Molecular and crystal structure of a copper(II) complex of sildenafil

1 Introduction

Sildenafil, 5-[2-ethoxy-5-(4-methylpiperazin-1-yl) sulfonyl-phenyl]-1-methyl-3-propyl-6H-pyrazolo[4,3-d]pyrimidin-7-one, is used in medicine to improve penile erections in men with erectile dysfunction by selectively inhibiting the cGMP-specific phosphodiesterase type 5 [1]. Sildenafil is a bioavailable pyrazolpyrimidine derivative structurally related to zaprinast, with vasodilating and potential anti-inflammatory activities [2] (Figure 1).

Figure 1:

Molecular structure of the base sildenafil.

The crystal structures of the base sildenafil [3], sildenafil citrate monohydrate [4], sildenafil saccharinate [5, 6] and a number of co-crystals of sildenafil [7] have been reported. Complexes of sildenafil citrate with some bivalent metals, for example, Mg²⁺, Ca²⁺, Zn²⁺ and Cd²⁺ were synthesized and their chemical composition and lattice parameters were reported [8]. Complexes of sildenafil with divalent metals are also of interest for coordination and bioinorganic chemistry.

The aim of the present study was to determine the crystal and molecular structure of a novel copper(II) complex of sildenafil by single-crystal X-ray diffraction analysis. For convenience we denote the pyrimidine, pyrazole, phenyl, and piperazine rings in the sildenafil molecule by capital letters A, B, C, and D, respectively (Figure 1).

2 Results and discussion

The complex crystallizes in the monoclinic space group P2₁/n with the Cu atom surrounded in tetrahedral mode with the monodentate sildenafil cation and three Cl⁻ ions. The Cu atom is coordinated by the cationic sildenafil ligand via the N2 atom of the pyrazolopyrimidine ring (Figure 2).

Figure 2:

ORTEP drawing of the molecular structure of the title compound.

In the given structure, sildenafil is protonated at the methylated N6 atom of the piperazine ring and it is a cation with a 1+ charge. That cationic form of sildenafil occurs in the crystal structure of sildenafil citrate monohydrate [4], i.e. sildenafil retains its cationic form in a complexation process with the Cu atom.

The coordination tetrahedron of the Cu atom is distorted: the Cu–N2 bond length is 2.051(2) and Cu–Cl bond lengths lie in the range 2.200(1)–2.2505 Å. The bond angles Cl–Cu–Cl are far from those in an ideal tetrahedron and equal to 99.19(5), 99.85(5) and 136.91(6)°. The bond angles N–Cu–Cl are 92.7(2), 102.3(1), 132.2(8) and 136.93(6)°. The endocyclic angle C1–N2–N1 (108.3(2)°) is more narrow in comparison with angle in the molecular structure of sildenafil citrate (111.25(19)°) due to the inclusion of the lone electron pair at the N2 atom in coordination bond with the metal. This effect is attributed to the VSEPR theory by Gillespie [9].

The pyrazolopyrimidine bicyclic system (A + B) and the phenyl ring (C) in the sildenafile base, citrate and sildenafil saccharinate are almost coplanar. In the structure of the title compound, the intramolecular hydrogen bond N4–H⋯O4 is broken and the pyrazolopyrimidine ring and the benzene ring are noncoplanar: the dihedral angle between these planes is 61.2(4)°.

The ethoxy groups of the above mentioned compounds lie also almost within the A + B + C plane. In the present complex, the ethoxy group is disordered in two positions and goes out of the above-mentioned plane. The propyl group is also situated out of the A + B + C plane. As in other sildenafil compounds [3], [4], [5], [6], the propyl group is on the same side as the methylpiperazine fragment. The torsion angles defining the conformation of sildenafil are presented in Table 1.

Two water molecules of crystallization and three chlorine ions increase the number of hydrogen bonds in the crystal structure (Table 2). The Cu(II) complex of sildenafil takes part in two hydrogen bonds as p-donor and in three hydrogen bonds as p-acceptor. Besides these, it forms five non-bonded short contacts with adjacent molecules. These bonds and short contacts link the structural units into a three-dimensional framework (Figure 3).

Figure 3:

Intermolecular hydrogen bonds in the title compound.

3 Conclusions

The molecular and crystal structure of a copper(II) complex of sildenafil have been determined by single-crystal X-ray diffraction. Coordination of the Cu atom by the sildenafil ligand occurs via the N2 atom of the pyrazolopyrimidine ring. Three chloride anions complete the tetrahedral environment of the Cu atom. The sildenafil molecule is protonated at the N6 atom of the pyrazolopyrimidine ring and thus, a ligand has a cationic form with a 1+ charge. The ethoxy and propyl groups are disordered over two positions. The presence of chloride anions and water molecules in the crystal structure increases the number of weak hydrogen bonds.

4 Experimental section

Crystals of title compound were prepared by slowly evaporation at room temperature of a hydroalcohol solution containing sildenafil citrate monohydrate (“Pharmaceuticals Ltd”, India) and CuCl₂⋅2H₂O (Sigma-Aldrich) in a molar ratio of 1:1. For synthesis of the Cu complex, 672 mg (1.0 mM) of sildenafile citrate monohydrate was dissolved in 10 mL of the water-alcohol solute (in a volume ratio of 1:1) and was added to 85.24 mg (0.5 mM) of a powder of CuCl₂⋅2H₂O with stirring on magnetic stirrer at 50 °C (Scheme 1). Green color crystals of thin and long prism form dissipated after two days.

Scheme 1:

Synthesis of the copper(II) complex of sildenafil.

Analysis of C, H and O were performed on a German Elementar Vario EL instrument. Yield: 88%. Elemental analysis for CuCl₃C₂₂H₃₁N₆O₄S⋅2H₂O (681.51): calcd. C 38.74; H 5.13; N 12.32%; found: C 38.65; H 5.38; N 12.72%.

Experimental and refinement details of the X-ray diffraction study are summarized in Table 3.