Any time a Carbocation is formed Rearrangements can occur.

CH3
Why does this
CH3
+ methanide + happen?
H3C C C CH3 H3C C C CH3
migration H
2° 3° H
H
CH3 H CH3 H
H C C
H
+ H
C C
CH3 CH3 H3C
+
methanide +
H3C H
H3C C CH2 H3 C C CH2 Lewis
Lewis
1° migration 3° acid
CH3 CH3 base

H
H H H
H H
+
hydride + C CH3
CH3CH2 CH CH2 CH3CH2 CH CH2 H2C +
migration 2° H C C
1°
H2C H

Sec. 6: Alcohols, Ethers 1

Hydride and methanide shifts are very fast (faster than SN1 or E1) which is
partially due to hyperconjugation in the carbocation weakening the C-H, or
C-C bond:

Primary carbocations are too unstable to be formed by rearrangement.

Secondary or tertiary carbocations equilibrate readily, leading to a
mixture of products when trapped by a nucleophile.

Sec. 6: Alcohols, Ethers 2

 What is the product of the following SN1 reaction?
OCH3 CH3 CH3 OCH3

CH3 Br H 3C C C CH3 H3 C C C CH3

CH3OH
H3C C C CH3 CH3 H CH3 H
weak base A) B)
CH3 H poor nucleophile
H3CO
CH3 CH2 CH3 CH3O

H3C C CH2 H3C C C CH3

CH3 CH3 H
C) D)
Mechanism

CH3 acid CH3 CH3OH

base + acid methanide OCH3 CH3
migration
+ base
H3C C C CH3 + Br H3C C C CH3 H3C C C CH3
H 2 3o
o
CH3 -H+
CH3 H CH3 H

Sec. 6: Alcohols, Ethers 3

 What is the major product formed in the following reaction?

CH3 H CH3
85% H3PO4 H3 C CH3
H3C C C CH3 H3C C CH CH2 C C
60°C H3 C H
CH3 OH CH3 B)
A)

CH3
H3 C CH3 H CH3
H 2C
C C H3C C C
C C CH3
H3C C) CH3 CH3 CH3 H3C
H
D) E)

Also look in Vollhardt

Chapter 11-11 (preparation
of alkenes by dehydration) Sec. 6: Alcohols, Ethers 4
 What is the Mechanism of the previous reaction?

CH3 H CH3 H
O
85% H3PO4
H3C C C CH3 H3C C C CH3 + O P OH

CH3 OH 60°C OH
O
CH3 O
+
H H
base O P OH H -H2O
a acid OH

H CH3 methanide CH3 H

O +
β C C shift
C CH3 H3C C C CH3
O P OH H 3° β +

OH H CH3 H CH3 2°
b β
b H3 C CH3
a
Zaitsev’s
CH3 C C Rule
H 2C
+ H3PO4 H3C CH3
C C CH3 major
H3 C
H

Sec. 6: Alcohols, Ethers 5

 What is the major product formed in the following reaction?

H H
85% H2SO4
H3C C C CH3

CH3 OH A) B)

C)
D)

H H Br
85% H2SO4
H3C C C CH3
NaBr Br
CH3 OH A) B)

H H

C)
D)

Sec. 6: Alcohols, Ethers 6

 The mechanism of 3-methyl-2-butanol with concentrated
H2SO4 and NaBr?
H H acid H H
85% H2SO4 HSO4
H3C C C CH3 H3C C C CH3 +
+
CH3 OH Na Br CH3 O
+
base H
H -H2O

weak base
good nucleophile H H hydride H H
+
β C C shift
C CH3 H3C C C CH3
Br H 3° β +
SN1 H CH3
CH3 H 2°

Br H If no NaBr present the only species present are

H2SO4, HSO4¯ and H2O, which are weak bases
H3C C C CH3
and poor nucleophiles. E1 reaction
CH3 H H3C CH3 H
H2C
C C
H3C H + C C CH3
major H 3C
H
Sec. 6: Alcohols, Ethers 7
 Primary alcohols may undergo rearrangement.
Alkyl and hydride shifts to primary carbons bearing leaving groups can
occur without the formation of primary carbocations.

Because this is not a simple primary bromoalkane, steric hindrance

interferes with direct attack by the bromide ion. Instead, water leaves at
the same time as the methyl group migrates, by passing the formation of
a primary carbocation.

Sec. 6: Alcohols, Ethers 8

 Making an ether by dehydration of an alcohol
OH

base conc. H2SO4

OH O
acid

H+ OH
OH base
OH
+ H2O
+
OH2 +
H H
2° 4
H H 2
1 +
3
+ HSO4 acid
H
benzylic
very stable
-H+
+
O O
1 H

2
3
4
Sec. 6: Alcohols, Ethers 9
 Conversion of Alcohols into Alkyl Halides
Hydroxyl groups are poor leaving groups, and as such, are often converted to
alkyl halides when a good leaving group is needed
Organic and Inorganic Esters from Alcohols
Organic esters are derivatives of carboxylic acids.
Inorganic esters are the analogous derivatives of inorganic acids.

