substitution and elimination

Substitution and EliminationReaction of Alkyl Halides

By: Ismiyarto, MSi

ALKIL HALIDA

1. Manfaat (Pestisida, Bahan Dasar Sintesis Alkohol, Alkena)

2. Struktur (Metil, Primer, Sekunder, Tersier, Benzil dan Vinil)

3. Reaksi (SN-2, SN-1, E-2 dan E-1)

PETA REAKSI ALKIL HALIDA

1. Metil Halida2. Alkil halida Primer3. Alkil Halida Sekunder4. Alkil Halida Tersier

5. Alil Halida6. Benzil Halida

SN-2

SN-2SN-2, SN-1 dan E-2

SN-2, SN-1 dan E-2

SN-2, SN-1

SN-2, SN-1

7. Vinil Halida8. Aril Halida

Dalam Pembahasan Tersendiri

-Organic compounds with an electronegative atom or an electron-withdrawing group bonded to a sp3 carbon undergo substitution or elimination reactions

Organic compounds with an electronegative atom or an electron-withdrawing group bonded to a sp3 carbon undergo substitution or elimination reactions

Substitution

Elimination

Halide ions are good leaving groups. Substitution reaction on these compounds are easy

and are used to get a wide variety of compounds

Halide ions are good leaving groups. Substitution reaction on these compounds are easy

and are used to get a wide variety of compounds

alkyl fluoride alkyl chloride alkyl bromide alkyl iodide

Alkyl Halides in Nature

Synthesized by red algae

Synthesized by sea harea sea hare

red algae

Substitution Reaction with Halides

If concentration of (1) is doubled, the rate of the

reaction is doubled.



bromomethane

(1) (2)





If concentration of (1) and (2) is doubled, the rate of the reaction quadruples.

If concentration of (1) and (2) is doubled, the rate of the reaction quadruples.

methanol

Substitution Reaction with Halides

bromomethane

(1) (2)

methanol

Rate law:

rate = k [bromoethane][OH-]

this reaction is an example of a SN2 reaction.S stands for substitutionN stands for nucleophilic 2 stands for bimolecular

Rate law:

rate = k [bromoethane][OH-]

this reaction is an example of a SN2 reaction.S stands for substitutionN stands for nucleophilic 2 stands for bimolecular

Mechanism of SN2 Reactions

The rate of reaction depends on the concentrations of both reactants.The rate of reaction depends on the concentrations of both reactants.

When the hydrogens of bromomethane are replaced with methyl groups the reaction rate slow down.

When the hydrogens of bromomethane are replaced with methyl groups the reaction rate slow down.

The reaction of an alkyl halide in which the halogen is bonded to an asymetric center leads to the formation of only one stereoisomer

The reaction of an alkyl halide in which the halogen is bonded to an asymetric center leads to the formation of only one stereoisomer

Alkyl halide Relative rate

1200

40

1

≈ 0


Hughes and Ingold proposed the following mechanism:Hughes and Ingold proposed the following mechanism:

Transition state

Increasing the concentration of either of the reactant makes their collision more probable.Increasing the concentration of either of the reactant makes their collision more probable.


activationenergy: G1

activationenergy: G2

Steric effectSteric effect

Inversion of configurationInversion of configuration

(S)-2-bromobutane (R)-2-butanol

Ener

gy

reaction coordinate reaction coordinate

Factor Affecting SN2 Reactions

relative rates of reaction pKa HX

HO- + RCH2I RCH2OH + I- 30 000 -10

HO- + RCH2Br RCH2OH + Br- 10 000 -9

HO- + RCH2Cl RCH2OH + Cl- 200 -7

HO- + RCH2F RCH2OH + F- 1 3.2

relative rates of reaction pKa HX

HO- + RCH2I RCH2OH + I- 30 000 -10

HO- + RCH2Br RCH2OH + Br- 10 000 -9

HO- + RCH2Cl RCH2OH + Cl- 200 -7

HO- + RCH2F RCH2OH + F- 1 3.2

The leaving group

The nucleophile

In general, for halogen substitution the strongest the base the better the

nucleophile.

