PHA111 Aromatic L4-1.ppt

MPharm Programme Aromatic Chemistry: Reactions of Substituted Benzenes Dr. Mark Gray Slide 1 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 Recap: Electrophilic Aromatic Substitution (EAS) NO2 SO3H Cl I O R R Slide 2 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 Br Reactions of Substituted Benz...

MPharm Programme Aromatic Chemistry: Reactions of Substituted Benzenes Dr. Mark Gray Slide 1 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 Recap: Electrophilic Aromatic Substitution (EAS) NO2 SO3H Cl I O R R Slide 2 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 Br Reactions of Substituted Benzenes Synthesis: – Alkylbenzenes → – Phenol – Metal-Halogen Exchange → – Functional group interconversions – Introduction to Aniline Slide 3 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 Alkylbenzenes + Br AlBr3 + minor Friedel Crafts alkylation provides the most direct route to alkylbenzenes major However, carbocation rearrangements limit synthetic utility. Slide 4 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 This does however have H some synthetic use…. O O O H O2 OH O H H O O H O O -H 1.5 million tons / yr Slide 5 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 H O H Some (of the many!!!) phenol derived drugs O O OH O O H N N O Aspirin analgesic HO N N H O S O N NH2 COOH HO Levodopa Parkinsons Disease N Viagra Erectile Dysfunction Slide 6 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 Expanding our range of aromatic acylations O O Cl + HCl AlCl3 O O O AlCl3 Slide 7 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 O O + HO The Gatterman-Koch formylation O HCl + CO O Pressure H H Cl + HCl AlCl3 Slide 8 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 Puzzle: Reaction with cyclic anhydrides O O O AlCl3 Slide 9 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 Ring closure – The Haworth Reaction. O OH H O Slide 10 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 Fused ring drug examples N N N O MeO HO O O O OH O OH Codeine Morphine O Heroin OH H H H Ethinylestradiol oral contraceptive HO Slide 11 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 O Alkylbenzenes via reduction of acylbenzenes O O R Cl R Zn(Hg), HCl R H2 Pd-C AlCl3 NH2NH2, HO After Friedel-Crafts acylation alkylbenzene can be prepared in one of 3 ways. Acidic: Clemmensen Reduction, Neutral: Catalytic Hydrogenation, Basic: Wolff-Kishner reaction. Slide 12 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 Examples of important alkylbenzene derivatives NH2 H N MeO OMe OMe methamphetamine mescaline (peyote cactus) Slide 13 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 Mechanism of the WolffKishner Reaction O N H N N H N H N H H H N O H H HO H2N NH2 H N H -N2 N N H H HO Slide 14 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 O H N H Adding functionality to alkylbenzenes O N Br Br O O O O O Br Br2  / h Slide 15 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 A brief mechanism of bromination H H H Br + HBr Br-Br O O Br H HBr + N Br O N H + Br-Br O Slide 16 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 The benzyl radical is unusually stable H H Slide 17 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 Benzylic bromides undergo all the normal alkyl halide reactions NH2 1) NH3 O 2) OH Br OH OH O CN NHMe Atomoxetine ADHD Treatment Slide 18 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 CN Metal-Halogen Exchange Aryl bromides & iodides can be converted to Grignard Reagents or Lithium salts.(X=Br, I) Mg X These products behave like aryl anions. MgX Et2O BuLi -78 oC synthon "behaves like" Li Slide 19 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 Grignard Reagents can be made in the presence of a chloro group Br MgBr Mg Cl Et2O Cl However, Grignard Reagents and Lithium salts are both strong bases. This means they will be deactivated if any acidic functionality is present. Slide 20 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 Uses of Grignard Reagents as nucleophiles: i) synthesis of benzoic acids Br O MgBr Mg Cl O CO2 Et2O O O H3O Cl Cl OH O O O O OH O O Aspirin analgesic OH O H2N NH O O O OH Paclitaxel Anti-cancer Benzocaine local anesthetic Slide 21 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 O HO OH O O O Cl Uses of Grignard Reagents as nucleophiles: ii) reaction with carbonyls OH Br MgBr Mg Et2O O 1) 2) H3O Slide 22 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 Examples of important benzylalcohols OH H N OH H N HO OH adrenaline Slide 23 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 ephedrine Puzzle: Uses of Grignard Reagents as nucleophiles: iii) reaction with epoxides Br MgBr Mg Et2O 1) O 2) H3O Hint: See Taxol Structure Slide 24 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 Functional Group Interconversions: some useful oxidation reactions of primary alcohols O OH + MnO2 H  O OH + KMnO4 OH  H O OH + Na2Cr2O7  H Slide 25 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 OH Functional Group Interconversions: some useful oxidation reactions of secondary alcohols O OH + MnO2  O OH + KMnO4 OH  H O OH + Na2Cr2O7  OH H Ketones produced under mild conditions. However, benzoic acids are again obtained with stronger reagents! Slide 26 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 In fact, we don’t need an alcohol at all…. O + KMnO4 O OH   + KMnO4 H OH H O  + KMnO4 OH H  + KMnO4 H Primary and secondary alkylbenzenes give benzoic acids too. However, tertiary alkyl substituted benzenes are unreactive. Slide 27 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 no reaction How does that work? H H H [Ox] O H -H [Ox] OH Mechanism is very complicated, and still under debate. However, it is believed that the key is formation of a benzylic cation. Slide 28 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 Functional Group Interconversions: some useful reduction reactions + H2 CN + H2 NO2 Pt Pt + H2 NH2 NO2 Pd-C 1) Sn, HCl 2) OH Slide 29 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 NH2 NH2 Aniline is an aromatic O amine NH2 Cl H N O Et3N CH2Cl2 O NH2 H N + H2O Aniline can react with acid chlorides to give amides and carbonyl compounds to give imines. However, it is significantly less reactive than alkyl amines. This is due to conjugation of the nitrogen lone pair with the benzene ring. Slide 30 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 Aniline derived drug examples NH2 H N Cl N Cl N H Clonidine Anti-hypertensive H N O N H O O Aminoglutethimide Anti-cancer Lidocaine local anesthetic NMe2 N NEt2 Imipramine tricyclic antidepressant Slide 31 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4 Aniline can also form diazonium salts…. But we’ll talk about that Next Time….. Slide 32 of 32 MPharm PHA111 Aromatic Chemistry Lecture 4