Chapter 11

Alcohols & Ethers

Ch. 11 - 1
1. Structure & Nomenclature
 Alcohols have a hydroxyl (–OH) group
bonded to a saturated carbon atom
(sp3 hybridized)

OH OH OH
1o 2o 3o
Ethanol 2-Propanol 2-Methyl-
(isopropyl 2-propanol
alcohol) (tert-butyl alcohol)
Ch. 11 - 2
 OH
OH

2-Propenol 2-Propynol
(allyl alcohol) (propargyl alcohol)

OH

Benzyl alcohol
Ch. 11 - 3
 Phenols
● Compounds that have a hydroxyl
group attached directly to a
benzene ring

OH OH Cl OH

H3C

Phenol 4-Methylphenol 2-Chlorophenol

Ch. 11 - 4
 Ethers
● The oxygen atom of an ether is
bonded to two carbon atoms
O
CH3
O

Diethyl ether tert-Butyl methyl ether

O O

Divinyl ether Ethyl phenyl ether

Ch. 11 - 5
1A. Nomenclature of Alcohols
 Rules of naming alcohols
● Identify the longest carbon chain
that includes the carbon to which
the –OH group is attached
● Use the lowest number for the
carbon to which the –OH group is
attached
● Alcohol as parent (suffix)
 ending with “ol”

Ch. 11 - 6
 Examples
OH OH

OH
OH
2-Propanol 1,2,3-Butanetriol
(isopropyl alcohol)

Ch. 11 - 7
 Example

OH
3-Propyl-2-heptanol
8

7 wrong
or 6

1 5 7 3 1
2 3 4 6 5 4 2

OH OH
Ch. 11 - 8
1B. Nomenclature of Ethers
 Rules of naming ethers
● Similar to those with alkyl halides
 CH3O– Methoxy
 CH3CH2O– Ethoxy

 Example
O

Ethoxyethane
(diethyl ether)
Ch. 11 - 9
 Cyclic ethers
O O

Oxacyclopropane Oxacyclobutane
or oxirane or oxetane
(ethylene oxide)

O
O
Oxacyclopentane 1,4-Dioxacyclohexane
(tetrahydrofuran or THF) (1,4-dioxane)
Ch. 11 - 10
2. Physical Properties of
Alcohols and Ethers
 Ethers have boiling points that are
roughly comparable with those of
hydrocarbons of the same molecular
weight (MW)
 Alcohols have much higher boiling
points than comparable ethers or
hydrocarbons

Ch. 11 - 11
 For example

O OH

Diethyl ether Pentane 1-Butanol

(MW = 74) (MW = 72) (MW = 74)
b.p. = 34.6oC b.p. = 36oC b.p. = 117.7oC

 Alcohol molecules can associate with

each other through hydrogen bonding,
whereas those of ethers and
hydrocarbons cannot
Ch. 11 - 12
 Water solubility of ethers and alcohols
● Both ethers and alcohols are able to
form hydrogen bonds with water
● Ethers have solubilities in water that are
similar to those of alcohols of the same
molecular weight and that are very
different from those of hydrocarbons
● The solubility of alcohols in water
gradually decreases as the hydrocarbon
portion of the molecule lengthens; long-
chain alcohols are more “alkane-like”
and are, therefore, less like water
Ch. 11 - 13
 Physical Properties of Ethers
Name Formula mp bp (oC)
(oC) (1 atm)
Dimethyl ether CH3OCH3 -138 -24.9
Diethyl ether CH3CH2OCH2CH3 -116 34.6
Diisopropyl ether (CH3)2CHOCH(CH3)2 -86 68
1,2-Dimethoxyethane CH3OCH2CH2OCH3 -68 83
(DME)
O
Oxirane -112 12

Tetrahydrofuran (THF) -108 65.4

O
Ch. 11 - 14
 Physical Properties of Alcohols
Name Formula mp bp (oC) *
(oC) (1 atm)
Methanol CH3OH -97 64.7 inf.
Ethanol CH3CH2OH -117 78.3 inf.
Isopropyl alcohol CH3CH(OH)CH3 -88 82.3 inf.
tert-Butyl alcohol (CH3)3COH 25 82.5 inf.
Hexyl alcohol CH3(CH2)4CH2OH -52 156.5 0.6

Cyclohexanol OH 24 161.5 3.6

OH
Ethylene glycol HO -12.6 197 inf.

