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The University of Southampton

CHEM6004 Advanced Organic Reactions

Module Overview

Aims and Objectives

Learning Outcomes

Learning Outcomes

Having successfully completed this module you will be able to:

  • Understand a range of more sophisticated approaches to synthesis (building on the knowledge from previous years) that exploit the properties of other elements (particularly phosphorous, sulphur, silicon, boron, lithium, lanthanides and certain transition metals)
  • Apply chemistry involving main group and transition metallic reagents to the synthesis of complex organic compounds;
  • Justify the selection of one reagent over another in terms of efficacy in relation to a particular synthetic problem;
  • Predict reaction pathways and outcomes on the basis of mechanistic understanding.


The syllabus, which is described in outline below, is aligned with the following QAA benchmark statements for chemistry at FHEQ Level 7 (Masters). • to extend students' comprehension of key chemical concepts and so provide them with an in-depth understanding of specialized areas of chemistry; • to develop in students the ability to adapt and apply methodology to the solution of unfamiliar types of problems; • to instil a critical awareness of advances at the forefront of the chemical science discipline; • to prepare students effectively for professional employment or doctoral studies in the chemical sciences; • the ability to adapt and apply methodology to the solution of unfamiliar problems; • knowledge base extends to a systematic understanding and critical awareness of topics which are informed by the forefront of the discipline; • problems of an unfamiliar nature are tackled with appropriate methodology and taking into account the possible absence of complete data. Organolithium reagents in organic synthesis. General summary of reactivity including choice of solvent, aggregate formation and impact, hazards, commercial organolithium reagents and how to assess their molarity. Preparation of organolithium reagents by reductive metallation (using Li, LN etc.), deprotonation (pKa and directed metallations), halogen - metal exchange, transmetallation and the Shapiro reaction. Stereochemical issues - configurational stability / lability of vinyl- and alkyllithium reagents. Influence of Lewis basic groups on the stability and reactivity of alkyllithium reagents. Retention versus inversion of configuration in their reactions and the importance of the HSAB principle. Organolithium reagents in synthesis. Applications of organolithium chemistry in total synthesis. Lanthanum reagents in organic synthesis. Organolanthanum complexes as non-basic, polar (hard) organometallics. Advantages compared to organolithium and Grignard reagents. Reactions with ketones, unsaturated ketones (c.f. RMgBr and R2CuLi), esters, unsaturated esters, lactones and carbon-nitrogen multiple bonds, including stereochemical issues and applications. Radical-polar crossover reactions. The concept of radical-polar crossover reactions is introduced and exemplified with reactions mediated by samarium diiodide and manganese triacetate. This section also includes a revision of key concepts in radical reactions. Organoboron chemistry. Borane, its structure and use in the preparation of organoboranes. Sequential hydroborations, regiospecificity and stereochemical issues. Use in functional group inter-conversions. Reduction of alkenes and alkynes, alkenes to haloalkanes (anti-Markovnikov), hydration of alkenes (anti-Markovnikov). Dummy ligands (thexyl and 9-BBN). Carbon-to-carbon bond formation by Michael addition / radical formation and carbonylation reactions. Organoboranes to ketone and 3°alcohols; haloalkyne to trans-alkenes and ketones, sp² – sp² coupling reactions. Silicon chemistry. General features: bond strengths/lengths, charge stabilisation (β-cations, α-anions), substitution chemistry. Reminder of use as a protecting group and in silyl enol ethers, and extension to acyloin reaction and silyl ketene acetals. Carbon-bound silanes: vinyl silanes (preparation from alkynyl silanes or using the Shapiro reaction), electrophilic substitution of vinyl silanes (retention or inversion), epoxy silanes [preparations and reactions at α-position (hydrolysis)], allyl silanes (preparations and allylation reactions); Peterson reaction. Phosphorus chemistry. General features; preparation of C–P bonds; nucleophilicity of P(III) reagents: phosphonium salts, Arbuzov reaction (phosphonates), Perkow reaction (enol phosphates); Corey–Winter reaction, Staudinger (azide to amine); Mitsunobu inversion; alkene synthesis: Wittig olefination and Schlosser modification, Horner–Wadsworth–Emmons reaction, Still-Gennari reaction. Sulfur (& Selenium) chemistry. General features: oxidation levels, nucleophilicity; electrophilic sulfur reagents (chiral sulfinate). Reminder of stabilisation of α carbanions by sulfur; dithiane formation, alkylation and hydrolysis (Hg(II)/H2O); sulfur ylides: epoxidation and cyclopropanation; Stabilisation of anions by sulfoxides and sulfones, Alkene synthesis via Julia coupling and Ramberg–Bäcklund reaction. Pummerer rearrangement; alkenes by elimination (ketone to α,β-unsaturated ketone (PhSSPh/PhSeSePh) Organic Synthesis Using Transition Metals Alkene metathesis and related reactions. Ring Opening Metathesis Polymerisation. Ring Closing metathesis (RCM), Cross metathesis. Enyne metathesis. Alkyne metathesis. Palladium catalysed reactions (mostly synoptic). Typical catalysts and ligands. Fundamental reactions types (oxidative insertion; reductive elimination; beta-hydride elimination; alkene and alkyne activation; carbometallations). Palladium catalysed cross couplings (mechanisms, and scope and limitations for each component; Stille; Negishi; Sonagashira; Buchwald/Hartwig C-N bond formation; C-O, C-P, C-Sn, and C-B bond formation; Suzuki cross coupling of boronates). Palladium catalysed additions to alkenes and alkynes: Heteronucleophile addition (O, N, including intramolecular), Wacker oxidation; Heck reaction including tandem processes; Heck combined with cross coupling; Pd-R and Pd-H initiated cyclisations. Allyl palladium chemistry: Palladium catalysed allylic displacements including asymmetric examples and the use of carbonates and alkenyl epoxides as precursors. Oxidative additions across dienes. Palladium catalysed carbonylations. Cobalt Chemistry: Pauson-Khand and [2+2+2] cyclisation reactions. Titanium and zirconium chemistry. Hydrozirconation. Titanium catalysed hydromagnesiation. Zirconium catalysed carboalumination. Ziegler-Natta polymerization. Low valent titanium and the McMurry reaction. Use of titanium and zirconium bound intermediates. Formation by ligand exchange and C-H activation (cyclometallation). Co-cyclisation reactions. Benzyne and imine complexes of zirconium. Elaboration of zirconacycles - carbonylation, carbenoid insertion, and via transmetallation to copper and nickel. Titanium and zirconium catalysed reactions: ethylmagnesiations, co-cyclisations, cyclocarbonylations

Learning and Teaching

Teaching and learning methods

Teaching methods: Lectures, directed reading, Problem classes, BlackBoard online support. Learning methods: Independent study, student motivated peer group study, student driven tutor support

Follow-up work40
Preparation for scheduled sessions60
Total study time150

Resources & Reading list

S.E.Thomas (1991). Organic Synthesis: The Roles of Boron and Silicon, Oxford Primer. 

J.Clayden, N. Greeves and S. Warren (2012). Organic Chemistry. 

John Hartwig. Organotransition Chemistry: From Bonding to Catalysis. 

Robert H. Crabtree. The Organometallic Chemistry of the Transition Metals. 



MethodPercentage contribution
Examination  (2 hours) 100%


MethodPercentage contribution
Examination  (2 hours) 100%

Repeat Information

Repeat type: Internal & External

Linked modules

CHEM3041 or CHEM3025

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