Carbon-carbon bond forming reactions lie at the heart of organic synthesis. In this course we will cover methods for carbon-carbon bond formation using carbanions and radicals, and through thermally and photochemically induced pericyclic processes. The significance and importance of the reactions discussed will be illustrated by examples taken from the literature, including applications to synthetic and natural organic compounds possessing useful properties (e.g. pharmacological activity). An overarching theme will be selectivity (e.g. chemoselectivity, regioselectivity and stereoselectivity), and the factors controlling aspects of selectivity for reactions of anions, radicals and pericyclic reactions.
CHEM3038 or CHEM6095.
Aims and Objectives
Having successfully completed this module you will be able to:
- Appreciate when a radical addition reaction is likely or unlikely based on nature of the radical intermediate and the radical acceptor.
- Illustrate how sulfones, phosphonium ylides and phosphonate can be used in synthesis for stereoselective olefination, and rationalise selectivity outcomes using stereoselectivity models.
- Delineate the mechanistic and stereochemical course of some sophisticated cascade radical reactions and appreciate their value in target oriented synthesis.
- 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.
- Appreciate the class of pericyclic reactions and be able to identify them and draw mechanisms.
- Understand how the energy levels and orbital coefficients of components affect the rates and regiochemistry of cycloaddition reactions.
- Appreciate problems associated with the use of organotin reagents and some of the ‘get rounds’ available.
- Apply their detailed knowledge of radical chain reactions to rationalise the outcome of previously unseen examples of this genre.
- Recognise situations where reactions may have different stereochemical outcomes, and be able to explain and/or predict the selectivity using appropriate stereoselectivity models.
- Use FMO theory to show that some pericyclic rections are allowed, others not, and that some have to take place with specific stereochemical consequences.
- Describe different approaches to the formation of carbanions, discuss their structures, stabilities/reactivities and applications in synthesis.
- Student should be able to plan syntheses using carbanions as nucleophiles or as precursors in palladium-catalysed C—C bond-forming reactions.
- Describe stereoselectivity models for a variety of reactions including additions carbonyl compounds and enolate formation, and apply fundamental concepts such as conformational, steric and stereo electronic effects in rationalising stereochemical outcomes.
- Describe different organometallic reagents. They should be able to discuss their relative reactivities, methods of preparation, and applications in 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.
- Appreciate the likely course of a radical addition reaction when myriad options are, in principle, available (e.g. in casdade radical reactions).
- Describe the importance of kinetics and bond strength on the outcome of a radical chain reaction.
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.
Learning and Teaching
Teaching and learning methods
Lectures and workshops. Some on-line resources provided on Blackboard including recorded lectures and worked examples.
|Preparation for scheduled sessions||40|
|Total study time||150|
Resources & Reading list
I. Fleming (1998). Pericyclic Reactions. Oxford Chemistry Primers, OUP.
A J Kirby (1996). Stereoelectronic Effects. OUP Oxford Chemistry Primers.
I. Fleming (1976). Frontier Orbitals and Organic Chemical Reactions. Wiley.
I. Fleming (2009). Molecular Orbitals and Organic Chemical Reactions Student Edition. Wiley.
F A Carey and R J Sundberg (1990). Advanced Organic Chemistry A and B. Oxford: Plenum.
Clayden, Greeves, Warren and Wothers (2001). Organic Chemistry. Oxford University Press.
Gilchrist and Storr (1979). Orbital Reactions and Orbital Symmetry. Cambridge University Press.
This is how we’ll formally assess what you have learned in this module.
This is how we’ll assess you if you don’t meet the criteria to pass this module.