In general, for halogen substitution the strongest the base the better the

nucleophile.

pKa Nuclephilicity

SN2 Reactions With Alkyl Halidesan alcohol

a thiol

an ether

a thioether

an amine

an alkyne

a nitrile

Substitution Reactions With Halides





If concentration of (2) is doubled, the rate of the reaction is not doubled.


Rate law:

rate = k [1-bromo-1,1-dimethylethane]

this reaction is an example of a SN1 reaction.

S stands for substitutionN stands for nucleophilic 1 stands for unimolecular

Rate law:


this reaction is an example of a SN1 reaction.

S stands for substitutionN stands for nucleophilic 1 stands for unimolecular

1-bromo-1,1-dimethylethane 1,1-dimethylethanol


The rate of reaction depends on the concentrations of the alkyl halide only.The rate of reaction depends on the concentrations of the alkyl halide only.

When the methyl groups of 1-bromo-1,1-dimethylethane are replaced with hydrogens the reaction rate slow down.

When the methyl groups of 1-bromo-1,1-dimethylethane are replaced with hydrogens the reaction rate slow down.

The reaction of an alkyl halide in which the halogen is bonded to an asymetric center leads to the formation of two stereoisomers

The reaction of an alkyl halide in which the halogen is bonded to an asymetric center leads to the formation of two stereoisomers

Alkyl halide Relative rate

≈ 0 *

≈ 0 *

12

1 200 000

* a small rate is actually observed as a result of a SN2


C-Br bond breaksC-Br bond breaks

nucleophile attacks the carbocation

nucleophile attacks the carbocation

Proton dissociationProton dissociation

slow

fast


G

Rate determining stepRate determining stepCarbocation intermediateCarbocation intermediate

R++ X-

R-OH2

+

R-OH


Same configuration as the alkyl halide

Same configuration as the alkyl halide

Inverted configuration

relative the alkyl halide

Inverted configuration

relative the alkyl halide

Factor Affecting SN1 reaction

Two factors affect the rate of a SN1 reaction:• The ease with which the leaving group dissociate from the carbon• The stability of the carbocation

Two factors affect the rate of a SN1 reaction:• The ease with which the leaving group dissociate from the carbon• The stability of the carbocation

The more the substituted the carbocation is, the more

stable it is and therefore the easier it is to form.

The more the substituted the carbocation is, the more

stable it is and therefore the easier it is to form.

As in the case of SN2, the weaker base is the leaving group, the less tightly it is

bonded to the carbon and the easier it is to break the bond

As in the case of SN2, the weaker base is the leaving group, the less tightly it is

bonded to the carbon and the easier it is to break the bond

The reactivity of the nucleophile has no effect on the rate of a SN1 reaction

The reactivity of the nucleophile has no effect on the rate of a SN1 reaction

Comparison SN1 – SN2

SN1 SN2

A two-step mechanism A one-step mechanism

A unimolecular rate-determining step A bimolecular rate-determining step

Products have both retained and inverted configuration relative to the reactant

Product has inverted configuration relative to the reactant

Reactivity order:3o > 2o > 1o > methyl

Reactivity order:methyl > 1o > 2o > 3o

Kestabilan Karbokation

H

H

H

H

H

H

H

+

propan-2-ylium Ethanylium

+H2C

H

H

H

Methanylium

CH3+

Elimination Reactions

1-bromo-1,1-dimethylethane 2-methylpropene

Rate law:

rate = k [1-bromo-1,1-dimethylethane][OH-]

this reaction is an example of a E2 reaction.E stands for elimination2 stands for bimolecular

Rate law:

rate = k [1-bromo-1,1-dimethylethane][OH-]

this reaction is an example of a E2 reaction.E stands for elimination2 stands for bimolecular

The E2 Reaction

A proton is removed

A proton is removed

Br- is eliminatedBr- is eliminatedThe mechanism shows that an E2

reaction is a one-step reactionThe mechanism shows that an E2

reaction is a one-step reaction








Rate law:


this reaction is an example of a E1 reaction.

E stands for elimination1 stands for unimolecular

Rate law:


this reaction is an example of a E1 reaction.

