chapter 11

Created byProfessor William Tam & Dr. Phillis

Chang Ch. 11 - 1

Chapter 11

Alcohols & Ethers

About The AuthorsThese Powerpoint Lecture Slides were created and prepared by Professor William Tam and his wife Dr. Phillis Chang.

Professor William Tam received his B.Sc. at the University of Hong Kong in 1990 and his Ph.D. at the University of Toronto (Canada) in 1995. He was an NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard University (USA). He joined the Department of Chemistry at the University of Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and Associate Chair in the department. Professor Tam has received several awards in research and teaching, and according to Essential Science Indicators, he is currently ranked as the Top 1% most cited Chemists worldwide. He has published four books and over 80 scientific papers in top international journals such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem.

Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She lives in Guelph with her husband, William, and their son, Matthew. Ch. 11 -

2

Ch. 11 - 3

OH OH OH

1. Structure & Nomenclature Alcohols have a hydroxyl (–OH)

group bonded to a saturated carbon atom (sp3 hybridized)

1o 2o 3o

Ethanol 2-Propanol(isopropylalcohol)

2-Methyl-2-propanol

(tert-butyl alcohol)

Ch. 11 - 4

OHOH

OH

2-Propenol(allyl alcohol)

2-Propynol(propargyl alcohol)

Benzyl alcohol

Ch. 11 - 5

Phenols●Compounds that have a

hydroxyl group attached directly to a benzene ringOH

Phenol

OH

4-Methylphenol

OH

2-Chlorophenol

Cl

H3C

Ch. 11 - 6

Ethers●The oxygen atom of an ether is

bonded to two carbon atoms

Diethyl ether tert-Butyl methyl ether

Divinyl ether

OO

CH3

O O

Ethyl phenyl ether

Ch. 11 - 7

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 - 8

ExamplesOH

OHOH

OH

2-Propanol(isopropyl alcohol)

1,2,3-Butanetriol

Ch. 11 - 9

Example

OH

OH

12 3 4

56

7

OH

125 4

3

67

8

or wrong

3-Propyl-2-heptanol

Ch. 11 - 10

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 - 11

Cyclic ethers

Oxacyclopropaneor oxirane

(ethylene oxide)

O O

O O

O

Oxacyclobutaneor oxetane

Oxacyclopentane(tetrahydrofuran or THF)

1,4-Dioxacyclohexane(1,4-dioxane)

Ch. 11 - 12

2. Physical Properties ofAlcohols 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 - 13

For example

O

Diethyl ether(MW = 74)

b.p. = 34.6oC

Pentane(MW = 72)b.p. = 36oC

OH

1-Butanol(MW = 74)

b.p. = 117.7oC Alcohol molecules can associate

with each other through hydrogen bonding, whereas those of ethers and hydrocarbons cannot

Ch. 11 - 14

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 - 15

Physical Properties of Ethers

Dimethyl etherDiethyl etherDiisopropyl ether1,2-Dimethoxyethane

CH3OCH3CH3CH2OCH2CH3(CH3)2CHOCH(CH3)2CH3OCH2CH2OCH3

-138-116-86-68

-24.934.6

6883

O

O

(DME)

Oxirane

Tetrahydrofuran (THF)

-112

-108

12

65.4

Name Formula mp(oC)

bp (oC)(1 atm)

Ch. 11 - 16

Physical Properties of Alcohols

MethanolEthanolIsopropyl alcoholtert-Butyl alcoholHexyl alcohol

Cyclohexanol

Ethylene glycol

CH3OHCH3CH2OHCH3CH(OH)CH3(CH3)3COHCH3(CH2)4CH2OH

-97-117-8825

-52

24

-12.6

64.778.382.382.5

156.5

161.5

197

inf.inf.inf.inf.0.6

3.6

inf.

OH

HOOH

Name Formula mp(oC)

bp (oC)(1 atm)

*

* Water solubility (g/100 mL H2O)

Ch. 11 - 17

4. Synthesis of Alcohols from Alkenes Acid-catalyzed Hydration of

AlkenesC C H

H2OC C

OHH

C COHH

HC CH

H⊕

H2O

H2O

Ch. 11 - 18

Acid-Catalyzed Hydration of Alkenes

●Markovnikov regioselectivity

●Free carbocation intermediate

●Rearrangement of carbocation possible

Ch. 11 - 19

Oxymercuration–Demercuration

●Markovnikov regioselectivity●Anti stereoselectivity●Generally takes place without

the complication of rearrangements

●Mechanism Discussed in Section 8.6

C C H2O, THF C CHgOAc

OHHg(OAc)2 C CH

OH

NaOHNaBH4

Ch. 11 - 20

Hydroboration–Oxidation

●Anti-Markovnikov regioselectivity

●Syn-stereoselectivity●Mechanism

Discussed in Section 8.7

1. BH3 THF2. H2O2, OH

OH

H

Ch. 11 - 21

R

R

OH

H

R

HOH

H+, H2O or1. Hg(OAc)2, H2O, THF2. NaBH4, NaOH

1. BH3 • THF2. H2O2, NaOH

Markovnikov regioselectivity

Anti-Markovnikov regioselectivity

Ch. 11 - 22

Example

OH

OHSynthesis?

