Dehydrohalogenation of Alkyl Halides E2 and E1 Reactions in Detail

Dehydrohalogenation of Dehydrohalogenation of

Alkyl Halides Alkyl Halides

E2 and E1 Reactions in Detail E2 and E1 Reactions in Detail

XX YY

dehydration of alcohols:dehydration of alcohols:X = H; Y = OHX = H; Y = OH

dehydrohalogenation of alkyl halides:dehydrohalogenation of alkyl halides:X = H; Y = Br, etc.X = H; Y = Br, etc.

CC CCCC CC ++ XX YY

-Elimination Reactions Overview-Elimination Reactions Overview

XX YY

dehydration of alcohols:dehydration of alcohols:acid-catalyzedacid-catalyzed

dehydrohalogenation of alkyl halides:dehydrohalogenation of alkyl halides:consumes baseconsumes base

CC CCCC CC ++ XX YY

-Elimination Reactions Overview-Elimination Reactions Overview

is a useful method for the preparation of alkenesis a useful method for the preparation of alkenes

(100 %)(100 %)

likewise, NaOCHlikewise, NaOCH33 in methanol, or KOH in ethanol in methanol, or KOH in ethanol

NaOCHNaOCH22CHCH33

ethanol, 55°Cethanol, 55°C

DehydrohalogenationDehydrohalogenation

ClCl

CHCH33(CH(CH22))1515CHCH22CHCH22ClCl

When the alkyl halide is When the alkyl halide is primaryprimary, potassium, potassiumterttert-butoxide in dimethyl sulfoxide is the -butoxide in dimethyl sulfoxide is the base/solvent system that is normally used. base/solvent system that is normally used.

KOC(CHKOC(CH33))33

dimethyl sulfoxidedimethyl sulfoxide

(86%)(86%)

CHCH22CHCH33(CH(CH22))1515CHCH

DehydrohalogenationDehydrohalogenation

BrBr

29 %29 % 71 %71 %

++

RegioselectivityRegioselectivity

follows Zaitsev's rulefollows Zaitsev's rule

More highly substituted double bond predominates = More highly substituted double bond predominates = More StableMore Stable

KOCHKOCH22CHCH33

ethanol, 70°Cethanol, 70°C

Zaitsev’s Rule

The more substituted alkene is obtained when a proton is removed from the -carbon that is bonded to the fewest hydrogens

Conjugated alkenes are preferred !

Steric hindrance effects the product distribution

more stable configurationmore stable configurationof double bond predominatesof double bond predominates

StereoselectivityStereoselectivity

KOCHKOCH22CHCH33

ethanolethanol

BrBr

++

(23%)(23%) (77%)(77%)

more stable configurationmore stable configurationof double bond predominatesof double bond predominates

StereoselectivityStereoselectivity

KOCHKOCH22CHCH33

ethanolethanol

++

(85%)(85%) (15%)(15%)

BrBr

Mechanism of theMechanism of theDehydrohalogenation of Alkyl Dehydrohalogenation of Alkyl

Halides:Halides:The E2 MechanismThe E2 Mechanism

FactsFacts

Dehydrohalogenation of alkyl halides Dehydrohalogenation of alkyl halides exhibits second-order kineticsexhibits second-order kinetics

first order in alkyl halidefirst order in alkyl halidefirst order in basefirst order in baserate = rate = kk[alkyl halide][base][alkyl halide][base]

implies that rate-determining step implies that rate-determining step involves both base and alkyl halide; involves both base and alkyl halide; i.e., it is bimoleculari.e., it is bimolecular

FactsFacts

Rate of elimination depends on halogenRate of elimination depends on halogen

weaker C—X bond; faster rateweaker C—X bond; faster raterate: RI > RBr > RCl > RFrate: RI > RBr > RCl > RF

implies that carbon-halogen bond breaks in implies that carbon-halogen bond breaks in the rate-determining stepthe rate-determining step

concerted (one-step) bimolecular processconcerted (one-step) bimolecular process

single transition statesingle transition state

C—H bond breaksC—H bond breaks

component of double bond formscomponent of double bond forms

C—X bond breaksC—X bond breaks

The E2 MechanismThe E2 Mechanism


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––

OORR..

