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Organic Chemistry 4th Edition Paula Yurkanis Bruice Chapter 21 More About Amines. Heterocyclic Compounds Irene Lee Case Western Reserve University Cleveland, OH ©2004, Prentice Hall Amines • An amine is a base as well as a nucleophile • Some amines are heterocyclic compounds (or heterocycles) • Most drugs, vitamins, and many other natural products are heterocycles • A natural product is a compound synthesized by a plant or an animal Alkaloids are natural products that contain one or more nitrogen heteroatoms More About Nomenclature of Heterocycles Cyclic amines CH3 H N NH N H azacylclopropane aziridine N H azacyclobutane azetidine CH3 3-methylazacyclopentane 3-methylpyrrolidine N CH2CH3 2-methylazacyclohexane 2-methylpiperidine N-ethylazacyclopentane N-ethylpyrrolidine Heterocycles with oxygen and sulfur heteroatoms O S oxacyclopropane oxirane ethylene oxide thiacyclopropane thiirane O oxacyclobutane oxetane O O oxacyclopentane tetrahydrofuran O O tetrahydropyran 1,4-dioxane The lone-pair electrons on nitrogen allows an amine to turn “inside out” rapidly at room temperature Amines are the most common organic bases Saturated heterocycles containing five or more atoms have physical and chemical properties typical of their acyclic analogs Reactions of Amines nucleophilic substitution reactions CH3CH2Br CH3NH2 + CH3CH2NHCH3 CH3CH2NH2CH3 + HBr Br nucleophilic acyl substitution reactions O O C CH3CH2 + Cl C 2 CH3NH2 CH3CH2 + NHCH3 CH3NH3Cl nucleophilic addition–elimination reactions O + N HN + H2O conjugate addition reactions CH3 CH3C CH3 O CHCH + CH3NH CH3 CH3C NCH3 CH3 O CH2CH Relative Reactivity of Amine most reactive least reactive RCH2F > RCH2OH ~ RCH2OCH3 > RCH2NH2 HF H2O RCH2OH NH3 pKa = 3.2 pKa = 15.7 pKa = 15.5 pKa = 36 The leaving group of a protonated amine cannot dissociate to form a carbocation or be replaced by a halide ion Reactions of Quaternary Ammonium Hydroxides A Hofmann elimination is an E2 reaction The leaving group of a quaternary ammonium ion has about the same leaving tendency as a protonated amino group The hydrogen is removed from the b-carbon bonded to the most hydrogens A strong base such as hydroxide ion must be used in the elimination reaction Quaternary ammonium salts are used as phase transfer catalysts in facilitating the reactions between certain ionic and organic reactants Consider the reaction between sodium cyanide and an alkyl halide … Oxidation of Amines oxd oxd R NH2 R NH OH R N O O O- R R R NH + H2O2 R H + OH- N+ R R N OH R R R + H2O2 R + H2O N OH R N+ R a nitroso compound a hydroxylamine R oxd N+ OH R + OH R N O_ + H2O R Amine Oxides Undergo a Cope Elimination Reaction The Gabriel Synthesis of Primary Amines Other Methods for Synthesizing Amines 1. CH3CH2CH2CH2Br N3 2. H2, Pd/C 1. NaCN, HCl 2. H2, Pd/C CH3CH2CH2CH2CH2NH2 CH3CH2CH2CH2NH2 O 1. LiALH4 R NH2 2. H2O RCH2NH2 O 1. LiALH4 R NHCH3 2. H2O RCH2NHCH3 1. LiALH4 RCH2NCH3 O R NCH3 CH3 2. H2O CH3 Reduction of Nitro Compounds Pd/C CH3CH2NO2 + NO2 H2 + CH3CH2NH2 H2 Pd/C NH2 Reductive Amination Secondary and tertiary amines can be prepared from imines and enamines by reducing the imines or enamines Aromatic Five-Membered Heterocycles Pyrrole is an extremely weak base The dipole moment in pyrrolidine (left) is attributed to the electron-withdrawing property of the nitrogen atom Pyrrole, furan, and thiophene undergo electrophilic substitution preferentially at C-2 The relative reactivities of the five-membered-ring heterocycles in Friedel–Crafts reaction The resonance hybrid of pyrrole indicates that there is a partial positive charge on the nitrogen Pyrrole is unstable in strongly acid solution because the protonated pyrrole polymerizes Pyrrole’s acidity is increased due to its conjugated base being stabilized by resonance N H O benzofuran indole S benzothiophene Aromatic Six-Membered-Ring Heterocycles The pyridinium ion is a stronger acid than a typical ammonium ion Pyridine Is a Tertiary Amine Pyridine undergoes electrophilic aromatic substitution at C-3 Pyridine undergoes nucleophilic aromatic substitution at C-2 and C-4 Bromination and Oxidation of Substituted Pyridine Diazotization of Aminopyridine The a-hydrogens of alkyl substituents can be removed by base to generate nucleophiles Quinoline and isoquinoline are known as benzopyridines Some Biologically Important Heterocycles Imidazole Porphyrin