(1)

Synthesis?(2)

Ch. 11 - 23

Synthesis (1)

OHH

●Need anti-Markovnikov addition of H–OH

●Use hydroboration-oxidation

OHH

1. BH3 • THF2. H2O2, NaOH

Ch. 11 - 24

Synthesis (2)H

OH

●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 - 25

H

H⊕

H2O

HO

Rearrangementof carbocation

(2o cation)

Acid-catalyzed hydration

Ch. 11 - 26

HOH

HgOAc

OHHg(OAc)2H2O, THF

Oxymercuration-demercuration

NaBH4NaOH

Ch. 11 - 27

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 - 28

OH

C–O & O–H bonds of an

alcohol are polarized

Protonation of the alcohol converts a poor leaving group (OH⊖) into a good one (H2O)

C O+ HH

C O H H A A+

alcohol strongacid

protonatedalcohol

Ch. 11 - 29

Once the alcohol is protonated substitution reactions become possible

C O HH

Nu + CNu + O HH

protonatedalcohol

SN2

The protonated –OHgroup is a good leavinggroup (H2O)

Ch. 11 - 30

6. Alcohols as Acids Alcohols have acidities similar to

that of waterpKa Values for Some Weak AcidsAcid pKa

CH3OH 15.5H2O 15.74CH3CH2OH 15.9(CH3)3COH 18.0

Ch. 11 - 31

Relative Acidity

H2O > ROH > > H2 > NH3 > RHRC CH

H2O & alcohols are thestrongest acids in this series

Increasing acidity

Relative Basicity

R > NH2 > H > > RO > HORC C

OH⊖ is the weakestacid in this series

Increasing basicity

Ch. 11 - 32

7. Conversion of Alcohols intoAlkyl Halides

●HX (X = Cl, Br, I)●PBr3●SOCl2

R OH R X

Ch. 11 - 33

OH Clconc. HCl25oC

+ HOH

(94%)

Examples

OH Br

(63%)

PBr3

Ch. 11 - 34

8. Alkyl Halides from the Reaction ofAlcohols with Hydrogen Halides

The order of reactivity of alcohols●3o

The order of reactivity of the hydrogen halides●HI > HBr > HCl (HF is generally

unreactive)

R OH R XHX+ + H2O

> 2o > 1o< methyl

Ch. 11 - 35

R OH NaX+ No Reaction!OH⊖ is a poorleaving group

R OH NaX+ H R X

R O HH

X

H3O⊕ is a goodleaving group

Ch. 11 - 36

8A.Mechanisms of the Reactions ofAlcohols with HX Secondary, tertiary, allylic, and

benzylic alcohols appear to react by a mechanism that involves the formation of a carbocation

Step 1

H O HHO

H + O HHO

H +

Hfast

Ch. 11 - 37

Step 2

OH

H

O HH

+slow

Step 3

+ ClClfast

Ch. 11 - 38

Primary alcohols and methanol react to form alkyl halides under acidic conditions by an SN2 mechanism

+X R C O HH

H

H

protonated 1o alcoholor methanol

RCH

HX O H

H+

(a goodleaving group)

Ch. 11 - 39

9. Alkyl Halides from the Reaction of Alcohols with PBr3 or SOCl2

Reaction of alcohols with PBr3

R OH R Br3 + + H3PO3PBr3(1o or 2o)

● 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 - 40

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 - 41

Mechanism

R OHBrP

Br Br+ R O

PBr2

HBr

protonatedalkyl dibromophosphite

+

R OPBr2

HBr

a goodleaving group

+ R Br + HOPBr2

Ch. 11 - 42

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 - 43

Mechanism

OOSCl Cl+HR O SR

H OClCl

O SRH O

Cl

Cl

O SRO

Cl+N

N

(C5H5N)

Ch. 11 - 44

+ O SRO

NCl

Mechanism

Cl⊖

O SRO

Cl+N

+ SO ON

ClO SR

ON

Ch. 11 - 45

10. Tosylates, Mesylates, & Triflates:Leaving Group Derivatives of Alcohols

OMs =

OTs = O SO

OCH3

O SO

OCH3

(Tosylate)

