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Pyrimidine
- 1. Synthesis, reactivity, aromatic characterand importance of Pyrimidine Prepared by Dr. Krishna swamy Faculty DOS & R in Organic Chemistry Tumkur University
- 2. Diazines are thesix membered heterocylic compounds derived from benzene by replacement of two -CH group by two nitrogen atoms. This replacement results in three isomeric forms (1) 1, 2- isomer (2) 1, 3-isomer (3) 1, 4-isomer N N N N N N Diazines Replace two CH group by two nitrogen atom
- 3. Nomenclature of heterocyclicrings will be done by three ways (1) Common names (2) Replacement nomenclature N N N N N N Pyridazine Pyrimidine Pyrazine 1, 4-diazabenzene (p-diazabenzene) 1, 3-diazabenzene (m-diazabenzene) 1, 2-diazabenzene (o-diazabenzene) N N N N N N Replace two CH group by two nitrogen atom
- 4. (3) Hantzsch-Wideman nomenclature Prefix+ Ring + Suffix Type of heteroatom Size of the ring Degree of unsaturation of ring Nitrogen 6-membered Aromatic Aza in e Azine N N N N N N 1, 4-diazine (p-diazine) 1, 3-diazine (m-diazine) 1, 2-diazine (o-diazine)
- 5. Diazines compounds belongto the category of π-deficient ring systems similar to pyridine. Diazines are aromatic in nature and lone pair on sp2 hybridized nitrogen are not involved involved in aromatic sextet. N N N N N N Lone pairs not involved in resonance
- 6. Diazines are weakerbases compared to pyridine due to inductive and electron withdrawing effect of second nitrogen atom. N N N N N N N >> > > pKa - 5.2 2.3 1.3 0.6
- 7. Pyrimidine ring systemhas wide occurance in nature as substituted and fused compounds which includes nucelic acid and thiamine (Vit-B1) 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. N N1 2 3 4 5 6 Pyrimidine N N NH2 N H N Adenine N N NH2 N S OH Br Vitamin B1
- 8. N N N N N N N N N N N N N N N NN1 1 3 N3 Pyrimidine ring hasthe following resonance contributors and positive charge will placed on the 2, 4 and 6-position carbons.
- 9. Acid or basecatalysed condensation reaction of 1, 3-dicarbonyl compounds with amidines or Guanidines yields pyrimidine derivatives is known as Pinner pyrimidine synthesis. R1 R2 O O H2N R3 NH NaOEt N N R2 R1 R3 Synthesis
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- 11. O O NH2 NH .HCl K2CO3 N N 2,4, 6-trimethyl pyrimidines O OEt O NH2 NH .HCl NaOH N N HO 2, 6-dimethyl-4-hydroxy pyrimidine 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. O OEt O NH2 NH .HCl NaOH N N HO 2-dimethyl-6-hydroxy-5-nitrile pyrimidine CN NC Pyrimidine derivatives canbe also be prepared from enol ethers by replacing 1, 3- dicarbonyl compounds.
- 13. From condensation reactionof malonic ester with urea in presence of base yields barbituric acid which tautomerizes to trihydroxy form. Finally reaction with POCl3 followed by refluxing with hot water and Zn dust yield pyrimidine. OEt OEt O O H2N NH2 O NH NH O O O NaOEt N N HO HO OH N N Cl Cl Cl N N POCl3 Zn Dust
- 14. 2-substituted pyrimidines canbe prepared by condensation followed by cyclization of carboxylic acid and 1, 3-diaminopropane, subsequent dehydrogenation in presence of catlayst give 2-substituted pyrimidines. H2N H2N N HN N N Ph 2-substituted pyrimidine R-COOH R Condensation Cyclization Dehydrogenation Base facilitated trimerization of alkane nitriles with free methylene group adjacent to cyano group results in pyrimidin-4-amine derivatives. Base R CN3 NN R NH2 R R
- 15. Reactions of Pyrimidines Pyrimidineundergoes 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 5th position. Nucleophilic substitution takes place at 2, 4 and 6th positions.
- 16. Reactions at Nitrogen Electrophilicaddition 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 N N E N N E
- 17. Protonation at Nitrogen Pyrimidinenitrogen form mono quaternary salts with mild acid and di quaternary salts strong acids. N N N N H H H N N H H
- 18. Pyrimidine reacts withalkyl 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 N N N N Me MeI N N Et Et3OBF4 MeOH, rt I Et BF4 BF4 Reflux
- 19. Electrophilic substitution ofpyrimidines is very difficult. Hence pyrimidines are bad at undergoing electrophilic aromatic substitution but under favorable condition pyrimidine ring reacts with electrophile only at 5th position. Reactions at Carbon N N N N N N N N N N N N N N N NN1 1 3 N3 At 5th position no positive charge hence it has some electron density Electrophilic substitution at carbon
- 20. N N N N O2N Nitration N N N N X Halogenation N N N N N Azo coupling N Activatinggroups (alkyl, OH, OMe) on pyrimidine ring increase basicity and assists in electrophilic substitution reaction at 5th position.
- 21. Pyrimidine undergoes nucleophilicsubstitution reaction easily at 2, 4 and 6th positions. Nucleophilic substitution of hydrogen next to nitrogen requires oxidation of resulting dihydro product to get pyrimidine. N N N NH Nu H N N Nu Dihydro product OxidationNu N N N NH Ph H N N Ph 4-Phenyl- 1, 6-dihydropyrimidine PhM M = Li, MgBr H3O+ O2 4-Phenylpyrimidine Nucleophilic substitution reactions
- 22. 130o C N N NH N H NHNH2 NH N H NHNH2 H N NH HN H NH H N NH N2H4 Nucleophilicsubstitution of pyrimidines are very susceptible to nucleophilic addition. Pyrimidine converts into pyrazole by reaction with hot hydrazine.