Org Chem 2 Ch 11 Reactions of Alkyl Halides

Learning Objectives

• Nucleophilic Substitution Reactions (SN1 and SN2): Understand the concepts, mechanisms, and effects of various factors that influence these reactions.
• Elimination Reactions (E1 and E2): Explore how alkyl halides undergo elimination and the impact of stereochemistry and reaction conditions.

Discovery of Nucleophilic Substitution Reactions

• Historical Background: 1896, Walden demonstrated that enantiomers can interconvert through substitution reactions.
• Key Example:
  • (-)-malic acid reacted with PCl5 results in (+)-chlorosuccinic acid.
  • Further reaction with silver oxide in water produces (+)-malic acid back from (+)-chlorosuccinic acid.
• Nucleophilic Substitution: Refers to the series of reactions termed the Walden cycle, essential for understanding chirality in organic chemistry.

The SN2 Reaction

• Definition: Substitution, Nucleophilic, Bimolecular; involves a simultaneous reaction between the nucleophile and substrate.
• Kinetics: Second-order reaction; rate depends on the concentration of both the nucleophile and the substrate.
• Reaction Mechanism: Transition state forms when a nucleophile approaches the alkyl halide and kicks out the leaving group.
  • Diagram representation:
    ext{Nu}: + ext{R-X}
    ightarrow ext{Nu-R} + ext{X}^-
• Stereochemistry: SN2 reactions lead to inversion at the chiral center due to backside attack of the nucleophile.

Characteristics of the SN2 Reaction

• Reactivity Patterns: Reactivity inversely correlated to steric hindrance; primary substrates react fastest, followed by secondary, and tertiary substrates are often unreactive.
• Nucleophile Characteristics: Neutral or negatively charged Lewis bases work as nucleophiles; negative charge increases reactivity.
• Leaving Groups: Good leaving groups are weak bases (e.g. I-, Br-), while strong bases (e.g. OH-) make poor leaving groups.

Solvent Effects on SN2 Reactions

• Protic Solvents: Slow down nucleophilic attack due to solvation of the nucleophile.
• Aprotic Solvents: Increase reaction rates as they do not solvate anions strongly, thus enhancing nucleophilic activity.

The SN1 Reaction

• Definition: Substitution, Nucleophilic, Unimolecular; involves dissociation to form a carbocation before nucleophilic attack.
• Kinetics: First-order reaction; rate depends solely on the concentration of the substrate.
• Mechanism:
  1. Dissociation of the alkyl halide forms a carbocation.
  2. Nucleophile attacks the carbocation.
  3. Proton transfer may occur to form the final alcohol product.
• Carbocation Stability: Stability is key for reaction rate; tertiary carbocations are the most stable and reactive.

Characteristics of the SN1 Reaction

• Stereochemistry: Leads to a racemic mixture due to the planar nature of the carbocation, allowing attack from either side.
• Reaction Rate Influencers:
  • Stability of carbocation (Hammond postulate).
  • Polar protic solvents increase rates by stabilizing the states involved in the reaction.

Elimination Reactions: Zaitsev's Rule

• Definition: Elimination reactions occur when a nucleophile removes both a hydrogen and the leaving group.
• Zaitsev's Rule: The more substituted alkene is generally favored as the major product in elimination reactions.
• E1 vs. E2 Reactions:
  • E1: Steps involve carbocation formation followed by deprotonation.
  • E2: Single concerted step that simultaneously removes a leaving group and a proton, producing an alkene.

Influences on E2 Reactions

• Geometry Requirements:
  • Periplanar geometry is necessary for E2 reactions for effective overlap of orbitals.
  • Types:
  • Syn periplanar (leaving group and hydrogen on the same side).
  • Anti periplanar (leaving group and hydrogen on opposite sides).
• Reaction Conditions: Strong bases are required for E2 eliminations and can often lead to different products based on substrate conformation.

Summary of Reactivity Patterns

• Primary Alkyl Halides: Favor SN2 reactions; require strong nucleophile.
• Secondary Alkyl Halides: Can undergo both SN2 and SN1 reactions; conditions dictate mechanism.
• Tertiary Alkyl Halides: Favor SN1 and E2 reactions; steric hindrance prohibits SN2.
• Leaving Group Ability: Influences both SN1 and SN2; better leaving groups enhance reaction rates.

Biological Reactions

• Biological systems frequently utilize SN1 and SN2 mechanisms for reactions involving organodiphosphates and terpenoid synthesis.

Key Takeaways

• Understand the difference between SN1 and SN2, how reaction mechanisms depend on conditions, and predicting products based on substrate structure. Elimination reactions are critically determined by stereochemistry and the stability of intermediates.