SCO1122

ORGANIC CHEMISTRY

Chapter: 2

Alcohols & Ethers

Copyright © 2021 by John Wiley & Sons, Inc. All rights reserved.
Table of Contents
1. Structure & Nomenclature
2. Physical Properties of Alcohols and Ethers
3. Important Alcohols & Ethers
4. Synthesis of Alcohols from Alkenes
5. Reactions of Alcohols
6. Alcohols as Acids
7. Conversion of Alcohols into Alkyl Halides
8. Alkyl Halides from the Reaction of Alcohols with Hydrogen Halides
9. Alkyl Halides from the Reaction of Alcohols with PBr 3 or SOCl2
10. Tosylates, Mesylates, and Triflates: Leaving Group Derivatives of
Alcohols
11. Synthesis of Ethers
12. Reactions of Ethers
13. Epoxides
14. Reactions of Epoxides
15. Anti 1,2-Dihydroxylation of Alkenes via Epoxides
16. Crown Ethers
17. Summary of Reactions of Alkenes, Alcohols, and Ethers
In this chapter we will consider:
 The structures, properties, and
nomenclature of common alcohols and
ethers

 Key molecules that contain such groups

 The reactivity of alcohols, ethers, and a

special group of ethers known as
epoxides
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)
 OH
OH

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

OH

Benzyl alcohol
 Phenols
• Compounds that have a hydroxyl
group attached directly to a
benzene ring

OH OH Cl OH

H3C

Phenol 4-Methylphenol 3-Chlorophenol

 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

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”
 Examples
OH OH

OH
OH
2-Propanol 1,2,3-Butanetriol
(isopropyl alcohol)
 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
1B. Nomenclature of Ethers
 Rules of naming ethers
• Similar to those with alkyl halides
 CH3O– Methoxy
 CH3CH2O– Ethoxy

 Example
O

Ethoxyethane
(diethyl ether)
 Cyclic ethers
O O

Oxacyclopropane Oxacyclobutane
or oxirane or oxetane
(ethylene oxide)
O

O
O
Oxacyclopentane 1,4-Dioxacyclohexane
(tetrahydrofuran or THF) (1,4-dioxane)
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
 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
 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
 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
 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)

3. Important Alcohols & Ethers
3A. Methanol
300-400oC
CO + 2 H2 CH3OH
200-300 atm
ZnOCr2O3
 Methanol is highly toxic
 Ingestion of even small quantities of
methanol can cause blindness
 Large quantities cause death
 Methanol poisoning can also occur by
inhalation of the vapors or by prolonged
exposure to the skin
3B. Ethanol
 Ethanol can be produced by
• Fermentation
yeast
C6H12O6 2 CH3CH2OH + 2 CO2
(~95% yield)

• Acid-catalyzed hydration of ethene

acid
+ H2O OH
3C. Ethylene and Propylene Glycols
OH
OH OH
HO
ethylene glycol propylene glycol

a good automobile as a low-toxicity,

anti-freeze environmentally
friendly alternative
to ethylene glycol
3D. Diethyl Ether
 Diethyl ether is a very low boiling,
highly flammable liquid

 Most ethers react slowly with oxygen

by a radical process called
autoxidation to form hydroperoxides
and peroxides
 Step 1
H
OR'
O O + C OR' O O H+ C

Hydrogen abstraction
adjacent to the ether oxygen
occurs readily
 Step 2
OO
OR'
C + O2 C OR'
 Step 3a
OO H OOH
OR'
C OR' + C OR' C OR' + C

A hydroperoxide

or Hydroperoxides and peroxides

Step 3b can be explosive
OO
OR'
C OR' + C R'O C OO C OR'

A peroxide
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
 Acid-Catalyzed Hydration of Alkenes

• Markovnikov regioselectivity

• Free carbocation intermediate

• Rearrangement of carbocation
possible
 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 8.5
 Hydroboration–Oxidation

OH
1. BH3 THF
H
2. H2O2, HO

• Anti-Markovnikov regioselectivity
• Syn-stereoselectivity
• Mechanism
 Discussed in Section 8.7
 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
 Example
Synthesis?
(1) OH

