Chapter 11 - Reactions of Alcohol (Compatibility Mode)

Types of Alcohol Reactions
Organic Chemistry,
8th Edition
L. G. Wade, Jr.
Chapter 11
Lecture
Reactions of Alcohols
Rizalia Klausmeyer
Baylor University
Waco, TX
Dehydration to alkene (learned)

Oxidation to aldehyde, ketone
Substitution to form alkyl halide
Reduction to alkane
Esterification
Tosylation
Williamson synthesis of ether (learned)
2013 Pearson Education, Inc.

Chapter 11
Chapter 11
Summary Table
Oxidation States
Inorganic chemistry:
Oxidation is a loss of electrons.
Reduction is a gain of electrons.
Organic
O
i chemistry
h i
Oxidation: Gain of O, O2, or X2; loss of H2.
Reduction: Gain of H2 (or H); loss of O or O2; and
loss of X2.
Neither: The gain or loss of H+, H2O, OH, HX, etc. is
neither an oxidation nor a reduction.
Chapter 11
Oxidation States of Carbons
Chapter 11
Oxidation of 2 Alcohols
A 2 alcohol becomes a
ketone.
Traditional oxidizing
agents are chromiumbased reagents such as
Na2Cr2O7 in H2SO4.
Active reagent probably is
H2CrO4 or HCrO4.
Color change is orange to
greenish-blue.
Chromium is highly toxic
and difficult to dispose of
properly.
Chapter 11
Chapter 11
Formation of the Acid

Chromate Ion
Oxidation Mechanism
CrO3 will also produce chromic acid in

the presence of H2SO4 and H2O.
Chapter 11
Chapter 11
Pyridinium Chlorochromate
(PCC)
Oxidation of 1 Alcohols to
Carboxylic Acids
PCC is a complex of
chromium trioxide,
pyridine, and HCl.
Oxidizes primary
alcohols to aldehydes.
Chromic acid reagent oxidizes primary

alcohols to carboxylic acids.
Chapter 11
PCC is a mild
oxidizing reagent.
Oxidizes secondary
alcohols to ketones.
The oxidizing agent is too strong to stop

at the aldehyde.
9
Pyridinium Chlorochromate
(PCC)
Chapter 11
10
3 Alcohols Cannot Be Oxidized

Carbon does not have hydrogen, so
oxidation is difficult and involves the
breakage of a CC bond.
Chromic acid test is for primary and
secondary alcohols because tertiary
alcohols do not react.
Chapter 11
11
Chapter 11
12
Swern Oxidation
Sodium Hypochlorite (NaOCl)
Dimethylsulfoxide (DMSO), with oxalyl chloride

and hindered base, oxidizes 2 alcohols to
ketones and 1 alcohols to aldehydes.
Sodium hypochlorite (household bleach)

can oxidize alcohols without heavy metals or
generating hazardous waste.
This is a much better option for acid-sensitive
compounds.
Chapter 11
Like PCC, Swern reagent is a mild oxydizing

agent.
13
Dess-Martin Periodinane
(DMP)
Chapter 11
14
Solved Problem 1
Suggest the most appropriate method for each of the
following laboratory syntheses:
(a) cyclopentanol > cyclopentanone
Solution
Can oxidize primary alcohols to aldehydes and

secondary alcohols to ketones.
Many reagents are available to oxidize a simple secondary alcohol to a ketone. For
a laboratory synthesis, however, dehydrogenation is not practical, and cost is not
as large a factor as it would be in industry. Most labs would have chromium
trioxide or sodium dichromate available, and the chromic acid oxidation would be
simple. PCC and the Swern oxidation would also work, although these reagents are
more complicated to prepare and use.
The reaction with DMP takes place under mild

conditions (room temperature, neutral pH) and
gives excellent yields.
Chapter 11
15
Solved Problem 1 (Continued)
Chapter 11
16
Biological Oxidation
Suggest the most appropriate method for each of the following

laboratory syntheses:
(b) 2-octen-l-ol > 2-octenal (structure below)
The liver produces alcohol dehydrogenase

