Synthesis, reactivity, aromatic character and importance of pyrazine has been discussed

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