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7.S: Nucleophilic Substitution Reactions (Summary)

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    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.
    • In addition:
      • 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.

    Contributors and Attributions

    This page titled 7.S: Nucleophilic Substitution Reactions (Summary) is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Tim Soderberg.