Alcohols and Ethers-2Alcohols and Ethers-2Dr AKM Shafiqul IslamDr AKM Shafiqul Islam

School of Bioprocess EngineeringSchool of Bioprocess Engineering

University Malaysia Perlis University Malaysia Perlis (UniMAP)(UniMAP)

Alcohols are not reactive in nucleophilic substitution or elimination reactions since hydroxide is a strong base, poor leaving group.

strongbaseno reaction in

either case

poor leavinggroup

SN1

SN2

Substitution Reactions of Substitution Reactions of AlcoholsAlcohols

R OH R+ + HO-XR OH RNu + HO-XNu

The situation improves under acid conditions. We change the leaving group to water, a neutral group.

neutral

Substitution Reactions of Substitution Reactions of AlcoholsAlcohols

R OH

H+

ORH

H

Nu-

Nu R + OH

H

R+Nu-

Nu R

- H2Oneutral

ElectrophilesElectrophiles

Molecules that contain atoms with empty orbital, which can accommodate electrons. Typically, these are positively charged.

Boron has only 6 valence electrons. BF3 is a Lewis acid.

BF3H CH3CH2

Examples:

NucleophilesNucleophiles

Molecules that contain atoms with lone pairs, which can donate electrons. Often these are negatively charged. Almost all the time they contain elements from groups 15–17 of the periodic table, since those have lone pairs.

CH3NH2 H2OHO Cl

Examples:

SSNN1 reaction1 reaction

► The The SSNN1 reaction1 reaction is a substitution reaction in is a substitution reaction in organic chemistry. "Sorganic chemistry. "SNN" stands for " stands for nucleophilicnucleophilic substitution and the "1" represents the fact substitution and the "1" represents the fact that the that the rate-determining steprate-determining step is is unimolecularunimolecular. .

► It involves a It involves a carbocationcarbocation intermediate and is intermediate and is commonly seen in reactions of secondary or commonly seen in reactions of secondary or tertiary tertiary alkyl halidesalkyl halides or, under strongly acidic or, under strongly acidic conditions, with conditions, with secondary or tertiary alcoholssecondary or tertiary alcohols. .

SSNN2 reaction2 reaction► The The SSNN2 reaction2 reaction (known as (known as bimolecular bimolecular

substitution nucleophilicsubstitution nucleophilic) is a type of ) is a type of nucleophilicnucleophilic substitutionsubstitution, where a lone pair from a , where a lone pair from a nucleophilicnucleophilic attacks an electron deficient attacks an electron deficient electrophilicelectrophilic center and center and bondsbonds to it, expelling to it, expelling another group called a another group called a leaving groupleaving group. Thus the . Thus the incoming group replaces the leaving group in one incoming group replaces the leaving group in one step. step.

► Since two reacting species are involved in the slow, Since two reacting species are involved in the slow, rate-determining steprate-determining step of the of the reactionreaction, this leads to , this leads to the name the name bibimolecular molecular nnucleophilic ucleophilic ssubstitutionubstitution, or , or SSNN22. .

► The somewhat more transparently named analog to The somewhat more transparently named analog to SSNN2 among inorganic chemists is the 2 among inorganic chemists is the interchange interchange mechanismmechanism..

Nucleophilic SubstitutionNucleophilic Substitution

+ :Nu + :X:..

..

_R X R Nu

substrate nucleophile product leaving group

chloridebromideiodidehydroxidewateralkoxidesalcoholscyanideaminessulfidesacetylidescarbanionscarboxylates

chloridebromideiodidewateralcoholssulfonatesamines

ExamplesExamples

HOHI

I + H2O

cyclohexanol iodocyclohexane

OHHCl

Cl + H2O

1-propanol 1-chloropropane

Mechanism of SubstitutionMechanism of Substitution►Secondary and tertiary alcohols Secondary and tertiary alcohols

undergo Sundergo SNN1 reaction.1 reaction.

