1.

Alcohols versus Phenols

Chapter 11 Alcohols have a hydroxyl (OH) group bonded to a saturated
Alcohols & Ethers carbon atom (sp3 hybridized)

Chapter 12 1o OH 2o
OH 3o OH
Ethanol 2-Methyl-2-propanol
2-Propanol
Alcohols from (isopropyl alcohol) (tert-butyl alcohol)
Phenols
Carbonyl Compounds Compounds that have a hydroxyl group attached directly
to a benzene ring
Oxidation-Reduction &
Organometallic
Compounds

Examples OH OH
1B. Nomenclature of Ethers
OH
Rules of naming ethers
OH Similar to those with alkyl halides
2-Propanol 1,2,3-Butanetriol CH3O Methoxy
(isopropyl alcohol) CH3CH2O Ethoxy
Example
3-Propyl-2-heptanol O
8
OH Ethoxyethane
which is correct? 6
7
(diethyl ether)
1
2 3 4
5
6
7 or 5 4
3
2
1

OH OH

2. Physical Properties of Physical Properties of Ethers

Alcohols and Ethers Name Formula mp bp (oC)
(oC) (1 atm)
Ethers have boiling points that are roughly
Dimethyl ether CH3OCH3 -138 -24.9
comparable with those of hydrocarbons of the
same molecular weight (MW) Diethyl ether CH3CH2OCH2CH3 -116 34.6
Alcohols ( BECAUSE OF H-BONDING) have much Diisopropyl ether (CH3)2CHOCH(CH3)2 -86 68
higher boiling points than comparable ethers or 1,2-Dimethoxyethane CH3OCH2CH2OCH3 -68 83
hydrocarbons (DME)
O
O OH Oxirane -112 12

Diethyl ether Pentane 1-Butanol Tetrahydrofuran (THF) -108 65.4

(MW = 74) (MW = 72) (MW = 74) O

o o o
b.p. = 34.6 C b.p. = 36 C b.p. = 117.7 C 2014 by John Wiley & Sons, Inc. All rights reserved.

1
 Physical Properties of Alcohols 6. Alcohols as Acids
Name Formula mp bp (oC) *
(oC) (1 atm) Alcohols have acidities similar to that of
Methanol CH3OH -97 64.7 inf. water
Ethanol CH3CH2OH -117 78.3 inf. pKa Values for Some Weak Acids
Isopropyl alcohol CH3CH(OH)CH3 -88 82.3 inf.
tert-Butyl alcohol (CH3)3COH 25 82.5 inf. Acid pKa
Hexyl alcohol CH3(CH2)4CH2OH -52 156.5 0.6 CH3OH 15.5

Cyclohexanol OH 24 161.5 3.6 H2O 15.74

OH
CH3CH2OH 15.9
Ethylene glycol HO -12.6 197 inf.
(CH3)3COH 18.0
* Water solubility (g/100 mL H2O)
2014 by John Wiley & Sons, Inc. All rights reserved. 2014 by John Wiley & Sons, Inc. All rights reserved.

H2O & alcohols are the 4. Alcohols from Alkenes (from CHAPTER 8)
Relative Acidity
strongest acids in this series You know this !
H2O > ROH > RC CH > H2 > NH3 > RH OxymercurationDemercuration
OH OH
Hg(OAc)2 NaBH4
Increasing acidity C C C C C C
H2O, THF NaOH
HgOAc H
Markovnikov regioselectivity

Relative Basicity HO is the weakest Anti stereoselectivity
acid in this series
HydroborationOxidation
R > NH2 > H > RC C > RO > HO

Increasing basicity
Anti-Markovnikov regioselectivity
2014 by John Wiley & Sons, Inc. All rights reserved. Syn-stereoselectivity

7. Conversion of Alcohols into 9. Alcohols with PBr3 or SOCl2

Reaction of alcohols with PBr3
Alkyl Halides
HX (X = Cl, Br, I)
R OH R X PBr3
The reaction does not involve the formation of a
carbocation and usually occurs without rearrangement of
SOCl2 the carbon skeleton (especially if the temperature is kept
below 0C)

OH conc. HCl Cl Mechanism PBr2

o
+ HOH Br R O + Br
25 C
R OH + P H
(94%) Br Br protonated
OH PBr3 Br alkyl dibromophosphite

PBr2
Br + R O R Br + HOPBr2
(63%) H

2
9. Alcohols with SOCl2 10. Tosylates, Mesylates, and Triflates:
O H O Leaving Group Derivatives of Alcohols
Cl
R O H + Cl S Cl R O S
Cl

O O
Cl
N +R O S Cl R O S N SN2 displacement of the mesylate or tosylate with a
nucleophile is possible

Cl OTs + Nu

O
O O
N + S R Cl + O S N
Nu + OTs

Example 11. Synthesis of Ethers

Retention of For unsymmetrical ethers
OH OTs configuration
TsCl
H2SO4
pyridine ROH + R'OH O
R R'
+
NaCN
DMSO 1o alcohols O Mixture
R R
of ethers
Inversion of +
configuration CN O
R' R'
+ NaOTs

2014 by John Wiley & Sons, Inc. All rights reserved. 2014 by John Wiley & Sons, Inc. All rights reserved.

