ESSENTIAL CORE ORGANIC CHEMISTRY
Organic Stereochemistry and Reactivity
Shapes of molecules; configuration, conformations and stereoisomers. The general principles of organic reaction mechanisms. Nucleophilic substitution; stereochemistry and reactivity in SN2 and SN1. Elimination (E2); regiochemistry and especially anti stereochemistry. Addition reactions of alkenes; regiochemistry (HX) and anti stereochemistry (X2) of addition. Resonance (and hyperconjugation). Acidity (especially terminal alkynes and alcohols). Oxidation (of alcohols) and reduction (of carbonyl compounds). Grignard reagents.
Organic Functional Groups
The structure, preparation, standard reactions of the carbonyl group in aldehydes and ketones including mechanisms. Reversibility in nucleophilic addition reactions; acid catalysis of nucleophilic addition; addition of standard O, N, S, C nucleophiles. Reduction (including hydride reduction), oxidation, hydration etc..
Functional Group Interconversions: synthesis and interconversion of carboxylic acids, esters, amides, and other acid derivatives. Reactions with standard reagents concentrating on substitution reactions (c.f. addition to aldehydes/ketones); relative reactivity in nucleophilic substitution reactions and reasons for differences.
Acidity of carboxylic acids and substituent effects on acidity. CH acidity in carbonyl compounds and enolate ion formation. Halogenation and alkylation α- to the CO group; mechanisms and uses of condensation reactions - aldol condensation, Claisen ester condensations.
Reactivity of amines (nucleophilicity & basicity) including preparation.
Peptides – synthesis (inc. protecting groups) and structure.
Bifunctional Molecules
Retrosynthetic analysis, synthons, synthetic equivalents, carbanions in nucleophilic substitution reactions (side reaction elimination) and carbanions in nucleophilic addition reactions to carbonyl compounds (side reaction enolisation), pKa, basicity, the effect of hybridisation on pKa.
Stabilisation of an anion * to a carbonyl group, bases: NaH, NaNH2, NaOEt/EtOH, LDA/THF, enolate reactivity C vs O, the malonic ester synthesis, the acetoacetic ester synthesis and the dianion, direct lithiation of ketones, esters and nitriles with LDA, kinetic and thermodynamic enolisation.
The aldol condensation; dehydration of the aldol product, acid catalysed aldol, mixed aldol, intramolecular aldol, the Claisen Condensation, mixed Claisen, intramolecular Claisen, Michael addition, hard and soft nucleophiles and electrophiles, cuprates, synthesis of 1,5-dicarbonyl compounds, enamines, the synthesis of 1,4-dicarbonyl compounds, the Robinson annulation, normal and inverted polarity, acyl anion SYNTHETIC EQUIVALENTS, acetylene anion, cyanide anion, cyanohydrins and the benzoin condensation, dithianes, vinyl ethers, nitroalkanes.
Phosphorus stabilised ylides and anions.
Introduction to biosynthesis – use of acetate and malonate to construct fatty acids and simple aromatic compounds (Claisen ester condensation; enoyl reduction transesterification etc); assembly of simple terpenes and steroids; methods for studying biosynthesis (radiolabelling, 13C labelling & highfield NMR spectroscopy); common late modifications (decarboxylation, oxygenation, methylation etc); familiarity with the structure and reactivity of common cofactors.
Chemical and enzymatic catalysis - Neighbouring group participation (e.g. reactivity of nitrogen mustards); fundamental concepts of chemical catalysis such as nucleophilic catalysis (e.g. tertiary amines, imidazole, carboxylates); general acid/base and specific acid/base catalysis; intramolecular catalysis; use of effective molarity to estimate proximity effects in enzyme cataysis; solvent kinetic isotope effects to distinguish general base and nucleophilic catalysis; the role of such catalytic processes in enzyme-catalysed reactions.
Chemistry of Rings
Alicyclic Chemistry - Shape (conformation) of cyclohexane, cyclohexene, substituted derivatives (axial and equatorial substituent groups), decalins. Conformational mobility. Steric effects (influence on reactivity). Stereoelectronic control of reactivity (addition, elimination, epoxide formation and ring opening, C=O reduction). Smaller (C3, C5) and larger (C7, C8) rings. Bridged rings.