E stands for elimination1 stands for unimolecular

1-bromo-1,1-dimethylethane 2-methylpropene

The E1 Reaction

The alkyl halide dissociate, forming a

carbocation

The alkyl halide dissociate, forming a

carbocation

The base removes a

proton

The base removes a

proton

The mechanism shows that an E1 reaction is a two-step reaction

The mechanism shows that an E1 reaction is a two-step reaction

Products of Elimination Reaction

2-bromobutane

2-butene

1-butene

80%

20%

The most stable alkene is the major product of the reaction

for both E1 and E2 reaction

The most stable alkene is the major product of the reaction

for both E1 and E2 reaction

The greater the number of alkyl substituent the more

stable is the alkene

The greater the number of alkyl substituent the more

stable is the alkeneFor both E1 and E2 reactions, tertiary alkyl halides

are the most reactive and primary alkyl halides are the least reactive

For both E1 and E2 reactions, tertiary alkyl halides are the most reactive and primary alkyl halides

are the least reactive

30% 50%

ELIMINATION REACTIONS:ALKENES, ALKYNES


C C

X Y

C C + X Y

Dehydrohalogenation (-HX) and Dehydration (-H2O) are the main types of elimination reactions.

Dehydrohalogenation (-HX)

strong

base

X = Cl, Br, I

+ " "C C

X

H XC C

H

The E2 mechanism

..:..

__

+

+ Br_

..:

concerted mechanism

H O

C C

Br

H

H O

H

C C

This reaction is done in strong base at high concentration, such as 1 M NaOH in water.

_

Kinetics

• The reaction in strong base at high concentration is second order (bimolecular):

Rate law: rate = k[OH-]1[R-Br]1

The E1 mechanism

1)

++ Br

_slow

+

2)..

:

+fast

O.. +O

C C

Br

C C

H

C C

HC C

H

H H

H

H

H

rate determining step

This reaction is done in strong base such as 0.01 M NaOH in water!! Actually, the base solution is weak!

Kinetics

• The reaction in weak base or under neutral conditions will be first order (unimolecular):

• Rate law: rate = k [R-Br]1

• The first step (slow step) is rate determining!

The E2 mechanism• Mechanism• Kinetics• Stereochemistry of reactants• Orientation of elimination (Zaitsev’s rule)• Stereochemistry of products• Competing reactions

E2 mechanism

..:..

__

+

+ Br_

..:

concerted mechanism

H O

C C

Br

H

H O

H

C C

This reaction is done in strong base at high concentration, such as 1 M NaOH in water.

Kinetics of an E2 reaction• The reactions are second order (bimolecular

reactions).

• Rate = k [R-Br]1[Base]1

second order reaction (1 + 1 = 2)High powered math!!

energy

Reaction coordinate

C C

H OH

Br-

..:..

__H O

C C

Br

H

..:H O

C C

H

Br

Transition State

Stereochemistry of reactants

• E2 reactions must go by an anti elimination• This means that the hydrogen atom and

halogen atom must be 180o (coplanar) with respect to each other!!

• Draw a Newman projection formula and place the H and X on opposite sides.

Stereochemistry of E2 Reaction

KOH

AlcoholSolventH

Br

H

HH

CCH3

CH3

CH3

C

H

CH3

CH3

CH3H

H

H and Br are anti structure in conformation!!!!!!!!!

(S,S)-diastereomer

KOHethanolheat

(E)-isomer (Z)-isomer

??? ???

C C

Br

HCH3

CH3

H

C C

CH3 CH3

H t-butyl

C C

H CH3

CH3 t-butyl

t-butyl

(E)-isomer

C C

CH3 CH3

H T-butyl

This one is formed!

(R,S)-diastereomer

KOHethanolheat

(E)-isomer (Z)-isomer

??? ???

C C

Br

HH

CH3

CH3

t-butyl

C C

CH3 CH3

H T-butyl

C C

H CH3

CH3 t-butyl

(Z)-isomer

C C

H CH3

CH3 t-butyl

This one is formed!

Orientation of elimination: regiochemistry/ Zaitsev’s Rule• In reactions of removal of hydrogen halides from

alkyl halides or the removal of water from alcohols, the hydrogen which is lost will come from the more highly-branched -carbon.