Exception 11B. The Williamson Ether Synthesis

R'O Via SN2 reaction,
cat. H2SO4 R X R O R' thus R is limited to 1o
R OH + R O (SN2) and some 2o (but R'
HO can be 1o, 2o or 3o)
+ HO H
(good yield)
H Na H
O O Na + H2
H

R OH Br

2014 by John Wiley & Sons, Inc. All rights reserved.

3
 Example 3 11E. Silyl Ether Protecting OH groups

I A hydroxyl group can also be protected

NaOH by converting it to a silyl ether group
O
H2O
OH
Me Me imidazole Me Me
R O H + Si t R Si t
However Cl Bu DMF O Bu
(HCl)
I tert-butylchloro (R O TBS )
NaOH
No epoxide observed! dimethylsilane
H2O (TBSCl)
OH Very common, useful protecting group
2014 by John Wiley & Sons, Inc. All rights reserved. 2014 by John Wiley & Sons, Inc. All rights reserved.

You want to make this, Direct reaction will not work

Synthesis of
2 4 6
Ph Na (Not Formed)
HO Ph
1 3
5 +
HO Ph
O
H I
2 4
from HO
1 3
I Instead

and Na Ph H Ph O
Ph Na +
6 5 +
O O
H I I
2014 by John Wiley & Sons, Inc. All rights reserved. 2014 by John Wiley & Sons, Inc. All rights reserved.

Need to block protect the OH group first 12A. Cleavage of Ethers

O + 2 HBr 2 Br + H2O
HO TBSCl TBSO
I I Cleavage of an ether
imidazole
DMF

O + H Br O + Br

H
Br H
+ Br H
O O + Br
H

O
2014 by John Wiley & Sons, Inc. All rights reserved. H H + Br

4
13. Epoxides (OXIRANE) 13B. Stereochemistry of Epoxidation
Epoxide (oxirane)
o Addition of peroxy acid across a C=C
A 3-membered ring containing an oxygen
bond
13A. Synthesis of Epoxides:
Electrophilic Epoxidation
A stereospecific syn (cis) addition
peroxy oO o
C C C C
acid

2014 by John Wiley & Sons, Inc. All rights reserved.

Mechanism 14. Ring Opening of Epoxides

R R carboxylic R 1) Using acids (H+)
peroxy acid acid
O O O C C + H O H C C + O H
O O O
O O O
O H O H
H H H
H
O H
H O H
epoxide H
H
alkene H
+
concerted O H O H
transition C C C C
state
2014 by John Wiley & Sons, Inc. All rights reserved.
H O H O

2) Using a Base catalyst In the acid-catalyzed ring opening of an

unsymmetrical epoxide the nucleophile
RO attacks primarily at the more substituted
R O + C C C C carbon atom
O O cat. HA
MeOH +
O MeO OH
R O H

MeOH +
RO O MeO OH
(protonated
C C + R O H
epoxide) H
OH o
This carbon resembles a 3 carbocation
2014 by John Wiley & Sons, Inc. All rights reserved. 2014 by John Wiley & Sons, Inc. All rights reserved.

5
 If the epoxide is unsymmetrical, in the 15. Anti 1,2-Dihydroxylation of
base-catalyzed ring opening, attack Alkenes via Epoxides
by the alkoxide ion occurs primarily at
Synthesis of 1,2-diols
the less substituted carbon atom
EtO
Et O +
O O
o
1 carbon atom is
less hindered

2014 by John Wiley & Sons, Inc. All rights reserved. 2014 by John Wiley & Sons, Inc. All rights reserved.

Anti-Dihydroxylation 16. Crown Ethers

A 2-step procedure via ring-opening
of epoxides Crown ether nomenclature: x-crown-y
x = # of atoms in ring
y = # of oxygen atoms in ring
O
O O O O
O O

OH H2O O O O O
O O
O
O
OH
(18-crown-6) (15-crown-5) (12-crown-4)
2014 by John Wiley & Sons, Inc. All rights reserved.

Several antibiotics call ionophores are 17. Summary of Reactions of

large ring polyethers and polylactones Alkenes, Alcohols, and Ethers
Me Me O Synthesis of alcohols

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

Nonactin MgBr
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6
 Reaction of alcohols Synthesis of ethers
OR
Br conc. H2SO4
R O R
RO 140oC
1. base
PBr3 2. R-X
R X R OH
OH
Cleavage reaction of ethers
SOCl2 (1o alcohol)
H X X
Cl R O R' R O R' ROH + R'X
H
2014 by John Wiley & Sons, Inc. All rights reserved. 2014 by John Wiley & Sons, Inc. All rights reserved.

