1. Nucleophilic Substitution
Chapter 6
Nucleophilic Substitution

2. FunctIonal-Group TransformatIon by nucleophIlIc substItutIon
Section 6.1
FunctIonal-Group TransformatIon by nucleophIlIc substItutIon

3. Nucleophilic Substitution
Formation of alkyl halides from alcohols is a substitution process
SN1:
SN2:
In these reactions halide serves as the nucleophile and H2O as the leaving group

4. Nucleophilic Substitution
Alkyl halides undergo an analogous process with nucleophiles M+Y–
Because the added reagent is nucleophilic, this is called nucleophilic substitution
electrophile

5. The Nucleophile
The nucleophile is typically a simple metal salt M+Y–, where M+ is Li+, K+, or Na+
The anion Y– can be any of a variety of organic or inorganic anions. Examples:
Nucleophilicity is related in general to basicity, since nucleophiles are Lewis bases

6. The partially positive carbon reacts as a Lewis acid.
The Electrophile
The electrophile must contain a C–LG bond polarized towards LG, the leaving group
Alkyl halides and pseudohalides (sulfonates) are most common
The electrophilic carbon must be sp3 hybridized
The partially positive carbon reacts as a Lewis acid.

7. RelatIve ReactIvIty of halIde LeavIng Groups
Section 6.2
RelatIve ReactIvIty of halIde LeavIng Groups

8. Leaving Group Ability
In a nucleophilic substitution reaction, the leaving group accepts electrons, just like an acid
Good leaving groups –X are associated with strong acids HX
Good leaving groups are also associated with weaker C–X bonds

9. The SN2 MechanIsm of NucleophIlIc SubstITutIon
Section 6.3
The SN2 MechanIsm of NucleophIlIc SubstITutIon

10. Kinetics of SN2
Substitution of primary and methyl alcohols and primary and methyl halides is found to be bimolecular
The rate law depends on the concentrations of both reactants
Both reactants are involved in the rate-determining transition state
In this TS, attack of the nucleophile and loss of the leaving group occur simultaneously

11. Reaction Coordinate Diagram

12. Stereochemistry of SN2
Studies of substitutions of optically active alkyl halides show that the nucleophile does not occupy the position where the leaving group was…
SN2 occurs with inversion of configuration
100%!
stereospecific

13. SterIc Effects and SN2 ReactIon Rates
Section 6.4
SterIc Effects and SN2 ReactIon Rates

14. Steric Hindrance in the Electrophile
Alkyl groups bound to the electrophilic carbon represent a hindrance toward backside attack of the nucleophile
We observe this in the relative rates of SN2 for methyl, primary, secondary, and tertiary alkyl bromides
The space “occupied” by the alkyl groups is called steric hindrance

15. Steric Hindrance in the Electrophile

16. The Neopentyl Effect: Adjacent Alkyl Groups
Even alkyl groups adjacent to the electrophilic carbon slow the rate of SN2
This is often called the neopentyl effect because neopentyl halides react very slowly in SN2
neopentyl bromide