* Water solubility (g/100 mL H2O) Ch. 11 - 15

4. Synthesis of Alcohols from Alkenes
 Acid-catalyzed Hydration of Alkenes
H
C C C C
⊕
H2O
H H OH
H2O

C C C C
H H2O H O H
H Ch. 11 - 16
 Acid-Catalyzed Hydration of Alkenes

● Markovnikov regioselectivity

● Free carbocation intermediate

● Rearrangement of carbocation
possible

Ch. 11 - 17
 Oxymercuration–Demercuration

OH OH
Hg(OAc)2 NaBH4
C C C C C C
H2O, THF NaOH
HgOAc H

● Markovnikov regioselectivity
● Anti stereoselectivity
● Generally takes place without the
complication of rearrangements
● Mechanism
 Discussed in Section 8.6
Ch. 11 - 18
 Hydroboration–Oxidation
OH
1. BH3 THF
H
2. H2O2, OH

● Anti-Markovnikov regioselectivity
● Syn-stereoselectivity
● Mechanism
 Discussed in Section 8.7

Ch. 11 - 19
 Markovnikov regioselectivity
OH
H+, H2O or
1. Hg(OAc)2, H2O, THF R
2. NaBH4, NaOH
H

1. BH3 • THF H
2. H2O2, NaOH
OH
R
Anti-Markovnikov regioselectivity
Ch. 11 - 20
 Example
Synthesis?
(1) OH

OH

Synthesis?
(2)
Ch. 11 - 21
 Synthesis (1)
H
OH

● Need anti-Markovnikov addition of

H–OH
● Use hydroboration-oxidation
H
OH
1. BH3 • THF
2. H2O2, NaOH
Ch. 11 - 22
 Synthesis (2)
OH
H

● Need Markovnikov addition of H–OH

● Use either
 acid-catalyzed hydration or
 oxymercuration-demercuration
● Acid-catalyzed hydration is NOT
desired due to rearrangement of
carbocation Ch. 11 - 23
 Acid-catalyzed hydration
HO

⊕
H

H2O

H
Rearrangement
o of carbocation
(2 cation)
Ch. 11 - 24
 Oxymercuration-demercuration
OH
H

Hg(OAc)2 OH NaBH4
H2O, THF NaOH

HgOAc

Ch. 11 - 25
5. Reactions of Alcohols
 The reactions of alcohols have mainly
to do with the following
● The oxygen atom of the –OH group
is nucleophilic and weakly basic
● The hydrogen atom of the –OH
group is weakly acidic
● The –OH group can be converted to
a leaving group so as to allow
substitution or elimination reactions
Ch. 11 - 26
 δ−
δ+ O C–O & O–H bonds of an
Hδ+
alcohol are polarized

 Protonation of the alcohol converts a

⊖
poor leaving group (OH ) into a good
one (H2O)
H
C O H + H A C O H + A

alcohol strong protonated

acid alcohol Ch. 11 - 27
 Once the alcohol is protonated
substitution reactions become possible
H H
SN2
Nu + C O H Nu C + O H

protonated
alcohol The protonated –OH
group is a good leaving
group (H2O)

Ch. 11 - 28
6. Alcohols as Acids
 Alcohols have acidities similar to that of
water
pK a Values for Some Weak Acids
Acid pKa
CH3OH 15.5
H2O 15.74
CH3CH2OH 15.9
(CH3)3COH 18.0
Ch. 11 - 29
 Relative Acidity H2O & alcohols are the
strongest acids in this series
H2O > ROH > RC CH > H2 > NH3 > RH

Increasing acidity

 Relative Basicity ⊖
OH is the weakest
acid in this series

R > NH2 > H > RC C > RO > HO

Increasing basicity
Ch. 11 - 30
7. Conversion of Alcohols into
Alkyl Halides

R OH R X

● HX (X = Cl, Br, I)
● PBr3
● SOCl2

Ch. 11 - 31
 Examples

OH conc. HCl Cl
o
+ HOH
25 C

(94%)

OH PBr3 Br

(63%)
Ch. 11 - 32
8. Alkyl Halides from the Reaction of
Alcohols with Hydrogen Halides

R OH + HX R X + H2O

 The order of reactivity of alcohols

● 3o > 2o > 1o < methyl
 The order of reactivity of the hydrogen
halides
● HI > HBr > HCl (HF is generally
unreactive)
Ch. 11 - 33
R OH + NaX No Reaction!
⊖
OH is a poor
leaving group

