IRELAND 5 Medicinal and Pharmaceutical Chemistry Notes on Nucleophilic Substitution Reactions of Alkyl Halides

Learning Outcomes and Alkyl Halides

  • Differentiate between primary, secondary, and tertiary alkyl halides.

    • Primary (1°): One alkyl group attached to the carbon which is bonded to the halide.
    • Secondary (2°): Two alkyl groups attached.
    • Tertiary (3°): Three alkyl groups attached.
    • SN2 reactions primarily occur with primary and secondary alkyl halides while tertiary often do not follow this pathway due to steric hindrance.

  • SN1 Mechanism:

    • Understand the mechanism as it involves the formation of a carbocation.
    • Types of alkyl halides favoring SN1 are tertiary and some secondary.
    • Energy profile diagrams illustrate the relative energies during reactions.

  • pKa and Leaving Groups:

    • The lower the pKa of a leaving group’s conjugate acid, the better the leaving group.
    • Good leaving groups stabilize negative charges after dissociation.

Nucleophilic Substitution Reaction Mechanisms

  • SN2 Reactions:

    • React in a single concerted step where the nucleophile attacks opposite to the leaving group.

    • Inversion of configuration occurs, making the product's stereochemistry opposite to that of the reactant.

    • Rate depends on concentration of both nucleophile and substrate: Rate = $[Nucleophile] imes [Substrate]$.

    • Relative Reactivity of substrates:

    • Primary > Secondary > Tertiary (no SN2)

  • SN1 Reactions:

    • A two-step process involving the formation of a carbocation, followed by nucleophile attack:
    1. Slow, rate-determining carbocation formation.
    2. Fast nucleophile attack on carbocation.
    • Rate depends solely on the concentration of the alkyl halide: Rate = $[Alkyl Halide]$.

Nucleophiles and Their Reactivity

  • Nucleophilic Strength:
    • Generally, stronger bases are better nucleophiles.
    • Relative rates of reaction for common nucleophiles (expressed approximately on relative scale):
    • Hydroxide (10,000) > Methoxide (25,000) > Cyanide (125,000) > Neutral species like Water (1).
  • Types of Nucleophiles:
    • Must possess lone pairs; can be either negatively charged or neutral.

Leaving Groups and Their Impact on Reaction Rates

  • Leaving Group Effectiveness:
    • Weak bases make good leaving groups.
    • Example: Conjugate acids of good leaving groups typically have lower pKa values, which stabilizes the leaving group post-displacement.

Alkyl Halides and Their Reactivity Profiles

  • Tertiary alkyl halides favor SN1 reactions while primary and secondary can follow either SN1 or SN2, depending on the conditions:
    • 1° Alkyl Halides: React via SN2.
    • 2° Alkyl Halides: Utilize both mechanisms; can be influenced by sterics and electronic effects in their environment (e.g., presence of benzene rings).
    • 3° Alkyl Halides: Favor SN1 due to stabilized carbocation formation.

Summary of SN1 and SN2 Reactions

  • SN2:

    • Concerted mechanism, single step, stereochemistry inversion, bimolecular.
    • Rate determined by both nucleophile and substrate.
    • Tertiary alkyl halides do not react.

  • SN1:

    • Two-step mechanism with intermediates (carbocations).
    • Predominates for tertiary alkyl halides, depends solely on alkyl halide concentration.
    • Racemic mixtures are a result for chiral centers due to the planar nature of the carbocation.

Practical Examples and Concepts to Remember

  • Understand nucleophilic strength correlated to basicity and leaving group effectiveness.
  • Anthesis of reactivity in SN1 and SN2 pathways relative to alkyl halides (tertiary = fastest in SN1, primary most reactive in SN2).
  • Comparative analysis of nucleophile reactivity should also be practiced across different functional groups.