PHA111 Aromatic Chemistry Lecture 3 PDF

MPharm Programme Aromatic Chemistry: Reactions of Benzene Dr. Mark Gray Slide 1 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 Reactions of Benzene Electrophilic Aromatic Substitution – Halogenation – Friedel-Crafts Alkylation – Friedel Crafts Acylation – Sulfonation – Nitration Slide 2 of 28 MPha...

MPharm Programme Aromatic Chemistry: Reactions of Benzene Dr. Mark Gray Slide 1 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 Reactions of Benzene Electrophilic Aromatic Substitution – Halogenation – Friedel-Crafts Alkylation – Friedel Crafts Acylation – Sulfonation – Nitration Slide 2 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 Benzene is electron rich Slide 3 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 The defining reaction is electrophilic aromatic substitution (EAS) E + E+ Slide 4 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 + H+ A general mechanism for EAS E H E H E H E E Addition of the electrophile creates a resonance stabilized intermediate. This species is sometimes called a s-complex, arenium ion or Wheland Intermediate. Slide 5 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 H A better look at the reaction profile d E H d E H d E H d DG E +H +E Reaction Coordinate Slide 6 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 Structure of a Wheland Intermediate Slide 7 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 Examples of EAS: Bromination Br FeBr3 + Br2 + HBr Br Cl N Br N O O N Lonafarnib farnesyl transferase inhibitor (anticancer) Slide 8 of 28 MPharm PHA111 Br NH2 Et N Me Me ptsa Bretylium (treatment for irregular heart rhythms) Aromatic Chemistry Lecture 3 Bromination Mechanism Br Br Br Br FeBr3 Br-FeBr4 Br-FeBr3 Br-FeBr3 Br H Br + HBr + FeBr3 Slide 9 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 Br H Br H Chlorination is very similar Cl AlCl3 + Cl2 + HCl COOH MeO N O O N N N N Cl Cl Indometacin NSAID (cyclooxygenase inhibitor) Slide 10 of 28 MPharm NH Cl PHA111 Clorgiline antidepressant (MAO-A inhibitor) Aromatic Chemistry Lecture 3 Cl Clozapine antipsychotic (dopaminergic receptor antagonist) Mechanism for chlorination Cl AlCl3 Cl Cl Cl Cl-AlCl3 Cl-AlCl3 Cl AlCl3 Cl H Cl + HCl + AlCl3 Slide 11 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 Cl H Cl H Iodination is easier [ox] eg HNO3 I2 or -e I :B Br I H I + HB Slide 12 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 Br H I BrI H 2I Phenyl Iodides in Medicinal Chemistry S O I O S O O HO MeO OH OH OMe OMe HO S S H O O N O H O H O N MeO O NHCO2Me Calicheamicin g1 Bacterial Natural Product (Antitumor: DNA Chain Cutter) Cl N CN Cu powder I I CN OH N 210 oC Losartan antihypertensive Slide 13 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 N N K N N Synthesis of Cumene HF Slide 14 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 Friedel-Crafts Alkylation R AlBr3 + R-Br OH Cl N HOOC Cl HO H N HO Chlorambucil DNA Alkylating agent (Anticancer) Slide 15 of 28 MPharm + H-Br PHA111 Dobutamine Adrenergic b1-Agonist (Cardiogenic shock treatment) Aromatic Chemistry Lecture 3 Mechanism of Friedel-Crafts Alkylation R AlBr3 R Br R Br-AlBr3 Br-AlBr3 Br-AlBr3 R H R + HBr + AlBr3 Slide 16 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 R H R H But for most alkanes it doesn’t work like that…... + Br AlBr3 + minor Slide 17 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 major So, why did that happen? Br AlBr3 AlBr4 AlBr4 Slide 18 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 Friedel-Crafts Acylation O R O + Cl R AlCl3 + HCl N H O O O OH HO S Raloxifene Oestrogen receptor antagonist (Breast Cancer Treatment) Slide 19 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 S Lucanthone Anti-parasitic (Bilharzia Treatment) NEt2 Puzzle: Mechanism of FriedelCrafts Acylation? O R Cl Slide 20 of 28 MPharm AlCl3 PHA111 O R Aromatic Chemistry Lecture 3 O R AlCl4 Warning, catalyst must be added in excess for Friedel-Crafts acylation R R O + AlCl3 Slide 21 of 28 MPharm MPH117 O AlCl3 3H2O Aromatic Chemistry Lecture 3 R O Al(OH)3 + 3HCl Sulfonation of benzene SO3H H2SO4 O S O O NH2 S O N N H H2N H2N Sulfanilamide First Antibacterial Agent Sulfadoxine Antibacterial (One dose / week) Slide 22 of 28 MPharm PHA111 N O OMe OMe Aromatic Chemistry Lecture 3 HOOC O N H Succinyl Sulfathiazole Antibacterial (Intestinal Infections) S O N N H S Sulfonation of Benzene: electrophile generation 2 H2SO4 SO3 + H3O + HSO4 Oleum O S O Slide 23 of 28 MPharm O PHA111 O S O O Aromatic Chemistry Lecture 3 O S O O Sulfonation of benzene: EAS O S O O O O S OH Slide 24 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 O O H S O O O S O Nitration of benzene NO2 HNO3 H2SO4 D Cl H HO Cl O H OH F3C S H N O O O2N O2N Chloramphenicol antibacterial (eye drops) Flutamide Antiandrogen (Prostate Cancer) Slide 25 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 P OEt OEt O2N Parathion Insecticide (Inactive against mammals) Nitration of benzene: electrophile generation O2N OH H O SO3H NO2 + H2O Slide 26 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 H O2N O H Puzzle: Nitration of benzene: EAS Slide 27 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 Summary NO2 SO3H Cl I O R R Slide 28 of 28 MPharm PHA111 Aromatic Chemistry Lecture 3 Br