Heterocyclic Compounds Organic Chemistry 6th Edition Paula Yurkanis Bruice Chapter 21 More About Amines Heterocyclic Compounds

Nomenclature of Heterocycles Cyclic amines (the names in quotes are preferred): Nitrogen is #1 when numbering the ring

Heterocycles with oxygen and sulfur heteroatoms (the names in quotes are preferred):

Acid–Base Properties of Amines Amines are the most common organic bases:

Saturated amine heterocycles containing five or more atoms have physical and chemical properties typical of acyclic amines:

Amines React as Bases and as Nucleophiles The lone-pair electron on the nitrogen of an amine causes it to be nucleophilic as well as basic:

Reactions of Amines Nucleophilic substitution reactions: Nucleophilic acyl substitution reactions:

Nucleophilic addition–elimination reactions:

Conjugate addition reactions:

Reactions of Quaternary Ammonium Hydroxides The Hofmann elimination is an E2 reaction: D 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: The least-substituted alkene elimination product is often called the Hofmann product

Quaternary ammonium ions, like alkyl fluorides, are poor leaving groups:

Hofmann elimination requires exhaustive methylation of the amine, followed by elimination: 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 Mechanism:

Tertiary Amine Oxides Undergo a Cope Elimination Reaction The proton is removed from the b-carbon bonded to the most hydrogens

Synthesis of Amines Because ammonia and amines are good nucleophiles, they readily undergo SN2 reactions with RX: It is difficult to control the desired number of alkyl substituents placed on the nitrogen

The Gabriel Synthesis of Primary Amines

Other Methods for Synthesizing Amines

Reduction of amides with LiAlH4:

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:

Electrophilic aromatic substitution reactions:

Structures of the intermediates that can be formed from the reaction of an electrophile with pyrrole at C-2 and C-3 Three resonance structures: more stable Two resonance structures: less stable

If both positions adjacent to the heteroatom are occupied, electrophilic substitution occurs at C-3:

Why? Because of cation stabilization by lone-pair resonance release:

The relative reactivities of the five-membered 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:

Five resonance structures for the anion Pyrrole is more acidic than pyrrolidine because of stabilization of its conjugated base by resonance Five resonance structures for the anion Localized anion

Indole, benzofuran, and benzothiophene all contain a five-membered aromatic ring fused to a benzene ring:

Aromatic Six-Membered-Ring Heterocycles

The pyridinium ion is a stronger acid than a typical ammonium ion Pyridine reacts like a tertiary amine:

Pyridine Is Aromatic The nitrogen lone pair is not released into the aromatic system because it is perpendicular to the  system. The nitrogen withdraws electrons by resonance, resulting in an electron-deficient ring system.

Pyridine undergoes electrophilic aromatic substitution at

The pyridine nitrogen is a meta director:

Pyridine is reactive toward nucleophilic aromatic substitution because of the presence of the electronegative nitrogen:

Pyridine undergoes nucleophilic aromatic substitution at C-2 and C-4:

If the leaving groups at C-2 and C-4 are different, the incoming nucleophile will preferentially substitute for the weaker base:

Bromination and Oxidation of Substituted Pyridine

Diazotization of Aminopyridine

The a-hydrogens of alkyl substituents can be removed by base to generate anionic nucleophiles: Pyridine a-hydrogen acidity is similar to that of ketone a-hydrogens

Reactions of pyridine-based anionic nucleophiles:

Quinoline and isoquinoline are ring-fused pyridine derivatives:

Some Biologically Important Heterocycles Imidazole

Purine and Pyrimidine

Porphyrin