.... ::

CC CC

HH

XX....::::

ReactantsReactants


––

OORR..

.... ::

CC CC

HH

XX....::::

ReactantsReactants


CC CC

––

OORR..

.... HH

XX....::::––

Transition stateTransition state


OORR....

.... HH

CC CC

––XX....

::::....

ProductsProducts


Stereoelectronic EffectsStereoelectronic Effects

Anti Elimination in E2 ReactionsAnti Elimination in E2 Reactions

Stereochemistry of the E2 Reaction

Remember: The bonds to the eliminated groups (H and X) must be in the same plane and anti to each

other

H

XMore stable conformation than syn-eclipsed

The best orbital overlap of the interacting orbitals is achieved through back side attack of the leaving

group X as in an SN2 displacement.

Regioselectivity

Configuration of the Reactant

Elimination from Cyclic Compounds

Configuration must be trans, which is (anti).

H

Br

H

Br

(CH(CH33))33CC

(CH(CH33))33CC

BrBr

KOC(CHKOC(CH33))33

(CH(CH33))33COHCOH

ciscis-1-Bromo-4--1-Bromo-4-tert-tert- butylcyclohexanebutylcyclohexane

Stereoelectronic effectStereoelectronic effectStereoelectronic effectStereoelectronic effect

(CH(CH33))33CC

(CH(CH33))33CCBrBr KOC(CHKOC(CH33))33

(CH(CH33))33COHCOH

transtrans-1-Bromo-4--1-Bromo-4-tert-tert- butylcyclohexanebutylcyclohexane


(CH(CH33))33CC

(CH(CH33))33CC

BrBr

(CH(CH33))33CCBrBr

KOC(CHKOC(CH33))33

(CH(CH33))33COHCOH

KOC(CHKOC(CH33))33

(CH(CH33))33COHCOH

ciscis

transtrans

Rate constant for Rate constant for dehydrohalogenation dehydrohalogenation of cis is 500 times of cis is 500 times greater than that of greater than that of transtrans


(CH(CH33))33CC

(CH(CH33))33CC

BrBr

KOC(CHKOC(CH33))33

(CH(CH33))33COHCOH

ciscis

H that is removed by base must be H that is removed by base must be anti anti periplanar to Brperiplanar to Br

Two anti periplanar H atoms in cis Two anti periplanar H atoms in cis stereoisomerstereoisomer

HHHH


(CH(CH33))33CC

KOC(CHKOC(CH33))33

(CH(CH33))33COHCOH

transtrans

H that is removed by base must be H that is removed by base must be anti anti periplanar to Brperiplanar to Br

No anti periplanar H atoms in trans No anti periplanar H atoms in trans stereoisomer; all vicinal H atoms are stereoisomer; all vicinal H atoms are gauche to Brgauche to Br

HHHH

(CH(CH33))33CCBrBr

HH

HH


ciscis

more reactivemore reactive

transtrans

less reactiveless reactive



An effect on reactivity that has its origin An effect on reactivity that has its origin in the spatial arrangement of orbitals or bonds in the spatial arrangement of orbitals or bonds is called a stereoelectronic effect.is called a stereoelectronic effect.

The preference for an The preference for an anti periplanar anti periplanar arrangement of H and Br in the transition arrangement of H and Br in the transition state for E2 dehydrohalogenationstate for E2 dehydrohalogenation is an is an example of a stereoelectronic effectexample of a stereoelectronic effect..

E2 in a cyclohexane ringE2 in a cyclohexane ringE2 in a cyclohexane ringE2 in a cyclohexane ring

E2 in a cyclohexane ringE2 in a cyclohexane ringE2 in a cyclohexane ringE2 in a cyclohexane ring

Cl

C

H

3

C

H

3

C

H

3

C

H

3

C

H

3

C

H

3

Cl

C

H

3

C

H

2

O

-

C

H

3

C

H

2

O

-

+

+

menthyl

neomenthyl

Can you predict the products?Can you predict the products?

Cis or trans?Cis or trans?

