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Amines and Heterocyclic Compounds Amines – Organic Nitrogen Compounds • Organic deriva7ves of ammonia, 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 addi7on to proteins and nucleic acids, a majority of pharmaceu7cal agents contain amine func7onal groups Proper7es 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 subs7tuents on nitrogen is chiral (in principle but not in prac7ce) : the lone pair of electrons is the fourth subs7tuent • Most amines that have 3 different subs7tuents on N cannot be resolved because the molecules interconvert by pyramidal inversion Amines Form H-­‐Bonds • Amines with fewer than five carbons are water-­‐soluble • Primary and secondary amines form hydrogen 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 electrophiles Rela7ve 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 • Addi7on of a proton occurs on O but this destroys the double bond character of C=O as a requirement of stabiliza7on by N= Basicity of Arylamines • The N lone-­‐pair electrons in arylamines are delocalized by interac7on with the aroma7c ring π electron system and are less able to accept H+ than are alkylamines Subs7tuted Arylamines • Can be more basic or less basic than aniline • Electron-­‐dona7ng subs7tuents (such as –CH3, –NH2, –OCH3) increase the basicity of the corresponding arylamine • Electron-­‐withdrawing subs7tuents (such as –
Cl, –NO2, –CN) decrease arylamine basicity Subs7tuted Arylamines (Cont’d) Biological Amines and the Henderson-­‐
Hasselbalch Equa7on Henderson-­‐Hasselbalch Equa7on: ⎡ A − ⎤
pH = p K a + log ⎣ ⎦
so
⎡⎣ HA ⎤⎦
⎡ A − ⎤
log ⎣ ⎦ = pH − p K a
⎡⎣ HA ⎤⎦
• 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 proper7es typical of acyclic amines. pKa Values Amines are the most common organic bases. Five-­‐Membered Ring Aroma7c 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 Imidazole • Pyrole is an amine and a conjugated diene, however its chemical proper7es are not consistent with either of these structural features Chemistry of Pyrole • Electrophilic subs7tu7on reac7ons occur at C2 because it is posi7on next to the N • A more stable intermediate ca7on 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 aroma7city. Dipole Moments The dipoles are in different direc7ons. Delocaliza7on Energy Delocaliza7on energy increases as the resonance contributors become more stable and more nearly equivalent. Electrophilic Aroma7c Subs7tu7on Reac7ons Why at the 2-­‐Posi7on? If the 2-­‐Posi7on Is Unavailable, Subs7tu7on will Occur at the 3-­‐Posi7on Rela7ve Reac7vites Five-­‐Membered Ring Aroma7c Heterocycles are More Reac7ve Than Benzene Protona7on Occurs at the 2-­‐Posi7on a proton is an electrophile so, like other electrophiles, it goes to the 2-position Pyrrole Polymerizes in Acid pKa Values Pyrrole is more acidic than pyrrolidine because its conjugated base is stabilized by electron delocaliza7on. pKa Values Pyridine is Aroma7c pKa Values The pyridinium ion is a stronger acid than a typical ammonium ion. Which is More Reac7ve in an Electrophilic Aroma7c Subs7tu7on Reac7on? Pyridine Can React as a Nucleophile The Resonance Contributors for Pyridine Electrophilic Subs7tu7on Occurs at the 3-­‐Posi7on Rela7ve Reac7vity Pyridine is Less Reac7ve Than Benzene in Electrophilic Aroma7c Subs7tu7on Reac7ons Pyridine Also Undergoes Nucleophilic Aroma7c Subs7tu7on Reac7ons the mechanism Nucleophilic Subs7tu7on Occurs at the 2-­‐Posi7on and the 4-­‐Posi7on Nucleophilic Aroma7c Subs7tu7on Reac7ons In nucleophilic aroma7c subs7tu7on reac7ons, the ring has a leaving group that can be replaced by a nucleophile. Reac7ons of the Side Chain Subs7tuted pyridines undergo the same side-­‐chain reac7ons that subs7tuted benzenes undergo. Forming Diazonium Ions The keto form is more stable than the enol form. The Methyl Group at the 2-­‐Posi7on or 4-­‐Posi7on is “Acidic” Some Reac7ons That Result from the Acidity of the Methyl Group Heterocyclic Amino Acids Imidazole The Nitrogens are Equivalent in Protonated Imidazole and in the Imidazole Anion An7histamines Purine and Pyrimidine The Porphyrin Ring System