Pharmaceutical Chemistry Lecture 5 PDF
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Robert Gordon University
Dr Alberto Di Salvo
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This document is a lecture on Pharmaceutical Chemistry, focusing on aromatic compounds, particularly aniline, its properties, synthesis and basicity. It provides a detailed overview and includes discussion points on various chemical structures.
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PL1001 Pharmaceutical Chemistry CHEMISTRY OF AROMATIC COMPOUNDS Lecture 5 Dr Alberto Di Salvo Lecture 5 - content Aniline Purification of amines Synthesis of sulpha drugs from Aniline Napthalene, Anthracene and Phenanthrene Aniline (aminobenzene)...
PL1001 Pharmaceutical Chemistry CHEMISTRY OF AROMATIC COMPOUNDS Lecture 5 Dr Alberto Di Salvo Lecture 5 - content Aniline Purification of amines Synthesis of sulpha drugs from Aniline Napthalene, Anthracene and Phenanthrene Aniline (aminobenzene) NH2 An amine has the general formula: RNH2 (primary amine), R2NH (secondary amine), or R3N (tertiary amine), where R = alkyl or aryl group. For example: where R=methyl → CH3NH2, (CH3)2NH, (CH3)3N etc. When an amino group (-NH2) is directly attached to the benzene ring, the compound is known as ANILINE. Aniline: physical properties Aniline, like all other amines, is a basic compound (Kb = 4.2 x 10-10) Aniline is a polar compound and can form intermolecular hydrogen bonds. Aniline has higher b.p. (184oC) than non-polar compounds of the same molecular weight. Aniline forms hydrogen bonds with water. Hydrogen bonding accounts for the solubility of aniline in water (3.7g/100g water). H H O H H N H H H N N H Basicity of aniline Arylamines are less basic than alkyl amines. The pKa of the anilinium ion is 4.63, whereas methylammonium ion has pKa =10.66. Arylamines (e.g. aniline) are less basic than alkylamines because the nitrogen’s lone-pair electrons are delocalised by interaction with the aromatic ring π electron system and are less available to bond with H+. Arylamines are stabilised with respect to alkylamines because of the five resonance structures that can be drawn: + + + : NH : NH NH2 NH2 NH2 2 2 -: :-.. - Basicity of aniline Resonance stabilisation is lost on protonation, because only two resonance structures are possible for the arylammonium ion. + + NH3 NH3 The free energy difference ΔGo between the protonated and non-protonated forms is higher for arylamines than it is for alkylamines. + Alkylammonium ion, RNH 2 E Arylammonium ion, ArNH + 2 Therefore arylamines are more o N G (alkyl) stable than alkylamines E Alkylamine, RNH 2 R o Resonance G G (aryl) stabilisation Y Arylamine, ArNH 2 Basicity of aniline Electron donating substituents (-CH3, -NH2, -OCH3) increase the basicity of aniline. Electron withdrawing substituents (-Cl, -NO2, -CN) decrease the basicity of aniline. Y NH2 Basicity of aniline Substituent, Y pKa Stonger base -NH2 6.15 Activating -OCH3 5.34 Activating -CH3 5.08 Activating -H 4.63 -Cl 3.98 Deactivating -CN 1.74 Deactivating Weaker base -NO2 1.00 Deactivating Y NH2 Synthesis of sulphonamide antibiotics (sulpha drugs) NH2 O O NHAc NHAc Sulpha drugs: ClSO3H O The amide of sulphanilic acid acetanilide SO2Cl (sulphanilamide) NHAc NH3 p- and certain related acetamidobenzenesulfonylchloride substituted amides. Antimicrobial agent. RNH2 SO2NH2 H+/H2O NH2 NH2 NHAc H+/H2O SO2NH2 SO2NHR SO2NHR sulphanilamide substituted sulphanilamide Isolation and purification of an amine A m ine + N eutral com pound D issolve in e th e r; a d d H Cl, w a ter Ether layer A queous layer (N eutral com pound) (A m ine salt) A d d Na O H, e th er Ether layer A queous layer (am ine) (N aC l) Polynuclear Aromatic Hydrocarbons naphthalene anthracene phenanthrene Polynuclear Aromatic Hydrocarbons are obtained from coal tar. Napthalene is the most abundant (5%) of all constituents of coal tar. Anthracene glycosides Based on the anthracene nucleus but most are derivatives of anthraquinone. O O Anthracene Anthraquinone An example of an anthraquinone glycoside is Rhein-8-O-glucoside. Glucose Aglycone = Rhein O O OH Sugar = Glucose COOH O Rhein-8-O-glucoside Anthracene glycosides An important class of anthracene glycosides are the sennosides. Sennoside A is commonly used as a Laxative. The aglycone increases the peristaltic action of the large intestine. Glucose O O OH COOH COOH Glucose O O OH Sennoside Sennoside is a dimer of Rhein-8-O-glucoside. Anthracene glycosides Another important anthracene glycoside is Doxorubicin (Adriamycin, Rubex) used in the treatment of breast, lung and ovarian cancer (among others). Doxorubicin consists of a modified O OH O anthraquinone aglycone, connected CH2OH to a modified pyranose sugar. OH OMe O OMe H O It belongs to the anthracyclines family of compounds. H3C O H HN It also displays antibacterial OH 2 properties but is not used as Doxorubicin an antibiotic due to its high cytotoxicity.