Substitution Reactions

Nucleophilic Substitution

Electrophilic Substitution

Free radical Substitution

Nucleophilic Substitution Reaction

nucleophilicsubstitution

Nucleophile

++ C NuC XNu - X-

leavinggroup

C-L bond cleaved C-Nu bond formed

Types of Nucleophilic Substitution

SN1 : substitution nucleophilic unimolecularSN2 : substitution nucleophilic bimolecularSNi : substitution nucleophilic intramolecular

Points to be discussed for SN1 and SN2Definition with examples MechanismKineticsStereochemistryFactors influencing the reaction rate

SN2 : Bimolecular nucleophilicsubstitution

Examples

Mechanism

The nucleophile and the alkyl halide combine to form a pentacoordinate transition state. This is the slow rate determining step (r.d.s); it entails two species, R-X and Nu . The dotted lines indicate partially formed or Өpartially broken covalent bonds.

C Br

H

HH

HO + C

H

H H

HO Br

δ- δ-

Transition state withsimultaneous bond breaking

and bond forming

C

H

HH

HO + Br -

Kinetics

The reaction involves a transition state in which both reactants R-X and OH- are together

Rate = k[RX][OH]

The study of rates of reactions is called kinetics

The rate is dependent of the concentration of two species, i.e. the alkyl halide and NaOH.

The transition state of an SN2 reaction has a planar arrangement of the carbon atom and the remaining three groups

Occurs with inversion of chiral center called Walden Inversion.

Stereochemistry

Tetrahedral Planar Transition state

SN1 : Unimolecular nucleophilic substitution

ExampleSolvolysis of tert-butyl bromide to give tertiary butyl alcohol.

MechanismStep 1: the leaving group dissociates to form a carbocation

C

CH3

CH3H3 C

+C

H3C

H3 C

Br

H3 C

slow, ratedetermining

A carbocation intermediate; carbon is trigonal planar

+ Br

Step 2: reaction of the carbocation (an electrophile) with water (a nucleophile) gives an oxonium ion

Step 3: proton transfer completes the reaction

CH3 O

H H3 C

C

CH3

CH3

OCH3

H

C

CH3

CH3

CH3

O

H3 C

HH3 C

H3 C

C

H3 C

O

CH3

H

fast ++ ++

++++ fastC

H3 CH3C

O

H3 C

OCH3

H

OHO

CH3CH3

H

H

CH3

H3C

CH3 C

H3C

HH

H

H

H

H H

H

Kinetics First order Rate-determining step is formation of carbocation Rate = k [RX] Depends only on the concentration of the substrate

SN2SN1

StereochemistryProceed with partial recemisation and some inversion

Recemisation : the nucleophile can attack from either face of the planar carbocation intermediate

(R)-Enantiomer Planar carbocation (achiral)

C

H

Cl

C6 H5

Cl

C+

C6 H5

H

Cl

CH3 OH-Cl-

-H+

+

A racemic mixture

Cl

C6H5 C6H5

C OCH3

H

CH3 O CH

Cl(R)-Enantiomer(S)-Enantiomer

Frequent complication: the Leaving Group will tend to block approach of the nucleophile leading to more inversion than retention for the SN1

SN1 in reality: Formation of ion pair

Factors influencing the rate of the reaction

Effect of Substituent Nature of the nucleophile Nature of the leaving group Solvent effect

Effect of substituents on SN reaction

governed by electronic factors namely the relative stabilities of carbocation intermediates

relative rates: 3° > 2° > 1° > methyl

SN1 reactions

SN2 reactions governed by steric factors namely the relative ease of approach

of the nucleophile to the site of reaction relative rates: methyl > 1° > 2° > 3°

The SN2 reaction is fastest with unhindered halides.

Nucleophile

Nucleophile is a neutral or negatively charged Lewis base.

