Physical Organic Chemistry

A mechanism is a hypothesis, and this is how you test it

About this course

Physical organic chemistry as evidence: activation parameters, Hammond's postulate, the Hammett equation and when its line breaks, kinetic isotope effects, acidity in water and in vacuum, solvent effects, stereoelectronics, carbocations, radicals and carbenes, Marcus theory, acid and base catalysis, and the Curtin-Hammett principle.

What you will be able to do

  • Read enthalpy and entropy of activation as evidence about a transition state
  • Apply Hammett and Taft correlations, and recognise a change of mechanism when the line breaks
  • Use kinetic isotope effects to weigh a bond as it breaks
  • Explain acidity, solvent effects and stereoelectronics on the same free-energy footing
  • Account for reactivity with Marcus theory, catalysis and the Curtin-Hammett principle

What this course covers

  • Electron transfer and the reorganization energy
  • The Marcus barrier from two intersecting parabolas
  • Hammond's postulate as a quantitative equation (Leffler–Brønsted α)
  • The Marcus inverted region and its experimental confirmation
  • Marcus theory extended to proton and group transfers; the cross relation
  • Practical use, pitfalls, and scope of Marcus theory
  • The transition state: nature and inaccessibility
  • Arrhenius law and the cricket thermometer
  • Eyring equation and the log-rate/free-energy relationship
  • Transition-state population and the free energy of activation
  • Every instrument as a derivative of log(rate)
  • Hammett substituent effects as a charge sensor
  • Kinetic isotope effects as bond-breaking detectors
  • Solvent effects and the Grünwald-Winstein scale
  • Mechanistic inference by convergence of instruments
  • The Hammett Sigma Scale
  • Positional Dependence of Sigma: Induction vs. Resonance
  • Linear Free Energy Relationships: Why the Line Is Straight
  • Rho as a Charge Sensor
  • Saponification of Ethyl Benzoates: Central Application
  • Practical Use, Limits, and Extended Sigma Scales
  • PKA as free energy and standard-state conventions
  • Thermodynamic cycle separating intrinsic acidity from solvation
  • Gas-phase acidity measurement and the alcohol order inversion
  • Polarizability as the gas-phase stabilisation mechanism
  • Solvation magnitude and the Born model of ion stabilisation
  • Delocalization vs. solvation: acetic acid and phenol
  • Framework for reading and testing any acidity argument
  • Historical inference of carbocations
  • Superacid generation and direct NMR observation of carbocations
  • Gas-phase carbocation stability: hydride affinities and the alkyl ladder
  • Hyperconjugation as the dominant stabilising force
  • Solution-phase stability: the pKR⁺ scale and Hammett connection
  • Delocalization, aromaticity, and solvent compression of stability differences
  • Carbocation stability as a synthetic design tool
  • Limitations of ordinary Hammett sigma
  • Extended sigma scales: σ⁺ and σ⁻ for through-conjugation
  • Mathematical basis of curved Hammett plots
  • Taft's separation of steric and polar effects
  • Mechanism diagnosis from plot shape
  • Practical procedure for a non-linear Hammett plot
  • Radical stability and bond dissociation energies
  • Radical ladder vs. carbocation ladder: hyperconjugation comparison
  • Radical clocks: principle and calibration
  • Carbene spin states: singlet vs. triplet
  • Skell's stereochemical test for carbene spin
  • Clock experiment design, assumptions, and limits
  • Specific vs. General Acid-Base Catalysis
  • The Brønsted Catalysis Relation
  • Marcus Theory Interpretation of the Brønsted Slope
  • Eigen's Proton-Transfer Rate Limits
  • Solvent Isotope Effects and Enzyme General Catalysis
  • Integrated Protocol for Reading Acid-Base Catalysis
  • Physical Meaning of Activation Enthalpy and Entropy
  • Standard-State Dependence of Bimolecular ΔS‡
  • Enthalpy–Entropy Compensation as a Statistical Artifact
  • Eyring Plot as a Two-Parameter Instrument
  • Cyclopropane and Claisen as Mechanistic Benchmarks
  • Mechanistic Reading of the Claisen Rearrangement
  • Best-Practice Checklist for Reporting Activation Parameters
  • Failure of the dielectric constant as a rate predictor
  • Hughes–Ingold rules for solvent effect direction
  • Grunwald–Winstein Y scale definition and values
  • M value as mechanistic diagnostic
  • Specific solvent interactions: hydrogen bonding and the failure of the continuum model
  • Extended Grunwald–Winstein equation and nucleophilic solvent assistance
  • Solvent effects as a mechanistic instrument: design and pitfalls
  • Hammond's Postulate: Early and Late Transition States
  • Bond Energies and Thermochemistry of Halogen Abstraction
  • Quantitative Selectivity: Leffler's Fraction from Propane Data
  • The Reactivity–Selectivity Principle and Its Failure
  • Hammond's Postulate as a Baseline, Not an Answer
  • Temperature Correction and Practical Use of Hammond's Postulate
  • The Curtin–Hammett Principle Stated
  • Menthyl Chloride as the Canonical Example
  • Derivation: Product Ratio from Transition-State Energies
  • Conditions for Validity: Fast vs. Slow Interconversion
  • Kinetic vs. Thermodynamic Control of Products
  • Winstein–Holness Expression for Observed Rate
  • Designing Experiments and Avoiding Misuse
  • Orbital alignment and hyperconjugation
  • The anomeric effect
  • Antiperiplanar requirement in E2 elimination
  • Bürgi–Dunitz trajectory for nucleophilic addition
  • Born-Oppenheimer basis for isotope effects
  • Zero-point energy origin of the primary kinetic isotope effect
  • Primary kinetic isotope effect ceiling (~7 at room temperature)
  • Secondary kinetic isotope effects and hybridization
  • Quantum tunneling and isotope effects beyond the ceiling
  • Designing and interpreting isotope experiments

Syllabus

  1. Mechanism as Hypothesis

    1. L1 · A Mechanism Is a Hypothesis About Something Nobody Can See
    2. L2 · Activation Parameters: What the Enthalpy and Entropy of Activation Say
    3. L3 · Hammond's Postulate, and the Selectivity That Does Not Follow

  2. Linear Free-Energy Relationships

    1. L4 · The Hammett Equation: Free Energies Add
    2. L5 · When the Line Breaks: Sigma-Plus, Taft and the Change of Mechanism
    3. L6 · Kinetic Isotope Effects: Weighing a Bond as It Breaks

  3. Acidity, Solvent and Orbitals

    1. L7 · Acidity in Water and in a Vacuum
    2. L8 · Solvent Effects: Five Powers of Ten From the Same Molecule
    3. L9 · Stereoelectronics: Orbitals That Must Line Up

  4. Reactive Intermediates

    1. L10 · Carbocations: Stability, Measured Two Ways
    2. L11 · Radicals and Carbenes, and Clocks to Time Them

  5. Catalysis and Selectivity

    1. L12 · Marcus Theory, and the Reaction That Slows Down When It Should Speed Up
    2. L13 · Acid and Base Catalysis: General, Specific, and the Bronsted Line
    3. L14 · Curtin-Hammett: The Minor Conformer, the Major Product