Invariom-based comparative electron density studies of iso-sildenafil and sildenafil

3.1 Structural properties

The structures of the molecules (I) and (II) and of the cation of (III) as present in the crystal structures are shown in Fig. 2 in Ortep representations [15], [16]. The atomic numbering scheme used in the literature was kept for all three models.

Fig. 2:

Ortep representations [15], [16] of (I), (II) and the cation of (III).

In addition to the chemical difference between sildenafil and the iso-analog (as mentioned above), the molecular conformations in the solid state are different, which can best be described by the seven torsion angles along the free rotatable bonds, which are τ₁ and τ₂ at the propyl group, τ₃ and τ₄ at the ethoxy group, τ₅ and τ₆ at the bonds from the phenyl ring via the sulfonyl S atom to the piperazine ring, and τ₇ linking the phenyl ring and the pyrazolopyrimidine fragment (see Table 2). The most important difference is seen for τ₇, which is close to zero in (II) and in (III) (planar form), but is 44.2(3)° in (I) (inclined form). This has consequences on the possible formation of an intramolecular hydrogen bond (HB) as will be discussed below. Further conformational differences, as expressed by τ₂, are found in the rotation of the propyl group; otherwise, the molecular conformations of (II) and (III) are alike and comparable.

3.2 Electron-density-derived properties

Invariom-based ED examination goes beyond “spherical” structure analysis with the IAM. The invariom approach provides non-spherical ED for a given structure and thus permits us to compute ED-derived properties, for both qualitative and quantitative methods of evaluation. Figure 3 gives a qualitative impression of the static deformation density in the main molecular plane of (III), consisting of the phenyl and the pyrazolopyrimidine rings. In contrast to IAM refinements, electron-density accumulations on all covalent bonds and in lone pair regions become visible.

Fig. 3:

Static deformation electron density in the common plane of the phenyl and the pyrazolopyrimidine rings of the cation of (III). Blue/black/red contour lines for positive/zero/negative densities. Contour intervals at 0.1 e Å⁻³.

Quantitative ED properties of the title compounds (I), (II) and the cation of (III) were obtained from an analysis according to Bader’s quantum theory of atoms in molecules (QTAIM) formalism [17]. This analysis provides both bond critical points (BCPs, defined by the property that the gradient ∇ρ(r) vanishes at this point) and atomic properties by integration over the atomic basins bound by the zero-flux surfaces of the gradient vector field, which subdivide a structure into transferable substructures.

BCPs were located on all covalent bonds and on the H(donor)···X(acceptor) (X=N, O) linkages of the HBs. Values of the ED, Laplacians and ellipticities [ρ(r_BCP), ∇²ρ(r_BCP), ε] were calculated, providing information about the strength and nature of a bond. Selected averages over these properties for C–C bonds and selected properties of bonds involving heteroatoms are given in Table 3. Atomic properties were calculated using the TOPOND algorithm as implemented [19] in the XD subprogram XDprop [14]. A selection of atomic volumes and charges for (I)–(III) is given in Table 4. Only those atoms where |q |>0.30 e for one of the contributing structures are listed.

It turned out that, as expected, the obtained covalent bond properties are practically the same for chemically equivalent bonds of (I)–(III), which also holds for the atomic properties of atoms with the same nearest neighbors.

For the 15 C(sp³)–C(sp³) bonds, the average ρ(r_BCP) value of 1.511(21) e Å⁻³ yields a bond order of 1.10 [17], [18]. From 27 averaged C(sp²)–C(sp²) bonds, a bond order of 1.58 is derived. As to N–C(sp³) bonds, the three bonds to the protonated nitrogen atom in (III) should in principle be considered separately. However, except for the slightly longer N–C bond in (III) there is no further difference in the bond-topological descriptors when compared to (I) and (II).

Strong charge concentration is seen for the hetero atoms (Table 4). The strongest positive charge is carried by the sulfur atom with q≈3 e. Such pronounced Bader charges are not uncommon. In a recent study on C/Si analogs of haloperidol and venlafaxine, positive charges close to +3 e were found at the Si atoms [20]. The strongly positive charge at the sulfur atom is compensated by the negative charges of the direct neighbor atoms. Their charge sum is −3.58/−3.82/−3.79 e for (I)/(II)/(III), so that an excess charge of more than −0.5 e is found in the direct environment of the sulfur atom.

The pyrazole and the ethoxy oxygen atoms both have charges close to −0.9 e. Consequently, the adjacent pyrimidine carbon atom has a positive charge of≈+1 e, whereas the charge at the ethoxy oxygen atom is balanced by the charge sum of the two adjacent carbon atoms being 0.66/0.68/0.69 e for (I)/(II)/(III).

All nitrogen atoms carry a significant negative charge, which also holds for the protonated nitrogen atom of the piperazine ring of (III). Its difference to the corresponding nitrogen atoms in (I) and (II) is visible in the atomic volumes, which is by 2.8 ų smaller for (III) compared to (I) and (II). A small difference with respect to the charges can be seen if the group charge of all atoms of the piperazine ring is considered. It is negative, −0.53 and −0.40 e, for (I) and (II), but slightly positive at +0.19 e for (III). As observed earlier [21], [22], [23], protonation causes a delocalization of charge over a wide range in the environment of the atom in question.

