Chemistry with Medicinal Chemistry-4H
Class Head: Prof. D.J. Robins
Course Documentation
Title: Medicinal Chemistry
Lecturer(s): Prof D J Robins
Aims: To provide an introduction to medicinal chemistry necessary to follow selected case histories
of the development of b1 -blockers, anti-asthmatics, and anti-ulcer drugs.
Objectives:
1. Understand the importance of enzymes, enzyme inhibitors and receptors.
2. Know about drug access and prodrugs.
3. Know about the different receptors involved in the sympathetic nervous system.
4. Be able to describe the development of propranolol and cardioselective b-blockers from
isoprenaline with their clinical effects and side effects.
5. Know about the synthesis of b-blockers in optically active form together with chemical and
spectroscopic methods for their identification.
6. Be able to discuss the development of salbutamol as an antiasthmatic drug, including
synthesis in optically active form plus chemical and spectroscopic methods used for its identification.
7. Know how understanding of histamine H2-receptors led to the discovery of the anti-ulcer
drugs cimetidine and ramitidine.
8. Be able to discuss the synthesis, chemistry and spectroscopic characteristics of anti-ulcer
compounds.
Outline:
Enzymes as catalysts, neurotransmitters such as acetylcholine, noradrenaline, dopamine and
histamine. Different types of receptors. Enzyme kinetics and inhibition. Enzyme substrates as drugs
- Parkinson’s disease. Enzyme inhibitors as drugs - irreversible, competitive and non-competitive
inhibitors. Drug access, lipophilicity, metabolism, drug formation, synthesis of analogues and
prodrugs such as aspirin and paracetamol. Sympathetic nervous system, a, b1, b2 receptors.
Isoprenaline as lead compound. Development of pronethalol, propranolol and cardiosselective b-
blockers such as practolol. Structure/activity relationships, synthesis of b-blockers in optically active
form, spectroscopy and chemical tests, clinical effects and side effects. Development of salbutamol as
a selective b2-stimulant bronchodilator. Structure/activity relationships, synthesis, chemical tests and
spectroscopy methods for anti-asthmatic drugs. Histamine receptors, discovery of cimetidine and
ranitidine as H2-receptor histamine antagonists. Synthesis, chemistry and spectroscopy of these anti-
ulcer drugs.
Title: Industrial Medicinal Chemistry
Lecturer(s): Dr D Rees, Dr A C Campbell and Dr T Sleigh (Organon)
Aims: To study case histories of the development of selected important medicinal compounds from
the perspective of industrial researchers who are familiar with these therapeutics areas.
Objectives:
1. Know about the discovery and chemical modification of lead compounds and structure
activity relationships.
2. Be able to describe how morphine was modified to produce useful analgesics.
3. Know about the synthesis and biological activity of kappa-selective opioids.
4. Be able to discuss the importance of combinatorial chemistry.
5. Know about the evolution of the anti-inflammatory steroids.
6. Be able to discuss the search for disease modifying anti-rheumatoid drugs.
7. Know about research on the neuromuscular blocking agents culminating in the development
of pancuronium bromide (Pavulon).
8. Be able to discuss the development of improved neuromuscular blocking agents typified by
vecuronium bromide (Nurcuron) and rocuronium bromide (Esmeron).
Outline:
Relationships between physical properties of organic compounds and biological activity,
structure activity relationships, discovery and modification of lead compounds, drug design and
combinatorial chemistry. Clinical use and limitations of morphine, chemical modifications, agonist
vs. antagonist activity, irreversible ligands and simplified morphine derivatives. Multiple opioid
receptors including kappa, developed of initial leads by synthesis, importance of stereochemistry on
biological activity. Need for combinatorial methods, solid phase peptide synthesis, peptide libraries,
solid phase synthesis of benzodiazepines. Structures, source and biochemistry of endogenous
corticosteroids, structural modifications to increase potency and reduce side effects. Pathogenic
mechanisms involved in the auto immune diseases such as rheumatoid arthritis and methods of
modulating them. Synthesis and biological activity of a novel steroidal potentially disease-modifying
anti-rheumatoid drug. Design and synthesis of non-steroidal anti-inflammatory agents by
pharmacophoric pattern searching. Natural sources of steroids and their conversion into useful
intermediates. Mode of action, design, synthesis and structure activity relationships of neuromuscular
blocking agents. Advantages and disadvantages of Pavulon, Norcuron and Esmeron.
Title: Advanced Organic Synthesis
Lecturer(s): Prof G W Kirby
Aims: To develop a logical and rational approach to the synthesis of complex organic molecules,
building on students' previously gathered knowledge and information.
Objectives:
1. Recall examples of reaction types, mechanisms, and protecting groups from other lecture
courses.
2. Understand, using simple examples, how these are applied in synthetic sequences.
3. Understand the concept of retrosynthesis.
4. Relate retrosynthesis to the planning and execution of some syntheses.
5. Understand illustrated examples of synthesis which concentrate on conceptual design and
principles of synthesis and reinforce latent knowledge.