(Mesylate)

Ch. 11 - 46

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 + No Reaction!Nu

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

Ch. 11 - 47

Mesylates (OMs) and Tosylates (OTs) are good leaving groups and they can be prepared easily from an alcohol

OHOSCH3 ClO

OS CH3OO

NH

Cl

OMs

+

+ +

same as

(a mesylate)

pyridine(methane sulfonyl chloride)

Ch. 11 - 48

Preparation of Tosylates (OTs) from an alcohol

OHOS ClO

OSOO

NH

Cl

OTs

+

+ +

same as

(a tosylate)

pyridineH3C

CH3

(p-toluene sulfonyl chloride)

Ch. 11 - 49

SN2 displacement of the mesylate or tosylate with a nucleophile is possible

OTs

Nu

Nu

OTs

+

+

Ch. 11 - 50

Example

+ NaOTs

OHTsCl

pyridine

OTs

NaCNDMSO

CN

Retention ofconfiguration

Inversion ofconfiguration

Ch. 11 - 51

Example

MsClpyridine

NaSMeDMSO

OH OMs

SMe

Retention ofconfiguration

Inversion ofconfiguration

Ch. 11 - 52

11.Synthesis of Ethers

OH

O

180oCH2SO4

H2SO4140oC

Ethene

Diethyl ether

11A. Ethers by Intermolecular Dehydration of Alcohols

Ch. 11 - 53

OH

H + OSO3H

OH

+ H2O

Mechanism+OH H OSO3H

OH

H2O

O

●This method is only good for synthesis of symmetrical ethers

Ch. 11 - 54

For unsymmetrical ethers

+R

OR'ROH + R'OH

+R

OR

R'O

R'

H2SO4

Mixtureof ethers

1o alcohols

Ch. 11 - 55

Exception

+R OH HOcat. H2SO4

R O

+ HO H

H

R OH

(good yield)

Ch. 11 - 56

R X R O R'R'O

(SN2)

11B. The Williamson Synthesis of Ethers

Via SN2 reaction, thus R is limited to 1o (but R' can be 1o, 2o or 3o)

Ch. 11 - 57

Example 1

OH

Na H O Na + H2

Br

O

Ch. 11 - 58

Example 2

NaOHH2OHO

Cl

O

Cl

O

Ch. 11 - 59

Example 3

NaOHH2OOH

IO

However

NaOHH2OOH

INo epoxide observed!

Ch. 11 - 60

R1. Hg(O2CCF3)2, R'OH2. NaBH4, NaOH

11C. Synthesis of Ethers by Alkoxy- mercuration–Demercuration

R

OR'

Hg(O2CCF3)

(1) (2)

R

OR'Markovnikov regioselectivity

Ch. 11 - 61

Example

O1. Hg(O2CCF3)2, iPrOH2. NaBH4, NaOH

Ch. 11 - 62

R OH R OH2SO4+

tert-butylprotecting

group

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

A tert-butyl ether can be used to “protect” the hydroxyl group of a 1o alcohol while another reaction is carried 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 - 63

Example

Synthesis ofHO

HO Br

BrMg

from

and

1

2

3

4

5

1

2

3

4

5

Ch. 11 - 64

●Direct reaction will not work

HOHO Br

BrMg

+ ☓(Not Formed)

●Since Grignard reagents are basic and alcohols contain acidic proton

O Br

BrMg

+H

BrMg O Br+ H

Ch. 11 - 65

●Need to “protect” the –OH group first

HO Br1. H2SO42. O Br

BrMg

OHOH H2O

tert-butyl protected alcohol

deprotonation

Ch. 11 - 66

+

tert-butylchlorodimethylsilane

(TBSCl)

R O HCl

Si tBu

Me Me

OSi tBu

Me MeR

imidazoleDMF

( HCl) R O TBS( )

11E. Silyl Ether Protecting Groups A hydroxyl group can also be

protected by converting it to a silyl ether group

Ch. 11 - 67

+R O HF

Si tBu

Me Me

OSi tBu

Me MeR

R O TBS( )

Bu4NF

THF

The TBS group can be removed by treatment with fluoride ion (tetrabutyl-ammonium fluoride or aqueous HF is frequently used)

Ch. 11 - 68

Example

Synthesis of HO

HO

Ph

from

and

1

2

3

4

5

1

2

3

5

Ph6

I4

Na6

Ch. 11 - 69

HO Ph

●Direct reaction will not work

+O

Ph

I

Na

H☓

(Not Formed)