Anions are usually more reactive than neutrals

More basic nucleophiles react faster

Better nucleophiles are lower in a column of the periodic

table

Order of nucleophilicity

NH2- > RO- >OH- >RNH- > ArO- >NH3

- > pyridine > F->H2O

I- >Br- > Cl- > F- (in polar protic solvents)

F- > Cl- > Br- > I- ( aprotic solvents)

Leaving group

Stable anions that are weak bases are usually excellent leaving groups and can delocalize charge

Protic solvent: a solvent that can form hydrogen bond (-OH, -NH)

these solvents favor SN1 reactions; the greater the polarity of the solvent, the easier it is to form carbocations in it

Aprotic solvent: does not contain an -OH group it is more difficult to form carbocations in aprotic solvents aprotic solvents favor SN2 reactions

Solvent effect

Solvent effect Solvents that can donate hydrogen bonds (-OH or –NH)

slow SN2 reactions by associating with reactantsEnergy is required to break interactions between reactant

and solventPolar aprotic solvents (NH, OH, SH) form weaker

interactions with substrate and permit faster reaction

Electrophilic Substitution

Chemical reactions in which an electrophile displaces a group in a compound.

Electrophilic aromatic substitution Electrophilic aliphatic substitution

R-X + E + R-E + X+

electrophile displaces a functional group in aliphatic compounds

Mechanism

Substitution electrophilic unimolecular (SE1)

Step-1 R X R X+

Step-2 R YR Y+

Slow

Substitution electrophilic bimolecular (SE2)

C XY

C Y X+

SE2 (back)Inversionof configuration

C X Y C

Y

X+

SE2 (front) Retention of configuration

Substitution electrophilic internal (SEi)

When the electrophile attacks from the front and a portion of it assists in the removal of leaving group

C X Y C

Y

X+

SEi Retention of configuration

ZZ

Nitrosation

Secondary amines and mono-N-substituted amides (RCONHR’) undergo N-nitrosation when treated with nitrous acid

Nucleophiles Cl-, SCN- and thiourea catalyze the reaction

Aliphatic diazonium coupling

Compounds containing active hydrogen (acidic C-H bond) couple with diazonium salts in presence of base

Z-CH2-Z’ + ArN2 Z C

Z'NHAr+

Z, Z’ = electron withdrawing groups such as NO2, CN, COOR, SO2R, COR

Reaction proceeds through SE1 mechanism

R2N-NOR2NH + HONO

Electrophilic aromatic substitution Atom appended to the aromatic ring, usually hydrogen, is replaced by

an electrophile

Mechanism: Arenium Ion

E

H

:A-

EH A+

Step-1

Step-2

slow E AE

H

E

H

E

H

Arenium ions

The proton is removed by any of the bases

X2, FeX3

(x = Cl, Br)

X

HX

R

CR

O

SO3H

NO2

HONO2

H2SO4

SO3

H2SO4

RCl, AlCl3

(R can rearrange)

RC Cl, AlCl3

O

H2O

HCl

HCl

+

+

+

+

Halogination

Nitration

sulfonation

Friedel-Crafts alkylation

Friedel-Crafts acylation

Substituent groups on a benzene ring affect electrophilic aromatic substitution reactions in two ways:

1) Reactivity activate (faster than benzene) or deactivate (slower than benzene)

2) Orientation ortho and para- direction or meta-direction

-NH2, -NHR, -NR2

-OH-OR-NHCOCH3

-C6H5

-R-H-X-CHO, -COR-SO3H

-COOH, -COOR-CN-NR3

+

-NO2

incr

easi

ng r

eact

ivit

y ortho/para directors

meta directors

If there is more than one group on the benzene ring:

The group that is more activating (higher on “the list”) will direct the next substitution.

Little or no substitution between groups that are meta- to each other.

CH3

OH

NHCOCH3

CH3

CHO

OCH3

Br2, Fe

HNO3, H2SO4

Cl2, Fe

CH3

OH

Br

NHCOCH3

CH3

NO2

CHO

OCH3

Cl

CHO

OCH3

Cl+

Free Radical Substitution Reaction

Alkanes undergo substitution reactions with halogens such as fluorine, bromine and chlorine in the presence of heat or light.

