Chemistry, Reactivity, Properties and Synthesis of Pyrimidine

Chemistry of Pyrimidine

Session Objectives

By the end of this session, students will be able to:

• Discuss the chemistry, reactivity, properties and method of synthesis of Pyrimidine

Chemistry of Pyrimidine

• Most important member occurs widely in living organisms

• Purines, uric acid, alkoxan, barbituric acid

• First isolated by Gabriel and Colman 1899

• Pyrimidine is symmetrical about line passing C-2 and C-5

• Positions C-4 and C-6 are equivalent and so are N-1 and N-3

• When a hydroxy or amino group is present at 2-, 4-, or 6- position then they are tautomeric with oxo and imino

Physical properties of Pyrimidine:

• Colorless compounds with melting point 225 ⁰C, boiling point 124 ⁰C

• Weakly basic with pKa 1.3 due to electron-withdrawing effect of 2^nd nitrogen atom present in the ring

• Presence of alkyl groups increase the basicity, 4-methylpyrimidine pKa-2.0, 4,6-dimethylpyrimidine pKa 2.8, 2- and 4-aminopyrimidines are more basic with pKa 3.54 and 5.71

Synthetic methods of Pyrimidine:

Most important method is in which ring is formed from two fragments which contribute C-C-C and N-C-N atoms

1) From malonic esters:

• Involves condensation between a malonic ester and urea in the presence of base to yield barbituric acid

2) From malic acid:

• α-formyl acetic acid formed insitu by decarboxylation of malic acid with conc. Sulfuric acid and then subsequent  reaction of β-keto acid(α-formyl acetic acid) with urea to form uracil.

• Then Uracil can be converted to pyrimidine by chlorination and reduction

Chemical reactions of Pyrimidine:

1) Reaction with acids:

• Though a weak base can be protonated in the presence of acids

• Diprotonation takes place in strong acids- possible because nitrogen atoms are not present in adjacent positions

2) Electrophilic substitution:

• Also resistant to electrophilic substitution

• Attack at 2-, 4-, 6- positions is particularly retarded because of electron deficiency

• 5- position also difficult because of inductive effect of two nitrogens

• Electrophilic substitution at 5- position becomes easy when one or more electron releasing groups are present on the ring

• Bromination of pyrimidine yields 5-bromopyrimidine

3) Reaction with nucleophilic reagents:

• Attack of nucleophile takes place easily

• Positions susceptible to attack are 2-, 4- and 6-.

• Stable in cold alkali but in boiling hydrazine it rearranges to pyrazole, via a ring opened intermediate

• Grignard and organo-lithium reagents readily add to 3,4- bond of pyrimidines at room temperature- phenyl magnesium bromide

• Intermediate on hydrolysis and subsequent oxidation yields 4-phenylpyrimidine

Summary

• Most important member occurs widely in living organisms

• Pyrimidine is symmetrical about line passing C-2 and C-5

• Positions C-4 and C-6 are equivalent and so are N-1 and N-3

• Electrophilic attack at 2-, 4-, 6- positions is particularly retarded because of electron deficiency