Aromatic & Heteroaromatic Chemistry- Must be able to discuss the mechanism of electrophilic aromatic substitution, nucleophilic aromatic substitution and the benzyne reaction. Must have a knowledge and understanding of the directing effects of substituents in electrophilic aromatic substitution and important reactions such as diazotisation.
In heteroaromatic chemistry, must be able to discuss that the chemistry of pyridine is dominated by nucleophilic aromatic substitution whereas pyrrole is much more reactive than benzene in electrophilic aromatic substitution and it occurs at C2.
Techniques in Chemistry
Introduction to NMR Spectroscopy
1H NMR spectroscopy: basics of the NMR method; chemical shift and factors affecting δ values; relative integration; multiplicity (n+1 rule); spin-spin coupling and J values; variation of J values (e.g. cis-/trans- alkenes, aryl rings); recognition of standard spin systems (AX, A2X3 etc.); coupling to non-equivalent nuclei (the doublet of doublets etc.); ‘reconstruction’ of more complex spin systems e.g. AMX.
Skills in solving simple structural problems making use of chemical shift, integration, multiplicity, and J values.
Structure, Reactivity and Selectivity
Spectroscopy in Organic Structure Determination – (Development of CH2052/5).
Simple basics of CW and FT NMR methods; 1H and 13C NMR spectra including a deeper knowledge of chemical shift ranges and factors influencing spin-spin coupling (including long-range coupling); the importance of J values in determining conformation and configuration (Karplus etc.); chemical and magnetic equivalence/non-equivalence; homotopic, enantiotopic, diastereotopic nuclei; 1st & 2nd-order spectra; methods for simplifying spectra (including increase of magnetic field; homo- and hetero-nuclear spin decoupling).
VT NMR; time-dependent processes (bond rotation; atom- and site-exchange; tautomerism).
Simple 2-D NMR techniques; homo-and heteronuclear shift-correlated (COSY) spectra and their value (but without practical details of multi-pulse methods).
Basics of mass spectrometry including common fragmentation processes and the basics of IR spectroscopy. Analysis of NMR spectra and the use of NMR (together with other spectroscopic methods) in solving structural and conformational problems.
Frontier molecular orbital analysis – basic concepts
Electrocyclic reactions – simple FMO analysis, con- disrotatory
Cycloadditions – focus on Diels-Alder (FMO analysis, stereospecificity / selectivity)
Sigmatropic rearrangements – FMO analysis of H-migrations, know examples of some common [3,3]-rearrangments.
Chemistry of Rings -Aromatic & Heteroaromatic Chemistry (Appendix)
1. Electrophilic Aromatic Substitution (EAS)
Typical Reagents: (i) Cl2, FeCl3; (ii) HNO3, H2SO4; (iii) SO3, H2SO4; (iv) RCl, AlCl3; (v) RCOCl, AlCl3.
2. Directing Effects of Substituents
Group 1: meta-directing and deactivating (react slower than benzene)
-+NR3, NO2, C≡N, SO3H, COR, CO2H, CO2R, CHO ← order of deactivation
Group 2: ortho-/para-directing and activating (react faster than benzene)
NH2, OH, OR, NHCOCH3, CH3, Ph ← increasing activation
Group 3: ortho-/para-directing and deactivating (react slower than benzene)
Halogens
N.B. If the directing effects of two groups oppose each other, the more powerful activating group has the dominant influence.
3. Diazotisation/Dediazoniation
(i) R=H2O, Z=OH; (ii) R=CuBr, Z=Br; (iii) R=CuCl, Z=Cl; (iv) R=CuCN, Z=CN; (v) R=H3PO2, Z=H.
4. Nucleophilic Aromatic Substitution (NAS)
Aryl halides that contain electron-withdrawing substituents can undergo NAS.
5. Benzyne
6. Chemistry of Pyridine
Pyridine is basic because the nitrogen lone pair of electrons is in an sp2 orbital in the plane of the ring and is not involved with the aromatic π system. Pyridines are very unreactive to normal EAS but are susceptible to nucleophilic aromatic substitution.
7. Chemistry of Pyrrole
Pyrrole is NOT BASIC because the lone pair is involved in the aromatic sextet.