(ADH), which is an enzyme that catalyzes the
oxidation of ethanol.
Solution
This synthesis requires more finesse. The aldehyde is easily overoxidized to a
carboxylic acid, and the double bond reacts with oxidants such as KMnO4. Our
choices are limited to PCC or the Swern oxidation.
O
Oxidizing
idi i agentt iis nicotinamide
i ti
id adenine
d i
dinucleotide (NAD+).
Ethanol oxidizes to acetaldehyde, then acetic
acid, which is a normal metabolite.
Chapter 11
17
Chapter 11
18
Biological Oxidation of
Methanol and Glycol
Enzymatic Oxidation of Ethanol
Methanol oxidizes to formaldehyde, then formic

acid, which is more toxic than methanol.
Ethylene glycol oxidizes to oxalic acid, which is

toxic.
Treatment for poisoning is excess ethanol.
Ethanol oxidizes to acetaldehyde, then acetic acid,
which is a normal metabolite.
Chapter 11
19
Alcohol as a Nucleophile
20
Alcohols are weak electrophiles because the OH

is not a good leaving group.
Alkoxides (RO) are strong nucleophiles.
Protonation of the hydroxyl group converts it

into a good leaving group (H2O).
New OC bond forms; OH bond breaks.

Chapter 11
Chapter 11
Alcohol as an Electrophile
Alcohols (ROH) are weak nucleophiles.
21
Tosylate Esters
Chapter 11
22
Alkyl Sulfonates
Sulfonyl chlorides are derived from
sulfonic acids
sulfonic acids are strong acids like sulfuric
acid
Alcohols can be converted to tosylate esters

(ROTs) through a condensation with ptoluenosulfonic acid.
O
R- S- Cl
O
A sulfonyl
chloride
O
R- S- OH
O
A sulfonic acid
(a very strong acid)
The tosylate group is an excellent leaving

group.
Chapter 11
23
Chapter 11
O
R- S- OO
A sulfonate anion
(a very weak base and
stable anion; a very
good leaving group
24
Substitution and Elimination

Reactions Using Tosylates
SN2 Reactions with Tosylates
TsCl is 4-Toluenesulfonyl chloride, also called Tosyl

Chloride
Chapter 11
25
The reaction shows the SN2 displacement of the

tosylate ion (OTs) from (S)-2-butyl tosylate with
inversion of configuration.
The tosylate ion is a particularly stable anion,
with its negative charge delocalized over three
oxygen atoms.
Chapter 11
26
Summary of Tosylate
Reactions
Tosylate esters are particularly
useful: They are great leaving
g
groups,
p , often better than halides.
Grignard reactions build alcohols,
which are easily converted to
tosylates for substitution or
elimination.
Chapter 11
27
Reduction of Alcohols
Chapter 11
28
Reaction of Alcohols with Acids
Dehydrate with concentrated H2SO4, then

add H2.
The hydroxyl group is protonated by an acid

to convert it into a good leaving group (H2O).
Make a tosylate, then reduce it with LiAlH4.
Once the alcohol is protonated, a substitution

or elimination reaction can take place.
Chapter 11
29
Chapter 11
30
SN1 Mechanism
Reaction of Alcohols with HBr
Step 1: Protonation.
Step 2: Formation of the carbocation.
OH of alcohol is protonated.
OH2+ is good leaving group.
Step 3: Bromide attacks the carbocation.
3 and 2 alcohols react with Br via SN1.

1 alcohols react via SN2.
Chapter 11
31
Chapter 11
32
SN2 Mechanism
Memorizing all these mechanisms is not
the best way to study this material.
Depending on the substrate, these
reactions can go by more than one
mechanism. Gain experience working
problems, then consider each individual
case to propose a likely mechanism.
Chapter 11
33
Reaction with HCl

Chloride is a weaker nucleophile than bromide
because it is small and less polarizable.
Addition of ZnCl2, which bonds strongly with
oxygen of the OH, promotes the reaction.
Lucas test: ZnCl2 in concentrated HCl:
1 alcohols react slowly or not at all.
2 alcohols react in 15 minutes.
3 alcohols react in less than 1 minute.
Chapter 11
Chapter 11
34
SN2 Reaction with the Lucas

Reagent
Primary alcohols react with the Lucas reagent

(HCl and ZnCl2) by the SN2 mechanism.
Reaction is very slow. The reaction can take from
several minutes to several days.
35
Chapter 11
36
SN1 Reaction with the Lucas

Reagent
Limitations of HX Reactions
Poor yields of alkyl chlorides from primary
and secondary alcohols.
Elimination competes with substitution.
Carbocation intermediate may undergo a
rearrangement.
Secondary and tertiary alcohols react with the Lucas

reagent (HCl and ZnCl2) by the SN1 mechanism.
Chapter 11
37
Solved Problem 2
When 3-methyl-2-butanol is treated with concentrated HBr, the
major product is 2-bromo-2-methylbutane. Propose a mechanism for
the formation of this product.
Limited ability to make alkyl halides.