OH

Synthesis?
(2)
 Synthesis (1) H
OH

• Need anti-Markovnikov addition of

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

• Need Markovnikov addition of H–OH

• Thus, could potentially use either
 acid-catalyzed hydration or
 oxymercuration-demercuration
• However, acid-catalyzed hydration is
NOT reasonable here due to likely
rearrangement of carbocation
 Acid-catalyzed hydration
HO

⊕
H

H2O

H
Rearrangement
o
of carbocation
(2 cation)
 Oxymercuration-demercuration
OH
H

Hg(OAc)2 OH NaBH4
H2O, THF NaOH

HgOAc
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
 
 O C–O & O–H bonds of an
H
alcohol are polarized

 Protonation of the alcohol converts a

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

alcohol strong protonated

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

Increasing acidity

 Relative Basicity HO⊖ is the weakest

acid in this series

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

Increasing basicity
7. Conversion of Alcohols into
Alkyl Halides

R OH R X

• HX (X = Cl, Br, I)
• PBr3
• SOCl2
 Examples

OH conc. HCl Cl
o
+ HOH
25 C
(94%)

OH PBr3 Br

(63%)
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)
R OH + NaX No Reaction!
⊖
HO is a poor
leaving group

H
R OH + NaX R X

X
R O H
⊕
H3O is a good H
leaving group
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
 Step 2

H + O H
O slow H
H

 Step 3

+ Cl
fast Cl
 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
9. Alkyl Halides from the Reaction
of Alcohols with PBr3 or SOCl2
 Reaction of alcohols with PBr3
3 R OH + PBr3 3R 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)
 Reaction of alcohols with PBr3

• Phosphorus tribromide is often

preferred as a reagent for the
transformation of an alcohol to the
corresponding alkyl bromide
 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
 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
 Mechanism
O H O
Cl
R O H + Cl S Cl R O S
Cl

(C5H5N)
O H O

N +R O S Cl R O S Cl
- HCl
Cl
 Mechanism
O O
 Cl
N +R O S Cl R O S N

Cl⊖

O
+ O O
N S R Cl + O S N
10. Tosylates, Mesylates, and
Triflates: Leaving Group
Derivatives of Alcohols
O
OTs = O S CH3 (Tosylate)
O

O
OMs = O S CH3 (Mesylate)
O
 Direct displacement of the –OH group
with a nucleophile via an SN2 reaction
⊖
is not possible since HO is a very poor
leaving group

OH + Nu No Reaction!

⊖
 Thus we need to convert the HO to a
better leaving group first
 Mesylates (OMs) and Tosylates (OTs)
are good leaving groups and they can
be prepared easily from an alcohol
(methanesulfonyl chloride) O
pyridine
OH + CH3 S Cl
O

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

OMs (a mesylate)
 Preparation of Tosylates (OTs) from an
alcohol (p-toluenesulfonyl chloride)
O
pyridine
OH + H3C S Cl
O

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

OTs (a tosylate)
 SN2 displacement of the mesylate or
tosylate with a nucleophile is possible

OTs + Nu

Nu + OTs
 Example
Retention of
OH OTs configuration
TsCl
pyridine

NaCN
DMSO

Inversion of
configuration CN
+ NaOTs
 Example Retention of
configuration
OH OMs
MsCl
pyridine

NaSMe
DMSO
Inversion of
configuration
SMe
11. Synthesis of Ethers
11A. Ethers by Intermolecular
Dehydration of Alcohols
H2SO4
180oC
Ethene
OH
H2SO4
o O
140 C
Diethyl ether
 Mechanism
OH + H OSO3H O H + OSO3H
H

OH

O O + H2O

H2O H

• This method is only good for the

synthesis of symmetrical ethers
 For unsymmetrical ethers

H2SO4
ROH + R'OH O
R R'
+
o
1 alcohols O Mixture
R R
of ethers
+
O
R' R'
 Exception
cat. H2SO4
R OH + R O
HO
+ HO H
(good yield)
H

