X-ray crystallographic investigations of some analgetic pyrazole derivatives and their crystalline complexes

Abstract

This thesis reports the single?crystal X?ray diffraction studies on:

Antipyrine, a 1:1 complex between antipyrine and salicylic acid (salipyrine), Amidopyrine, Phenylbutazone, and a 2:1 complex between phenylbutazone and piperazine.

All the structures, except that of phenylbutazone, were refined to R values below 0.08 with a standard deviation of 0.01 Å or better for bond lengths involving non?hydrogen atoms. The positions of hydrogen atoms were also determined in these structures. The crystals of phenylbutazone, however, did not diffract well at high angles, and therefore its structure analysis was less accurate.

Chapter 1 – Introduction A brief survey of non?narcotic anti?inflammatory analgesics is presented in the first chapter. Recent investigations on the inhibition of prostaglandin biosynthesis by these compounds and the X?ray crystallographic studies on them have also been reviewed.

Chapter 2 – Structure of Antipyrine The second chapter deals with the crystal and molecular structure of the first analgesic pyrazole derivative to be introduced into medical practice, namely 1?phenyl?2,3?dimethyl?5?pyrazolone, commonly known as antipyrine. The molecular geometry of antipyrine in this structure differs substantially from that observed earlier in some metal–antipyrine complexes. The differences in dimensions indicate that the antipyrine molecule is considerably less polar in the free state than in the complexes. The two hetero?nitrogen atoms in the pyrazolone ring are also more pyramidal in free antipyrine.

Chapter 3 – Structure of Salipyrine (1:1 Antipyrine–Salicylic Acid Complex) The crystal structure of a 1:1 hydrogen?bonded complex between antipyrine and salicylic acid (salipyrine) is presented in Chapter 3. In this complex, the antipyrine molecule is more polar than in its free form, but less polar than in metal complexes. The pyramidal character of the nitrogen atoms in the pyrazolone ring is intermediate between that in free antipyrine and that in metal complexes.

Chapter 4 – Structure of Amidopyrine The crystal and molecular structure of amidopyrine, a dimethylamino derivative of antipyrine, is reported in the fourth chapter. The two crystallographically independent molecules in the structure have comparable dimensions. The average molecular dimensions of amidopyrine are similar to those of antipyrine. Interestingly, the molecular geometry of amidopyrine closely resembles that in two of its hydrogen?bonded complexes. This chapter also attempts to correlate the polarity of the molecule with the pyramidal character of the hetero?nitrogen atoms in the pyrazolone ring of antipyrine, amidopyrine, and their complexes.

Chapter 5 – Structure of Phenylbutazone The fifth chapter reports the crystal and molecular structure of 4?butyl?1,2?diphenyl?3,5?pyrazolidinedione, commonly known as phenylbutazone. The two crystallographically independent molecules in the structure show nearly identical dimensions. The two nitrogen atoms in the five?membered ring are pyramidal, with the attached phenyl groups lying on opposite sides of the ring plane. The carbon atom in the 4?position is tetrahedral, bonded to a butyl group and a hydrogen atom. The C–C and C–O bonds in the pyrazolidinedione group correspond to single and double bonds, respectively.

Chapter 6 – Structure of 2:1 Phenylbutazone–Piperazine Complex The crystal structure of a 2:1 complex between phenylbutazone and piperazine is presented in the sixth chapter. The phenylbutazone molecule exists as an anionic species in this structure due to deprotonation at the 4?position. As a result, the deprotonated carbon atom becomes trigonal, and the orientation of the butyl group relative to the pyrazolidinedione moiety changes significantly compared to free phenylbutazone. The deprotonation also causes considerable electron delocalization along the C–O and C–C bonds in the pyrazolidinedione ring. These changes in geometry and electronic structure resulting from interaction with another molecule are of considerable interest with respect to the biological activity of phenylbutazone.