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Substitution and Elimination. Reaction of Alkyl Halides By: Ismiyarto, MSi. ALKIL HALIDA. Manfaat (Pestisida, Bahan Dasar Sintesis Alkohol, Alkena) Struktur (Metil, Primer, Sekunder, Tersier, Benzil dan Vinil) Reaksi (SN-2, SN-1, E-2 dan E-1). 7. Vinil Halida 8. Aril Halida.

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Substitution and Elimination

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Substitution and elimination

Substitution and Elimination

Reaction of Alkyl Halides

By: Ismiyarto, MSi


Alkil halida

ALKIL HALIDA

  • Manfaat (Pestisida, Bahan Dasar Sintesis Alkohol, Alkena)

  • Struktur (Metil, Primer, Sekunder, Tersier, Benzil dan Vinil)

  • Reaksi (SN-2, SN-1, E-2 dan E-1)


Peta reaksi alkil halida

7. Vinil Halida

8. Aril Halida

Dalam Pembahasan Tersendiri

SN-2

PETA REAKSI ALKIL HALIDA

SN-2

SN-2, SN-1 dan E-2

SN-2, SN-1 dan E-2

SN-2, SN-1

SN-2, SN-1

Metil Halida

Alkil halida Primer

Alkil Halida Sekunder

Alkil Halida Tersier

Alil Halida

Benzil Halida


Substitution and elimination

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

alkyl fluoride

alkyl chloride

alkyl bromide

alkyl iodide


Alkyl halides in nature

Alkyl Halides in Nature

Synthesized by red algae

red algae

Synthesized by sea hare

a sea hare


Substitution reaction with halides

Substitution Reaction with Halides

(1)

(2)

bromomethane

methanol

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

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

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


Substitution reaction with halides1

Substitution Reaction with Halides

(1)

(2)

bromomethane

methanol

Rate law:

rate = k [bromoethane][OH-]

this reaction is an example of a SN2 reaction.

S stands for substitution

N stands for nucleophilic

2 stands for bimolecular


Mechanism of sn2 reactions

Mechanism of SN2 Reactions

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.

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


Mechanism of sn2 reactions1

Mechanism of SN2 Reactions

Hughes and Ingold proposed the following mechanism:

Transition state

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


Mechanism of sn2 reactions2

Mechanism of SN2 Reactions

Steric effect

activation

energy: DG2

activation

energy: DG1

Energy

reaction coordinate

reaction coordinate

Inversion of configuration

(S)-2-bromobutane

(R)-2-butanol


Factor affecting sn2 reactions

Factor Affecting SN2 Reactions

The leaving group

relative rates of reactionpKa 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 nucleophile

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

pKa

Nuclephilicity


Sn2 reactions with alkyl halides

SN2 Reactions With Alkyl Halides

an alcohol

a thiol

an ether

a thioether

an amine

an alkyne

a nitrile


Substitution reactions with halides

Substitution Reactions With Halides

1-bromo-1,1-dimethylethane

1,1-dimethylethanol

Rate law:

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

this reaction is an example of a SN1 reaction.

S stands for substitution

N stands for nucleophilic

1 stands for unimolecular

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

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


Mechanism of sn1 reactions

Mechanism of SN1 Reactions

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.

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

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


Mechanism of sn1 reactions1

Mechanism of SN1 Reactions

nucleophile attacks the carbocation

slow

C-Br bond breaks

fast

Proton dissociation


Mechanism of sn1 reactions2

Mechanism of SN1 Reactions

Rate determining step

Carbocation intermediate

DG

R++ X-

+

R-OH2

R-OH


Mechanism of sn1 reactions3

Mechanism of SN1 Reactions

Inverted configuration relative the alkyl halide

Same configuration as the alkyl halide


Factor affecting sn1 reaction

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

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

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


Comparison sn1 sn2

Comparison SN1 – SN2


Kestabilan karbokation

Kestabilan Karbokation


Elimination reactions

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 elimination

2 stands for bimolecular


The e2 reaction

The E2 Reaction

A proton is removed

Br- is eliminated

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


Elimination reactions1

Elimination Reactions

1-bromo-1,1-dimethylethane

2-methylpropene

Rate law:

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

this reaction is an example of a E1 reaction.