OH

H3C

H3CH3C BrH

O

H3C

H3CH3C H

H

CH3

H3C CH3

CH2

H3C CH3

Br- HBr

Br

carbocation

tert-butanol

tert-butyl chloride

- H2O

Mechanism of SubstitutionMechanism of Substitution► Primary alcohols undergo SPrimary alcohols undergo SNN2 reaction. 2 reaction.

Primary carbocations are too unstable to be Primary carbocations are too unstable to be formed.formed.

OH1-butanol

BrH

O

H

H

Attack from back-side

O

H

H

Br

Br

1-bromobutane

- H2O

EliminationElimination►Elimination of water, dehydration, is Elimination of water, dehydration, is

commonly obtained using sulfuric acid commonly obtained using sulfuric acid (H(H22SOSO44) as a catalyst.) as a catalyst.H3C

CH3

OH H2SO4

H3CHC CHCH3 + H2O

The acid is mandatory to convert the poor leaving group OH– into a good leaving group H2O.

EliminationElimination►First step is protonation of the hydroxyl group.First step is protonation of the hydroxyl group.

H3C

CH3

OH H2SO4

H3C

CH3

O

H

H

H3C

CH3

O

H

H - H2O H3C

CH3

Loss of water leads to a carbocation.

EliminationElimination

►Second, a base removes a proton Second, a base removes a proton to to the carbocation center.the carbocation center.H3C

CH3H H

OSO3H

H3CHC CHCH3

+

H2SO4

Notice that this reaction is an E1 reaction.

•Rate-determining step is the formation of the carbocation.

EliminationElimination

► In case we have a choice between In case we have a choice between several several -hydrogens, the most stable -hydrogens, the most stable alkene is formed preferentially.alkene is formed preferentially.

CH3CHCH2CH3

CH3

OH

CH

H3C

H3C

CH3

+ CH2

H3C

H2C

CH3

H3PO4

84 % 16 %

EliminationElimination

►As a result of the E1 mechanism, the As a result of the E1 mechanism, the ease of dehydration follows the order:ease of dehydration follows the order:

OH

R

R

R

OH

R

H

R

OH

H

R

H> >

R

R

R

R

H

R

H

RH

> >

That directly reflects the stability of the

intermediate carbocations.

EliminationElimination► Primary alcohols undergo dehydration by Primary alcohols undergo dehydration by

an E2 pathway.an E2 pathway.► First, however, we generate the good First, however, we generate the good

leaving group.leaving group.OH

H+

O

H

H

H3C O

H

H

H

OSO3H

H3C

CH

CH2

The subsequent steps, removal of water and

deprotonation, take place simultaneously.

Substitution of EthersSubstitution of Ethers►The behavior of ethers is comparable The behavior of ethers is comparable

to alcohols.to alcohols. ppKKaa of the leaving group is comparable. of the leaving group is comparable.

H OH H OCH3

pKa 15.7 15.5

R O R' + HI R O R'

H

R I R' OH+

Activation by acid allows substitution.

Substitution of EthersSubstitution of Ethers

►The mechanism involves first a The mechanism involves first a protonation step.protonation step.

R O R' + HI R O R'

H

The subsequent steps are determined by the stability of the intermediates.

• Stable carbocation SN1

• Unstable carbocation SN2

Substitution of EthersSubstitution of Ethers

►ExamplesExamples

OCH3

CH3

H3C

CH3

H+ I-

OCH3

CH3

H3C

CH3

HSN1

CH3

H3C

CH3

I

CH3

H3C

CH3

I

attack of nucleophile

stable carbocation

Substitution of EthersSubstitution of Ethers

OCH3

H3CH+ I-

OCH3

H3CH

SN2

Primary carbocations are unstable; thus, reaction proceeds via SN2.

OH3C

H

CH3SN2

I

OH

H3C

+ CH3I

Reaction takes place on the less hindered of the two alkyl groups.

