Synthetic Methods in Organic Chemistry

Learning Outcomes

Learning Outcomes

Having successfully completed this module you will be able to:

• Appreciate problems associated with the use of organotin reagents and some of the ‘get rounds’ available.
• Appreciate the class of pericyclic reactions and be able to identify them and draw mechanisms.
• Illustrate how organosulfur compounds can be used in synthesis, with a focus on C—C bond formation and olefination.
• Describe several groups of organosulfur compounds (e.g. thioethers, sulfoxides, sulfones, and dithianes) and their structures. They should be able to discuss their reactivities, and methods of preparation.
• Describe the importance of kinetics and bond strength on the outcome of a radical chain reaction.
• Student should be able to plan syntheses using carbanions as nucleophiles or as precursors in palladium-catalysed C—C bond-forming reactions.
• Appreciate the likely course of a radical addition reaction when myriad options are, in principle, available (e.g. in casdade radical reactions).
• Use FMO theory to show that some pericyclic rections are allowed, others not, and that some have to take place with specific stereochemical consequences.
• Recognise the stabilisation of carbanions alpha to sulfenyl, sulfinyl and sulfonyl groups, and be able to explain the origins of the stabilisation.
• Understand how the energy levels and orbital coefficients of components affect the rates and regiochemistry of cycloaddition reactions.
• Apply their detailed knowledge of radical chain reactions to rationalise the outcome of previously unseen examples of this genre.
• Describe different approaches to the formation of carbanions, discuss their structures, stabilities/reactivities and applications in synthesis.
• Describe stereoselectivity models for a variety of reactions including additions carbonyl compounds and enolate formation
• Appreciate when a radical addition reaction is likely or unlikely based on nature of the radical intermediate and the radical acceptor.
• Describe the concept of chiral auxiliaries and their application in diastereoselective alkylation reactions. They should be able to explain the origins of the observed diastereoselectivity.
• Delineate the mechanistic and stereochemical course of some sophisticated cascade radical reactions and appreciate their value in target oriented synthesis.
• Describe the mechanistic course of various palladium catalysed coupling reactions (including Heck, Sonogashira, Negishi, Kumada Corriu, Stille, Suzuki etc.) and appreciate their value in synthesis.

Carbon-carbon bond forming reactions and functional group transformations represent two crucial areas of organic synthesis. In presenting modern methods and describing new reagents, principles of selectivity will be emphasised e.g. chemoselectivity, regioselectivity and various aspects of stereoselectivity.

The importance of various carbon-carbon bond-forming processes will be illustrated by examples taken from the literature. Cyclisation reactions will be discussed in detail, with reference to synthetic and natural organic compounds possessing useful properties (e.g. pharmacological activity).

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 using reactivity of other carbanions (e.g. organocopper, organolanthanide, organozinc chemistry). Applications in synthesis, some brief and basic structural discussion of solution structures and additive effects).

Other stabilised carbanions: introduction to sulfur-stabilised carbanions in synthesis: umpolung and Julia olefination. P-stabilised anions in olefination, selective alkene synthesis.

Stereoselectivity models: Felkin-Ahn and Chelation control explanation for stereoselectivity of addition to aldehydes and ketones. 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.

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.

Teaching and learning methods

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

Resources & Reading list

Textbooks

A J Kirby (1996). Stereoelectronic Effects. OUP Oxford Chemistry Primers.

Clayden, Greeves, Warren and Wothers (2001). Organic Chemistry. Oxford University Press.

I. Fleming (1976). Frontier Orbitals and Organic Chemical Reactions. Wiley.

Gilchrist and Storr (1979). Orbital Reactions and Orbital Symmetry. Cambridge University Press.

I. Fleming (1998). Pericyclic Reactions. Oxford Chemistry Primers, OUP.

F A Carey and R J Sundberg (1990). Advanced Organic Chemistry A and B. Oxford: Plenum.

I. Fleming (2009). Molecular Orbitals and Organic Chemical Reactions Student Edition. Wiley.

Summative

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

Referral

This is how we’ll assess you if you don’t meet the criteria to pass this module.