6. Develop the above protocol to more complex examples.
7. Develop confidence in your ability to cope with problems in synthesis.
Outline:
This course, following on earlier student exposure to synthetic methods, is targetted at the rational
design of complex molecule synthesis. The basis, the disconnective (retrosynthetic) approach,
emphasises functional group protection and interactions, mechanistic stereoelectronics and structural
and stereochemical architectural problems. The ideas all ullustrated by syntheses of specific target
molecules, e.g. shikimic acid.
Title: Biophysical Chemistry
Lecturer(s): Prof N W Isaacs
Aims: To develop an awareness of some methods used to study the physical properties of biological
molecules.
Objectives:
1. Discuss the variety of biological molecules and describe the properties of amino acids,
peptides and proteins.
2. Discuss methods of separation and purification of proteins and techniques for the
determination of molecular weight and amino acid sequencing.
3. Discuss the study of protein conformation using spectroscopic and diffraction techniques.
4. Discuss the binding of ligands to macromolecules, enzyme kinetics and molecular dynamics.
5. Use information provided to discuss topics concerning the structure, function, and
characterisation of proteins and other biological macromolecules.
Outline:
This course of lectures will introduce some physical chemistry aspects of biological molecules.
The nature of biological molecules; the properties of amino acids, peptides and proteins;
methods of purification: salt fractionation, chromatography, electrophesis;
methods forestablishing molecular weight;
determination of the composition of proteins: amino acid analysis, amino sequencing; sequencing at
the DNA level;
immunological methods of detection;
UV absorption spectroscopy: effects of pH, polarity, etc.; applications;
fluorescence spectroscopy: effects of pH, temperature, ligand binding, etc.; applications
circular dichroism: the measurement of protein secondary structure content;
NMR: use of 2D-NMR to derive protein structure; use of 31P-NMR to measure effects in whole cells
diffraction methods: differences between protein and small molecule crystallography; examples of
protein structures; chymotrypsin, trypsin and elastase specificities; neutron scattering; phase
contrast techniques; molecular dynamics: application to ligand binding, structure and determination;
binding of ligands to macromolecules: enzyme kinetics.
Title: Reactivity of Transition Metal Organometallic Compounds
Lecturer(s): Dr L J Farrugia
Aims: To understand some of the basic reactions of organic ligands which are coordinated to
transition metals, and how certain ligands may be stabilised upon coordination.
Objectives:
1. Understand the bonding in, and types of compounds formed by the cyclopentadienyl ligand;
know about the electrophilic substitution and metallation reactions of ferrocene.
2. Know some examples of the differing substitution rates in dienyl versus cyclopentadienyl
compounds and the reasons and evidence for ring slippage.
3. Understand how some unstable and non-existent molecules are stabilised by coordination to
transition metals; know some examples such as cyclobutadiene and trimethylene methane.
4. Understand how the bonding within butadiene is changed by coordination to Fe(CO)3, and
be able to provide evidence for this; know the Green/Mingos/Davis rules for deciding the site of
nucleophilic attack at coordinated polyenes, and be able to use these rules in concrete examples.
5. Know how both Fischer and Schrock carbenes are made and the reasons for their different
reactivities.
Outline:
Metallocenes and revision of bonding therein; versatility of the C5H5 ligand - occurrence in
both high and low oxidation state compounds; half sandwich compounds, bent metallocenes and triple
decker sandwiches; structure and syntheses of main group analogues of Cp such P5, As5, C4H4P,
C4H4BMe, etc.; aromaticity of ferrocene and electrophilic substitution reactions.
Stabilisation of unstable molecules such as cyclobutadiene, trimethylene methane, benzyne
and Bi2 by co-ordination to transition metals.
Hückel approach to binding in butadiene and how this is affected by co-ordination to
Fe(CO)3; structural and 13C NMR evidence; nucleophilic attack at co-ordinated polyenes; the
Green/Mingos/Davis rules for determining the site of nucleophilic attack.
Nucleophilic attack at CO, the formation of Fischer carbenes; nucleophilic reactions of the
Fischer carbene; synthesis of Shrock carbenes, and the reason for their different reactivity.
.
Title: Aromatic Systems
Lecturer(s): Dr P H McCabe
Aims: To appreciate the variability of aromatic character and reactivity within benzene derivatives,
non-benzenoid carbocycles (neutral or charged) and heterocycles; to be aware of general synthetic
routes to simple heterocycles; to be able to apply this knowledge to unfamiliar cases.
Objectives:
1. Be able to recognise aromatic structures by simple p-electron counting.
2. Appreciate the factors (p-electron delocalisation, ring size, planarity, non-bonded
interactions, charges) which influence stability and be familiar with the term “stabilisation energy”.