Chapter 11
38
Solved Problem 2 (Continued)

Solution (Continued)
A hydride shift transforms the secondary carbocation into a more stable tertiary
cation. Attack by bromide leads to the observed product.
Solution
The alcohol is protonated by the strong acid. This protonated secondary alcohol
loses water to form a secondary carbocation.
Chapter 11
39
Reactions with
Phosphorus Halides
Chapter 11
40
Examples
Good yields with 1 and 2 alcohols.

y chlorides ((but SOCl2
PCl3 for alkyl
better- Thionyl chloride).
PBr3 for alkyl bromides.
P and I2 for alkyl iodides (PI3 not stable).
Chapter 11
41
Chapter 11
42
Mechanism with PBr3
Reaction of Alcohols with Thionyl

Chloride
Thionyl chloride (SOCl2) can be used to

convert alcohols into the corresponding alkyl
chloride in a simple reaction that produces
gaseous HCl and SO2.
Oxygen attacks the phosphorus, displacing

one of the halides.
Br- attacks back-side (SN2).
Chapter 11
The reaction should be carried in HOOD.

43
Chapter 11
44
Mechanism of Thionyl Chloride

Reaction
Thionyl chloride reacts with alcohols
by various mechanisms that depend
on the substrate,, the solvent,, and the
temperature. Be cautious in
predicting the structure and
stereochemistry of a product unless
you know the actual mechanism.
Chapter 11
45
Chapter 11
46
Dehydration of ROH
Dehydration Reactions
CH3 CH2 OH
OH
H2 SO 4
CH2 = CH2
180C
H2 SO 4
H2 O
+ H2 O
140C
Concentrated H2SO4 produces alkene.

Carbocation intermediate for 2 and 3 alcohols.
Zaitsev product.
Bimolecular dehydration produces ether.
Low temp, 140 C and below, favors ether formation.
High temp, 180 C and above, favors alkene formation.
Chapter 11
47
Cyclohexanol
CH3
CH3 COH
CH3
2-Methyl-2-propanol
(tert- Butyl alcohol)
Cyclohexene
H2 SO 4
50C
CH3
CH3 C= CH2 + H2 O
2-Methylpropene
(Isobutylene)
Chapter 11
48
Dehydration of ROH
Dehydration of Alcohols
where isomeric alkenes are possible,

the alkene having the greater number
of substituents on the double bond
usually predominates (Zaitsev rule)
OH
CH 3 CH 2 CHCH 3
2-Butanol
Alcohol dehydration generally takes place through

th E1 mechanism.
the
h i
Rearrangements are possible.
The rate of the reaction follows the same rate as
the ease of formation of carbocations: 3o > 2o > 1o.
8 5 % H 3 PO 4
heat
CH 3 CH= CH CH 3 + CH3 CH2 CH= CH 2 + H 2 O
2-Butene
1-Butene
(80%)
(20%)
Chapter 11
49
Primary alcohols rearrange, so this is not a good

reaction for converting 1 alcohols into alkenes.
Dehydration of ROH
Chapter 11
50
Energy Diagram, E1
Dehydration with rearrangement occurs by a

carbocation rearrangement
H+
+
OH - H 2 O
3,3-DimethylA 2 carbocation
2-butanol
intermediate
+ H3 O +
2,3-Dimethyl2-butene
+
A 3 carbocation
intermediate
H2 O
Chapter 11
H2 O
2,3-Dimethyl1-butene
+ H3 O +
51
Solved Problem 3
Predict the products of sulfuric acid-catalyzed dehydration of 1methylcyclohexanol
Solution
1-Methylcyclohexanol reacts to form a tertiary carbocation. A proton may
be abstracted from any one of three carbon atoms. The two secondary atoms are
equivalent, and abstraction of a proton from one of these carbons leads to the
trisubstituted double bond of the major product. Abstraction of a methyl
proton leads to the disubstituted double bond of the minor product.
Chapter 11
52
Unique Reactions of Diols

Vicinal diols can undergo the following
two reactions:
Pinacol rearrangement
Periodic acid cleavage
Chapter 11
53
Chapter 11
54
Mechanism of the Pinacol