●Instead

+O

Ph

I

Na

HO

I

H Ph+

O

Ch. 11 - 70

I IHO TBSOTBSCl

imidazoleDMF

●Need to “protect” the –OH group first

Na Ph

TBSOPh

Bu4N FTHF

HOPh

Ch. 11 - 71

12.Reactions of Ethers

O + HBr BrOH

+

an oxonium salt

Dialkyl ethers react with very few reagents other than acids

Ch. 11 - 72

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 H2O+Br2

Cleavage of an ether

Ch. 11 - 73

BrOH

+ OH + Br

Mechanism

H BrO + BrOH

+

HBr

Br+HO

H

Ch. 11 - 74

13.Epoxides

O

Epoxide (oxirane)●A 3-membered ring containing

an oxygen

Ch. 11 - 75

13A. Synthesis of Epoxides: Epoxidation

C C C COperoxy

acid

Electrophilic epoxidation

Ch. 11 - 76

R CO

O OH

Peroxy acids (peracids)

●Common peracids

H3C CO

O OHCO

O OH

Cl

meta-chloroperbenzoid acid(MCPBA)

peracetic acid

Ch. 11 - 77

O

O H

O

R

Mechanism

O

O H

O

R

O

O H

O

Rperoxy acid

alkeneconcertedtransition

state

carboxylicacid

epoxide

Ch. 11 - 78

13B. Stereochemistry of Epoxidation

O

O

MCPBA

MCPBA

(trans)

(cis)

(trans)

(cis)

Addition of peroxy acid across a C=C bond

A stereospecific syn (cis) addition

Ch. 11 - 79

OMCPBA(1 eq.)

Electron-rich double reacts faster

Ch. 11 - 80

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 - 81

+ O HH

CCOH

O HH

+ HCCO

Acid-catalyzed ring opening of epoxide

O HH

C CO

O HH

H

O HH+

H

C CO

O H

H

Ch. 11 - 82

+ CCO

OR

Base-catalyzed ring opening of epoxide

CCRO

O

OR H

+CCRO

OHOR

Ch. 11 - 83

+O

OEt

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

O

EtO

OH+ OEt

EtOH1o carbon atom isless hindered

Ch. 11 - 84

+O

MeOHMeO OH

cat. HA

In the acid-catalyzed ring opening of an unsymmetrical epoxide the nucleophile attacks primarily at the more substituted carbon atom

This carbon resembles a 3o carbocation

+O

MeOHMeO OH

H H(protonated

epoxide)

Ch. 11 - 85

15.Anti 1,2-Dihydroxylation of Alkenes via Epoxides

Synthesis of 1,2-diolsOH

OH

OH

OH

1. MCPBA2. H, H2O

cold KMnO4, OH or1. OsO42. NaHSO3

Ch. 11 - 86

Anti-Dihydroxylation●A 2-step procedure via ring-

opening of epoxides H

H

OMCPBA

H

H

O HH

H2O

H2OOH

OH

Ch. 11 - 87

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 - 88

Crown ether names: x-crown-y●x = ring size●y = number of oxygen

OO

O

OO

O

O O

O OO O

OOO

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

Ch. 11 - 89

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 - 90

Many important implications to biochemistry and ion transport

OO

O

OO

OK

OO

O

OO

O

KMnO4benzene MnO4

(18-crown-6) (purple benzene)

Ch. 11 - 91

Several antibiotics call ionophores are large ring polyethers and polylactones

O

OO

O

Me

O

O

O Me

O OO

Me

O

Me

Me

O

Me

Me Me

Nonactin

Ch. 11 - 92

17.Summary of Reactions of Alkenes, Alcohols, and Ethers

Synthesis of alcohols

OH

(1o alcohol)

XOH

1. BH3 THF2. H2O2, NaOH

MgBr

1. 2. H2O

O

Ch. 11 - 93

Synthesis of alcohols

OH

(2o alcohol)

1. BH3 THF2. H2O2, NaOH

1. Hg(OAc)2, H2O2. NaBH4

or

H+, H2O

Ch. 11 - 94

Synthesis of alcohols

(3o alcohol)OH

H2OX

1. Hg(OAc)2, H2O2. NaBH4H+, H2O

Ch. 11 - 95

Reaction of alcohols

OH

(1o alcohol)

OR

1. base2. R-X H+, heat

OTS

TsClpyridineSOCl2

Cl

X

H-X

Br

PBr3

Ch. 11 - 96

Synthesis of ethers

R O R

R OH

conc. H2SO4140oC

R X

RO

Cleavage reaction of ethers

R O R' H X X ROH+R'XR O R'H

Ch. 11 - 97

END OF CHAPTER 11