Control and Selectivity in
Molecular Synthesis
Module Handbook
2024 – 2025
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Control and Selectivity in Molecular
Synthesis
Module Handbook
2024 – 2025
Contents
1 Module Team ......................................................................................................................................... 2
2 Module Summary ................................................................................................................................... 3
3 Course Aims / Learning Objectives......................................................................................................... 3
4 Lectures / Tutorials / Scheduling............................................................................................................ 7
5 Assessment ............................................................................................................................................ 7
1 Module Team
Module Leader:
Professor Chris Braddock (DCB)
c.braddock@imperial.ac.uk
Module Lecturers:
Professor Chris Braddock (DCB)
Professor Donald Craig (DC)
Dr Reuben White (RMW)
Professor James Bull (JAB)
c.braddock@imperial.ac.uk
d.craig@imperial.ac.uk
reuben.white@imperial.ac.uk
j.bull@imperial.ac.uk
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2 Module Summary
Welcome to this course on Control and Selectivity in Molecular Synthesis. The course will further develop
your understanding of Organic Synthesis building on your year one modules of Language of Chemistry
and Reactivity at Carbon Centres. The key themes running through these lectures will be on control of
chemical reactions and how to achieve (chemo-, regio-, and/or stereo-) selectivity. We will start with an
introduction to synthesis and then introduce the new concept of 'retrosynthesis' which will help you
when planning a synthetic sequence. We will look at the synthesis of polar organometallic reagents and
their (chemo-, regio-, and/or stereo-) selective reactions with carbonyl groups. We will revisit oxidation
and reduction chemistries from year one and expand your chemical toolkit of reagents, with an emphasis
on selectivity as underpinned by mechanistic understanding. We will revisit enolates and note their preeminent position as nucleophilic intermediates for carbon-carbon bond formation, and we will see new
methods for the formation of carbon-carbon double bonds. We will extend your understanding of
aromatic compounds by considering aromatic ring systems with a heteroatom in the ring
('heteroaromatics') and see also that the Diels-Alder reaction is not alone as a carbon-carbon bond
forming reaction that can simply be achieved by thermal methods. Finally, we will show you state-ofthe art chemical syntheses of complex organic molecules of biological relevance and you will be amazed
by how much you will understand!
3 Course Aims / Learning Objectives
Learning Outcomes:
Lecture 1:
 Define and identify different types of selectivity;
 Describe selectivity with regard to different electrophile types;
 Identify structural features that can influence 1,2-, vs 1,4 addition to enones (direct vs
conjugate addition);
 Describe kinetic vs thermodynamic control.
Lecture 2:
 Define retrosynthesis and the terms used in retrosynthetic analysis;
 Choose good disconnections based on some general guidelines;
 Recognise synthons of natural (and non-natural) polarity and identify their synthetic
equivalents;
 Apply the mechanics of retrosynthesis to one-group and two group C-C disconnections and
recognise the corresponding forward reactions;
 Define functional group interconversion and explain its role in synthetic tactics.
Lecture 3:
 Know the synthetic protocols to polar organometallic compounds, R-Li and R-MgX, and
subsequent transmetallation routes to access other R-M compounds of less electropositive
metals;
 Understand the factors influencing the basicity of organolithium (R-Li) and Grignard (R-MgX)
reagents using pKa as a proxy;
 Appreciate the thermal stability and solvent compatibility of polar carbanion equivalents;
 Understand the reactivity of these anions as nucleophiles, especially in C-C bond formation,
and appreciate potential side reactions;
 Understand increased reaction selectivity afforded by organocuprate and organozinc reagents
based on bond polarity and hard/soft characteristics;
 Appreciate that diminished R-M reactivity leads to greater functional group tolerance.
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Lecture 4:
 Understand the factors that control chemoselective and regioselective addition of a given
nucleophile to a carbonyl derivative;
 Use the Felkin-Anh model to predict the major diastereoisomer of addition of a nucleophile to
an α-chiral carbonyl.
Lecture 5:
 Appreciate the main classes of reducing agents available for functional group interconversion;
 Recognise the need for different reagents to reduce various carbonyl and carboxylic acid
derivatives;
 Select an appropriate reagent for the reduction of various carbonyl and carboxylic acid
derivatives to a given product;
 Be able to explain, at the level of your colleagues, the mechanistic rationale underpinning any
issues of selectivity in the reaction.
Lecture 6:
 Recognise the different modes of reduction of alkynes, alkenes and aromatics;
 Select an appropriate reagent for the selective reduction of alkynes, alkenes and aromatics;
 Be able to explain, at the level of your colleagues, the mechanistic rationale underpinning any
issues of selectivity in the reaction.
Lecture 7:
 Recognise the different modes of oxidation of alkenes;
 Select an appropriate reagent for the oxidation of an alkene to a given product;
 Be able to explain, at the level of your colleagues, the mechanistic rationale underpinning any
issues of selectivity in the reaction.
