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