Biological Chemistry FIRST YEAR ORGANIC CHEMISTRY

1. Biological ChemistryFIRST YEAR ORGANIC CHEMISTRY Lecture Five Aromatics, Heterocycles Amines and Alkaloids Convenor: Dr. Fawaz Aldabbagh

2. An Aromatic Hydrocarbon is a cyclic compound that does not readily undergo addition reactions Reactivity is different to other unsaturated compounds-Substitution rather than Addition is favoured. Benzene C6H6 High Carbon content – burn with a smoky flame Delocalisation, Resonance -Stabilise molecules, so make them less reactive Resonance Structure - Rearrange the bonding electrons Delocalised or Conjugated System – p-bonding electrons can move within the molecule

3. Kekul said that he dreamt the structure of benzene – so called Kekul structure of benzene Each carbon atom uses the sp2 hybrids to form sigma bonds with two other carbons and one hydrogen atom. In aromatic compounds the C atoms are sp2 hybrids, so that each C atom has one remaining p-electron involved in p-bonding Three sp2 hybrid orbitals arrange themselves as far apart as possible - which is at 120° to each other in a plane. The remaining p orbital is at right angles to them. Each carbon atom uses the sp2 hybrids to form s-bonds with two other carbons and one hydrogen atom. This extensive sideways overlap produces a system of p-bonds which are spread out over the whole carbon ring. Because the electrons are no longer held between just two carbon atoms, but are spread over the whole ring, the electrons are said to be delocalised.

4. Flat (Planar) Molecule Regular Hexagon p-Electron Density Rings above and below the plane of the ring – Susceptible to electrophilic attack Benzene is a colourless odourless liquid that is a suspected carcinogen Benzene and its derivatives are said to be aromatic - a term coined because of the strong fragrance of some of the derivatives of benzene Non-aromatic compounds are said to be aliphatic Michael Faraday first isolated benzene in 1825

5. Electrophilic Aromatic Substitution Electrophilic attack – Slow Rate Determining Step Transition State Delocalised Cyclohexadienyl cation

6. Loss of a proton – fast step e.g. The Nitration of benzene Sir Christopher Ingold's ideas (1930s), terminology and nomenclature for reaction mechanisms (e.g. electrophilic, nucleophilic, inductive, mesomeric, SN1, SN2 etc) were generally accepted and employed everywhere.

7. Mechanism Friedel-Crafts Alkylation Lewis Acid Catalyst is used to activate the alkyl halide A catalyst is usually a molecule which speeds up a reaction, and is required in only a small amount. It is regenerated at the end of the reaction

8. Friedl-Crafts Alkylation

9. HALOGENATION Professor Charles Friedel and Professor James Crafts The Halogen is polarised

10. Naming Aromatic Hydrocarbons Fluorobenzene Ethylbenzene Toluene Aniline -ortho -meta Phenol Benzoic Acid 1,2-Dichlorobenzene 1,3-Dichlorobenzene -para o-Xylene m-Bromostyrene 1,4-Dichlorobenzene 2,4,6-Trinitrotoluene (TNT)

11. Rules for Aromaticity • Must be cyclic • Must be planar • Each atom of the ring must have a p orbital and these p orbitals must be perpendicular to the plane of the ring • Must contain 4n+2 p-electrons (where n = 0, 1, 2, ...) –Hückel Rule 10 p-electrons 14 p-electrons

12. HETEROCYCLES Aromatics with one non-carbon or Heteroatom Pyridine Pyrrole Imidazole N atom in Pyridine, one of the N atoms in Imidazole and both N atoms in Pyrimidine possess a basic lone pair of electrons Thiophene Pyrimidine Indole Most Pharmaceutical compounds are Heterocycles and derivatives • ALL ARE AROMATIC • Planar • Uninterrupted Cycle of p-orbitals • All Atoms are sp2 hybridized • Obey Hückel’s Rule

13. Amines are organic bases Aromatic Amine Aliphatic Amines

14. Alkaloids Extractions from bark, leaves, berries and fruits yields nitrogen containing bases called alkaloids Name comes from “alkali or base-like” – most react with acids to give soluble salts. Common ending ine, reflecting the fact they are all amines. The names are all non-systematic. Most produce striking physiological effects that vary from alkaloid to alkaloid.

15. Erythroxylum coca 1% is cocaine

16. Papaver somniferum (opium poppy) Morphine is a potent analgesic Used in medicine to relieve “deep” pain Addiction + depression + respiratory falure Professor Marshall Gates – In 1952 First Synthesis + Conformation of the structure of morphine

17. Alkaloids containing Indole or Reduced Indole Ring Gramine Strychnine Death results from paralysis of the respiratory muscles Small doses stimulate the respiratory centre, larger doses paralyse it. Juice of the fresh bark is used in cholera and dysentery. The dried bark is given either as a decoction or as a paste. A poultice made of leaves is used for chronic ulcers. The seeds boiled in milk, are pounded into a paste and given to opium addicts: this is believed to be effective in curing addiction Strychnos nuxvomica