Lecture 8:
 Recognise the commonality of mechanism for the oxidation of alcohol and carbonyl groups
using high oxidation state reagents;
 Select an appropriate reagent for the oxidation of alcohols and carbonyls to a given product;
 Be able to explain, at the level of your colleagues, the mechanistic rationale underpinning any
issues of selectivity in the reaction.
Lecture 9:
 Understand the factors that control enolate reactivity;
 Suggest different forms of enolate-equivalent reagents for use with different electrophiles,
based on their properties;
 Explain the stereoelectronic requirements for enolate formation.
Lecture 10:
 Suggest and explain reaction conditions for the regioselective formation of enolates, by
deprotonation at either at less hindered (kinetic) or more hindered (thermodynamic) positions;
 Suggest occasions for the formation and use of other milder activating groups (enamines, or
1,3-dicarbonyls) which react at less substituted positions controlled by pKa/steric hindrance;
 Understand the outcome of the reaction of extended enolates;
 Explain the reactivity of di-enolates (dianions).
Lecture 11:
 Explain the stabilisation of anions stabilised at the alpha position of S, P and Si functional
groups;
 Describe the reactivity of these alpha-anions as nucleophiles;
 Suggest and explain reaction conditions for the stereoselective formation of alkenes (C=C);
 Determine the stereoselectivity outcome in alkene formation, given a set of reaction
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conditions, for the different double bond forming reactions covered.
Lecture 12:
 Recognise the major heteroaromatic structural types and be aware of their significance in
pharmaceuticals, agrochemicals and materials;
 Understand the aromaticity of heteroaromatics in terms of their structures, bonding and
electronic configurations;
 Recognise the oxidation level of carbon atoms in heterocyclic systems, including
heteroaromatics;
 Devise syntheses of pyrroles, furans and thiophenes from carbonyl-containing starting
materials;
 Understand and predict the reaction outcomes of heteroaromatics in SEAr, electrophilic
addition, cycloaddition and metallation processes.
Lecture 13:
 Devise syntheses of indoles, pyridines and quinolines from carbonyl-containing starting
materials;
 Understand and predict the reaction outcomes of these heteroaromatics in SEAr, electrophilic
addition, cycloaddition and metallation processes.
Lecture 14:
 Recognise pericyclic reactions as key carbon–carbon bond-forming transformations in organic
synthesis;
 Appreciate the stereospecificity and stereoselectivity of thermal pericyclic processes;
 Predict reaction outcomes and stereoselectivity based on knowledge and understanding
of pericyclic processes.
Lecture 15:
 There are no specific ILOs for this lecture, but the case studies will highlight aspects of chemo-,
regio- and stereo- selectivity, and demonstrate the use of reagents you have come across
before in a complex synthetic setting.
Module Content:
L1: Introduction, electrophile types, and kinetic vs thermodynamic control (JAB)
L2: Introduction to retrosynthesis & functional group interconversion (DCB)
L3: Polar organometallic reagents (RMW)
L4: Selective reactions of organometallic reagents with carbonyl derivatives (DCB)
L5: Reduction of carbonyl and carboxylic acid groups (DCB)
L6: Reduction of C–C multiple bonds (DCB)
L7 and L8: Oxidation of alkenes / oxidation of alcohol and carbonyl groups (DCB),
L9: Control of enolate reactivity (JAB)
L10: Regioselective enolate formation (JAB)
L11: Ylides and anions for controlled alkene synthesis (JAB)
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L12: Synthesis and reactions of electron-rich heteroaromatics (DC)
L13: Synthesis and reactions of electron-poor heteroaromatics (DC)
L14: C–C bond forming reactions promoted by heat (DC)
L15: Case study in synthesis (JAB, DC & DCB)
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4 Lectures / Tutorials / Scheduling
This course is delivered in the Autumn Term, with assessment by examination in January.
The 14 examinable lectures in this module are timed at two per week starting in week 2 of Term,
thereby finishing in week 8 and allowing consolidation of the material in weeks 9-11.
Your five organic tutorials in this term in weeks 3, 5, 7, 9 & 11 are devoted to this module (although
your tutor may well also explore aspects of organic NMR spectroscopy with you too).
There are also four workshops in weeks 4, 6, 8 & 10 to support this module. The workshops are
delivered by the module team members.
Course Scheduling
Week Lectures
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Tutorial/
Workshop
Content Covered
Assessment
Welcome week
2xL
2xL
2xL
2xL
2xL
2xL
2xL
1xL
Selectivity; Retrosynthesis
T
W
T
W
T
W
T
W
T
Organometallic Reagents; Reaction with Carbonyl derivatives
Reductions of Organic Functional Groups
Oxidations of Organic Functional Groups
Enolate chemistry
Alkene synthesis; Heteroaromatics
Heteroaromatics; Thermal C-C bond formation
Case study (non-examinable)
CHRISTMAS VACATION
Exam
5 Assessment
The module is assessed by examination in January. Specimen/past papers with outline answers can be
found in the module folder on blackboard. Working knowledge from previous organic chemistry
modules (Language of Chemistry, Reactivity at Carbon Centres) will be assumed.
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