X=F, Cl, Br, I

CH4 + X2 CH3X + HX hν

or heat

Radical halogenation can yield a mixture of halogenated compounds because all hydrogen atoms in an alkane are capable of substitution

Monosubstitution can be achieved by using a large excess of the alkane

Bromine is less reactive but more selective than chlorine

The reaction mechanism has three distinct stepsMechanism

Initiation

Propagation

Involves the production of free radicals in presence of light or heat

Involves the reaction of free radicals with molecules to produce free radicals

A single chlorine radical can lead to thousands of chain propagation cycles

Termination

Involves the reaction of free radicals to produce a molecule

Occasionally the reactive radical intermediates are quenched by reaction pathways that do not generate new radicals

The reaction of chlorine with methane requires constant irradiation to replace radicals quenched in chain-terminating steps

30

• Halogenation at an allylic carbon often results in a mixture of products. Consider the following example:

• A mixture results because the reaction proceeds by way of a resonance stabilized radical.

Radical Reactions

Radical Halogenation at an Allylic Carbon:

Reactivity

Stereochemistry

The alkyl radical having planar structure is attacked from both faces with equal ease to form racemic mixture

Electrophilic Addition Reactions

Unsaturated hydrocarbon: contains one or more carbon-carbon double or triple bonds undergo electrophilic addition reactions

The π electrons are less tightly held and acts as a source of electrons (nucleophile).It reacts with electron deficient compounds (electrophile) forming addition product

Addition reactions are exothermic (two stronger σ bonds formed in expanse of one π bond)

KineticsSecond order

Rate = [alkene] [E-Nu]

Stereochemistry

Two modes of addition is possible

Anti addition: E+ and Nu- added from same side

Syn addition: E+ and Nu- added from same side

Carbocations are planar -> attack from both sides possible!!

Bromination of alkene

Mechanism

CH3-CH=CH2 + HCl

CH3-CH=CH-CH3 + HCl CH3-CH-CH2-CH3

ClSymmetrical Symmetrical

Unsymmetrical

CH3-CH=CH2 + Br2 CH3-CH-CH2-BrBrSymmetrical

only one possible product

CH3-CH2-CH2-ClCl

CH3-CH-CH3+

Two possible productMarkovnikov product

Markovnikov’S Rule:

In the ionic additions of an unsymmetrical reagent to a double bond, the positive portion of the adding reagent attaches itself to a carbon atom of the double bond so as to yield the MORE STABLE CARBOCATION as an INTERMEDIATE

UnsymmetricalUnsymmetrical

H

H3C

H

H

H ClH

H3C

H

H

H

H

H3C

H

H

H ClH

H3C

H

H

Cl

H3C

H

H

H

Cl

HH

fabourable secondary carbocation

unstable primary carbocation

Markovnikov product

Addition is regioselective (regioselective reaction: a reaction in which one direction of bond-forming or bond-breaking occurs in preference to all other directions

Another example

Addition of HBr

Peroxide

(-O-O-)

Markovnikov product

Anti-Markovnikov product

In absence of peroxide (ionic mechanism)

Markovnikov product

In presence of peroxide (free radical mechanism)

Radical addition leads to the formation of the more stable radical, which reacts with HBr to give product and a new bromo radical.

Anti-Markovnikov product

Carbocation rearrangement

favourable tertiary carbocation

Alkenes –Addition of halogens in water under basic conditions -> Epoxides

Alkenes –Addition of halogens in water -> Halo alcohol (halohydrin)

Alkenes –Addition of BH3 followed by oxidation-> Anti-Markovinkov addition of water

Alkynes –Addition of halides

HR2HBr

H

H

H

Br

Br

R

Elimination ReactionsNucleophilic substitution reaction there must be the possibility of competing elimination reactions

The nucleophiles can attack the electrophilic site to give the substitution product or they can act as bases giving the elimination products

Elimination

Substitution

Substrate compound must have nucleophilic group as leaving group

Common leaving groups

X (Br, Cl, F), OH, OR, N3, N2+, OTs, NR3

+, H2O+, SR2+

Elimination usually produce a new π-bond in the modified substrate

CH3-CH-CH2-L CH3-CH=CH2 + H+ + L-

HLeaving group

In some elimination a new sigma bond is produced instead of π-bond

Br

H

BBH Br+ +

New σ-bond

π-bond in the product

Elimination reaction

E1 (Elimination unimolecular) Reactions – one molecule (the substrate) in r.d.s. E2 (Elimination Bimolecular) Reactions -two molecules (the substrate and base/nucleophile) in r.d.s.