3. Be familiar with the activating/deactivating effects of substituents and heteroatoms and with
the terms p-excessive and p-deficient.
4. Be familiar with selected spectroscopic characteristics of aromatics.
5. Be familiar with the range of electrophilic substitution reactions and of addition, elimination,
nucleophilic and radical reactions of carbocyclic aromatics and heterocycles.
6. Be familiar with the general syntheses and reactivity of furans, pyrroles, thiophenes,
imidazoles, indoles, pyridines, quinolines, isoquinolines, diazines and purines.
Outline:
Aromatics as 4n + 2 p-electron systems. Benzene, [10]-, [14]-, [18]annulenes. Planarity.
Diagmagnetic ring current. Chemical shift of outside and inside hydrogens.
Benzene rectivity and selected reactivity of annulenes.
Cyclopropenium, cyclobutadiene dication, cyclopentadienide anion, tropylium.
Furan, pyrrole and thiophene. Paal-knorr synthesis. p-excessive. Reactivity.
Indole. Fischer synthesis. Imidazole. Electrophilic and nucleophilic substitution,
Chichibabin reaction.
Pyridine and pyrimidine. p-deficient. Hantzsch and Traube syntheses. Pyridine N-oxide.
Syntheses of quinoline (Skraup), isoquinoline (Bischler-Napieralski) and reactivity.
Title: Elements of Molecular Biology for Chemists
Lecturer(s): Dr A G Cairns Smith
Aims: To introduce molecular biology to chemistry students who could have no previous experience
of it.
Objectives:
1. Understand the genetic theory of organisms and how information can be held in molecules.
2. Understand with examples the linkage systems in oligo and poly-sacchardes.
3. Know the primary structures of DNA, RNA and their nucleotides.
4. Understand in formal terms how genetic information in DNA molecules replicates, and the
formal relationship between genes and protein molecules.
5. See the need for a genetic code in translating information from nucleic acids to protein, and
to understand at a simple level the roles of messenger, transfer, and ribosomal RNA in these
processes.
6. Understand the terms primary, secondary, and tertiary structures in proteins.
7. Appreciate the limited yet varied character of the amino acid set, and the enormous variety of
possible proteins.
8. Discuss the physiochemical factors controlling the secondary and tertiary folding of
polypeptide chains in proteins.
9. Discuss, with examples, some of the factors thought to account for enzyme action.
10. Be able to provide plausible mechanisims for three enzyme catalysed reaction types.
Outline:
The genetic theory of organisms; the distinction between genotype and phenotype; "the molecules of
life" structures of DNA, RNA and their nucleotides; the replication of information in DNA
molecules; relationship between genes and proteins the character of the amino acid set; types of
proteins; primary and secondary structures factors controlling the secondary and tertiary folding of
polypeptide chains; domains; quaternary structures enzymes; general factors thought to account for
enzyme action; lysozyme and chymotrypsin examples; coenzymes as reagents; NAD+ example;
lessons for organic chemistry and likely future trends.
Title: Statistical Thermodynamics
Lecturer(s): Dr J H Dymond
Aims: To show how equilibrium thermodynamic property data for dilute gases and solids, and
chemical reaction rates, can be related to properties of the individual molecules
Objectives:
1. Derive the number of ways of distributing n indistinguishable particles among g degenerate
energy states.
2. Give the corrected Boltzmann statistics for the total number of arrangements of N particles,
where ni are in energy level ei which has a degeneracy gi
3. State the Boltzmann distribution law, and use it to determine the relative populations of
different energy levels.
4. Appreciate the meaning and importance of the molecular partition function, and relate it to
the total energy of a system.
5. Factorise the molecular partition function.
6. Give the expression for the translational partition function, and hence the contribution to the
energy and heat capacity at constant volume for an ideal gas
7. Give a statistical thermodynamic explanation for ideal gas expansion at constant
temperature.
8. Appreciate the impossibility of obtaining absolute energies.
9. Give the expression for the rotational partition function, and know the meaning of the
characteristic rotational temperature and the symmetry number.
10. Give the contribution to the energy and heat capacity at constant volume from rotational
motion.
11. Give the expression for the vibrational partition function, and know the meaning of the
characteristic vibrational temperature.
12. Calculate the contribution to the energy and heat capacity at constant volume arising from
vibrational motion.
13. Describe ortho and para-states of diatomic molecules, and understand the alternating
intensities to be found in rotational Raman spectra.
14. Calculate enthalpy changes for reactions.
15. Account for the temperature dependence of the heat capacities of solids.
16. Relate the Boltzmann expression for entropy to the classical entropy.
17. Give the statistical thermodynamic expression for entropy in terms of energy and the
molecular partition function.
18. Give the Sackur-Tetrode equation, and demonstrate that the dependence of entropy for an
ideal gas on T at constant V, and on V at constant T, agree with classical results.