H
R OH + NaX R X

X
R O H
⊕
H3O is a good H
leaving group
Ch. 11 - 34
8A. Mechanisms of the Reactions of
Alcohols with HX
 Secondary, tertiary, allylic, and benzylic
alcohols appear to react by a
mechanism that involves the formation
of a carbocation
 Step 1

H + H O H H + O H
O fast O
H H
H Ch. 11 - 35
 Step 2

H + O H
O slow H
H

 Step 3

+ Cl
fast Cl

Ch. 11 - 36
 Primary alcohols and methanol react to
form alkyl halides under acidic
conditions by an SN2 mechanism

H H H H
X + R C O H X C R + O H
H H (a good
protonated 1o alcohol leaving group)
or methanol

Ch. 11 - 37
9. Alkyl Halides from the Reaction
of Alcohols with PBr3 or SOCl2
 Reaction of alcohols with PBr3
3 R OH + PBr3 R Br + H3PO3
o o
(1 or 2 )
● The reaction does not involve the
formation of a carbocation and usually
occurs without rearrangement of the
carbon skeleton (especially if the
temperature is kept below 0°C)
Ch. 11 - 38
 Reaction of alcohols with PBr3

● Phosphorus tribromide is often

preferred as a reagent for the
transformation of an alcohol to the
corresponding alkyl bromide

Ch. 11 - 39
 Mechanism
Br
PBr2
R OH + P R O + Br
Br Br
H
protonated
alkyl dibromophosphite

PBr2
Br + R O R Br + HOPBr2
H
a good
leaving group
Ch. 11 - 40
 Reaction of alcohols with SOCl2
● SOCl2 converts 1o and 2o alcohols to
alkyl chlorides
● As with PBr3, the reaction does not
involve the formation of a
carbocation and usually occurs
without rearrangement of the
carbon skeleton (especially if the
temperature is kept below 0°C)
● Pyridine (C5H5N) is often included to
promote the reaction
Ch. 11 - 41
 Mechanism
O H O
Cl
R O H + Cl S Cl R O S
Cl

N
− Cl
(C5H5N)
O H O
N +R O S Cl R O S Cl

Ch. 11 - 42
 Mechanism
O O
− Cl
N +R O S Cl R O S N

⊖
Cl

O
+ O O
N S R Cl + O S N

Ch. 11 - 43
10. Tosylates, Mesylates, & Triflates:
Leaving Group Derivatives of
Alcohols
O
OTs = O S CH3 (Tosylate)
O

O
OMs = O S CH3 (Mesylate)
O

Ch. 11 - 44
 Direct displacement of the –OH group
with a nucleophile via an SN2 reaction
⊖
is not possible since OH is a very poor
leaving group

OH + Nu No Reaction!

⊖
 Thus we need to convert the OH to a
better leaving group first

Ch. 11 - 45
 Mesylates (OMs) and Tosylates (OTs)
are good leaving groups and they can
be prepared easily from an alcohol
(methane sulfonyl chloride) O
pyridine
OH + CH3 S Cl
O

O
O S CH3 + + Cl
N
O
same as H

OMs (a mesylate) Ch. 11 - 46

 Preparation of Tosylates (OTs) from an
alcohol
(p-toluene sulfonyl chloride)
O
pyridine
OH + H3C S Cl
O

O
O S CH3 + + Cl
N
O
same as H

OTs (a tosylate)
Ch. 11 - 47
 SN2 displacement of the mesylate or
tosylate with a nucleophile is possible

OTs + Nu

Nu + OTs

Ch. 11 - 48
 Example
Retention of
OH OTs configuration
TsCl
pyridine

NaCN
DMSO

Inversion of
configuration CN
+ NaOTs

Ch. 11 - 49
 Example Retention of
configuration
OH OMs
MsCl
pyridine

NaSMe
DMSO
Inversion of
configuration
SMe

Ch. 11 - 50
11. Synthesis of Ethers
11A. Ethers by Intermolecular
Dehydration of Alcohols
H2SO4
180oC
Ethene
OH
H2SO4
o O
140 C
Diethyl ether

Ch. 11 - 51
 Mechanism
OH + H OSO3H O H + OSO3H
H

OH

O O + H2O

H2O H

● This method is only good for

synthesis of symmetrical ethers
Ch. 11 - 52
 For unsymmetrical ethers

H2SO4
ROH + R'OH O
R R'
+
o
1 alcohols O Mixture
R R
of ethers
+
O
R' R'

