6 IRELAND Medicinal Chemistry - Alkyl Halides and Methylation

Learning Outcomes

  • Recognize the mechanism link between alkylation chemistry in a beaker and in biological systems.
  • Understand the interaction of organo-halogen drugs with DNA.
  • Describe how methylation reactions occur in living systems.
  • Recall the structure of S-adenosyl methionine (SAM).
  • Describe the reaction mechanism of methylation in living systems.

General SN1 Reaction Mechanism

  • SN1 Reaction: Unimolecular nucleophilic substitution.
    • Definition: Involves one species in the rate-determining step, which is the formation of the carbocation.
    • Steps:
    • First step: Slow formation of the carbocation.
    • Second step: Fast reaction between the nucleophile and the carbocation.

Nucleophile Addition and Tertiary Alkyl Halides

  • SN1 Reaction of Ethoxide with 2-Chloro-2-methylpropane: Shows that all SN1 mechanisms are generally the same regardless of the nucleophile or substrate.
  • Transition States:
    • SN1 reactions have two transition states.
    • The rate depends solely on the concentration of the alkyl halide.

Chiral Alkyl Halides and Racemic Mixtures

  • Starting with a pure chiral (S) or (R) enantiomer yields a racemic mixture as the reaction occurs through a planar carbocation, which allows for equal possibility of nucleophilic attack from either side.
    • Example: For a pure (S) enantiomer, both (S) and (R) products are produced in equal amounts.
  • Determining Racemic Outcome:
    • Record optical activity using a polarimeter. No optical rotation indicates a racemic mixture.

Loss of Chirality via SN1 Reactions

  • Example: (S)-3-bromo-3-methylhexane gives a racemic mixture during the reaction, highlighting the loss of chirality due to the formation of a planar carbocation.

Summary of SN1 and SN2 Mechanisms

  • SN2 Mechanism:
    • One-step mechanism with one transition state.
    • Involves no intermediates.
    • Primary alkyl halides react fastest.
    • Rate depends on both nucleophile and alkyl halide concentrations.
    • Chiral substrates exhibit inversion of configuration.
  • SN1 Mechanism:
    • Multi-step mechanism with the first step being the slowest.
    • Carbocation intermediates are formed.
    • Tertiary alkyl halides react fastest while primary react slowest.
    • Rate depends on alkyl halide concentration only.
    • Chiral alkyl halides produce racemic mixtures.

Organo-halogen Drugs and DNA Interaction

  • Mechanism:
    • Organo-halogen drugs can interact with DNA guanine (7-nitrogen is nucleophilic), leading to potential disruptions in DNA function.
    • Example: Methyl chloride can react with guanine through an SN2 reaction.
    • Cross-linking of DNA can inhibit replication by forming bonds between different strands.

Biological Methylation Processes

  • Methylation in biological systems generally involves SN2 mechanisms, transferring a -CH3 group from SAM to nucleophiles.
  • Electrophilic Donor: S-adenosylmethionine (SAM) which contains a charged sulfur atom.
  • The leaving group in the biological reaction is S-adenosylhomocysteine (SAH), which is replaced during the methylation reaction.

Example: Biosynthesis of Adrenaline

  • The nucleophilic nitrogen of norepinephrine attacks the electrophilic methyl carbon of SAM, leading to the production of adrenaline and the displacement of SAH.