19. Explain what is meant by residual entropy, and calculate values for this for certain systems.
20. Relate the Helmholtz and Gibbs energies to the molecular partition function.
21. Give approximate values for the translational, rotational, vibrational and electronic
contributions to the molecular partition function.
22. Explain chemical equilibrium in terms of the distribution of molecules among energy levels,
and hence understand the molecular factors that influence the position of equilibrium.
23. Describe transition state theory and derive and expression for absolute reaction rates
24. Calculate steric factors for reactions involving molecules of differing complexity
Outline:
This course is designed to show how equilibrium thermodynamic data for dilute gases and solids, and
chemical reaction rates, depend upon the properties of the constituent molecules.
Introduction - derivation of the numbers of ways of distributing indistinguishable particles among
degenerate energy levels corrected Boltzmann statistics and simple applications; the molecular
partition function (q); dependence of the internal energy on q factorisation of q; the contribution from
translational motion, and translational energy; absolute energies rotational partition functions and the
symmetry number; rotational energy and heat capacity contribution vibrational partition function, the
characteristic vibrational temperature and the contribution to the heat capacity electronic partition
function; effects of nuclear spin - ortho and para forms; relative intensities of rotational Raman
spectra enthalpy changes for chemical reactions; classical and statistical entropies.
Sackur-Tetrode equation for monatomics; residual entropy for simple diatomics and glasses; free
energy changes chemical equilibrium; simple collision theory of reaction rates activated complex
theory, and examples.
Title: Chemistry and Pharmacology of Anti-cancer Drugs
Lecturer(s): Prof D J Robins, Dr A D Lewis (Quintiles)
Aims: To discuss the main agents used in the treatment of cancer in terms of synthesis, chemistry,
metabolism and mode of action.
Objectives:
1. Know about abnormal cell growth and its causes and possible treatments.
2. Recognise different types of alkylating agents, their synthesis, mechanism of action and
pharmacology.
3. Understand the concept of antimetabolites with synthesis and mode of action of examples
such as 5-fluorouracil and methotrexate.
4. Understand hypoxia in tumours and selectivity of action achieved by bioreductive agents
containing quinones or N-oxides; know about the mode of activation and action of bioreductive agents
such as mitiomycin C.
5. Know about natural products used as anticancer agents, particularly doxorubicin with partial
synthesis and mode of action; topoisomerase inhibitors and microtubule inhibitors.
6. Understand the importance of growth factors and inhibition of signalling processes by drugs
as new targets.
7. Know about the synthesis, spectroscopy and instability of tyrosine kinase inhibitors and
erbstatin.
Outlines:
Cancer Biology: a disease of abnormal growth and cellular proliferation; causes and methods of
treatment; development of anti-cancer drugs; importance of selectivity; classes of anti-cancer agents
including alkylating agents, antimetabolites, bioreducible compounds, natural products and
compounds which interfere with cell signalling processes; pharmacokinetics and mechanism of
action; drug design and drug resistance; drug development based on mechanism of action.
Chemistry of anticancer drugs: alkylating agents including nitrogen mustards, cyclophosphamide,
nitrosourea (synthesis action and interaction with DNA); antimetabolites including 5-fluorouracil and
methotrexate (synthesis and mechanism of action); natural products such as doxorubicin and taxol
(partial synthesis, spectroscopic characterisation); tyrosine kinase inhibitors including active
compounds made in this Department ( synthesis and spectroscopic characterisation).
Title: Chirality
Lecturer(s): Dr R D Peacock
Aims: The aims of the course are to provide an introduction to the occurrence and importance of
chirality; to explain how chiral molecules may be detected, resolved or synthesised and to give an
appreciation of circular dichroism spectroscopy and its use in determining the absolute configuration
of chiral molecules.
Objectives:
1. Understand the basic definitions of chirality - enantiomer, diasterioisomer, racemate. Have
an appreciation of the importance of chirality in the interaction of chiral molecules with natural
systems such as man.
2. Appreciate the idea of a chromophore. Know the common types of chromophore and the
transitions which they undergo.
3. Understand the concept of the polarisation of an electronic transition, of plane
polarised light and of plane polarised absorption spectroscopy. Understand how the polarisation of
a transition can be derived by multiplying the phase of the HOMO with that of the LUMO (or
higher unoccupied molecular orbital).
4. Be able to use phase multiplication to determine the polarisations of the p -> p* transition
of ethene and the d -> d* transition of the Mo2 chromophore and appreciate how the method can be
used to determine the polarisation (long or short axis) of the transitions of polyacenes such as
substituted benzenes, naphthalene and anthracene.
5. Understand how in the twisted Mo2 chromophore there is a transient helical charge
distribution during the d -> d* transition and how this charge distribution interacts differently with
left and right circularly polarised light leading to circular dichroism. Appreciate how the sense of
twist of the chromophore (and hence the absolute configuration) is related to the sign of the CD
spectrum.