Ch. 11 - 53
 Exception
cat. H2SO4
R OH + R O
HO
+ HO H
(good yield)
H

R OH
Ch. 11 - 54
11B. The Williamson Synthesis of
Ethers

R'O
R X R O R'
(SN2)

 Via SN2 reaction, thus R is limited to 1o

(but R' can be 1o, 2o or 3o)

Ch. 11 - 55
 Example 1

Na H
O O Na + H2
H

Br

Ch. 11 - 56
 Example 2
Cl
NaOH
Cl
HO H2O
O

O
Ch. 11 - 57
 Example 3
I
NaOH
O
H2O
OH

 However
I
NaOH
No epoxide observed!
H2O
OH

Ch. 11 - 58
11C. Synthesis of Ethers by Alkoxy-
mercuration–Demercuration
Markovnikov regioselectivity
OR'
1. Hg(O2CCF3)2, R'OH
R R
2. NaBH4, NaOH

(1) (2)
OR'

R
Hg(O2CCF3)
Ch. 11 - 59
 Example

i O
1. Hg(O2CCF3)2, PrOH
2. NaBH4, NaOH

Ch. 11 - 60
11D. tert -Butyl Ethers by Alkylation
of Alcohols: Protecting Groups

H2SO4
R OH + R O

 A tert-butyl ether can be used to tert-butyl

“protect” the hydroxyl group of a 1o protecting
alcohol while another reaction is carried group
out on some other part of the molecule
 A tert-butyl protecting group can be removed
easily by treating the ether with dilute aqueous
acid
Ch. 11 - 61
 Example
1 3 5
Synthesis of
HO 2 4

1 3
from
HO 2
Br

5
and BrMg
4

Ch. 11 - 62
 ● Direct reaction will not work
BrMg (Not Formed)
+ ☓ HO
HO Br
● Since Grignard reagents are basic
and alcohols contain acidic proton
BrMg

+ BrMg O Br
H O Br
+ H
Ch. 11 - 63
 ● Need to “protect” the –OH group
first tert-butyl protected alcohol

1. H2SO4
HO Br O Br
2.

BrMg

H
HO O
H2O
deprotonation
Ch. 11 - 64
11E. Silyl Ether Protecting Groups
 A hydroxyl group can also be protected
by converting it to a silyl ether group

Me Me imidazole Me Me
R O H + Si t R Si t
Cl Bu DMF O Bu
(−HCl)
tert-butylchloro (R O TBS )
dimethylsilane
(TBSCl)

Ch. 11 - 65
 The TBS group can be removed by
treatment with fluoride ion (tetrabutyl-
ammonium fluoride or aqueous HF is
frequently used)
Me Me Bu4N+F− Me Me
R Si t R O H + Si t
O Bu THF F Bu

(R O TBS )

Ch. 11 - 66
 Example
2 4 6
Synthesis of HO Ph
5
1 3

2 4
from HO
1 3
I

and
Ph Na
6 5

Ch. 11 - 67
 ● Direct reaction will not work
Ph Na (Not Formed)
+
☓ HO Ph
O
H I

● Instead

Na Ph H Ph O
+ +
O O
H I I Ch. 11 - 68
 ● Need to “protect” the –OH group
first
HO TBSCl TBSO
I I
imidazole
DMF
Na Ph

TBSO
Ph

Bu4N F
THF

HO
Ph

Ch. 11 - 69
12. Reactions of Ethers
 Dialkyl ethers react with very few
reagents other than acids

O + HBr O + Br

H
an oxonium salt

Ch. 11 - 70
12A. Cleavage of Ethers

 Heating dialkyl ethers with very strong

acids (HI, HBr, and H2SO4) causes
them to undergo reactions in which the
carbon–oxygen bond breaks

O + 2 HBr 2 Br + H2O

Cleavage of an ether

Ch. 11 - 71
 Mechanism

O + H Br O + Br

Br H
H
O + Br O + Br
H

O
H H + Br Ch. 11 - 72
13. Epoxides
 Epoxide (oxirane)
● A 3-membered ring containing an
oxygen

Ch. 11 - 73
13A. Synthesis of Epoxides:
Epoxidation
 Electrophilic epoxidation

peroxy O
C C C C
acid

Ch. 11 - 74
 Peroxy acids (peracids)

O
R C O OH

● Common peracids
Cl
O O
C O OH H3C C O OH

meta-chloroperbenzoid acid peracetic acid

(MCPBA)
Ch. 11 - 75
  Mechanism
R R carboxylic R
peroxy acid acid
O O O
O O O
O O O
H H H

epoxide
alkene
concerted
transition
state
Ch. 11 - 76
13B. Stereochemistry of Epoxidation
 Addition of peroxy acid across a C=C
bond
 A stereospecific syn (cis) addition
O
MCPBA

(trans) (trans)

O
MCPBA

(cis) (cis)
Ch. 11 - 77
 Electron-rich double reacts faster

MCPBA
O
(1 eq.)

