The aim of the course 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 retrosynthetic approach is then developed, enabling students to devise syntheses of a range of target molecules. Concurrently, the basic concepts and techniques of physical organic 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 modern 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.

Organic synthesis and reactions (20 lectures)

• 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

• Stereochemistry from chair-like transition states
• Making γ,δ-unsaturated carbonyl compounds
• What determines whether these pericyclic reactions go &# 8216;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

• 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, medi um and large rings can be made in this way
• Double bond geometry can be controlled
• Using fragmentations in synthesis

• 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.       ;

• Stereospecific eliminations reactions      

• Wittig, Peterson and Julia reactions        

• Reduction of alkynes        

o Disconnections, synthons, synthetic equivalents, target molecules         

o Chemoselectivity· Functional group interconversion       
  

o C-X disconnections: one and two group disconnections.         

o C-C bond disconnections: One group disconnections, Two group disconnections:         

o 1,X-dioxygenated systems (X = 1,3,5) and natural reactivity.        

o 1,2 and 1,4 disconnections and Umpolung reactivity        

Physical organic chemistry (12)

o SN2, SN1         

o E1, E2, E1cb        

o Electrophilic addition and substitution reactions        

o Nucleophili
c substitution at carbonyls         

o Revision of basic thermodynamics: DGo = -RTln(K) = DHo - TDSo        

o Acid-base equilibria: pKa of common acids         

o Reaction coordinate, transition state, microscopic reversibility        

o Connection between equilibrium and rate constants K = k1/k-1        

o Hammond's postulate         

o Thermodynamic v
s. kinetic control         

o Curtin-Hammett principle         

o Revision of elementary kinetics         

o Multistep reactions, bottlenecks, rate determining step and steady state 


approximation, connection with free energy diagrams          

o Primary deuterium kinetic isotope effect        

o Substituent constants     

o Correlation of rates and reaction constants    
o Correlation of equilibria and reaction constants     
o Physical basis of LFER     

This module consists of 32 50-minute lectures to be in the first semester.  The material presented at the lectures is supported by four 1-hour tutorials (common to CHEM331) given fortnightly.  Four sets of assignment problems, the first two common to CHEM331, will also be provided, the solutions to be worked through later in lectures.  The last two assignments for CHEM333 are challenging, requiring quantitative application of physical concepts and retrosynthetic analysis.

 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).