Organic Chemistry 4 th 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 H N azacylclopropane aziridine NH azacyclobutane azetidine N H CH 3 3-methylazacyclopentane 3-methylpyrrolidine N H CH 3 N 2-methylazacyclohexane 2-methylpiperidine CH 2 CH 3 N-ethylazacyclopentane N-ethylpyrrolidine
Heterocycles with oxygen and sulfur heteroatoms O S O oxacyclopropane oxirane ethylene oxide thiacyclopropane thiirane oxacyclobutane oxetane O O oxacyclopentane tetrahydrofuran O tetrahydropyran O 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 CH 3 CH 2 Br + CH 3 NH 2 CH 3 CH 2 NH 2 CH 3 Br CH 3 CH 2 NHCH 3 + HBr nucleophilic acyl substitution reactions O O CH 3 CH 2 C Cl + 2 CH 3 NH 2 CH 3 CH 2 C NHCH 3 + CH 3 NH 3 Cl
nucleophilic addition elimination reactions O + HN N + H 2 O conjugate addition reactions CH 3 O CH 3 O CH 3 C CHCH + CH 3 NH CH 3 C CH 2 CH CH 3 NCH 3 CH 3
Relative Reactivity of Amine most reactive least reactive RCH 2 F > RCH 2 OH ~ RCH 2 OCH 3 > RCH 2 NH 2 HF H 2 O RCH 2 OH NH 3 pk a = 3.2 pk a = 15.7 pk a = 15.5 pk a = 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 -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 R NH 2 R NH OH R N O R N+ a hydroxylamine a nitroso compound O- O R R R R NH + H 2 O 2 R N+ OH H + OH - R N OH + H 2 O R R R R N R + H 2 O 2 R N+ R + OH - R N R OH O_ + H 2 O
Amine Oxides Undergo a Cope Elimination Reaction
The Gabriel Synthesis of Primary Amines
Other Methods for Synthesizing Amines - 1. N 3 CH 3 CH 2 CH 2 CH 2 Br CH 3 CH 2 CH 2 CH 2 NH 2 2. H 2, Pd/C 1. NaCN, HCl 2. H 2, Pd/C CH 3 CH 2 CH 2 CH 2 CH 2 NH 2
O 1. LiALH 4 R NH 2 2. H 2 O RCH 2 NH 2 O 1. LiALH 4 R NHCH 3 2. H 2 O RCH 2 NHCH 3 O R NCH 3 CH 3 1. LiALH 4 2. H 2 O RCH 2 NCH 3 CH 3
Reduction of Nitro Compounds CH 3 CH 2 NO 2 + H 2 Pd/C CH 3 CH 2 NH 2 Pd/C NO 2 + H 2 NH 2
Reductive Amination econdary and tertiary amines can be prepared from mines 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 N H O benzofuran 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 -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