5_Medicinal and Pharmaceutical Chemistry - Alkyl Halides II: Nucleophilic Substitution Reactions

Learning Outcomes

  • Understand the differences between primary, secondary, and tertiary alkyl halides, and why tertiary alkyl halides, and in some cases secondary, do not undergo SN2 mechanisms.

  • Describe the SN1 nucleophilic substitution reaction mechanism, including:

    • Type of alkyl halide involved

    • Formation of carbocation

    • Stereochemistry of products

    • Rate of reaction

    • Draw an energy profile diagram for an SN1 reaction.

  • Correlate the pKa of a leaving group with its reactivity profile.

Types of Alkyl Halide

  • Primary Alkyl Halides (1°): Alkyl halides with one alkyl group attached to the carbon bonded to halogen (e.g., iodomethane).

  • Secondary Alkyl Halides (2°): Alkyl halides with two alkyl groups attached.

  • Tertiary Alkyl Halides (3°): Alkyl halides with three alkyl groups attached.

Nucleophilic Substitution Reaction Mechanisms

  • Classified based on the reaction mechanism into SN1 and SN2:

    • SN1 (Substitution Nucleophilic Unimolecular): Rate-determining step involves carbocation formation. Slowest step is unimolecular, meaning it involves one species.

    • SN2 (Substitution Nucleophilic Bimolecular): Rate-determining step involves two species. Takes place in a single concerted step, resulting in inversion of configuration.

SN1 Mechanism Details

  • Rate-Determining Step: Formation of carbocation is the slowest step in SN1 reactions, followed by a fast reaction between the nucleophile and carbocation.

  • Energy profile includes two transition states.

  • Rate depends solely on the concentration of the alkyl halide only.

SN2 Mechanism Details

  • Transition State: Contains both nucleophile and substrate; forms as the nucleophile approaches the carbon and displaces the leaving group.

  • Inversion of Configuration: The nucleophile approaches from the opposite side of the leaving group.

  • Reaction Rate: Rate is determined by both nucleophile and substrate concentrations; increases when either are in greater concentration: extRate=k[extNucleophile][extSubstrate]ext{Rate} = k[ ext{Nucleophile}][ ext{Substrate}]

Nucleophiles

  • Any species with a lone pair of electrons can act as a nucleophile. Negatively charged nucleophiles tend to be more reactive than neutral ones.

Leaving Groups

  • Weak bases make good leaving groups. The strength of a leaving group is correlated with the pKa of its conjugate acid; lower pKa implies better leaving group capacity.

Reactivity Profiles

  • For SN2 Reactions: Primary > Secondary > Tertiary (tertiary alkyl halides do not undergo SN2 due to steric hindrance).

  • For SN1 Reactions: Tertiary > Secondary > Primary (primary does not undergo SN1).

Summary of Differences between SN1 and SN2

  • SN1:

    • More than one step

    • Rate depends only on the alkyl halide concentration

    • Carbocation intermediates

    • Chiral alkyl halides yield racemic mixtures

  • SN2:

    • Single concerted step

    • Rates depend on both nucleophile and substrate concentration

    • Products show inversion of configuration