6. Understand the concept of chirally coupled (organic) chromophores. Understand how the CD
spectrum of such a system is related to the chirality of the molecule. Be able to determine the chirality
of a pair of coupled chromophores from the sign of its CD spectrum.
7. Understand how enantiomers can interact in homochiral or heterochiral pairs of stacks.
Appreciate the molecular basis of diastereomeric interactions ("three point model").
8. Know the common methods of resolving chiral molecules.
9. Be able to describe, and appreciate the molecular basis of, the various methods of detecting
chiral molecules - chiral chromatography, chiral NMR reagents, chiral sensors.
10. Appreciate the molecular basis of asymmetric catalysis - particularly as applied to the
examples given in lectures.
Outline:
General definitions of chirality etc.; chromophores; polarisation of electronic transitions; the
alkene and dimolybdenum chromophores; twisted chromophores and circular dichroism; coupled
chromophores - bianthryls etc, use in determining absolute configuration; diasteriomeric interactions;
resolution of enantiomers; chiral GLC, chiral HPLC, chiral NMR shift reagents, chiral sensors;
asymmetric catalysis
Title: Homogeneous Catalysis
Lecturer(s): Dr R J Cross
Aims: To obtain knowledge of the operations of a wide range of homogeneous catalysis systems in
actual applications, and to understand how information is derived about the working of such systems.
Objectives:
These will be issued during the course.
Outline:
Survey and revision of the reactions of transition metal and organometallic compounds which
operate in homogeneous catalysed reactions. Place of electron counting schemes in rationalising
catalysis reaction steps, illustrated by some simple catalysed reactions.
Ways of obtaining mechanistic information on catalytic processes, illustrated by
hydrogenation reactions at Williamson’s catalyst.
Operation of specific processes, including Zelgles-Natta polymerisations, Wacker process,
SHOP process and olefin metallesis.
Chiral catalysis. Relationship of homogeneous processes to heterogeneous catalysis, and
ways of exploiting the advantages of both.
Title: Main Group Chemistry - Noble-Gas Chemistry
Lecturer(s): Prof T M Klapötke
Aims: To develop a knowledge of the main properties of noble-gas compounds and of their physical
nature.
Objectives:
1. Have a knowledge and understanding of the chemistry of binary noble-gas halides, and be
familiar with their structure and bonding.
2. Have a knowledge and understanding of the chemistry of binary xenon oxides and ternary
xenon oxofluorides, and be familiar with their structure and bonding.
3. Have a knowledge and understanding of the chemistry of xenon-carbon compounds, and be
familiar with their structure and bonding.
4. Have a knowledge and understanding of the chemistry of xenon-nitrogen and krypton-
nitrogen, and be familiar with their structure and bonding.
5. Know about theoretical aspects and ab initio computations concerning the existence of
ternary noble-gas compounds of the type NgBeO (Ng = noble-gas) and know about preparative aspects
of modern noble-gas chemistry and matrix isolation techniques.
6. Have a knowledge of the existence of noble-gas tungsten compounds and know about
preparative aspects of modern noble-gas chemistry and matrix isolation techniques.
Outline:
The course covers all areas of noble-gas chemistry: (i) structure and bonding, (ii) ab initio
computations (iii) orbital symmetry effects and kinetics, (iv) thermodynamics and (v) preparative
aspects.
It is assumed that the student has completed the relevant first, second and third year courses
on inorganic chemistry. Some elementary but very important topics, such as the VSEPR model
applied to noble-gas compounds are included for review and emphasis.
Data from advanced experimental techniques such as NMR (14N, 17O 19F, 129Xe) and
vibrational data obtained from matrix isolated species have been included where appropriate.
Structure and bonding; the VSEPR model, the electron domain model.
Thermodynamics; estimation of the heat of reaction by using a simple Born-Haber energy
cycle, estimation of the crystal lattice energy by using the Bartlett equation.
Title: Protein Structures - Design and Engineering
Lecturer(s): Prof N W Isaacs
Aims: To develop ideas relating the structure and function of proteins and the present strategies and
techniques for modifying the structure to alter the function.
Objectives
1. Discuss the nature of protein structures in terms of primary, secondary, tertiary and
quaternary structures and be cognisant of the forces contributing to the stability of protein structures.
2. Know the basic concepts of protein crystallography and be able to assess the quality and
reliability of protein structures
3. Know the common motifs found in protein structures and discuss methods for the prediction
of protein structures.
4. Have a good knowledge of the concepts of protein engineering and be able to discuss
applications of the technique in theoretical and practical studies
5. make use of information gained in the course to discuss any topic association with the
objectives given above
Outline:
The first part of this course (protein design), will discuss the three-dimensional structures of proteins
and the relation between the structure and its function; the second part (protein engineering) will
consider strategies and techniques for modifying the protein structure in order to change its function.
Some recent examples of protein engineering will be discussed.