Ch. 11 - 78
14. Reactions of Epoxides
 The highly strained three-membered
ring of epoxides makes them much
more reactive toward nucleophilic
substitution than other ethers

Ch. 11 - 79
 Acid-catalyzed ring opening of epoxide

C C + H O H C C + O H
O H O H
H
O H
H O H
H
H
H
+
O H O H
C C C C
H O H O
Ch. 11 - 80
 Base-catalyzed ring opening of epoxide

RO
R O + C C C C
O O

R O H

RO
C C + R O
OH
Ch. 11 - 81
 If the epoxide is unsymmetrical, in the
base-catalyzed ring opening, attack
by the alkoxide ion occurs primarily at
the less substituted carbon atom
EtO
Et O +
O O
o
1 carbon atom is EtOH
less hindered
EtO
+ Et O
OH Ch. 11 - 82
 In the acid-catalyzed ring opening
of an unsymmetrical epoxide the
nucleophile attacks primarily at the
m ore substituted carbon atom
cat. HA
MeOH +
O MeO OH

MeOH +
O MeO OH
(protonated
epoxide) H H
o
This carbon resembles a 3 carbocation Ch. 11 - 83
15. Anti 1,2-Dihydroxylation of
Alkenes via Epoxides
 Synthesis of 1,2-diols
− OH
cold KMnO4, OH or
1. OsO4
2. NaHSO3 OH

1. MCPBA OH
2. H+, H2O

OH
Ch. 11 - 84
 Anti-Dihydroxylation
● A 2-step procedure via ring-opening
of epoxides
H H
MCPBA H+
O O H
H2O
H H

OH H2O

OH Ch. 11 - 85
16. Crown Ethers

 Crown ethers are heterocycles

containing many oxygens

 They are able to transport ionic

compounds in organic solvents –
phase transfer agent

Ch. 11 - 86
 Crown ether names: x-crown-y
● x = ring size
● y = number of oxygen

O
O O O O
O O
O O O O
O O
O
O
(18-crown-6) (15-crown-5) (12-crown-4)

Ch. 11 - 87
 Different crown ethers accommodate
different guests in this guest-host
relationship
+
● 18-crown-6 for K
+
● 15-crown-5 for Na
+
● 12-crown-4 for Li

 1987 Nobel Prize to Charles Pedersen

(Dupont), D.J. Cram (UCLA) and J.M.
Lehn (Strasbourg) for their research on
ion transport, crown ethers
Ch. 11 - 88
 Many important implications to
biochemistry and ion transport

O O
O O O O
KMnO4
K MnO4
benzene
O O O O
O O

(18-crown-6) (purple benzene)

Ch. 11 - 89
  Several antibiotics call ionophores are
large ring polyethers and polylactones
Me Me O

O O O
O Me
O Me O
Me
Me O
O O O

O Me Me

Nonactin
Ch. 11 - 90
17. Summary of Reactions of
Alkenes, Alcohols, and Ethers
 Synthesis of alcohols
X
OH

O OH
1. 1. BH3 THF
2. H2O 2. H2O2, NaOH
(1o alcohol)

MgBr
Ch. 11 - 91
 Synthesis of alcohols

1. BH3 THF
2. H2O2, NaOH

OH 1. Hg(OAc)2, H2O
+
H , H2O 2. NaBH4
(2o alcohol)

or
Ch. 11 - 92
 Synthesis of alcohols

H2O

1. Hg(OAc)2, H2O
H+, H2O OH 2. NaBH4
(3o alcohol)

Ch. 11 - 93
 Reaction of alcohols
OR
Br

1. base
PBr3 2. R-X H+, heat

OH
TsCl
SOCl2 (1o alcohol) pyridine

Cl H-X OTS

X
Ch. 11 - 94
 Synthesis of ethers
conc. H2SO4
R O R
RO 140oC

R X R OH

 Cleavage reaction of ethers

H X X
R O R' R O R' ROH + R'X
H
Ch. 11 - 95
 END OF CHAPTER 11 

Ch. 11 - 96