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
