Synthetic Methods in Organic Chemistry

Learning Outcomes

Learning Outcomes

Having successfully completed this module you will be able to:

• Describe different organometallic reagents. They should be able to discuss their relative reactivities, methods of preparation, and applications in synthesis.
• Describe different approaches to the formation of carbanions, discuss their structures, stabilities/reactivities and applications in synthesis.
• Illustrate how sulfones, phosphonium ylides and phosphonate can be used in synthesis for stereoselective olefination, and rationalise selectivity outcomes using stereoselectivity models.
• Recognise situations where reactions may have different stereochemical outcomes, and be able to explain and/or predict the selectivity using appropriate stereoselectivity models.

Carbon-carbon bond forming reactions lie at the heart of organic synthesis. Various methods for carbon-carbon bond formation will be covered, and their importance illustrated by examples taken from the literature where synthetic and natural organic compounds possessing useful properties (e.g. pharmacological activity) have been targeted. In presenting synthetic methods, principles of selectivity will be emphasised e.g. chemoselectivity, regioselectivity and stereoselectivity. The course will build understanding of factors controlling aspects of selectivity for reactions of anions, radicals and pericyclic reactions. Carbanions in Synthesis. Formation of carbon-carbon bonds using carbanions: Methods for the formation of organolithium and organomagnesium compounds (including directed lithiation and dianions). Introduction to structure and reactivity of organolithium compounds (basic overview of solution structures and information from x-ray crystal structures). Selective methods in synthesis by controlling reactivity of organometallic species through choice of metal (e.g. organocopper, organocerium, and organozinc chemistry). Stereocontrolled formation of C-C double bonds using sulfur-stabilised and phosphorus-stabilised carbanions (Julia olefination, Wittig olefination, and use of phosphonate reagents). Stereoselectivity models: Felkin-Ahn and Chelation control models to account for stereoselectivity of addition to aldehydes and ketones containing adjacent chiral centres. Regio- and stereocontrolled enolate formation, and stereoselective additions of enolates to aldehydes (syn/anti selectivity in the aldol reaction). Chiral auxiliaries (Evans) used to carry out stereoselective alkylation of enolates. Radical reactions: Formation of carbon-carbon bonds using radicals: tin-mediated intermolecular additions, intramolecular cyclisations and tandem and cascade processes. Baldwin’s guidelines for cyclisation reactions are discussed. Organopalladium Chemistry: Formation of carbon-carbon bonds using organopalladium catalysis: Cross coupling (including Buchwald-Hartwig); Sonogashira; Heck Reaction; Allyl palladium chemistry. Frontier Molecular Orbital (FMO) control of pericyclic reactions. FMO’s and orbital symmetry control of pericyclic reactions: Diels-Alder-, 1,3-dipolar- and related 6e cycloadditions. [6+4] and [8+2] cycloadditions. Photochemical selection rules and cycloadditions; Concerted electrocyclic ring opening and closure reactions (stereochemistry). Sigmatropic rearrangements (1,n-hydrogen and alkyl shifts, Claisen, Cope, Sommelet and Wittig rearrangements). Reactivity, regiochemistry, and stereochemistry in the Diels-Alder and related reactions. Periselectivity.

Lectures and workshops. Some on-line resources provided on Blackboard including recorded lectures and worked examples.

Summative

This is how we’ll formally assess what you have learned in this module.