The aim of this module is to consolidate and extend second year knowledge of synthetic and physical organic chemistry. Basic synthetic reactions are reviewed and more advanced synthetic methodology introduced. The retro synthetic approach is developed, enabling students to devise syntheses of a range of target molecules. Concurrently, the basic concepts and techniques of physicalorganic chemistry are explained, providing a deeper understanding of organic mechanisms and reactivity.

By the end of the module, students should:

• Have a good understanding of core synthetic reactions and their mechanisms.
• Be able to perform retrosynthetic analyses and devise plausible syntheses of a variety of target molecules.
• Be able to deduce mechanisms on the basis of kinetic and other evidence.
• Be able to solve challenging organic problems involving quantitative aspects of physical concepts and sophisticated retrosynthetic planning.

Organic synthesis and reactions (Dr N Greeves)

Pericyclic reactions 1: cycloadditions

• The rules that govern cycloadditions
• Photochemical reactions: reactions that need light
• Making six-membered rings by the Diels--Alder reaction
• Making four-membered rings by [2 + 2] cycloaddition
• Making five-membered rings by 1,3- dipolar cycloaddition
• Using cycloaddition to functionalize double bonds stereospecifically
• Using ozone to break C=C double bonds

Pericyclic reactions 2: Sigmatropic and electrocyclic reactions

• Stereochemistry from chair-like transition states
• Making γ,δ-unsaturated carbonyl compounds
• What determines whether these peric yclic reactions go 'forwards' or 'backwards'
• Fischer Indole synthesis
• Why substituted cyclopentadienes are unstable
• What 'con'- and 'dis'-rotatory mean
• Reactions that open small rings and close larger rings

Rearrangements and Fragmentations

• Participation means acceleration and retention of stereochemistry and may mean rearrangement
• Participating groups can have lone pairs or π-electrons
• Carbocations often rearrange by alkyl migration
• Ring expansion by rearrangement
• Using rearrangements in synthesis
• Electron donation and electron withdrawal combine to create molecules that fragment
• Anti-periplanar conformation is essential
• Small rings are easy to fragment, medium and large rings can be made in this way
• Double bond geometry can be controlled
• Using fragmentations in synthesis

Radical reactions

• Radical reactions follow different rules to those of ionic reactions
• Bond strength is very important
• Radicals can be formed with Br, Cl, Sn, and Hg
• Efficient radical reactions are chain reactions
• There are electrophilic and nucleophilic radicals
• Radicals favour conjugate addition
• Cyclization is easy with radical reactions
• Dissolving metal reductions with metal-ammonia systems applied to aromatic systems (Birch reduction) and enones and their synthetic applications. Dissolving metal reductions applied to carbonyl groups - Pinacol coupling and acyloin condensation.

· Synth esis of alkenes -- controlling double bond geometry

• Stereospecific eliminations reactions
• Wittig, Peterson and Julia reactions
• Reduction of alkynes

Retrosynthesis

• Disconnections, synthons, synthetic equivalents, target molecules
• Chemoselectivity· Functional group interconversion
• C-X disconnections: one and two group disconnections.
• C-C bond disconnections: One group disconnections, Two group disconnections:
• 1,X-dioxygenated systems (X = 1,3,5) and natural reactivity.
• 1,2 and 1,4 disconnections and Umpolung reactivity

Organic Mechanisms (Dr. R P Bonar-Law)

• Equilibrium
  • Revision of basic thermodynamics: ΔG^o = -RTln(K) = ΔH ^o - TΔS^o, effect of temperature (van't Hoff)
  • Acid-base equilibria: pK_a of common acids
  • Estimating an equilibrium constant using bond enthalpies
• Rates
  • Reaction coordinate, transition state: revision of activation free enegy for unimolecular reaction, temperature dependance (Arrhenius)
  • Connection between equilibrium and rate constants K = k₁/k _-1
  • Enthalpy and entropy of activation.
• Rates, Equilibria and Free Energy Diagrams
  • Hammond's postulate
  • Thermodynamic vs. kinetic control
  • Curtin-Hammett principle
• Kinetics
  • Revision of elementary kinetics
  • Multistep reactions, bottlenecks, rate determining step and steady state approximation
  • Primary kinetic isotope effect
• Nucleophilic substitution at saturated carbon, S_N2
  • Mechanism, kinetics, stereochemistry, nucleophile, leaving group, structure of substrate, solvent
• Nucleophilic substitution at saturated carbon, S_N1
  • Mechanism, kinetics, structure of substrate, solvent, nucleophile, leaving group, stereochemistry and ion pairs·
  • Neighbouring group participation
• The Hammett Equation
  • Correlation of rates, reaction and substituent constants
  • Deviations
  • Physical basis of LFER
  • Correlation of equilibria
• Elimination
  • Elimination to give alkenes: E₁, E₂, E_1c B, kinetics, Hammett, k_H /k_D, leaving group, regio/stereochemistry
  • Mechanistic continuum
• Addition
  • Electrophilic addition of HX, X₂ and H₂O to alkenes: kinetics, Hammett, regio/stereochemistry
  • Synthetic applications.
• Nucleophilic Substitution at Carbonyls
  • Tetrahedral intermediates
  • Common mechanisms of ester hydrolysis, B_Ac2, A_ac 2, kinetics, Hammett, labelling
  • Less common mechanisms: A_Ac1, A_Al1 kinetics, Hammett, labelling.

This is a distance learning module.  Students work through the course text book in conjunction with lecture notes according to the schedule provided.  Six assignments are completed at regular intervals throughout the semester, with marked work and model answers being returned to the students. Problems are dealt with mainly by email and discussion forum; the student's academic and industrial supervisors are also available to help.

Essential:

• "Organic Chemistry", Clayden, Greeves, Warren and Wothers, Oxford University Press (2001)

Additional Reading:

• "Organic Synthesis: Strategy and Control", S. Warren and P. Wyatt, Wiley (2007).
• "Mechanisms of Organic Reactions", H. Maskill, Oxford University Press (1996)
• "Organic Synthesis", C. L. Willis and M. R. Wills, Oxford University Press (1996).
• "Organic Synthesis - The Disconnection Approach", 2nd Edition S. Warren and P. Wyatt, Wiley (2008).
• "Workbook in Organic Synthesis - The Disconnection Approach", S. Warren, Wiley (1982).
• "Advanced Organic Chemistry", F. A. Carey and R. J. Sundberg, Plenum/Rosetta (1997).