Nucleophilic Substitution

Announcements

  • NMR Lab Report: Due Sept 19. Short, handwritten report. Complete questions 1-6 from Chapter 11 and question 7 for unknown identification. Refer to NMR lecture notes and ICON for compound formula.

  • Extraction Lab Report: Due Sept 26. Formal report per Chapter 4 instructions. Pre-lab readings from Chapters 5-7 are essential for understanding techniques used (e.g., vacuum filtration, gas chromatography).

Nucleophilic Substitution

  • Substitution: A reaction where two reactants exchange parts to form products.

  • Nucleophile: Electron-rich species (nucleus-loving).

  • Electrophile: Electron-deficient species (electron-loving).

Nucleophilic Substitution in Biology

  • SAM (S-adenosylmethionine): Key biological methylating agent; transfers methyl groups via nucleophilic substitution to various biomolecules (DNA, proteins, carbohydrates).

Nucleophiles

  • Neutral Nucleophiles: H2O, ROH, NH3, RNH2, R2NH, RSH, RSR.

  • Negatively Charged Nucleophiles: Stronger and more reactive; includes HO–, RO–, NH2–, RS–.

Mechanisms of Nucleophilic Substitution

  1. Unimolecular (SN1):

    • Rate depends solely on the substrate concentration: ext{Rate} = k[ ext{RX}].

    • More stable carbocation (3° > 2° > 1° > methyl) increases likelihood.

  2. Bimolecular (SN2):

    • Single-step concerted reaction; rate depends on both substrate and nucleophile concentrations: ext{Rate} = k[ ext{RX}][ ext{Nu}].

    • Less steric hindrance favors reaction (methyl > 1° > 2° > 3°).

Activation Energy

  • Lower with more alkyl substituents, facilitating leaving group dissociation.

Experimental Design for Nucleophilic Substitution

  • Goal: Determine if reaction follows SN1 or SN2 mechanism.

  • Competition Experiment: Use large excess of alkyl halide for constant concentration; chemical shifts and multiplicities for products will be analyzed in NMR.

Experimental Procedures

  • Set up heating apparatus under reflux: round-bottom flask, water-cooled condenser, sand bath, and magnetic stir plate.

  • Safety: Handle NaOH and alkyl halides with care; work in a hood.

  • Post-reaction: Use separatory funnel for unreacted materials; employ rotary evaporator for solvent removal.

  • Submit NMR sample after adding solvent for analysis.