Alcohols react with carboxylic acids to give organic esters.

Esterification is the reaction of alcohols with carboxylic acids in the
presence of catalytic amounts of a strong inorganic acid (H2SO4 or HCl)
which yields esters and water.
This is an equilibrium process which can be shifted in either direction.

Sec. 6: Alcohols, Ethers 10

 Haloalkanes can be made from alcohols through inorganic esters.
As an alternative to the acid-catalyzed conversions of alcohols into
haloalkanes, a number of inorganic reagents can convert the alcoholic
hydroxyl group into a good leaving group under milder conditions.
The reaction of PBr3 with a secondary alcohol yields a bromoalkane
and phosphorous acid (all three bromine atoms can be utilized).

Can use if
the alcohol
is tertiary Sec. 6: Alcohols, Ethers 11
 Iodoalkanes can be prepared using PI3, which, because
of its reactivity, is generated from red phosphorous and
iodine in the reaction mixture itself.

Chloroalkanes are commonly prepared using thionyl

chloride by warming an alcohol in its presence.

An amine such as triethyl amine is usually added to consume the generated HCl.
Sec. 6: Alcohols, Ethers 12
 Alkyl sulfonates are versatile substrates for substitution reactions.
Alkyl sulfonates are excellent leaving groups and can be generated by the reaction
of an alcohol with the corresponding sulfonyl chloride. Pyridine or a tertiary amine
is used to remove the HCl formed.

Alkyl sulfonates are often crystalline solids and can be isolated and purified before
further reaction.
What is the major product formed in the following reaction?
OH SCN SCN

CH3SO2Cl NaSCN
?
pyridine acetone

A) B) C)

Sec. 6: Alcohols, Ethers 13

 Ethers as solvents
Ethers are very good solvents because they are fairly unreactive and slightly polar

Cyclic ethers are members of the class of cycloalkanes called heterocycles, in

which one or more carbon atoms have been replaced by a heteroatom.
Cyclic polyethers based on the 1,2-ethanediol unit are called crown ethers. The
crown ether 18-crown-6 contains 18 total atoms and 6 oxygen atoms.

The smaller alkoxyalkanes

Note that the inside of the
ring is electron rich.
are water soluble, however
solubility decreases with
increasing hydrocarbon size.
Methoxymethane-
completely water soluble
Ethoxyethane -10% aqueous
solution

Sec. 6: Alcohols, Ethers 14

 Polyethers solvate metal ions: crown ethers and ionophores.
Crown ethers can render salts soluble in organic solvents by chelating the metal
cations. This allows reagents such as KMnO4 to act as an oxidizing agent in the
organic solvents.

The size of the central cavity can be tailored to selectively bind cations of
differing ionic radii.

Three-dimensional analogs of crown ethers are polyethers called cryptands.

These are highly selective in alkali and other metal cation binding.

Sec. 6: Alcohols, Ethers 15

 Synthesis of Ethers
Williamson Ether Synthesis

NaH Cl
OH ONa O
DMSO DMSO 1-butoxybutane

What is the major product produced in the following reaction?

O
NaOH
Br OH HO(CH2)5OH -(O(CH2)5O)-
n
dilute solution O
A) B) C) D)

The intramolecular reaction is usually much faster than the intermolecular

reaction. If necessary, the intermolecular reaction can be suppressed by using a
high dilution of the haloalcohol.
Sec. 6: Alcohols, Ethers 16
What is the major product produced in the following reaction?
O O
HO H
Br NaOH
H D H H
H H H H D
H D A) B)

Does the following reaction proceed by an A) SN1 or B) SN2 mechanism?

15% aqu. H2SO4

OH +
OH O
40oC
excess

2-ethoxy-2-methylpropane

Sec. 6: Alcohols, Ethers 17

What is the major product produced in the following reaction?
O
+ 1) BrMgCH2CH3
OH (CH3)3COH, H ? ?
H 2) H2O, H+
Br Br OH
O OH O
A) B) C)

OH
OH
OH
O
E)
D)

OH

O OH
H
OH2 O
H

OH H
O O
O MgBr H
OH
H O
H

Sec. 6: Alcohols, Ethers 18

What is the major product produced in the following reaction?
CH3 H OH
HO
CH2CH3 H
O H CH3
A) SCH3 H3CS CH2CH3
H B)
1) CH3SNa
H CH3
H SCH3
H CH2CH3 2) H2O, H+ H3CS CH3
H
CH2CH3
CH3
HO H
CH2CH3 D) OH
C) H

Ethers are unreactive towards basic nucleophiles because alkoxides are very poor
leaving groups. Why would the above reaction occur? What is the driving force for this
reaction?

The driving force is the release of strain that occurs in the displacement reaction

Sec. 6: Alcohols, Ethers 19

Hydride and organometallic reagents convert strained ethers into alcohols
LiAlH4 can open the rings of oxacyclopropanes to yield alcohols. (Ordinary ethers do not react.)
In asymmetrical systems, the hydride attacks the less substituted side.

