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 modification, agonist vs. antagonist activity, irreversible ligands and simplified morphine derivatives. Multiple opioid receptors including kappa, development of initial leads by synthesis, importance of stereo- chemistry on biological activity. Need for combinatorial methods, solid phase peptide synthesis, peptide libraries, solid phase synthesis of benzodiazepines. Description of routes of administration and their importance in optimising a drug effect. The concepts of prodrugs and soft drugs and examples with common metabolic pathways. Synthesis and biological activity of a novel steroidal intra- venous anaesthetic drug.

Lecturer(s): Dr A Lapthorn

Aims: To develop an awareness of some methods used to study the physical properties of biological molecules.

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 for establishing molecular weight and physical properties; determination of the composition of proteins: amino acid analysis, amino acid sequencing; sequencing at the DNA level; 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 cell. Diffraction methods: differences between protein and small molecule crystallography; examples of protein structures; chymotrypsin, trypsin and elastase specificities; Solution scattering: low angle X-ray scattering; neutron scattering; phase contrast techniques; measurement of binding of ligands to macromolecules:

Lecturer(s): Dr R C Hartley

Aims: To introduce new methods of forming carbon-carbon bonds. To illustrate these methods with syntheses of biologically active molecules and to show the importance of organometallics in carrying out unconventional transformations.

1. Suggest reagents for alkylidenation of carbonyl compounds, describe the mechanisms of alkylidenation reactions and apply these reactions to synthesis.

2. 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).

3. Describe mechanisms for palladium(0)-catalysed cross-coupling and carbonylative cross-coupling reactions (in general and for particular examples), explain any restrictions to the substrates, and apply these reactions to synthesis.

4. Suggest appropriate syntheses of organoboron, organosilicon, organosulfur, and organometallic compounds (i.e. those of lithium, magnesium, tin, zinc etc.), understand their reactivity, give mechanisms for their reactions and apply these compounds to synthesis.

5. Devise suitable syntheses of organic halides.

6. Describe mechanisms for the reactions of allylborons and allylsilanes, apply these reagents to synthesis and explain diastereoselectivity in the reactions of crotylboronates and crotylsilanes.

Alkylidenation reactions: Wittig (revision), Julia, Peterson, Petasis and Takeda alkylidenation reactions. Synthesis of alkenes from alkynes. Fundamental organotransition metal chemistry (electron count in complexes). Pd(0) and Ni(0) catalysed cross-coupling reactions and their application to synthesis. Synthesis and use of organolithiums, Grignard reagents (revision), organozincs, organoborons, organotins, and other organometallics. Synthesis and use of organic halides. Allylborons, allylsilanes, crotylborons and crotylsilanes and the synthesis of homoallylic alcohols; Sakurai and related reactions.

Title: Pericyclic Reactions

Lecturer(s): Dr S K Armstrong

Aims: To develop an understanding of cycloadditions and pericyclic rearrangement reactions, and of their importance in organic chemistry, based on frontier orbital interactions and the Woodward-Hoffmann Rules.

1. Appreciate that the outcomes of many cycloaddition and rearrangement reactions may be understood in terms of frontier orbital interactions.

2. Recall or derive the p -orbital systems of alkenes, dienes, and allyl systems, whether substituted or not.

3. Predict and rationalise the outcomes of Diels-Alder cycloadditions, including stereospecificity, regioselectivity, and stereoselectivity, in terms of primary and secondary orbital interactions.

4. Predict and rationalise the outcomes of other cycloaddition reactions, including 1,3-dipolar and [2+2] cycloadditions. Understand, recall and apply the Woodward-Hoffmann Rules as applied to cycloaddition reactions in thermal or photochemical conditions.

5. Predict and rationalise the outcomes of [3,3]-sigmatropic rearrangements, including regioselectivity and stereoselectivity, in terms of primary and secondary orbital interactions.

6. Predict and rationalise the outcomes of other rearrangements, in particular [2,3]-sigmatropic rearrangements, in terms of frontier orbital interactions and the Woodward-Hoffmann Rules.

7. Apply the above understanding to examples published in the chemical literature.

Introduction Shape of bonding and anti-bonding s and p orbitals; extended p systems; energy levels; orbitals in control of familiar reactions such as S_N2. Diels-Alder Cycloaddition The basic reaction: a reminder. Orbitals involved and their implications for transition state geometry. Stereospecificity with respect to diene and dienophile. Substituted dienes and dienophiles and their orbitals. Orbital energy and its effect on reaction rate. Regioselectivity determined by orbital coefficients. Stereoselectivity (exo/endo) governed by secondary orbital interactions. Intramolecular reactions. Other Cycloadditions 1,3-Dipolar cycloadditions. [2+2] Cycloadditions. Woodward-Hoffmann Rules as applied to cycloadditions. Pericyclic Rearrangements [3,3]- and [2,3]-sigmatropic rearrangements, including Claisen and related rearrangements, and rearrangements involving sulfur and selenium. Orbital involvement; chair-shaped transition states; stereochemical control.

Lecturer(s): Dr E W Colvin

Aims: To present the essential features of heterocyclic chemistry, dealing with the synthesis of selected ring systems and their varied reactivity. The main emphasis will be on unsaturated ring systems.

1. Understand aromaticity as it applies to unsaturated heterocycles.

2. Be aware of the synthesis of pyrroles, thiophenes and furans, including the Paal-Knorr synthesis, and understand their electrophilic substitution and anion chemistry.

