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Home , Pyrrole

Amines and Heterocyclic Compounds – Organic Compounds

• Organic derivaves of , NH3 • Nitrogen atom with a lone pair of electrons, making amines both basic and nucleophilic • Occur in plants and animals Heterocyclic Amines • A heterocycle is a cyclic compound that contains atoms of two or more elements in its ring, usually C along with N, O, or S Why this Chapter? • Amines and carbonyl compounds are the most abundant and have rich chemistry

• In addion to proteins and nucleic acids, a majority of pharmaceucal agents contain funconal groups Properes of Amines

• Bonding to N is similar to that in ammonia – N is sp3-hybridized – C–N–C bond angles are close to 109° tetrahedral value Chirality Is Possible (But Not Observed)

• An amine with three different substuents on nitrogen is chiral (in principle but not in pracce) : the lone pair of electrons is the fourth substuent • Most amines that have 3 different substuents on N cannot be resolved because the molecules interconvert by pyramidal inversion Amines Form H-Bonds

• Amines with fewer than five are water-soluble • Primary and secondary amines form bonds, increasing their boiling points Basicity of Amines

• The lone pair of electrons on nitrogen makes amines basic and nucleophilic • They react with acids to form acid–base salts and they react with Relave Basicity

• Amines are stronger bases than alcohols, ethers, or water • Amines establish an equilibrium with water in which the amine becomes protonated and hydroxide is produced • The most convenient way to measure the basicity of an amine (RNH2) is to look at the acidity of the corresponding ammonium + ion (RNH3 ) • High pKa → weaker acid and stronger conjugate base. Amides

• Amides (RCONH2) in general are not proton acceptors except in very strong acid • The C=O group is strongly electron-withdrawing, making the N a very weak base • Addion of a proton occurs on O but this destroys the double bond character of C=O as a requirement of stabilizaon by N= Basicity of Arylamines

• The N lone-pair electrons in arylamines are delocalized by interacon with the aromac ring π electron system and are less able to accept H+ than are alkylamines Substuted Arylamines • Can be more basic or less basic than

• Electron-donang substuents (such as –CH3, –NH2, –OCH3) increase the basicity of the corresponding arylamine • Electron-withdrawing substuents (such as – Cl, –NO2, –CN) decrease arylamine basicity Substuted Arylamines (Cont’d) Biological Amines and the Henderson- Hasselbalch Equaon Henderson-Hasselbalch Equaon: ⎡A− ⎤ ⎡A− ⎤ pH = p K + log ⎣ ⎦ so log ⎣ ⎦ = pH − p K a ⎡HA⎤ ⎡HA⎤ a ⎣ ⎦ ⎣ ⎦ • In what form do amines exist at physiological pH inside cells? Saturated Heterocyclic Compounds

Saturated amine heterocycles containing five or more atoms have physical and chemical properes typical of acyclic amines. pKa Values

Amines are the most common organic bases. Five-Membered Ring Aromac Heterocyclic Compounds Common Names of Heterocyclic Amines

• If the nitrogen atom occurs as part of a ring, the compound is designated as being heterocyclic • Each ring system has its own parent name Polycyclic Heterocycles Pyrole and

• Pyrole is an amine and a conjugated , however its chemical properes are not consistent with either of these structural features Chemistry of Pyrole

• Electrophilic substuon reacons occur at C2 because it is posion next to the N

• A more stable intermediate caon having 3 resonance forms • At C3, only 2 resonance forms The Resonance Contributors for Pyrrole

Pyrrole is an extremely weak base because its lone pair is needed for its aromacity. Dipole Moments

The dipoles are in different direcons. Delocalizaon Energy

Delocalizaon energy increases as the resonance contributors become more stable and more nearly equivalent. Electrophilic Aromac Substuon Reacons Why at the 2-Posion? If the 2-Posion Is Unavailable, Substuon will Occur at the 3-Posion Relave Reacvites Five-Membered Ring Aromac Heterocycles are More Reacve Than Protonaon Occurs at the 2-Posion

a proton is an so, like other electrophiles, it goes to the 2-position Pyrrole Polymerizes in Acid pKa Values

Pyrrole is more acidic than because its conjugated base is stabilized by electron delocalizaon. pKa Values is Aromac pKa Values

The pyridinium ion is a stronger acid than a typical ammonium ion. Which is More Reacve in an Electrophilic Aromac Substuon Reacon? Pyridine Can React as a The Resonance Contributors for Pyridine Electrophilic Substuon Occurs at the 3-Posion Relave Reacvity Pyridine is Less Reacve Than Benzene in Electrophilic Aromac Substuon Reacons Pyridine Also Undergoes Nucleophilic Aromac Substuon Reacons

the mechanism Nucleophilic Substuon Occurs at the 2-Posion and the 4-Posion Nucleophilic Aromac Substuon Reacons

In nucleophilic aromac substuon reacons, the ring has a leaving group that can be replaced by a nucleophile. Reacons of the Side Chain

Substuted undergo the same side-chain reacons that substuted undergo. Forming Diazonium Ions

The keto form is more stable than the enol form. The Methyl Group at the 2-Posion or 4-Posion is “Acidic” Some Reacons That Result from the Acidity of the Methyl Group Heterocyclic Amino Acids Imidazole The are Equivalent in Protonated Imidazole and in the Imidazole Anion Anhistamines Purine and The Ring System