Rearrangement
Pinacol Rearrangement
Protonation and loss of a water molecule

to produce a carbocation.
In the pinacol rearrangement, a vicinal diol
converts to the ketone (pinacolone) under
acidic conditions and heat.
The reaction is classified as a dehydration since
a water molecule is eliminated from the
starting material.
Chapter 11
55
Mechanism of the Pinacol

Rearrangement (Continued)
Chapter 11
56
Periodic Acid Cleavage of

Glycols
Methyl shift to form a resonance-stabilized

carbocation, which upon deprotonation by
water yields the pinacolone product.
Glycols can be oxidatively cleaved by

periodic acid (HIO4) to form the
corresponding ketones and aldehydes.
Useful for determining the structure of
sugars.
Chapter 11
57
Chapter 11
Oxidation of Glycols
Mechanism of HIO4 Cleavage
the glycol undergoes a two-electron

oxidation
C OH
C O
C OH
C O
+ 2H
HIO 4
+ 2H
+ 2e
Periodic acid
Chapter 11
+ 2e
periodic acid undergoes a two-electron

reduction
The cleavage of a glycol probably

involves a cyclic periodate intermediate.
58
59
HIO 3 + H 2 O
Iodic acid
Chapter 11
60
10
Esterification
Periodic acid cleaves a diol to give

the same products as ozonolysis
reduction
d ti (O3 followed
f ll
d by
b Me
M 2S) off
the alkene.
Chapter 11
61
Fischer: Alcohol + carboxylic acid

Tosylate esters
Sulfate esters
Nitrate esters
Phosphate esters
Chapter 11
62
Reaction of Alcohols with Acyl

Chlorides
Fischer Esterification
Reaction of an alcohol and a carboxylic acid

produces an ester.
p
Sulfuric acid is a catalyst.
Th
The esterification
t ifi ti reaction
ti achieves
hi
b tt
better
results by reacting the alcohol with an acyl
chloride.
The reaction is an equilibrium (-means wont

complete) between starting materials and
products, and for this reason the Fischer
esterification is seldom used to prepare esters.
The reaction is exothermic and produces the

corresponding ester in high yields with only
HCl as a by-product.
Chapter 11
63
Nitrate Esters
Chapter 11
64
Phosphate Esters
The best-known nitrate ester is nitroglycerine,

whose systematic name is glyceryl trinitrate.
Glyceryl nitrate results from the reaction of
glycerol (1,2,3-propanetriol) with three molecules
of nitric acid.
Chapter 11
65
Chapter 11
66
11
Alkoxide Ions: Williamson Ether

Synthesis
Phosphate Esters in DNA
Ethers can be synthesized by the reaction of alkoxide

ions with primary alkyl halides in what is known as the
Williamson ether synthesis.
This is an SN2 displacement reaction and as such, works
better with primary alkyl halides to facilitate back-side
attack.
If a secondary or tertiary alkyl halide is used, the
alkoxide will act as a base and an elimination will take
place.
Chapter 11
67
Chapter 11
Thiols: oxidation
68
Bovine Insulin
Thiols are oxidized to disulfides by a variety

of oxidizing agents, including O2.
they are so susceptible to this oxidation that
they must be protected from air during storage
2 RSH +
A thiol
1 O
2 2
RSSR + H 2 O
A disulfide
the most common reaction of thiols in

biological systems in interconversion between
thiols and disulfides, -S-S-
Chapter 11
69
Complete the following reactions.
Insulin is composed of two separate peptide chains,

the A chain, containing 21 amino acid residues, and
the B chain, containing 30.
Chapter 11
70
Complete each acid-base reaction. Use curved arrows to show

the flow of electrons.
HBr
(CH3)2CHOH
+
(a) CH 3 CH2 OH + HOH
H
NaBr
CH3CH2CH2CH2OH
H2SO4
(b)
PBr3
CH3CH2CH2OH
CH3 CH2 OCH 2 CH3 + HOSOH

O
(c) CH3 CH2 CH 2 CH2 CH 2 OH + HI

SOCl2
O
O
(d) CH3 CH 2 CH 2 COH + HOSOH
O
CH3CH2CH2OH
TsCl
CH3CH2CH2OH
(e)
1. TsCl, pyridine
CH3CH2CH2OH
OH + BF3
pyridine
(f) CH3 CH= CH CH CH 3
+ HOH
2. LiAlH4
Chapter 11
71
Chapter 11
72
12
Complete each equation, but do not balance

(a)
Show how to bring about each conversion.