EthersEthers

►Only hydrogen halides react with Only hydrogen halides react with ethersethers

►Ethers commonly used as solventsEthers commonly used as solvents►Often used solvents are:Often used solvents are:

OO O

O

tetrahydrofuranTHF tetrahydropyran 1,4-dioxan

CH3CH2OCH2CH3 CH3OCH2CH2OCH3

diethyl ether"ether"

dimethoxyethaneDME

EpoxidesEpoxides

► A special group of ethers are epoxides.A special group of ethers are epoxides.► Here the oxygen is incorporated into a Here the oxygen is incorporated into a

three- membered ring.three- membered ring.H2C CH2

O

H2C CH

O

CH3

propylene oxide

H2C CH2

O

ethylene oxide

We name epoxides commonly by using the name

of the parent alkene followed by oxide.

EpoxidesEpoxides

►Alternatively we can use the name of the Alternatively we can use the name of the parent alkane with an “epoxy” prefixparent alkane with an “epoxy” prefix

H2C C

O

CH3

CH3H2C CH

O

CH2

CH3

1,2-epoxy-2-methylpropane 1,2-epoxybutane

R

RCOOH

O

R

O

+ + RCOH

O

Formation of epoxides can be accomplished

by a reaction of a peracid with an alkene

EpoxidesEpoxides

►Reaction with hydrogen halides Reaction with hydrogen halides proceeds as with other ethers.proceeds as with other ethers.

H2C CH2

O

ethylene oxide

+ HBr H2C CH2

O

H

Br

HO

Br

EpoxidesEpoxides

►Reaction with water and alcohols can Reaction with water and alcohols can be accomplished via acid catalysis.be accomplished via acid catalysis.

H2C CH2

O

ethylene oxide

+ H+ H2C CH2

O

H

HO R

HO

OR

EpoxidesEpoxides► For unsymmetrical epoxides we have to For unsymmetrical epoxides we have to

inspect the individual steps in the reaction inspect the individual steps in the reaction more carefully.more carefully.

H3C

O H+

H3C

O

H

CH3OH

H3C

OHO

CH3acidic conditions

H3C

O CH3O

H3C

OCH3OH+

H3C

OCH3OH

basic conditions

We obtain different results depending on the reaction conditions used.

EpoxidesEpoxides►Acidic conditions:Acidic conditions:

First step is the formation of an oxonium First step is the formation of an oxonium species.species.

H3C

O H+

H3C

O

H

H3C

O

H

• Attack of the nucleophile can take place

at two positions.

EpoxidesEpoxides

► For the process of breaking the C-For the process of breaking the C-O O bond of the bond of the epoxide we have to assume that the oxygen is epoxide we have to assume that the oxygen is keeping the bonding electrons, thus creating a keeping the bonding electrons, thus creating a partial positive charge on the neighboring carbon.partial positive charge on the neighboring carbon.

H3C

O

H +

+ secondarycarbocation

Now we have carbocation-type carbons that can be distinguished via their stability.

tertiarycarbocation

H3C

O

H+

+

EpoxidesEpoxides

►Reaction proceeds at the tertiary Reaction proceeds at the tertiary centercenter

CH3

O

H

+

+

H3C

O

H+

+CH3OH

H3C

OHO

CH3H

+

H3C

OHO

CH3H- H+

H3C

OHO

CH3

EpoxidesEpoxides► Under basic reaction conditions the Under basic reaction conditions the

situation changes.situation changes. First we generate an alcoholate anionFirst we generate an alcoholate anion Attack takes place on the less hindered side.Attack takes place on the less hindered side.

CH3

OCH3OH

baseCH3O

EpoxidesEpoxides

►Finally, the reaction is completed by Finally, the reaction is completed by taking up a proton.taking up a proton.

CH3

OCH3O

CH3

OCH3O H+

CH3

OCH3O H

EpoxidesEpoxides►Ring opening of epoxides is an Ring opening of epoxides is an

important reaction in organic chemistry. important reaction in organic chemistry. A wide variety of nucleophiles can be A wide variety of nucleophiles can be used for this reaction. used for this reaction.

CH2

O

H3C

+ (CH3)2NHOH

CH2 CH3NH3C

CH3

CH2

O

H3C

+ CH3CH2CH2CH2

-Li+ OH

CH2 CH3CH2CH2

H2CH3C