# 7.11: Nucleophilic Substitution Reactions (Summary)


Before you move on to the next chapter, you should be comfortable with the following concepts and skills:

## Nucleophilic substitution basics

• Illustrate the transition state for an $$S_N2$$ reaction
• Draw a complete mechanism for an $$S_N1$$ reaction, in particular a hydrolysis or other solvolysis $$S_N1$$ reaction.
• Illustrate all transition states that are part of an $$S_N1$$ reaction.
• Understand that non-enzymatic $$S_N1$$ reactions result in both inversion and retention of configuration (racemization) at the electrophilic carbon. Enzymatic $$S_N1$$ reactions are stereospecific, usually resulting in inversion at the electrophilic carbon.

## Nucleophiles

• Be able to recognize the nucleophile, electrophile, and leaving group in an SN1 or SN2 reaction.
• Understand that – with the exception of the vertical periodic trend in protic solvents – in most cases anything that makes something a stronger base also makes it a more powerful nucleophile:
• The vertical periodic trend in nucleophilicity for reactions in polar aprotic solvents: chloride ion is a better nucleophile than bromide ion in acetone solvent.
• Inductive effect: electron-withdrawing groups decrease nucleophilicity
• Resonance effects:
• Delocalization of negative charge/electron density decreases nucleophilicity. For example, methoxide ion (CH3O-) is a stronger nucleophile than acetate ion.
• The vertical periodic trend in protic solvent (water or alcohol) is opposite the trend in basicity: for example, thiols are more nucleophilic than alcohols.
• Electrophiles
• Less hindered electrophiles will react faster in SN2 reactions: for example chloromethane is a better electrophile than a primary alkyl chloride.

## Leaving groups

• Common laboratory leaving groups are halides and para-toluenesulfonate (abbreviated tosyl, or OTs).
• Common biochemical leaving groups are phosphates and sulfide.

## Carbocation stability

• More substituted carbocations are more stable: for example, a tertiary carbocation is more stable than a secondary carbocation.
• The presence of electron-withdrawing groups (by inductive or resonance effects) decreases carbocation stability.
• The presence of a heteroatom can stabilize a nearby carbocation by the resonance-based electron donating effect. Otherwise, heteroatoms act as weakly electron withdrawing carbocation-destabilizing groups by inductive effects.

## General concepts and skills

• Be able to predict whether a given substitution reaction is likely to proceed by $$S_N2$$ or $$S_N1$$ mechanisms, based on the identity of the nucleophile, the electrophile, and the solvent.
• $$S_N1$$ reactions involve weaker nucleophiles relatively stable carbocations, and are accelerated by protic solvents.
• Be able to 'think backwards' to show the starting compounds in a substitution reaction, given a product or products.
• Understand how $$S$$-adenosylmethionine (SAM) acts as a methyl group donor in biochemical $$S_N2$$ reactions.
• Be able to select appropriate alkyl halide and alcohol starting compounds to synthesize a given ether product, using the Williamson ether synthesis procedure.