R OH
11B. The Williamson Ether Synthesis

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

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

and some 2o (but R' can be 1o, 2o or 3o)
 Example 1

Na H
O O Na + H2
H

Br

O
 Example 2
Cl
NaOH
Cl
HO H2O
O

O
 Example 3
I
NaOH
O
H2O
OH

 However
I
NaOH
No epoxide observed!
H2O
OH
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)
 Example

i O
1. Hg(O2CCF3)2, PrOH
2. NaBH4, NaOH
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
 Example
1 3 5
Synthesis of
HO 2 4

1 3
from
HO 2
Br

5
and BrMg
4
 • Direct reaction will not work
BrMg (Not Formed)
+
☓ HO
HO Br
• Reason: Grignard reagents are basic
and alcohols contain an acidic proton
BrMg

+ BrMg O Br
H O Br
+ H
 • Need to “protect” the –OH group first
tert-butyl protected alcohol

1. H2SO4
HO Br O Br
2.

BrMg

H
HO O
H2O
deprotection
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)
 Very common, useful protecting group
 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 )
 Example
2 4 6
Synthesis of HO Ph
5
1 3

2 4
from HO
1 3
I

and
Ph Na
6 5
 • Direct reaction will not work
Ph Na (Not Formed)

O
+
☓ HO Ph

H I

• Instead

Na Ph H Ph O
+ +
O O
H I I
 • Need to “protect” the –OH group first

HO TBSCl TBSO
I I
imidazole
DMF
Na Ph

TBSO

Ph
Bu4N F
THF

HO

Ph
12. Reactions of Ethers
 Dialkyl ethers react with very few
reagents other than acids

O + HBr O + Br

H
an oxonium salt
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
 Mechanism

O + H Br O + Br

Br H
H
O + Br O + Br
H

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

O
13A. Synthesis of Epoxides:
Epoxidation
 Electrophilic epoxidation

peroxy O
C C C C
acid
 Peroxy acids (peracids)
O
R C O OH

• Common peracids
Cl
O O
C O OH H3C C O OH

meta-chloroperoxybenzoic acid peracetic acid

(MCPBA)
  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
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)
 More electron-rich double reacts faster

mCPBA
O
(1 equiv.)
14. Reactions of Epoxides
 The highly strained three-membered
ring of epoxides makes them much
more reactive toward nucleophilic
substitution than other ethers
 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
 Base-catalyzed ring opening of epoxide

RO
R O + C C C C
O O

R O H

RO
C C + R O
OH
 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
 In the acid-catalyzed ring opening of an
unsymmetrical epoxide the nucleophile
attacks primarily at the more substituted
carbon atom
cat. HA
MeOH +
O MeO OH

MeOH +
O MeO OH
(protonated
epoxide) H H
o
This carbon resembles a 3 carbocation
15. Anti 1,2-Dihydroxylation of
Alkenes via Epoxides
 Synthesis of 1,2-diols
 Anti-Dihydroxylation
• A 2-step procedure via ring-opening
of epoxides
H H
mCPBA H
O O H
H2 O
H H

OH H2O

OH
Copyright © 2017 by John Wiley & Sons, Inc. All rights reserved.
16. Crown Ethers

 Crown ethers are cyclic compounds

containing many oxygen atoms

 They are able to transport (i.e.

dissolve) ionic compounds in organic
solvents – phase transfer agent
 Crown ether nomenclature: x-crown-y
● x = # of atoms in ring
● y = # of oxygen atoms in ring

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

  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
17. Summary of Reactions of
Alkenes, Alcohols, and Ethers
 Synthesis of alcohols
X
HO

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

MgBr
 Synthesis of alcohols

1. BH3 THF
2. H2O2, NaOH

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

or
 Synthesis of alcohols

H , H2O

1. Hg(OAc)2, H2O
H , H 2O OH 2. NaBH4
(3o alcohol)
 Reaction of alcohols
OR
Br

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

OH
TsCl
SOCl2 (1o alcohol) pyridine

Cl OTs
 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
 END OF CHAPTER 2 

Copyright © 2021 by John Wiley & Sons, Inc. All rights reserved.