Title: Modern Synthetic Methods
Lecturer(s): Dr E W Colvin
Aims: To introduce unfamiliar reactions and concepts of high current activity and interest, and to
give a fairly detailed overview of the methodology of modern synthetic organic chemistry.
Objectives:
1. Appreciate the concept of polarity reversal, or umpolung.
2. Understand and be able to discuss, Sharples enantioselective epoxidation and kinetic
resolution of allylic alcohols.
3. Understand, and be able to discuss, enantioselective epoxidation and dihydroxylation of
simple alkenes.
4. Understand the use of tin hydrides in reductive deoxygenation, and deselenylation, and
appreciate the synthetic value of the intramolecular trapping of the intermediate radicals.
5. Understand the basis of the control that the b -effect and a -anionoid stabilisation can play in
organosilicon chemistry.
6. Understand the chemistry of vinylsilanes, in terms of their preparation and reactivity.
7. Understand the chemistry of allylsilanes, in terms of their preparation and reactivity
8. Understand the chemistry of arylsilanes, in terms of their preparation and reactivity.
9. Know the principles and synthetic utility of Peterson Olefination.
10. Understand the chemistry of a,b-epoxysilanes, in terms of their preparation and reactivity.
11. Know the principles and synthetic utility of the oxidative cleavage of C-Si bonds.
12. Understand the chemistry of silyl ethers, in terms of their preparation and utility.
13. Understand the chemistry of silyl enol ethers, in terms of their preparation and wide synthetic
utility.
14. Understand the basic principles of organosulphur chemistry.
15. Understand the chemistry of thioacetals, in terms of their preparation and synthetic utility.
16. Understand the varied chemistry of sulphoxides.
17. Understand the chemistry of anions to sulphur in its various oxidation states.
18. Understand the chemistry of sulphonium and sulphoxonium ylides as methylene transfer
reagents.
Outline:
Ti/Mn/Os: Sharpless enantioselective epoxidation of allylic alcohols; kinetic resolution of
allylic alcohols; Jacobsen enantioselective epoxidation of simple alkenes; Sharpless enantioselective
dihydroxylation.
Sn: use of tin hydrides in reductive dehalogenation, including cyclisation of radical
intermediates with examples; Barton deoxygenation; selenolactonisation and reductive removal.
Si: basic principles; b-effect and a-anion (oid) stabilisation; growth of organosilicon
chemistry.
Vinylsilanes: preparation; reactivity towards electrophiles; ipso desilylation and
stereochemistry.
Allylsilanes: preparation; reactivity towards electrophiles - regiochemistry and stereochemistry;
formal anion generation.
Arylsilanes: preparation; ipso desilylation.
b-Hydroxysilanes: preparation; Peterson Olefination.
a, b-Epoxysilanes: preparation; acid-catalysed opening.
Oxidative cleavage of C-Si bonds: mechanism; synthetic utility.
ROSiMe3 and ROSiMe2 tBu: preparation, use, cleavage.
Silyl enol ethers and ketene acetals: preparation; spectrum of reactivity including [4+2], Ireland-
Claisen.
S and Se: nomenclature in various oxidation states; basic principles; formation and cleavage of C-S
bonds; thioacetal preparation and cleavage - hydrolytic and reductive.
Reactions of sulphoxides: DMSO as and oxidant; Swern and mechanism; Corey DMS/NCS/Et3N;
Pummerer rearrangement.
[2,3]-Sigmatropic rearrangements: allylic sulphoxides; retro-ene (also with selenoxides); penicillin ®
cephalosporin.
a-Anions: thioethers, 1,3-dithianes; DMSO, chiral sulphoxide anions; sulphones, Julia Coupling,
chrysanthemic acid synthesis.
Sulphonium and sulphoxonium ylides: dimethylsulphonium methylide (hard) and
dimethylsulphoxonium methylide (soft); contrasting chemoselectivity with enones.
Title: Surface Chemistry and Catalysis
Lecturer(s): Drs D Lennon and D Stirling
Aims: To gain an understanding of what is meant by a catalyst surface and how the nature of the
active sites on the surface can be determined using a range of characterisation techniques. Also to
provide an understanding of how the mechanisms of surface catalysed reactions can be elucidated
using spectroscopic, kinetic and isotopic tracer techniques.
Objectives:
1. To have a knowledge of single crystal surfaces of metals and selected ultra-high vacuum
techniques than can be used for their characterisation, including X-ray and ultraviolet photoelectron
spectroscopies (XPS), (UPS), low energy electron diffraction (LEED), electron energy loss
spectroscopy (EELS) and Auger electron spectroscopy (AES).
2. To have an appreciation of the surfaces of typical catalysts and how the techniques
mentioned in (1) together with more conventional techniques such as infrared and uv/visible
spectroscopies used to gain information on the surfaces of these catalysts.
3. To have a knowledge of other characterisation techniques applicable to supported metal and
supported metal oxide catalysts including total surface area determination (BET), chemisorption
temperature programmed and diffraction techniques.
