 minutes
(if at all)
ZnCl2, HCl
Cl
<5 minutes
Cl
1-2 seconds
Cl
Other Simple Qualitative Tests

Alkenes
Br
Br2
reddish-brown
OH
colorless
Br
Alcohols
Na2Cr2O7
OH
H2SO4
orange
Cr(VI)
green
Cr(IV)
CO2H
1 and 2 Alcohols: best to use

SOCl2, PBr3, or P/I2
o
All are SN2 Reactions

SOCl2
pyridine
OH
PBr3
P, I2
(in situ prep.
of PI3)
Cl
Br
I
Thionyl chloride mechanism

in Pyridine SN2, Inversion
O
Cl
OH
O
O
H
Cl
SOCl2
Cl + SO2 + HCl
pyridine
O
Cl
Cl
H
N
Cl
-H
Cl
O
Cl
Dehydration of Alcohols E1
OH
H
H2SO4 (aq) cat.
+ H2O
H
regenerated
HSO4
or H2O
H
-H2O
Methide Shift is Faster than

+
Loss of H
OH
CH3
CH3
CH3
CH3
CH3
H2SO4 (aq)
CH3
distill
major
minor
+ H 2O
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
H
CH3CH2CH2-OH
CH3CH2CH2OH
CH3CH2CH2OCH2CH2CH3
+ H2O
loss of H2O
CH3CH2CH2OCH2CH2CH3
H2O
Williamson Ether Synthesis

Preparation of Unsymmetrical Ethers
Mechanism, SN2
Na O
OH
Na, THF
I
o
1 alkyl halide
SN2
Protection of Alcohols
Suppose you wanted to carry out the following transformation:
CH2OH
CH2OH
CH3
OH
Would the following Grignard sequence work?

1) CH3MgBr
+
2) H3O
Nope.
Alcohol is acidic enough to

react preferentially.
CH2OH
CH2OMgBr
1) CH3MgBr
2) H3O
+ CH4
Chlorotrimethylsilane (TMS-Cl)
Protecting groups temporarily convert reactive functional
groups into unreactive groups in a simple, high-yielding reaction.
ROH + ClSi(CH3)3
TMS-Cl
pyridine
or Et3N
dilute H3O
deprotection
ROSi(CH3)3 + HCl
Mechanism is SN2
OH
CH3
CH3
CH3
H
Si
Cl
O
SN2
Cl
Si(CH3)3
OSi(CH3)3
+ HCl
Protect as trimethylsilyl ether

CH2OH
CH2OH
CH3
3) H3O
protonates
& deprotects
1) ClSi(CH3)3
in pyridine
CH2OSi(CH3)3
CH2OSi(CH3)3
2) CH3MgBr
dry ether
O
OH
OMgBr
CH3
Give the Reagents

OH
OCH3
No Protection needed
OH
1) Na metal
2) CH3I
3) CH3CH2MgBr 4) H3O
5) TsCl, pyridine
+
6) LiAlH4 7) H3O
OCH3
+
Road Map Problem

Br
MgBr
O
1) CH3CH2CH
2) H3O
Na2Cr2O7
H2SO4
1) CH3MgBr
2) H3O
Synthesize using cyclohexane,

2-butanol and methanol
OH
CH3OH
only organic starting materials
OCH3
Determine Where New Bonds

are Formed
*CH3OH
Williamson
*
OH
*
*
Grignard
CH3
CH3OH
OH
1) Br2, h
PCC or
+
Na2Cr2O7, H
2) Mg
P/I2
or
CH3I
MgBr
H3O
+
O
OCH3
1) Na
2) CH3I
OH
Provide a sequence of steps

OH
Br
OH
HO
2 Approaches
OH
Br
HO
OH
PCC
in CH2Cl2
O
Br
KOH, DMSO
OH
1) CH3MgBr in ether
H
2) H3O
Br
Alternate Approach
OH
Br
HO
OH
ClSi(CH3)3
pyridine
Br
1) CH3MgBr
in ether
2) H3O
OSi(CH3)3
KOH, DMSO
(SN2)
HO
OSi(CH3)3
PCC
in CH2Cl2
OSi(CH3)3
O
Protection is needed in order to elaborate the other end.

KOH is used as a nucleophile (SN2)
Numbering in product is opposite to starting material.
Br
1
1) Br
2) HO
OH
1) TMS-Cl, pyr.
2) KOH, DMSO
3) PCC
4) CH3MgBr
+
5) H3O
OSi(CH3)3
3)
OH
HO
4
OSi(CH3)3
O
OSi(CH3)3
5)
OH
OH
Mechanisms
Thinking Logically
Do not use reagents that are not given.
Is the product a result of a rearrangement? Only
intermediates can rearrange.
Is one of the reagents H3O+? If so, use it in the 1st
step. Do not create negatively charged species in
acid.
CH2
H3C
CH3
CH3
OH
H , heat
H3C
CH3
+ H2O
Only Five Arrows

CH2
H3C
CH3
CH3
OH
H , heat
CH3
H3C
+ H2O
H2O
H3C
CH3
CH3
OH
H
H3C
CH3
CH3
H
H3C
CH2
CH3
Propose a Mechanism
OCH2CH3
H3O
Where do you protonate?
O
+ CH3CH2OH
Both approaches seem logical

H
H
OCH2CH3
OCH2CH3
H
OCH2CH3
H
OCH2CH3
H
Take the Blue Route

OCH2CH3
H3O
H
+ CH3CH2OH
OCH2CH3
H2 O
H
OH2
O
H
CH2CH3
H
HOCH2CH3

Reactions of Alcohols

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Reactions of Alcohols

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Reactions of Alcohols

Alcohols are Synthetically

Oxidation of 2 Alcohols with

PCC oxidizes 1 Alcohols to

Conversion of Alcohol into a

Best to use p-TsCl with

pyridine reacts with

Alcohols to Alkyl Halides

SN1: Carbocations can Rearrange

CH3CCl forms in seconds

Qualitative test for Alcohol

Other Simple Qualitative Tests

1 and 2 Alcohols: best to use

All are SN2 Reactions

Thionyl chloride mechanism

Methide Shift is Faster than

Williamson Ether Synthesis

Would the following Grignard sequence work?

Alcohol is acidic enough to

Protect as trimethylsilyl ether

Give the Reagents

Road Map Problem

Synthesize using cyclohexane,

Determine Where New Bonds

Provide a sequence of steps

Protection is needed in order to elaborate the other end.

Only Five Arrows

Where do you protonate?

Both approaches seem logical

Take the Blue Route

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