The University of Southampton

CHEM6004 Advanced Organic Reactions

Module Overview

Aims and Objectives

Module Aims

The aims of the module are: The aim of this course is to introduce synthetic organic methods in which other elements play a key role, in particular Boron, Lithium, Lanthanides, Sulfur, Phosphorous, Silicon and Transition metals. The mechanisms of the various reactions are emphasised, together with prediction of any stereo- or regio-chemical consequences.

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 organometallic reagents in a key transformation;
  • Apply chemistry involving main group and transition metallic reagents to the synthesis of complex organic compounds;
  • Justify the selection of one organometallic 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. Lithium, Boron and Lanthanum Reagents in Organic Synthesis. 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 alkyl-lithiums. Influence of Lewis basic groups on the stability and reactivity of alkyllithiums. Retention versus inversion of configuration in their reactions and the importance of the HSAB principle. Homochiral additives, focussing on the use of (–)-sparteine for the resolution of racemates and an introduction to the principle of dynamic kinetic resolution. O'Brien's reagent. Organolithiums 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 or 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. Diels Alder and hetero- Diels Alder cycloadditions. Radical-anion crossover reactions mediated by samarium diiodide. Also included is the concept of radical-cation crossover reactions exemplified with the reactions of manganese triacetate and a revision of key concepts associated with 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. Organic Synthesis using Sulfur, Phosphorous and Silicon reagents. Silicon chemistry. General features: bond strengths/lengths, charge stabilisation (ß-cations, a-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 a-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, desulfurisation of episulfides (Eschenmoser sulfide contraction), inversion of alkene geometry via epoxides, 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 a carbanions by sulfur; dithiane formation, alkylation and hydrolysis (Hg(II)/H2O); sulfur ylides: epoxidation and cyclopropanation; Pericyclic reactions: allyl sulfoxide–allyl sulfenate ester; SO2 addition to dienes and the reverse; syn-elimination of sulfoxides; 2,3-sigmatropic reactions of sulfur ylids. Stabilisation of anions by sulfoxides and sulfones sulfones, Alkene synthesis via Julia coupling and Ramberg–Bäcklund reaction. Pummerer rearrangement; sulfonyl hydrazone chemistry (Shapiro, Kishner, abnormal Kishner, Bamford-Stevens; alkenes by elimination (ketone to a,ß-unsaturated ketone (PhSSPh/PhSeSePh) and from alcohol (Grieco). 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

Preparation for scheduled sessions72
Follow-up work40
Total study time150

Resources & Reading list

John Hartwig. Organotransition Metal  Chemistry: From Bonding to Catalysis. 

L.S. Hegedus. Transition metals in the synthesis of complex molecules. 

S.G.Davies. Organotransition Metal Chemistry: Applications to Organic Synthesis. 

A.J.Pearson. Metallo-organic Chemistry. 

M. Schlosser. Organometallics in Synthesis. 

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

J.P.Collman. Principles and Applications of Organotransition Metal Chemistry. 

Comprehensive Organometallic Chemistry series I and II. 



MethodPercentage contribution
Examination  (2 hours) 100%


MethodPercentage contribution
Examination  (2 hours) 100%

Linked modules

CHEM3041 or CHEM3025

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