Heterocyclic Compounds 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 azacylclopropane aziridine azacyclobutane azetidine 3-methylazacyclopentane 3-methylpyrrolidine 2-methylazacyclohexane 2-methylpiperidine N-ethylazacyclopentane N-ethylpyrrolidine

Heterocycles with oxygen and sulfur heteroatoms oxacyclopropane oxirane ethylene oxide thiacyclopropane thiirane oxacyclobutane oxetane oxacyclopentane tetrahydrofuran 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 nucleophilic acyl substitution reactions

nucleophilic addition–elimination reactions conjugate addition reactions

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 oxd a hydroxylamine a nitroso compound

Cope Elimination Reaction Amine Oxides Undergo a Cope Elimination Reaction

The Gabriel Synthesis of Primary Amines

Other Methods for Synthesizing Amines

Reduction of Nitro Compounds

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

indole benzofuran 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

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