PHA111 Aromatic L1.ppt

MPharm Programme Introductory Aromatic Chemistry Dr. Mark Gray Slide 1 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 Recommended Reading Bruice, P. Y. “Organic Chemistry”, 4th Ed. Chapter 7: Electron Delocalization & Resonance Chapter 15: Aromaticity, Reactions of Benzene Chapter 16: Reactions of...

MPharm Programme Introductory Aromatic Chemistry Dr. Mark Gray Slide 1 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 Recommended Reading Bruice, P. Y. “Organic Chemistry”, 4th Ed. Chapter 7: Electron Delocalization & Resonance Chapter 15: Aromaticity, Reactions of Benzene Chapter 16: Reactions of Substituted Benzenes Slide 2 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 Many Drugs are Aromatic Compounds O N O H N OH O O O OH O N H O Aspirin Tamoxifen Slide 3 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 Lopinavir N NH O Infamous Aromatic Drugs N O H N O H N O O O O O Methamphetamine Heroin MDMA OH N O N OH O O O H HN Lysergic Acid Diethylamide O N O O N N OH O OH N Cocaine Slide 4 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 O N S O Sildenafil Citrate N O N H O 86 / 100 drugs are aromatic. Slide 5 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 Aromatic Compounds are found throughout Nature Tryptophan Tyrosine Histidine Phenylalanine O H H2N C C OH CH2 O H H2N C C OH CH2 O H H2N C C OH CH2 O H H2N C C OH CH2 N NH HN OH http://images2.clinicaltools.com/images/gene/dna_bases_nhgri.jpg http://www.scripps.edu/newsandviews/e_20010226/vancomycin.gif Slide 6 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 Why Study Aromatic Chemistry? OH O OH O O O Uses include medicines, perfumes, plastics, dyes, explosives, and LCDs. Slide 7 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 OH N N N OH O Synthetic Aromatic compounds are very common. N OH O O N H O O N S O O H N n O N H n NO2 O2 N NO2 N NO2 N N Aromatic Hydrocarbons Sources i) oCoal 1000 C C oal Inert Atm C oal Tar Fractional Distillation b.p. (°C) 80 m.p. (°C) 80 111 138 216 Slide 8 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 139 144 71 Aromatic Hydrocarbons Sources ii) Oil 500 oC Catalyst Pressure Petroleum contains few aromatics by nature. They can be formed synthetically under extreme conditions. The growth of the petrochemical industry has meant that this is the most widespread method today. Slide 9 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 The Benzene Mystery How did our understanding of Benzene develop to what we now know? How does the chemistry of Benzene compare to other ‘unsaturated’ compounds? How can we describe the properties of benzene in terms of Resonance Stabilisation? Slide 10 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 Benzene First Isolated by Faraday from illuminating gas (1825). C 6H5C O 2H + C aO He called the new compound ‘bicarburet of hydrogen’. Molecular formula (C6H6) Mitscherlich (1834), established by vapour density. C 6H6 + C aC O 3 He re-named the substance benzin (later, benzene) due to its relationship to a known compound: benzoic acid. Slide 11 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 But, what is benzene’s structure? H C H C H C C H C H C H H HH H H H H3C C C C C CH3 C6H6 indicates 4 degrees of unsaturation or ring systems. Many early candidate structures were proposed. Slide 12 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 None explained the reactivity of benzene. no reaction KMnO4 no reaction HCl Benzene H2/Pd no reaction Slide 13 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 Br2 no reaction But, Benzene is not totally unreactive C6H6 + Br2 C6H5Br + Br2 FeBr3 FeBr3  C6H5Br + HBr A: C6H4Br2 B: C6H4Br2 + HBr C: C6H4Br2 Using a metal catalyst benzene can be brominated. Reaction gives substitution, not addition!!! Further reaction gives 3 di-brominated compounds. Slide 14 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 Kekulé got a lot closer First monocyclic hexagonal structure proposed by Kekulé (1865). Problem: Carbon needs a 4th Valence, which broke his own theory (1859). He then suggested that benzene was cyclohexatriene. Slide 15 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 H H H H C C C C H C C H H C C H C C C C H H H H Problems with Cyclohexatriene (i) H H C C H C C H C C H Br2 X H H Br Br C H C H C C C H C H H It is an alkene. We know benzene doesn’t react like an alkene. Slide 16 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 Problems with Cyclohexatriene (ii) H Br H H C C C C H C C H H Br2 FeBr3 H H C C FeBr3 Br2 Slide 17 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 C C H C C H + HBr H What about an Equilibrium? Kekulé then suggested that two isomers of benzene exist in rapid equilibrium. This accounts for the ‘missing’ isomer of dibromo benzene. But, it does not explain why substitution occurs instead of addition. H H H H C C C C H C C H Br C C H C C C C H H Br H Slide 18 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 H H H H C C C C H C C H Br C C H C C C C H H Br H Fast forward to the 1930s…… X-ray and electron diffraction were now available. They showed that benzene has a symmetric hexagonal structure. The C-C bond length is intermediate between single (~1.54 Å) and double (~1.33 Å). Slide 19 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 1.40Å 1.08Å Can we describe benzene as a resonance hybrid? Slide 20 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 Examples of Resonance Hybrids (i) Ethanoate (Acetate) O O O = O O O Chemical resonance hybrids are only available for compounds containing delocalised electrons. This allows for electrons to move freely from one part of a molecule to another. Slide 21 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 Freedom of electron movement increases stability. Slide 22 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 Examples of Resonance Hybrids (i) 1,3-Butadiene Only electrons can move, never nuclei. Only electrons in -bonds and lone pairs can take part. The total charge and the number of electrons (paired / unpaired) must stay constant. Slide 23 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 Benzene is a resonance hybrid H H H H H H C C C C C C H H C C H C C C C H H H H H H H H C C C C Slide 24 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 C C H H C C H C C C C H H H H Common representations of benzene  H Ph-H Remember, left structure is benzene not cyclohexatriene. But, drawing double bonds lets us count electrons easily. Slide 25 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 Can we quantify the unusual stability of benzene? H2, Ni o 250 C, 25 atm H° = -208 kJ/mol Slide 26 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 We can compare the reduction of benzene to ‘cyclohexatriene’. 360 Energy kJ/mol (152) 231 208 120 Slide 27 of 29 MPharm MPH117 Aromatic Chemistry Lecture 1 What about a real triene? + 3H2 Ho = -337 kJ/mol + 3H2 Ho = -208 kJ/mol The closest alkene that exists to cyclohexatriene is (Z)-1,3,5-hexatriene. Benzene has an enthalpy of hydrogenation ~130 kJ/mol lower than the alkene. Therefore, cyclic conjugated systems are essential for aromaticity. Slide 28 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1 Summary Aromatic compounds have a wide range of applications. Benzene, the archetypal aromatic compound is unusually unreactive compared to alkenes. When benzene does react, it prefers to undergo substitution rather than addition. We can explain these properties using resonance. Slide 29 of 29 MPharm PHA111 Aromatic Chemistry Lecture 1