E stands for elimination

1 stands for unimolecular

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

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


The e1 reaction

The E1 Reaction

The base removes a proton

The alkyl halide dissociate, forming a carbocation

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


Products of elimination reaction

Products of Elimination Reaction

50%

30%

80%

2-butene

20%

2-bromobutane

1-butene

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

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


Elimination reactions alkenes alkynes

ELIMINATION REACTIONS:ALKENES, ALKYNES


Elimination reactions2

Elimination Reactions

Dehydrohalogenation (-HX) and

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


Dehydrohalogenation hx

Dehydrohalogenation (-HX)


T he e2 mechanism

The E2 mechanism

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

_


Kinetics

Kinetics

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

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


T he e1 mechanism

The E1 mechanism

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


Kinetics1

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!


T he e2 mechanism1

The E2 mechanism

  • Mechanism

  • Kinetics

  • Stereochemistry of reactants

  • Orientation of elimination (Zaitsev’s rule)

  • Stereochemistry of products

  • Competing reactions


E2 mechanism

E2 mechanism

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


Kinetics of an e2 reaction

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!!


Substitution and elimination

d-

d-

Transition State

energy

Reaction coordinate


Stereochemistry of reactants

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

Stereochemistry of E2 Reaction

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


S s diastereomer

(S,S)-diastereomer


Substitution and elimination

This one is formed!


R s diastereomer

(R,S)-diastereomer


Substitution and elimination

This one is formed!


Orientation of elimination regiochemistry zaitsev s rule

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 hydrogenwhich is lost will come from the more highly-branchedb-carbon.

More branched

Less branched

A. N. Zaitsev -- 1875


Product formed from previous slide

Product formed from previous slide

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


Typical bases used in e2 reactions

Typical bases used in E2 reactions

High concentration of the following >1M

If the concentration isn’t given, assume

that it is high concentration!

  • Na+-OH

  • K+-OH

  • Na+-OR

  • Na+-NH2


Orientation of elimination regiochemistry zaitsev s rule1

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

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

Competing reactions

  • The substitution reaction (SN2) competes with the elimination reaction (E2).

  • Both reactions follow second order kinetics!


T he e1 mechanism1

The E1 mechanism

  • Mechanism

  • Kinetics

  • Stereochemistry of reactants

  • Orientation of elimination (Zaitsev’s rule)

  • Stereochemistry of products

  • Competing reactions


E1 mechanism

E1 mechanism

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


E1 reactions

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.


Substitution and elimination

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).


However

However!!!!

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


Structure of the carbocation intermediate

Structure of the Carbocation Intermediate


Carbocation stability order

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

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!!


Substitution and elimination

d-

d+

d+

d+

+

energy

intermediate

Reaction coordinate


Stereochemistry of the reactants

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

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 products1

Stereochemistry of products

E1 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 reactions1

Competing reactions

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

  • Both reactions follow first order kinetics!


Whenever there are carbocations

Whenever there are carbocations…

  • They can undergo elimination (E1)

  • They can undergo substitution (SN1)

  • They can rearrange

    • and then undergo elimination

    • or substituion


Rearrangements

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!!


C omparison of e2 e1

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.


C omparison of e2 e11

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


B ulky leaving groups hofmann elimination

Bulky leaving groupsHofmann Elimination

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


Orientation of elimination regiochemistry hofmann s rule

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 hydrogenthat is lost will come from the LEAST highly-branchedb-carbon.

More branched

Less branched


Product from previous slide

Product from previous slide


Elimination with bulky bases

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

Comparing Ordinary and Bulky Bases


1 butene watch out for competing reactions

1-butene: watch out for competing reactions!


Highlights

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

Competition Between SN2/E2 and SN1/E1

SN1

SN2

E1

E2

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

  • 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

Competition Between Substitution and Elimination

  • SN2/E2 conditions:

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

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

10%

90%

75%

25%

100%


Competition between substitution and elimination1

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%)


Summary

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


Reaksi adisi alkena

REAKSI ADISI ALKENA


Addition reaction of alkene

Addition Reaction of Alkene

  • HX Addition

    • Electrophilic Addition (Markovnikov Product)

    • Free Radical Mechanism (Anti-Mark Product)

  • Hydration (+ H2O)

  • Halogenation/ Hydrohalogenation

  • Reduction or Hydrogenation (+ H2 )

  • Oxidation

  • Multi-step Synthesis


Addition of halogens to alkenes

+X2

C

C

C

X

C

X

Addition of Halogens to Alkenes

  • electrophilic addition to double bond

  • forms a vicinal dihalide

X2 = Cl2 or Br2

F2; explosive I2 ; endothermic


Example

Example

Br2

CH3CHCHCH(CH3)2

CH3CH

CHCH(CH3)2

Br

Br

(100%)


