nucleophilic substitution and elimination...

by Daniel Berger

NucleophilicNucleophilic Substitution Substitution and Elimination Reactionsand Elimination Reactions

Self-Study Material

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NucleophilicNucleophilic Aliphatic SubstitutionAliphatic Substitution

nucleophile leaving group

Nu CR

R

R

X C RNu

R

R

X+ +

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NucleophilicNucleophilic Aliphatic SubstitutionAliphatic Substitutionleaving group nucleophile

Nu CR

R

R

X C RNu

R

R

X+ +

in reversein reverse

NucleophilicNucleophilic Substitution Substitution in Synthesisin Synthesis

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The SThe SNN2 Mechanism2 MechanismC Br

H3C

CH3CH2

HHO +

CHOCH3

CH2CH3H Br+

The nucleophile attacks the alkylhalide 180o awayfrom the halogen

C

CH3

CH2CH3HHO Br

Transition state withsimultaneous bond breaking and bond forming

δ− δ−

(R)-2-bromobutane

(S)-2-butanol

The configurationat carbon is inverted

On the web

C

CH3

CH2CH3H

A planar carbocation

Br+slow rate-limiting step

methanol1.

The SThe SNN1 Mechanism1 MechanismC

CH3

CH2CH3H2.

CH3OHOC

H3C

CH2CH3H

CH3

Hfastfast

O CCH3

CH2CH3H

H3C

H

CH3OH

O CCH3

CH2CH3H

H3C

3.

HOCH3

OCH3C

CH2CH3H

CH3

CH3OH

(S)-2-methoxybutane (R)-2-methoxybutane

a racemicmixture

C BrH3C

CH3CH2

H

On the web

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Whether a reaction is SWhether a reaction is SNN1 or S1 or SNN221. Structure of nucleophile

– Also affects side reactions

2. Structure of alkyl halide substrate

3. Structure of leaving group

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What makes a good What makes a good nucleophilenucleophile

Bronsted basicity

• Negative charge– OH- > H2O

• Polarizability– Less electronegative– Larger

• Basicity– Brønsted– Lewis

nucleophilicity

C N O F

P S Cl

Br

I

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Common Common nucleophilesnucleophiles and their and their electrophilicitieselectrophilicities

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Side reactions in the SN1 mechanismSide reactions in the SN1 mechanism

NaI

Br I

H2O

Br OH+

Br

NaOH

Basicity

of nucleophile

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Whether a reaction is SWhether a reaction is SNN1 or S1 or SNN221. Structure of nucleophile

– Also affects side reactions

2. Structure of alkyl halide substrate

3. Structure of leaving group

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Structure of Alkyl HalideStructure of Alkyl Halide

R3CX R2CHX RCH2X CH3X(tertiary) (secondary) (primary) (methyl)

Increasing stability of carbocation intermediate

H

HH

H

HR

H

RR

R

RR

SN1

Increasing ease of access to site of reaction

C XH

H

HC XH

RHC X

H

RRC X

RR

R

SN2Governed bysteric factors

Governed byelectronic factors

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StericSteric Hindrance of SHindrance of SNN22

CH3CH2Br CH3CCH2Br

CH3

CH3

Rate = 1 Rate = 10-30

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Whether a reaction is SWhether a reaction is SNN1 or S1 or SNN221. Structure of nucleophile

– Also affects side reactions

2. Structure of alkyl halide substrate

3. Structure of leaving group

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Leaving Group Ability Leaving Group Ability Correlates with Acid StrengthCorrelates with Acid Strength

strength of conjugate acid

reactivity as a leaving group

> > >> > > > >I Br Cl F CH3CO

O

HO CH3O H2N

Protonated leaving groups are good, because the conjugate acids of neutral molecules are more acidic.

(In other words, the leaving groups are less basic.)

On the web

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NucleophilicNucleophilic substitution will not substitution will not occur with a poor leaving group!occur with a poor leaving group!

good leaving groups poor leaving groups TsO– ≥ X– ≈ RS– > HOR ≈ HNR2 CN– > OR– > NR2

–

Summary: SSummary: SNN1 vs. S1 vs. SNN2 Reactions2 ReactionsType of Alkyl Halide SN2 SN1

methyl CH3X Favored. Does not occur because of cation instability.

primary RCH2X Favored. Rarely occurs because of cation instability.

secondary R2CHX Favored in aprotic solvents with good nucleophiles

Favored in protic solvents with poor nucleophiles

tertiary R3CX Does not occur because of sterics.

Favored because of cation stability.

stereocenter Inversion Racemization

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ββ--EliminationElimination

BHB+

C C

H OH2

C C

H

C C

E1C CC C

H XC C

H

X

H2O

+ HBB

C C

H X

C C

B

++ HB XE2

On the web

E2 MechanismE2 Mechanism

E1 MechanismE1 Mechanism

SN2 vs. E2SN2 vs. E2

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Substitution vs. eliminationSubstitution vs. elimination