![N
NH2N
H2N
-H2O
N
H
H
N
Piperazine
Pyrazine
O
[O]
From epoxide ring opening reaction with ethylenediamine followed by
oxidation leads to formation of pyrazine derivatives.](https://image.slidesharecdn.com/pyrazine-200419165814/85/Synthesis-and-reactions-of-Pyrazine-9-320.jpg)
Synthesis and reactions of Pyrazine
- 1. Synthesis, reactivity, aromatic character and importance of Pyrazine Prepared by Dr. Krishna swamy Faculty DOS & R in Organic Chemistry Tumkur University
- 2. Pyrazine is a six membered heterocyclic compound of the Diazines type derived from benzene by replacement of two -CH group by two nitrogen atoms at 1st and 4th position. N N N N N N Diazines Replace two CH group by two nitrogen atom
- 3. Pyrazine occurs naturally but not in appreciable amount and following pyrazine ring system occurs in nature. N N N N Pteridine N N Phenazine N N N N NH O COOH HOOC NH H2C OH NH2 Folic acid
- 4. Pyrazine belong to the category of π-deficient ring systems similar to pyridine. Pyrazine is aromatic in nature and lone pair on sp2 hybridized nitrogen are not involved involved in aromatic sextet.
- 5. Pyrazine is very weak base (pKa = 0.6) compared to pyridine due to inductive and electron withdrawing effect of second nitrogen atom.
- 6. Pyrazine ring has the following resonance contributors and positive charge will placed on the 2, 3, 5 and 6-position carbons. N N N N N N N N N N
- 7. From alpha nitroso / nitro / azide Ketones by chemo selective reduction (Zn/CH3COOH) followed by spontaneous dimerization and subsequent oxidation leads to formation of pyrazine derivatives. Synthesis R1 OR2 NO R1 OR2 NO2 R1 OR2 N3 R1 OR2 NH2 R1 NR2 N R2 R1 R1 NR2 N R2 R1 Chemoselective reduction Dimerization -H2O Oxidation
- 8. R1 OR2 O R1 NR2 N R2 R1 R1 NR2 N R2 R1 Oxidation R1 H2N R2 H2N -2H2O From condensation reaction of alpha diketone with 1, 2-diaminoalkanes n followed by oxidation in presence of CuCrO4 at 300oC leads to formation of pyrazine derivatives.
- 9. N NH2N H2N -H2O N H H N Piperazine Pyrazine O [O] From epoxide ring opening reaction with ethylenediamine followed by oxidation leads to formation of pyrazine derivatives.
- 10. Intermolecular deaminocyclization of ethylenediamine followed by dehydrogenation over copper chromite catalyst gives pyrazine. N N N H N NH2 NH2 -2NH3 N H H N -H2 N H N -H2 -H2 Piperazine tetrahydropyrazine dihydropyrazine Pyrazine 2
- 11. Reactions of Pyrazine Pyrazine undergoes reaction at Nitrogen as well as at Carbon similar to Pyridine. Electrophilic addition reaction like Protonation and alkylation occurs at ring nitrogen Electrophilic substitution reaction less facile because of decreased basicity and under favorable conditions reaction occurs. Nucleophilic substitution.
- 12. Reactions at Nitrogen Electrophilic addition at Nitrogen Lone pair of electrons on the ring nitrogen undergoes electrophilic addition reaction with electrophiles only at one nitrogen and under drastic condition both nitrogen undergo electrophilic addition. This electrophilic addition results in the formation of pyrazinium salts. BOTH ARE AROMATIC N N E N N E
- 13. Protonation at Nitrogen Pyrazine nitrogen form mono quaternary salts with mild acid and di quaternary salts strong acids. N N N N H H N N H Mild acid Strong acid
- 14. Pyrazine reacts with alkyl halide to give mono quaternary salts but it is unstable and are best prepared at temperature below 40oC. Alkylation at Nitrogen N N N N R RX X < 40o C
- 15. Pyrazine under favorable condition i.e. presence of electron donating group reacts with electrophile. Reactions at Carbon Electrophilic substitution at carbon N N Cl2 CH3 CCl4 N N CH3 Cl
- 16. Pyrazine reacts with NaNH2 in liquid NH3 similar to pyridine to form 2- aminopyrazine. Nucleophilic substitution reactions Chichibabin reactions NaNH2 / liq NH3 N N N N NH2
- 17. Alkyl Pyrazine reacts with NaNH2 in liquid NH3 to form anion intermediate and it undergoes nucleophilic substitution reaction with alkyl halides and ester derivatives. N N NaNH2 liq. NH3 CH3 N N CH2 N N CH2 R RX (CH3)3CCOOC2H5 N N C H2 O