E1 Mechanism

The first step of E1 and SN1 mechanisms is identical

Kinetics

First order

Rate = k [R-X]

Rate: R3CX > R2CHX > RCH2X

More substituted halides react fastest

Favored by weaker bases such as H2O and ROH

Polar protic solvents that solvate the ionic intermediate favours the E1 mechanism

Major product is according to Saytzeff ruleThy hydrogen is removed from the β-carbon bonded to the lowest hydrogens

Two elimination productIntermediate carbocation

70%

30%

+

Thermodynamically stable product

Generally, the more substituted the alkene, the more stable it is.

Hofmann Elimination product (Less substituted alkene) When the base is bulky Steric hindrance at β-carbon When the leaving group is a pore leaving group such as F, NR3

+ and SR2+

When the alkyl halide contains one more double bonds

H3C C

CH3

CH3

H2C

CH3

Br

CH3 CH3O H3C C

CH3

CH3

CH

C

CH3

CH3

H3C

CH3

CH3

H2C C

CH3

CH2+ +

12% 88%

Crowding at β-carbon

+H2C

HC CH

CH3

CH3Br

CH

CH

CH

CH3

CH3

H2C C

HC

CH3

CH3

major product minor productPoor leaving group

Contains one or more double bonds

CH3O+ +30%70%

H3CH2C C

HCH3

F

H3CH2C C

HCH2 H3C C

HCH

CH3

H3C C

CH3

Br

H2C CH3 +

20%80%

H3C C

CH3

Br

O H2C C

CH3H2C CH3 + H3C C

CH3

CH

CH3

Bulky base

Elimination products: Hofmann VS. Saytzeff

Bulky bases increase the proportion of the less substituted alkene (Hofmann product)

Bulky base (tertiary alkoxide)

The H’s on the less substituted β carbon are more sterically accessible to the base than the H’s on the more substituted β carbon

Substitution versus elimination: SN1 Vs E1

C

H3C

H3CH3C

Br slow

H2O, EtOH CH3

CH3C C

H

H H

Br+

OHH

CH3

CH3C C

H

H H

OH H

kelim

ksub

CH3

CH3C C

H

H

H3O

C O

H3C

H3CH3C

H

H H2O C O

H3C

H3CH3C

H64% SN1 product

37% E1 product

H3O

+

+

Step-1

Step-2

As E1 reaction involves the formation of carbocation intermediate, rearrangement of the carbon skeleton can occur before the proton lost.

E2 Mechanism

KineticsSecond order

Rate = k [R-X] [base]

R3CX > R2CHX > RCH2X Favored by strong base Favored by Polar aprotic solvent

Relative reactivities of alky halide in an E2 reaction

Stereochemistry of the E2 reaction

The leaving group and the H atom can be syn or anti to each other

Syn-elimination (substituents removed from same side)Anti-elimination (substituents removed from opposite side)

Favored in E2 reaction

H3C CCH3

H3CBr H3CH2C O

H3CC

CH2

CH3

100%

CH3CH2BrH3CH2C O

H3CH2C O CH2CH3 99%

Substitution versus elimination: SN2 Vs E2Because many good nucleophiles are also good bases, SN2 often competes with E2 for those substrates that are good for SN2

H3C CCH3

H Br H3CH2C O

H3C CCH3

HOCH2CH3

H3C CCH2

H

21%

79%

substitution product elimination product

To promote E2 over SN2 we want to use strong bases that or non-nucleophilic.

elimination product

substitution product