Introductory description

N/A

Module web page

Module aims

Outline syllabus

This is an indicative module outline only to give an indication of the sort of topics that may be covered. Actual sessions held may differ.

Revision lectures on aromaticity
Aromaticity, aromatic ions and annulenes, orbital explanation of aromaticity, cyclobutadiene (distortion), cyclooctatetraene. Electrophilic substitution, o, m, and para, directing, activating and deactivating groups in benzene.

Further chemistry of benzene derivatives
Halogenation, Freidel Crafts acylation and alkylation, sulfonation, formylation, ipso substitution. Sulfonation of naphthalene (kinetic verses thermodynamic), polyaromatics, C60
Electrophilic substitution reactions of disubstituted aromatics. Nucleophilic aromatic substitution, aryne formation.
Birch reduction, reduction of nitroaromatics, azo and diazonium salts and their transformations.

Deficient heterocycles
Pyridine, electrophilic substitution, nucleophilic substitution, pyridine-N-oxides, Chichibabin reaction. Electrophilic and Nucleophilic substitution of pyrimidines and quinolones. Synthesis of pyridines.

Excessive heterocycles
Pyrrole, substitution at N and C, furan, thiophene and reactions with electrophiles, cycloadditions Imidazole, Indole, reations with electrophiles. Synthesis of pyrrole, furan, thiophenes and indole

Saturated heterocycles and carbohydrates
Synthesis of 3-6 membered oxygen and nitrogen saturated heterocycles (lactones and lactams). Effect on rate of cyclisation of ring size (entropy and enthalpy). Synthesis of epoxides, aziridines and thiiranes, the bonding orbitals that form the ring
How ring strain dominates the reactivity of small rings (ring opening epoxides/penicillin
Acetonides/acetals as protective groups (synthesis and hydrolysis)

Organopalladium chemistry to make biaryl C-C bonds
Advantages/disadvantages compared to electrophilic aromatic substitution.
Pd(0) (electron rich) oxidative insertion into “electron poor” bonds via Pd complex.
Generation of the Pd(0) catalyst from Pd(OAc)2
Displacement of halide from complex by other organometallic coupling partner (Grignard organo zinc/tin/borate and how to make them
Reductive elimination to make C-C bond (or C-N with nitrogen nucleophiles).
Sonogashira coupling and Bergmann cyclisation
Generating aromatic systems from linear precursors

Making C–C bonds using Organometallics
Organometallic Reagents. Formation by deprotonation with strong bases, Grignard and alkyl lithium formation by oxidative insertion, halogen-metal exchange. Useful C–C bond formation by reacting organometallics with carbon dioxide, aldehydes/ketones, carboxylic acids, use of 1,3-dithianes.
Grignard Reagents. Synthesis by insertion. Reactions with formaldehyde, aldehydes and ketones, esters, nitriles, addition to enones in absence/presence of Cu(I).
Organozinc Reagents. Reformatsky reaction.
Organocopper Reagents. Synthesis by transmetallationand their use in conjugate additions, SN2-displacements, epoxide openings and reactions with acid chlorides.

Making C–C bonds using enolates
Enolate formation using strong bases, C- vs O-alkylation, thermodynamic vs kinetic enolate formation, alkylation of enolate anions, crossed-aldol reactions, stereocontrolled aldols with E- and Z-lithium and boron enolates, Zimmerman-Traxler transition states. Alternatives to enolates: enamines and silyl enol ethers (Mukaiyama aldol). Use of enolates to make rings: Dieckmann reaction, Robinson annulation.

Making C=C bonds
Wittig reaction including: formation of phosphonium ylids, cycloaddition mechanism, reactivity comparison with sulfur ylids, E-alkenes from stabilised ylids, Z-alkenes using non-stabilised ylids. Alternatives to the Wittig reaction including (i) Horner-Wadsworth-Emmons reaction to make E-alkenes, use of Arbuzov reaction to make phosphonate esters; (ii) Peterson reactions under acidic and basic conditions, (iii) Julia reaction of sulfone anions. Use of elimination reactions to make alkenes including (i) dehydrations; (ii) pyrolytic syn-eliminations involving esters, N-oxides, sulfoxides and selenoxides; (iii) from 1,2-diols (Corey-Winter).

Making C≡ C bonds
Corey-Fuchs reaction.

Functionalisation of alkenes
Oxymercuration/reduction. Hydration by hydroboration including mechanism, stereochemical issues, improved regio- and chemoselectivity with 9-BBN. Synthesis of C–C and C–N bonds using organoboranes.

Oxidation
Oxidation of Allylic C-H Bonds
Using selenium dioxide and singlet oxygen.
Important Methods for the Oxidation of Alcohols
Jones oxidation, PCC including allylic transposition with tertiary allylic alcohols, manganese dioxide for selective oxidation of allylic/benzylic alcohols, Dess-Martin periodinane, DMSO based oxidations including Swern and Corey-Kim procedures. DMSO based oxidation of C–X bonds.

Oxidative cleavage of alkenes
Using NaIO4 and cat. OsO4/NaIO4 (cf ozonolysis).

Reduction of C=O and C=N Bonds
Reduction of esters using lithium aluminium hydride and DIBAL, reduction of carboxylic acids using borane, use of sodium borohydride to reduce aldehydes/ketones, ‘exhaustive’ reduction of ketones to alkanes using (i) Clemmensen reduction, (ii) Wolff-Kishner, and (iii) dithioacetal

Reductive approaches to amine formation
Reduction of amides using LiAlH4 and borane, use of azides to make amines, reduction of C=N bonds using sodium cyanoborohydride.
Reduction of C–X Bonds
Reduction of halides and pseudohalides with LiAlH4, use of Appel reaction to prepare halides from alcohols.

Learning outcomes

By the end of the module, students should be able to:

• Differentiate the ring substituents on benzene into activating and deactivating, and ortho/para or meta directing.
• Understand the role hetero atoms play in the chemistry of heteroaromatic systems.
• Describe the synthesis and chemistry of aliphatic heterocyclic compounds.
• Understand how & when to use organopalladium chemistry in biaryl and alkyne aryl synthesis.
• Develop a solid grounding of the mechanisms of a wide range of organic chemical reactions and transformations.
• Learn to use software packages to search the chemical literature using key words, structural and partial structural queries to find reaction conditions to guide retrosynthetic analysis of target organic molecules and source spectral data and physical properties.
• Understand and apply a wide range of important chemical transformations of use in modern organic synthesis. As well as revision, further application of important organic reactions seen in year 1 and the exposure to a significant number of new reactions.
• Develop solutions to problems in organic chemistry using retrosynthetic analysis.

Indicative reading list

1. Organic Chemistry J. Clayden, N. Greeves, S. Warren, OUP, 2012 2nd Edn [CGWW].
   Further Reading

2. Mechanism in Organic Chemistry R. W. Alder, R. Baker, J. M. Brown Wiley, 1971. QD 1722.A5.

3. The search for organic reaction pathways P. Sykes Longman, 1972.

4. Advanced Organic Chemistry, J. March, 4th Edn., Wiley, 1992, QD 1722.M2.

5. Heterocyclic Chemistry, J. A. Joule, G. F. Smith, Reinhold.

6. Aromatic Chemistry, M. Sainsbury, Oxford University Press.

Research element

e.g. essay, dissertation, individual or group research, research skills activity, etc.

Subject specific skills

Problem solving
Teamwork
Organisation and time management

Transferable skills

Problem solving
Teamwork
Organisation and time management