A. N. Zaitsev -- 1875 C C C C

H

H

H H

X

H

H

HH

CH3

Less branchedMore branched

Product formed from previous slide

C

C CC

H

HH

H

HCH3

HH

More substituted alkene is more stable!!!!!!!!

Typical bases used in E2 reactions

High concentration of the following >1MIf the concentration isn’t given, assumethat it is high concentration!• Na+ -OH• K+ -OH• Na+ -OR• Na+ -NH2

Orientation of elimination: regiochemistry/ Zaitsev’s Rule

Explaination of Zaitsev’s rule:When you remove a hydrogen atom from the more branched position, you are forming a more highly substituted alkene.

Stereochemistry of products• The H and X must be anti with respect to each

other in an E2 reaction!• You take what you get, especially with

diastereomers! See the previous slides of the reaction of diastereomers.

Competing reactions• The substitution reaction (SN2) competes with

the elimination reaction (E2).• Both reactions follow second order kinetics!

The E1 mechanism• Mechanism• Kinetics• Stereochemistry of reactants• Orientation of elimination (Zaitsev’s rule)

• Stereochemistry of products• Competing reactions

E1 mechanism

1)

++ Br

_slow

+

2)..

:

+fast

O..+O

C C

Br

C C

H

C C

HC C

H

H H

H

H

H

water helpsto stabilizecarbocation

This reaction is done in strong base at low concentration, such as 0.01 M NaOH in water)

E1 Reactions • These reactions proceed under neutral

conditions where a polar solvent helps to stabilize the carbocation intermediate.

• This solvent also acts as a weak base and removes a proton in the fast step.

• These types of reactions are referred to as solvolysis reactions.

• tertiary substrates go by E1 in polar solvents, with little or no base present!

• typical polar solvents are water, ethanol, methanol and acetic acid

• These polar solvents help stabilize carbocations

• E1 reactions also occur in a low concentration of base (i.e. 0.01M NaOH).

•With strong base (i.e. >1M), goes by E2

However!!!!

Structure of the Carbocation Intermediate

C CH3

CH3

CH3

Carbocation stability order

Tertiary (3o) > secondary (2o) > primary (1o)

It is hard (but not impossible) to get primary compounds to go by E1. The reason for this is that primary carbocations are not stable!

Kinetics of an E1 reaction• E1 reactions follow first order (unimolecular)

kinetics:Rate = k [R-X]1

• The solvent helps to stabilize the carbocation, but it doesn’t appear in the rate law!!

energy

Reaction coordinate

C

H

C

Br

C

H

C

Br-

C C

H

C C

H

C C + H+

intermediate

Stereochemistry of the reactants• E1 reactions do not require an anti coplanar

orientation of H and X. • Diastereomers give the same products with E1

reactions, including cis- and trans products.• Remember, E2 reactions usually give different

products with diastereomers.

Orientation of elimination• E1 reactions faithfully follow Zaitsev’s rule!• This means that the major product should be

the product that is the most highly substituted.

Stereochemistry of productsE1 reactions usually give the thermodynamically most stable product as the major product. This usually means that the largest groups should be on opposite sides of the double bond. Usually this means that the trans product is obtained.

Competing reactions

• The substitution reaction (SN1) competes with the elimination reaction (E1).

• Both reactions follow first order kinetics!

Whenever there are carbocations…• They can undergo elimination (E1)• They can undergo substitution (SN1)

• They can rearrange– and then undergo elimination– or substituion

Rearrangements• Alkyl groups and hydrogen can migrate in

rearrangement reactions to give more stable intermediate carbocations.

• You shouldn’t assume that rearrangements always occur in all E1 reactions, otherwise paranoia will set in!!

Comparison of E2 / E1• E1 reactions occur under essentially neutral

conditions with polar solvents, such as water, ethyl alcohol or acetic acid.

• E1 reactions can also occur with strong bases, but only at low concentration, about 0.01 to 0.1 M or below.

• E2 reactions require strong base in high concentration, about 1 M or above.