(a)
OH
(c)
OH
(b)
OH
OH
OH + H 2 Cr O4
(b)
OH + SOCl 2
OH
O
(c)
OH
OH
(d)
+ HCl
H
O
OH +
(d) HO
HBr
(excess)
CH 2
(e)
CH 2 Cl
O
CCH 3
OH
+ H2 Cr O4
(e)
CHCH3
(f)
OH
+ HIO 4
(f)
O
CH3 ( CH2 ) 6 CH
(g) CH3 ( CH2 ) 6 CH 2 OH
OH
OH
OH
(h)
1 . Os O4 , H 2 O 2
(g)
(h)
OH
2 . HIO 4
OH
SOCl 2
73
Propose a mechanism for the following pinacol rearrangement.

HO
CH 2
(i)
Chapter 11
O
COH
Chapter 11
74
Show how to bring about this conversion.
OH
BF3 Et 2 O
OH
+ H2 O
Propose
p
a mechanism for this reaction.
H
A rSO3 H
O CH2 OH
Tetrahydrofurfuryl
alcohol
Propose a structural
P
t t l formula
f
l for
f the
th product
d t off this
thi reaction
ti and
d
a mechanism for its formation.
H2 O
OH
O
Dihydropyran
75
Propose a mechanism for the formation of the products of this

solvolysis.
H2 O
T sO
C7 H1 2 O
OT s
Chapter 11
N aOH
Chapter 11
76
Show how to convert cyclohexene to each compound.

O
(a)
OH
OCH3
(c)
(b)
DMSO
Chrysanthemyl tosylate
O
+
OH
Artemisia alcohol
Chapter 11
OH
(d)
(e) H
O
Yomogi alcohol
77
Chapter 11
78
13

Chapter 11 - Reactions of Alcohol (Compatibility Mode)

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Chapter 11 - Reactions of Alcohol (Compatibility Mode)

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Types of Alcohol Reactions

Dehydration to alkene (learned)

2013 Pearson Education, Inc.

2013 Pearson Education, Inc.

Oxidation States of Carbons

2013 Pearson Education, Inc.

2013 Pearson Education, Inc.

2013 Pearson Education, Inc.

Formation of the Acid

CrO3 will also produce chromic acid in

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Chromic acid reagent oxidizes primary

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The oxidizing agent is too strong to stop

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3 Alcohols Cannot Be Oxidized

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2013 Pearson Education, Inc.

Sodium Hypochlorite (NaOCl)

Dimethylsulfoxide (DMSO), with oxalyl chloride

Sodium hypochlorite (household bleach)

Like PCC, Swern reagent is a mild oxydizing

2013 Pearson Education, Inc.

Can oxidize primary alcohols to aldehydes and

The reaction with DMP takes place under mild

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Solved Problem 1 (Continued)

Suggest the most appropriate method for each of the following

The liver produces alcohol dehydrogenase

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2013 Pearson Education, Inc.

Enzymatic Oxidation of Ethanol

Methanol oxidizes to formaldehyde, then formic

Ethylene glycol oxidizes to oxalic acid, which is

Alcohols are weak electrophiles because the OH

Alkoxides (RO) are strong nucleophiles.

Protonation of the hydroxyl group converts it

New OC bond forms; OH bond breaks.

Alcohols (ROH) are weak nucleophiles.

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2013 Pearson Education, Inc.

2013 Pearson Education, Inc.

Alcohols can be converted to tosylate esters

The tosylate group is an excellent leaving

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Substitution and Elimination

SN2 Reactions with Tosylates

TsCl is 4-Toluenesulfonyl chloride, also called Tosyl

The reaction shows the SN2 displacement of the

2013 Pearson Education, Inc.

2013 Pearson Education, Inc.

Reaction of Alcohols with Acids

Dehydrate with concentrated H2SO4, then

The hydroxyl group is protonated by an acid

Make a tosylate, then reduce it with LiAlH4.

Once the alcohol is protonated, a substitution

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Reaction of Alcohols with HBr

Step 2: Formation of the carbocation.

Step 3: Bromide attacks the carbocation.

3 and 2 alcohols react with Br via SN1.

2013 Pearson Education, Inc.

2013 Pearson Education, Inc.