Acids catalyze oxacyclopropane ring opening

Ring opening of oxacyclopropane by acid catalysis proceeds through
an initial cyclic alkyloxonium ion.

This acid catalyzed

ring opening is
both regioselective
and stereospecific.

Sec. 6: Alcohols, Ethers 20

 What is the major product produced in the following reaction?
CH3 H OH
HO
CH2CH3 H
O H CH3
OCH3 H3CO
H A) B) CH2CH3
H2SO4
H CH3
CH2CH3 CH3OH H OCH3
H H3CO CH3
H
CH2CH3
CH3
HO H
CH2CH3 D) OH
C) H

In the alkyloxonium ion, more positive charge is located on the tertiary carbon
than on the primary carbon. This effect counteracts the effect of steric hindrance
and the alcohol attacks the tertiary carbon. Because inversion of configuration
occurs during ring opening, free carbocations cannot be involved in the reaction
mechanism.
Sec. 6: Alcohols, Ethers 21
Ethers are unreactive towards basic nucleophiles and are very weak
bases and thus are generally good solvents. However ethers will react
(ether cleavage) with strong acids in the presence of a good
nucleophile, ie HBr, HI or NaBr, NaI in H2SO4.

Order the intermediates and final product in the reaction of

oxacylclopentane (tetrahydrofuran) with excess HBr
H
O
O HO
excess conc HBr. Br 2)
1)

Br H2O
Br Br
3) 4)

A) 1, 2, 3, final product 4
B) 2, 1, 4, final product 3
C) 2, 4, 1, final product 3
D) 1, 4, 3, final product 2

Sec. 6: Alcohols, Ethers 22

What is the major product produced in the following reaction?
O
1) Mg /Et2O
1) LiAlH4 /Et2O PBr3 /Et2O 1) NaH
? ? ? ?
H 2) CH3Br
2) H3O + 2) H2CO
3) H3O+

O O
Br
A) C)
B)
O
OH
O
O O
D) E)

Sec. 6: Alcohols, Ethers 23

 Sulfur Analogs of Alcohols and Ethers
The IUPAC system calls the sulfur analogs of alcohols, R-SH, “thiols.” The –SH
group in more complicated compounds is referred to as “mercapto.”

The sulfur analogs of ethers are called “sulfides” (common name, thioethers). The
RS group is called “alkylthio,” and the RS- group is called “alkanethiolate.”

Thiols are less hydrogen-bonded and more acidic than alcohols. Thiols are
more acidic than water and can therefore be easily deprotonated by
hydroxide and alkoxide ions:

Sec. 6: Alcohols, Ethers 24

Thiols and sulfides react much like alcohols and ethers
The sulfur in thiols and sulfides is more nucleophilic than the oxygen in the
analogous compounds.
Thiols and sulfides are readily made through nucleophilic attack by RS¯ or HS¯
on haloalkanes:

A large excess of HS¯ is used to prevent the reaction of the product with
the starting halide.

The nucleophilicity of the generated thiolates is much greater than that of

hydroxide which eliminates the competing SN2 substitution by hydroxide ion.

Sec. 6: Alcohols, Ethers 25

 Sulfides can attack haloalkanes to form sulfonium ions.

Sulfonium ions are subject to nucleophilic attack, the leaving group being a sulfide.

Sulfides can also be oxidized to sulfoxides

Valence-shell expansion of sulfur and then sulfones:
accounts for the special reactivity of
thiols and sulfides.
Sulfur can expand its valence
shell from 8 to 10 or 12
electrons using its available 3d
orbitals, allowing oxidation
states not available to its
oxygen analogs.
Oxidation of thiols with strong
oxidizing agents (H2O2, KMnO4)
gives the corresponding
sulfonic acids: Sec. 6: Alcohols, Ethers 26
 Milder oxidizing agents (I2) yield disulfides.
These can be reduced back to thiols by alkali metals

Reversible disulfide formation is important in stabilizing the

folding of biological enzymes:

Sec. 6: Alcohols, Ethers 27

 The polymer chain crosslinking of rubber is called vulcanization.
CH 3 CH 3
CH 3 CH 3

CH 3 CH 3 CH 3
CH 3 C H2 C H2 C H2
CH 2
C H2 C H2 C H2 CH 3
CH 3 CH 3
H2 C
n
CH 3 CH 3 CH 3
H2 C n Sx

H2 C
S CH 3 CH 3
CH 3
CH 2
heat C H2 C H2 C H2

H2 C
CH 3 CH 3 CH 3 CH 3
CH 3 CH 3 CH 3
m
C H2 C H2 C H2

x = 1 (sulfide or thioether crosslink)

CH 3 CH 3
CH 3 CH 3
m
x > 1 (polysulfide crosslink)

N N
SH S Sx H
S S

mercaptobenzothiazole a hypothetical intermediate

(MBT) acelerated vulcanization

In older vulcanization processes, the co-polymer was simply heated with elemental
sulfur to form sulfide or poly sulfide crosslinks, however this reaction is usually very
slow.
Current vulcanization processes use so-called vulcanization accelerators such as MBT

Sec. 6: Alcohols, Ethers 28