4. To have an appreciation of surface catalysed reactions and how spectroscopic, kinetic and
tracer techniques can be used to elucidate the mechanisms of these reactions.
5. To be able to interpret previously unseen mechanistic data using the skills developed in
objectives 1 to 4.
Outline:
This course will introduce the concepts of surface science an how techniques originally used
in the study of single crystals can be applied to supported catalysts typical to those used in an
industrial environment. The main emphasis will be on catalyst characterisation techniques and how
these can be used to gain mechanistic information in typical surface catalysed reactions.
Title: Laser Spectroscopy
Lecturer(s): Dr J K Tyler
Aims: This course is intended to introduce the principles of laser operation in general and the
details of specific devices. Some important applications of lasers in chemistry and spectroscopy are
touched on.
Objectives:
1. The nature of radiative transitions and basic laser theory.
2. Ways of achieving population inversions.
3. Optical gain and feedback, and the criteria for pulsed and continuous operation.
4. Rare gas discharge lasers, molecular infrared gas lasers, hydrogen halide chemical lasers and
organic dye solution lasers.
5. Diode lasers.
6. Excimer lasers and super-radiance.
7. The laser as a spectroscopic source and as an excitation source for Raman spectroscopy.
8. Flash photolysis with lasers.
9. Multiphoton processes and infrared photochemistry.
Outline:
Radiative and non-radiative energy changes. Spontaneous and stimulated radiative processes
and basic laser theory. Practical realisation of laser action. Population inversion. The ammonia
maser. Optical gain and feedback. The ruby and neodymiun ion lasers. Criteria for pulsed and
continuous operation. Rare gas discharge lasers. Details of the He/Ne device. Molecular gas lasers
operating in the infrared region exemplified by the CO2/N2 system. Hydrogen halide chemical lasers.
Organic dye solution lasers.
Semiconductor levels and diode lasers. The N2 laser. Super-radiance. Excimer and
exciplex lasers. The nature of laser radiation. The laser as a spectroscopic source. Tunability. The
laser as an excitation source for Raman spectroscopy. Flash photolysis with lasers. Multiphoton
processes. Infrared photochemistry. Laser separation of isotopes.
Title: Asymmetric synthesis
Lecturer(s): Dr R C Hartley
Aims: To introduce the different types of asymmetric synthesis. To concentrate on methods of
asymmetric induction which involve the formation of C-C bonds. To illustrate these methods with
syntheses of biologically active molecules and to show the importance of organometallics in carrying
out unconventional transformations.
Objectives:
1. Describe the different types of asymmetric synthesis; assess the advantages and
disadvantages of each approach with particular reference to atom economy and enantiomeric purity;
explain the importance of enantiopure drugs.
2. Explain how enolate geometry is controlled and how chelation control gives rise to
diastereoselectivity in aldol reactions (E enolate gives anti; Z enolate gives syn).
3. Describe the chiral auxiliary approach to asymmetric synthesis using Evans' oxazolidine
chemistry, apply Evans' oxazolidine chemistry to the synthesis of enantiopure compounds, and
explain how absolute and relative stereochemistry is controlled in reactions using this chemistry.
4. Count electrons in a metal complex, recognise and explain the importance of coordinative
saturation, and describe the basic types of reaction found in most catalytic cycles (association and
dissociation; oxidative addition and reductive elimination; ligand to metal migration and metal to
ligand migration; nucleophilic attack on ligands).
5. Describe the mechanism of Pd0 catalysed cross-coupling reactions (in general and for
particular examples), explain any restrictions to the substrates, and apply these reactions to synthesis.
6. Describe and give examples of the different types of ligand chirality (centre, planar, axial),
and assign R and S configuration to the different chiral entities.
7. Explain dynamic kinetic resolution and its application in asymmetric cross-coupling
reactions.
8. Describe the mechanism of Pd0 catalysed allylic alkylations (in general and for particular
examples) and apply these reactions to synthesis.
9. Explain the ligand design in asymmetric Type I and Type IIa allylic alkylation reactions, in
particular the use of C2 symmetric and P,N ligands, and give examples of known C2 ligands and P,N
ligands.
Outline:
Overview of asymmetric synthesis (including concept of atom economy); Evans' oxazolidone
chemistry: (i) asymmetric enolate alkylation (ii) asymmetric aldol condensation (chelation control,
face selectivity) (iii) applications in synthesis. Basic organotransition metal chemistry (electron
count in complexes). Pd0 catalysed cross-coupling reactions and their application to synthesis.
Different types of ligand chirality. Catalytic asymmetric cross-coupling and dynamic kinetic
resolution. Pd0 catalysed allylic alkylation. Asymmetric type I, and type IIa (C2 symmetric and P,N
ligands) allylic alkylations.