Axial or equatorial?Axial or equatorial?

a,e a,e e,a e,a

e,e e,e a,a a,a

C

H

3

C

H

3

C

H

3

C

H

3

C

H

3

C

H

3

+

80% 20%

Can you explain the products?Can you explain the products?

C

H

3

C

H

3

C

H

3

100%

Cyclohexane Stereochemistry RevisitedCyclohexane Stereochemistry RevisitedCyclohexane Stereochemistry RevisitedCyclohexane Stereochemistry Revisited

http://www.csir.co.za/biochemtek/newsletter/aug/menthol.html

l-menthol l-menthol http://www.library.ucsf.edu/tobacco/batco/html/9000/9036/

How many stereoisomers are possible for menthol?How many stereoisomers are possible for menthol?

A Different Mechanism for Alkyl A Different Mechanism for Alkyl

Halide Elimination:Halide Elimination:


CHCH33 CHCH22CHCH33

BrBr

CHCH33

Ethanol, heatEthanol, heat

++

(25%)(25%) (75%)(75%)

CC

HH33CC

CHCH33

CC CC

HH33CC

HH

CHCH22CHCH33

CHCH33

CCHH22CC

ExampleExample

1. Alkyl halides can undergo elimination in 1. Alkyl halides can undergo elimination in absence of base.absence of base.

2. Carbocation is intermediate2. Carbocation is intermediate

3. Rate-determining step is unimolecular 3. Rate-determining step is unimolecular ionization of alkyl halide.ionization of alkyl halide.


slow, unimolecularslow, unimolecular

CCCHCH22CHCH33CHCH33

CHCH33

++

CHCH33 CHCH22CHCH33

BrBr

CHCH33

CC

::....::

::....:: BrBr.... ––

Step 1Step 1


CHCH33

++


CHCH22

++ CCCHCHCHCH33CHCH33

CHCH33

– – HH++

Step 2Step 2

Which alkene is more stable and why?Which alkene is more stable and why?

Reaction coordinate diagram for the E1 reaction of2-chloro-2-methylbutane

Must consider possible carbocation rearrangement

Stereochemistry of the E1 Reaction

E1 Elimination from Cyclic Compounds

E1 mechanism involves both syn and anti elimination

Summary & Applications (Synthesis)Summary & Applications (Synthesis)

S SNN1 / E1 vs. S1 / E1 vs. SNN2 / E22 / E2

E2 and E1 Reactions

Substitution vs. Elimination

Alkyl halides can undergo SN2, SN1, E2 and E1 Reactions

1) Which reaction conditions favor SN2/E2 or SN1/E1?

•SN2/E2 reactions are favored by a high concentration of nucleophile/strong base

•SN1/E1 reactions are favored by a poor nucleophile/weak base

2) What will be the relative distribution of substitution product vs. elimination product?

Consider the Substrate

NOTE: a bulky base encourages elimination over substitution

Returning to Sn2 and E2:Returning to Sn2 and E2:Considering the differences Considering the differences

Returning to Sn2 and E2:Returning to Sn2 and E2:Considering the differences Considering the differences

Can you predict the products?Can you predict the products?

Br

O

C

H

3

B

r

C

H

3

O

-

+

+

O

C

H

3

Can you explain the products?Can you explain the products?

Substitution and Elimination Reactions in Synthesis

A hindered alkyl halide should be used if you want to synthesize an alkene

Which reaction produces an ether?

CH3CH2Br CH3CO-CH3

CH3

+

CH3CH2O- CH3CBrCH3

CH3

+

Consecutive E2 Elimination Reactions:Alkynes

Intermolecular vs. Intramolecular Reactions

• A low concentration of reactant favors an intramolecular reaction• The intramolecular reaction is also favored when a five- or six-membered ring is formed

Three- and four-membered rings are less easily formed

Three-membered ring compounds are formed more easily than four-membered ring compounds

The likelihood of the reacting groups finding each other decreases sharply when the groups are in compounds that would form seven-membered and larger rings.

Designing a synthesis …

?

?CH3 CH3

Br

Br

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Dehydrohalogenation of Alkyl Halides E2 and E1 Reactions in Detail