Pyrimidine

Synthesis and reactions of Pyrimidine hetero cyclic compound is discussed

1. Synthesis, reactivity, aromatic character and importance of Pyrimidine Prepared by Dr. Krishna swamy Faculty DOS & R in Organic Chemistry Tumkur University

2. Diazines are the six membered heterocylic compounds derived from benzene by replacement of two -CH group by two nitrogen atoms. This replacement results in three isomeric forms 1, 2- isomer 1, 3-isomer 1, 4-isomer

3. Nomenclature of heterocyclic rings will be done by three ways Common names (2) Replacement nomenclature

4. (3) Hantzsch-Wideman nomenclature

5. Diazines compounds belong to the category of π -deficient ring systems similar to pyridine. Diazines are aromatic i n nature and lone pair on sp2 hybridized nitrogen are not involved involved in aromatic sextet.

6. Diazines are weaker bases compared to pyridine due to inductive and electron withdrawing effect of second nitrogen atom.

7. Pyrimidine ring system has wide occurance in nature as substituted and fused compounds which includes nucelic acid and thiamine (Vit-B 1 ) Pyrimidine ring has symmetry along C-2 and C-5, hence C-4 & C-6 as well as N-1 & N-3 are equivalent to each other. Pyrimidine

8. Pyrimidine ring has the following resonance contributors and positive charge will placed on the 2, 4 and 6-position carbons.

9. Acid or base catalysed condensation reaction of 1, 3-dicarbonyl compounds with amidines or Guanidines yields pyrimidine derivatives is known as Pinner pyrimidine synthesis. Synthesis

10. Mechanism

11. By applying Pinner’s procedure variety of pyrimidine derivatives can be prepared from different 1,3-dicarbonyl starting materials like acetylacetone and ethyl acetoacetate .

12. Pyrimidine derivatives can be also be prepared from enol ethers by replacing 1, 3-dicarbonyl compounds.

13. From condensation reaction of malonic ester with urea in presence of base yields barbituric acid which tautomerizes to trihydroxy form. Finally reaction with POCl 3 followed by refluxing with hot water and Zn dust yield pyrimidine .

14. 2-substituted pyrimidines can be prepared by condensation followed by cyclization of carboxylic acid and 1, 3-diaminopropane, subsequent dehydrogenation in presence of catlayst give 2-substituted pyrimidines . Base facilitated trimerization of alkane nitriles with free methylene group adjacent to cyano group results in pyrimidin-4-amine derivatives.

15. Reactions of Pyrimidines Pyrimidine 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 at 5 th position. Nucleophilic substitution takes plac e at 2, 4 and 6 th positions.

16. 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 pyrimidinium salts. BOTH ARE AROMATIC

17. Protonation at Nitrogen Pyrimidine nitrogen form mono quaternary salts with mild acid and di quaternary salts strong acids .

18. Pyrimidine reacts with alkyl halide to give mono quaternary salts less readily compared to pyrdine . Dialkylation cannot be achieved with simple alkyl halides, however more reactive trialkoxonium tetrafluoroborates converts pyrimidine to di quaternary salts. Alkylation at Nitrogen

19. Electrophilic substitution of pyrimidines is very difficult. Hence pyrimidines are bad at undergoing electrophilic aromatic substitution but under favorable condition pyrimidine ring reacts with electrophile only at 5 th position. Reactions at Carbon At 5 th position no positive charge hence it has some electron density Electrophilic substitution at carbon

20. Activating groups (alkyl, OH, OMe ) on pyrimidine ring increase basicity and assists in electrophilic substitution reaction at 5 th position.

21. Pyrimidine undergoes nucleophilic substitution reaction easily at 2, 4 and 6 th positions. Nucleophilic substitution of hydrogen next to nitrogen requires oxidation of resulting dihydro product to get pyrimidine . Nucleophilic substitution reactions

22. Nucleophilic substitution of pyrimidines are very susceptible to nucleophilic addition. Pyrimidine converts into pyrazole by reaction with hot hydrazine.