Title: Modern Molecular Calculations
Lecturer(s): Dr B C Webster
Aims: The aims of the course are to introduce the computer based methods which are available for
the ab-initio and semi-empirical calculation of molecular properties and to review and develop some
of the concepts which were introduced in third year courses in quantum mechanics and bonding
theory.
Objectives:
1. Appreciate the need for and the validity of approximate calculations and relate them to the
approximations inherent in measurement.
2. Appreciate calculation strategies on large computers without becoming involved in the
details of the programming.
3. Approach with a more critical attitude results obtained from the use of large established
computer programes.
4. Describe the general structure of calculations of Hartree Fock/Self Consistent Field (HF/SCF)
wavefunctions.
5. Describe the various approximations involved in HF/SCF calculations.
6. Describe what is meant by a minimal basis set and an extended basis set and describe various
commonly used basis sets of Gaussian functions matched to Slater type orbitals: STO-3G, 3-21G, 3-
21G(*), 6-21G, 6-31G*, 6-31G**.
7. Explain why the number of basis functions used in a calculation is limited by available
computing time.
8. Describe how molecular geometry can be optimised.
9. Describe the effects of neglecting electron correlation.
10. Describe the general structure of calculations of configuration interaction (CI) calculations.
11. Describe the various approximations involved in CI calculations.
12. Explain the need to use limited CI methods to reduce computer time.
13. Describe the trade off between accuracy of calculation and computing time and how this is
related to molecular size.
14. Explain why ab-initio methods cannot at present be applied to very large molecules and the
need for semi-empirical methods.
15. Describe the basis of the main types of semi-empirical methods: NDDO, INDO and CNDO
including the main approximations made and the major variants.
16. Explain the value of parametrisation in semi-empirical methods.
17. Assess the likely accuracy of properties such as equilibrium geometries, vibrational
frequencies, absolute entropies, barriers to internal rotation and inversion, electronic dipole moments
and bond dissociation energies calculated using ab-initio and semi-empirical methods.
18. Describe the Born-Oppenheimer approximation and its effect.
19. Write the molecular Hamiltonian operator in atomic units within the Born-Oppenheimer
approximation for any molecule.
20. State the requirements for a satisfactory electron wavefunction.
21. Describe the relationship of Slater-type orbitals and Gaussian-type atomic functions to
hydrogenic wavefunctions.
Outline:
Revision of some quantum mechanical concepts. The HARTREE-FOCK-ROOTHAAN
method. Basis sets. Strategies for solution of HFR equations. Electron correlation. Semi-empirical
techniques.
Title: Enzymes in Organic Chemistry
Lecturer(s): Dr R A Hill
Aims: To understand the methods involved in determining enzyme mechanisms and the knowledge
of these mechanisms can be applied to using enzymes as reagents and the design of model enzymes.
Objectives:
1. Understand generally the structures of enzymes.
2. Understand how determination of the stereochemical features of enzyme reactions can be
used to determine the mechanisms of these reactions.
3. Describe how the stereochemistry features of alcohol dehydrogenase reactions were
established.
4. Describe how the stereochemistry of various enzymic addition/elimination reactions was
determined and how this gives an insight into the way enzymes work.
5. Understand how enzymes are such efficient catalysts and how they may be used in organic
synthesis.
6. Describe some of the ways enzymes are used in industry.
7. Discuss the use of reductases in synthetic organic chemistry to produce homochiral
compounds from achiral compounds and racemic mixtures.
8. Describe the mechanisms and stereochemical features of hydroxylating enzymes.
9. Discuss the use of hydrolytic enzymes in organic reactions.
10. Describe how the concepts of enzymic catalysis have been tested and utilised using enzyme
models and biomimetric reactions.
11. Apply the principles of this course in solving problems of related enzyme reactions.
Outline:
The mechanism and stereochemistry of alcohol dehydrogenase and how a knowledge of the
stereochemical outcome of of alcohol dehydrogenases help the understanding of other enzyme
reactions; a series of elimination/addition enzyme reactions will be studied to look at the various
methods of examining enzyme mechanisms and to make generalisations about the requirements for
efficient enzyme reactions. The enzymes involved are: phenylalanine ammonia lyase, fumarase,
aconitase, dehydroquinate dehydrase and aldose-ketose isomerase.The use of enzymes as organic
reagents, their advantages and disadvantages; some industrial applications of enzymes; the use of
alcohol dehydrogenases including the stereospecific and regiospecific aspects, use in resolution of
enantiomers and generation of chiral compounds from achiral substrates; hydroxylating enzymes and
the mechanism of hydroxylation of unactivated carbons and aromatic compounds including
phenylalanine hydroxylase and tyrosine hydroxylase (mention of NIH shift). Mono and dioxygenases
and phenol oxidative coupling as examples of enzymes for performing “chemically difficult”
reactions.
Biomimetic chemistry, including intramolecular catalysis, Breslow’s benzophenones,
cyclodextrins, cyclophanes, crown ethers and related compounds.
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