Comparison of E2 / E1• E1 is a stepwise mechanism (two or more);

Carbocation intermediate!• E2 is a concerted mechanism (one step)

No intermediate!• E1 reactions may give rearranged products• E2 reactions don’t give rearrangement• Alcohol dehydration reactions are E1

Bulky leaving groupsHofmann Elimination

+

OH_

heat

+

6%

94%

CH3 CH2 CH2 CH CH3

N

CH3

CH3CH3

CH3 CH2 CH CH CH3

CH3 CH2 CH2 CH CH2

This give the anti-Zaitsev product (least substituted product is formed)!

Orientation of elimination: regiochemistry/ Hofmann’s Rule • In bimolecular elimination reactions in the presence

of either a bulky leaving group or a bulky base, the hydrogen that is lost will come from the LEAST LEAST highly-branched -carbon.

C C C C

H

H

H H

X

H

H

HH

CH3

Less branchedMore branched

Product from previous slide

CC

C

H

H

H

HCH3

HH

C

H

Elimination with bulky bases

• Non-bulky bases, such as hydroxide and ethoxide, give Zaitsev products.

• Bulky bases, such as potassium tert-butoxide, give larger amounts of the least substituted alkene (Hoffmann) than with simple bases.

Comparing Ordinary and Bulky Bases

CH3 C CH CH3

Br

NaOC2H5

C2H5OHheat

C CHCH3 CH3

CH3 C CH CH3

Br

KOC(CH3)3

(CH3)3COHheat

C CHCH3 CH2

Major

H

CH3 CH3

CH3

H

CH3

Major

H

1-butene: watch out for competing reactions!

H3C CH2 CH2 CH2 Br

KOCH3

Non-bulky

SN2

H3C CH2 CH2 CH2 O-CH3

H3C CH2 CH CH2

bulky baseKO-t-butyl

E2

Highlights• Dehydrohalogenation -- E2 Mechanism• Zaitsev’s Rule• Dehydrohalogenation -- E1 Mechanism• Carbocation Rearrangements -- E1• Elimination with Bulky Leaving Groups and Bulky

Bases -- Hofmann Rule -- E2

Competition Between SN2/E2 and SN1/E1

rate = k1[alkyl halide] + k2[alkyl halide][nucleo.] + k3[alkyl halide] + k2[alkyl halide][base] rate = k1[alkyl halide] + k2[alkyl halide][nucleo.] + k3[alkyl halide] + k2[alkyl halide][base]

SN1SN1 SN2SN2 E1E1 E2E2

• SN2 and E2 are favoured by a high concentration of a good nucleophile/strong base• SN1 and E1 are favoured by a poor nucleophile/weak base, because a poor nucleophile/weak base disfavours SN2 and E2 reactions

• SN2 and E2 are favoured by a high concentration of a good nucleophile/strong base• SN1 and E1 are favoured by a poor nucleophile/weak base, because a poor nucleophile/weak base disfavours SN2 and E2 reactions

Competition Between Substitution and Elimination

• SN2/E2 conditions:In a SN2 reaction: 1o > 2o > 3o

In a E2 reaction: 3o > 2o > 1o In a SN2 reaction: 1o > 2o > 3o

In a E2 reaction: 3o > 2o > 1o

90% 10%

25% 75%

100%

Competition Between Substitution and Elimination

• SN1/E1 conditions:

All alkyl halides that react under SN1/E1 conditions will give both substitution and elimination products (≈50%/50%)

All alkyl halides that react under SN1/E1 conditions will give both substitution and elimination products (≈50%/50%)

Summary

• Alkyl halides undergo two kinds of nucleophilic subtitutions: SN1 and SN2, and two kinds of elimination: E1 and E2.

• SN2 and E2 are bimolecular one-step reactions• SN1 and E1 are unimolecular two step reactions• SN1 lead to a mixture of stereoisomers• SN2 inverts the configuration od an asymmetric carbon• The major product of a elimination is the most stable alkene• SN2 are E2 are favoured by strong nucleophile/strong base• SN2 reactions are favoured by primary alkyl halides• E2 reactions are favoured by tertiary alkyl halides

substitution and elimination

Documents

reaction rate slow

methanolsubstitution

reaction quadruples

dimethylethanethis reaction

small rate

sn2alkyl haliderelative

benzil dan vinilreaksi

s stands