Alcohols from 1A. Reactions of Carbonyl Compounds with Nucleophiles

Chapter 12 Carbonyl Compounds One of the most important reactions of carbonyl
Carbonyl compounds compounds is nucleophilic addition to the carbonyl group
O
O
~ 120o O + nucleophilic
Nu C C
~ 120o O O addition Nu
C
~ 120o Two important nucleophiles:
R H R R' Hydride ions (from NaBH4 and LiAlH4)
Carbanions (from RLi and RMgX)
Carbonyl carbon: sp2 hybridized Aldehyde Ketone
Planar structure Another important reaction:
OH O
O O O oxidation
C
R' R R H
R OH R OR' R N H reduction
H
Carboxylic acid Ester Amide R"
1o alcohol aldehyde

2. Oxidation-Reduction Reactions in Organic

Chemistry 3. Alcohols by Reduction of
The opposite reaction of reduction is oxidation. Increasing the oxygen content of an organic molecule or
decreasing its hydrogen content is oxidation
[O] OH [O] O [O] O
Carbonyl Compounds
RCH3 H [H]
[H] R H [H] R H [H] R OH
lowest H highest R O
oxidation oxidation OH [H] H H
state state
(1o alcohol)
[O] [O] [O]
Ar CH3 R O R OH
Ar CH2Cl Ar CHCl2 Ar CCl3
[H] [H] [H] OR'
[H]
H H O O O
R O
H C H < H C OH < C < C < C
O
H H H OH [H] HO H
H H O
R R' R R'
-4 -2 0 +2 +4 2014 by John Wiley & Sons, Inc. All rights reserved.

7
 3A. Lithium Aluminum Hydride Mechanism
O H O
O 1. LiAlH4, Et2O OH
(1) + H Al H R OR'
R OH 2. H+, H2O R H R OR'
H H H
O
O 1. LiAlH4, Et2O OH R'O +
(2) + HOR' R H
R OR' 2. H+, H2O R H H
H
O H Al H
OH O
O 1. LiAlH4, Et2O OH H H H
(3) R H R H
R H 2. H+, H2O R H H H
H
Esters are reduced to 1o alcohols
2014 by John Wiley & Sons, Inc. All rights reserved. 2014 by John Wiley & Sons, Inc. All rights reserved.

3B. Sodium Borohydride (less reactive) 3C. LiAlH4 versus NaBH4 Reactivity
O NaB H 4 OH
(1 )
H
reduced by LiAlH4
R H H 2O R
H
O OH
NaB H 4 reduced by NaBH4
(2 )
R R' H 2O R R' O O O O
H
< < <
H O
O R O R OR' R R' R H
+ H B H R R' ease of reduction
+
R R' H
H
Mechanism
O
Aldehydes are OH H H
reduced to 1 alcohols
& ketones are R'
reduced to 2 alcohols R
H

4. Oxidation of Alcohols 4B. Swern Oxidation

Swern oxidation of a 1
alcohol to an aldehyde

Swern oxidation of a 2
alcohol to a ketone
2014 by John Wiley & Sons, Inc. All rights reserved.

8
4C. Chromic Acid (H2CrO4) Oxidation Jones oxidation
Reagent: CrO3 + aqueous H2SO4
A Cr(VI) oxidant
CrO3 O
R OH + Cr(III)
H2SO4
R OH
(orange solution) (green)
Chromic acid (H2CrO4) usually prepared OH CrO3 O
+ Cr(III)
by [CrO3 or Na2Cr2O7] + aqueous H2SO4 H2SO4
R R' R R'
(orange solution) (green)
OH
Jones reagent CrO3
No Reaction
R" H2SO4
R
2014 by John Wiley & Sons, Inc. All rights reserved.
R' 2014 by John Wiley & Sons, Inc. All rights reserved.

CrO3 O
A R OH + Cr(III) 4E. Potassium Permanganate (KMnO4)
H2SO4
Chemical (orange solution)
R OH
(green)
Test for OH CrO3 O
Primary + Cr(III)
H2SO4
R R' R R'
and (orange solution) (green)
OH
Secondary CrO3
No Reaction
Alcohols R R" H2SO4
R' 5. Organometallic Compounds
Compounds that contain carbon-metal bonds are called
organometallic compounds

+
PCC = [CrO3Cl] C M C : M C M
N
H
primarily ionic primarily covalent
(Pyridinium chlorochromate)
(M = Na or K) (M = Mg or Li) (M = Pb, Sn, Hg or Tl)