3. Be aware of the synthesis of oxazoles, imidazoles and thiazoles, and understand their electrophilic and nucleophilic substitution and anion chemistry.

4. Be aware of the synthesis of quinolines and isoquinolines, including the Skraup and Bischler-Napieralski syntheses, and understand their electrophilic and nucleophilic substitution and anion chemistry.

5. Be aware of the synthesis of indoles, including the Fischer synthesis, and understand their electrophilic substitution and anion chemistry.

6. If time permits, coumarins, chromones and pyrimidines will also be discussed.

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.

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.

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 as 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 ¹³ C 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.

Lecturer(s): Dr J Dymond

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 n_i are in energy level e_i which has a degeneracy g_i

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, agrees with classical results.

19. Explain what is meant by residual entropy, and calculate its values 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.

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 gases; free energy changes; chemical equilibrium; simple collision theory of reaction rates; activated complex theory, and examples.

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.

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.

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 neodymium 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.

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.

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).

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.

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: At the end of this course students should be able to show:

1. An ability to recognise and classify the types of organotransition metal reactions occurring in catalytic cycles, and a knowledge of how they operate.

2. A knowledge of hydroformylation, isomerisation, SHOP, metathesis, Ziegler-Natta, Wacker, alkene hydrogenations, and CH bond activation processes.

3. An understanding of how the mechanisms of these processes are elucidated, using spectroscopic, kinetic and isotopic labelling techniques.

4. An ability to interpret mechanistic data and apply these interpretational skills to previously unseen reactions and examples.

5. A knowledge of the merits and demerits of homogeneous and heterogeneous catalysts and an understanding of the basis for catalyst and reaction phase selection for a given process.

6. A knowledge of the methods for introducing asymmetry for enantioselective catalysts.

7. A knowledge of examples of converting molecular catalysts to multi-phase systems by use of surface adsorption, polymer-bound materials or encapsulation.

This course covers many types of homogeneous catalysis and includes modern applications ranging from bulk tonnage processes to fine chemical and pharmaceutical manufacture. The reaction types of organo-transition-metal compounds will be related to the operating mechanisms of the catalysts, and emphasis will be placed on the techniques used to obtain and interpret detailed mechanistic information. The techniques described will include modern spectroscopic methods, kinetic studies and the use of isotopic labels. The links between homogeneous and heterogeneous catalysis will be examined, and the advantages and disadvantages of using each type briefly discussed in terms of the factors which govern the choice of suitable catalysts.

Processes examined will include hydroformylation, the SHOP process, Ziegler-Natta polymerisation, Wacker olefin oxidation, olefin hydrogenations (including asymmetric hydrogenations), CH bond activations and the use of anchored transition metal complexes as catalysts.

Lecturer(s): Professor J M Winfield

Aims: To develop the principles that underpin the chemistry of difluorine, fluoride anion, hydrogen fluoride and simple fluorine compounds containing F covalently bound to nitrogen or oxygen.

1. Understand the reasons why F₂ is anomolous compared with other X₂ halogen molecules and know the implications that these have for fluorine chemistry.

2. Understand the factors that govern the use of F^- anion as (i) a strong base and (ii) a good nucleophile.

3. Understand and have some knowledge of, the role of solid oxide supports and catalysts in the use of F^- and HF as reagents.

4. Understand the importance of proton donation and hydrogen bonding in the chemistry of HF.

5. Understand the difference between F⁺ and `electrophilic (positive) fluorine’ in the context of N-F and O-F species.

The fluorine anomaly, bond energy and e^--e^- repulsion considerations. Range of binary fluorides that is known. Ionic fluorides, lattice energy and solvation considerations in nucleophilic fluorination of organics; `naked’ fluoride. Some chemistry derived from F^- ion; reactions with Lewis acids, perfluorocarbanions, catalytic behaviour of F^- and oxide-supported F^- in chlorofluorination of SF₄. Structural chemistry of HF, solid, liquid and vapour. Hydrogen bonding and H⁺ donation in simple HF-base complexes. Catalytic activation of HF, catalytic fluorination of C-Cl bonds under heterogeneous conditions. Complexes between F₂ and H₂O or amines; electrophilic F and reagents for electrophilic fluorination.

2. To understand the synthetic methods employed to synthesise target receptor molecules.

3. To appreciate how physical methods provide information about the thermodynamics and kinetics of host-guest interactions.

4. To appreciate how special properties, such as drug formulation or enzyme-like catalysis, can be achieved by appropriate host-guest design.

5. To understand the current position on the design of crystalline host lattices: the concepts of symmetry-directed design and the supramolecular synthon.

6. To be familiar with examples of stereochemical control in solid-state reactions; and appreciate the importance of solid-state reactions.

7. To obtain knowledge of existing and potential applications of supramolecular technology.

Overview of classical discoveries of key organic clathrates and crown ethers; importance of preorganisation — bicyclic and tricyclic effects; electrides; Cram’s chiral crowns, and spherands; Collet’s design of cryptophanes; dynamic NMR studies; cucurbituril catalysis; approaches to crystal design; the supramolecular synthon; solid-state reactions; applications of supramolecular technology; anion activation, optical resolution, supramolecular storage of reagents, inclusion polymerisation; sensor systems.

Lecturer(s): Dr R A Hill

Aims: To understand the methods involved in determining enzyme mechanisms and to learn how these mechanisms can be applied to using enzymes as reagents and to the design of model enzymes and catalytic antibodies.