The University of Southampton

CHEM6004 Advanced Organic Reactions

Module Overview

Aims and Objectives

Module Aims

The aim of this course is to introduce synthetic organic methods in which other elements play a key role, in particular Boron, Lithium, Lanthanides 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. Additions to carboxylic esters, acids and amides. Additions to alkenes including ketene dithioacetals, Michael additions and intramolecular additions to unpolarised alkenes, alkynes and allenes (including the stereochemical course of such reactions and key differences between these and classical radical cyclisation methodologies). 1,2- and 2,3-Wittig rearrangements of benzylic, propargylic and allylic ethers. 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. Lanthanum(III) salts as Lewis acids in Friedel Crafts alkylation and acylation reactions, aldol type reactions, 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 Transition Metals Introduction to transition metal chemistry. Counting electrons and determining formal oxidation states of the metal. Why unique reactivity possible for transition metal complexes. Advantages over p-block chemistry. Alkene metathesis and related reactions. Ring Opening Metathesis Polymerisation. Ring Closing metathesis (RCM), Cross metathesis. Enyne metathesis. Alkyne metathesis. Chromium Arene chemistry. Formation; stabilization of aryl anions, and benzyl-anions and -cations; Addition / elimination reactions of substituted chromium arene complexes; Stereochemical consequences of arene coordination to chromium. Chromium carbene complexes: Formation; alkylation chemistry; as source of ketenes (ß-lactam formation); Dotz benzannulation. Palladium catalysed reactions. Typical catalysts and ligands. Fundamental reactions types (oxidative insertion; reductive elimination; ?-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. Access to allylpalladium chemistry via carbopalladation; Trimethylenemethane; Metallo-ene reaction. Palladium catalysed carbonylations . Cobalt Chemistry. Nicholas, Pauson-Khand and [2+2+2] cyclisation reactions. Titanium and zirconium chemistry. Use as selective nucleophiles. Exhaustive methylation. Hydrozirconation. Titanium catalysed hydromagnesiation. Zirconium catalysed carboalumination. Ziegler-Natta polymerization. Titanocene carbene complexes, and use to alkenylidenate esters. Low valent titanium and the McMurry reaction. Ti(III) induced radical reactions of epoxides. Use of titanium and zirconium ?²-bound intermediates. Formation by ligand exchange and C-H activation (cyclometallation). Co-cyclisation reactions. Benzyne and ?²-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

Comprehensive Organometallic Chemistry series I and II. 

M. Schlosser. Organometallics in Synthesis. 

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

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

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

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

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

A.J.Pearson. Metallo-organic Chemistry. 



MethodPercentage contribution
Examination  (2 hours) 100%


MethodPercentage contribution
Examination  (2 hours) 100%

Linked modules

Pre-requisites: CHEM3025 Advanced Chemistry II For Students On Placement – Distance Learning 2016-17, CHEM3041 Synthetic Methods In Organic Chemistry 2016-17

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