Substitution and elimination

H

Br2

H

Br

Br

H

H

trans-1,2-Dibromocyclopentane80% yield; only product

Stereochemistry of Halogen Addition

  • anti addition

Anti Addition ; Two Bromines add to opposite

sides of the ring


Example1

H

Cl

H

Cl

Example

H

Cl2

H

trans-1,2-Dichlorocyclooctane73% yield; only product


Mechanism is electrophilic addition

Mechanism is electrophilic addition

  • Br2 is not polar, but it is polarizable

  • two steps(1) formation of bromonium ion &

  • electrophilic attack

  • (2) nucleophilic attack on bromonium ion by bromide

NET REACTION

CH2=CH2 + Br2 -> Br-CH2-CH2-Br


Step 1a formation of bromonium ion

Br

–

Br

Br

Br

+

+

Step 1a: Formation of Bromonium Ion

Mutual polarizationof electron distributionsof Br2 and alkene

Electrons flow from alkenetoward Br2


Step 1b electrophilic addition to form bromonium ion

Step 1b; Electrophilic Addition to form Bromonium Ion

Part i

+ Br-


Step 1b lone pair on bromine stabalizes carbocation and forms cyclic bromonium ion

+

Br

Step 1b; Lone Pair on Bromine Stabalizes Carbocation and Forms Cyclic Bromonium Ion

Part ii

+ Br-


Step 2 bromide ion must attack from oppositte side of cyclic bromonium ion anti addition

Br

+

Br

Step 2; Bromide Ion Must Attack from Oppositte Side of Cyclic Bromonium Ion (anti addition)


Example2

H

H

Br

Br

H

H

Example

Br2

trans-1,2-Dibromocyclopentane80% yield; only product


Substitution and elimination

C

C

C

C

C

C

C

C

+ X2

X

X

alkenes react with X2 to form vicinal dihalides

alkenes react with X2 in water to give vicinal halohydrins

+ H2O

+ X2

X

OH

+ H—X


Examples

H

H

OH

Cl

H

H

Examples

H2O

+

Br2

BrCH2CH2OH

H2C

CH2

(70%)

Cl2

H2O

anti addition: only product


Substitution and elimination

Mechanism; 1) Cl2 is polarized and adds across double bond. 2) Ion formed is stabalized by lone pair of Cl.


Substitution and elimination

3) Water attacks chloronium ion from side opposite (anti addition) carbon-chlorine bond. This gives trans isomer


Regioselectivity

CH3

H3C

Br2

CH3

C

C

CH2Br

CH2

H2O

H3C

OH

Regioselectivity

  • Markovnikov's rule applied to halohydrin formation: the halogen adds to the carbon having the greater number of hydrogens.

(77%)


Hydrogenation reduction h 2 of ethylene

H

H

H

H

C

C

H

H

C

C

H

H

H

H

Hydrogenation (Reduction, +H2) of Ethylene

  • exothermic H° = –136 kJ/mol

  • catalyzed by finely divided Pt, Pd, Rh, Ni

Metal

Catalyst

+ H—H


Two spatial stereochemical aspects of alkene hydrogenation

H

CO2CH3

CO2CH3

H2, Pt

CO2CH3

CO2CH3

H

Two spatial (stereochemical) aspects ofalkene hydrogenation:

  • (1) syn addition of both H atoms to double bond

  • (2) hydrogenation is stereoselective, corresponding to addition to less crowded face of double bond


Syn additon versus anti addition

syn-Additon versus anti-Addition

syn addition

anti addition


Syn addition metal catalyst breaks h h bonds

H

H

H

H

syn-Addition; Metal catalyst breaks H-H bonds.

B

Y

C

C

A

X


Syn addition addition of h 2 across double bonds takes place in two steps

B

Y

X

A

H

H

C

C

H

H

syn-Addition; Addition of H2 across double bonds takes place in two steps.


Example of stereoselective reaction

H3C

CH3

H

H3C

H3C

H3C

CH3

CH3

H

H

H

H

H3C

H

H3C

H

Example of Stereoselective Reaction

H2, cat

Both productscorrespond tosyn additionof H2.


Example of stereoselective reaction1

H3C

CH3

H

H3C

H3C

CH3

H

H

H3C

H

Example of Stereoselective Reaction

H2, cat

Top face of doublebond blocked bythis methyl group

But only thisone is formed.

H2 adds to bottom face of double bond.


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