In the pyrazole ring, where the methylation is different between (I) and (II)/(III), only marginal differences in bond-topological and atomic properties are seen for the endocyclic carbon atoms (Fig. 4). On the one hand, the methylated nitrogen atoms have comparable atomic properties for (I) and (II)/(III), which also holds on the other hand for the non-methylated ones. There is thus a considerable difference in atomic properties between the methylated and the non-methylated nitrogen atoms. We note a volume difference of more than 5 ų, accompanied by a difference of the negative charges of about 0.2 e.

Fig. 4:

ρ(r_BCP) values in e Å⁻³ and atomic properties (charges in e, volumes in ų, both in red rectangular frames) for the pyrazole ring in (I) (left) and in (II)/(III) (right).

Intra- and intermolecular contacts in terms of potential HBs are summarized in Table 5. It was tried to determine all BCPs on all possibly attractive interactions listed in Table 5. It turned out that a strong intramolecular HB between the pyrazole N–H and the ethoxy oxygen exists with a properly identified BCP for both sildenafil structures (II) and (III). This is not the case for iso-sildenafil (I) in the solid state. Although the geometric situation indicates close N…O and H…O contacts typically found for HBs, no critical point is found at this site, so that from the QTAIM analysis no intramolecular HB exists for (I). However, this situation differs for the structure obtained from a gas-phase geometry optimization with the functional/basis-set combination B3LYP/6-31G(d,p), where coplanar rings and an intramolecular HB are indeed found.

Obviously the above-mentioned non-co-planarity along the torsion τ₇ is unfavorable for the formation of an intramolecular HB in the solid state. Instead, a strong intermolecular HB was found for (I) generating a dimeric structure via a crystallographic inversion center. For (II) only a weak C–H…O intermolecular HB exists, so that solid-state packing of (I) and (II) are completely different.

Figure 5 illustrates this hydrogen bonding situation for (I) and (II). In addition, Fig. 5 also shows the corresponding Hirshfeld surfaces. Molecular surfaces and the corresponding surface properties play an important role in drug–receptor recognition processes, because the mutual recognition takes place via surface interactions in a first step. Hirshfeld surfaces are defined by the ratio of the molecular ED to the crystal density [25], [26] when equal to 0.5. When the aspherical ED is mapped by a color code onto this surface, ED concentrations are emphasized so that sites and strengths of intermolecular interactions become visible (see Figs. 5 and 6) [27]. For (I), two strong deeply colored signals are seen at the donor and acceptor sites of the intermolecular HB, and no further significant signals exist. For (II), the rather weak HB C(8)–H(2)···O(2) (Table 5) is illustrated by corresponding weak signals on the Hirshfeld surfaces. There are a few further weak ED concentrations visible on this surface of (II). They are all based on weak intermolecular approaches in the crystal structure, so the Hirshfeld surface is a fine instrument to make intermolecular contacts visible.

Fig. 5:

Dimeric and non-dimeric structures for (I) and (II), Schakal representations (left) [24] and corresponding Hirshfeld surfaces (right) [25], [26], drawn with Moliso [27].

Fig. 6:

Hydrogen bond contacts in the cation–anion complex (III) (left) [15], [16] and the corresponding illustration on the Hirshfeld surface of the cation (right) [27].

In case of (III), no cation···cation HB exists, but a quite strong N–H···N HB links the cation and the saccharinate anion. In addition, some further weak C–H···O contacts are listed in Table 5. They are all displayed as ED concentrations on the corresponding Hirshfeld surface in Fig. 6.

For the understanding of molecular polarization, reactivity behavior and the intermolecular substrate/acceptor recognition, the electrostatic potential (ESP) plays a helpful role. That is why it was calculated by using the method of Volkov et al. [28] with the XDprop subprogram of XD2006 [14] and color coded onto the 0.0067 e Å⁻³ (=0.001 a.u.) electron-density isosurface (see Figs. 7–9) [27].

Fig. 7:

Electrostatic potentials of (I) and (II) mapped onto the electron-density isosurface ρ=0.0067 e Å⁻³; the representation was generated with Moliso [27].

Fig. 8:

Electrostatic potential of the iso-sildenafil dimer of (I) [27]. For further details see the legend of Fig. 7.

Fig. 9:

Electrostatic potential of the sildenafil saccharinate acetonitrile complex (III). Left: representation of the cation only. Right: complete complex, consisting of the cation, the anion and the acetonitrile solvent molecule [27].

The ESP surfaces of (I) and (II) show considerable differences in the regions where the methylation is different (Fig. 7). At the N–H unit, which is the donor of the intermolecular HB, a strongly positive potential exists in (I), accompanied by negative ESP on the accepting oxygen. Both pronounced potentials are not seen in (II), where the intermolecular HB does not exist; see the discussion above. Figure 8 shows the ESP surface of the iso-sildenafil dimer generated by the intermolecular HB. We note that the dimer is enveloped by an almost positive ESP shell. It can be speculated that this surface property reduces the interaction ability so that the iso form is pharmaceutically less active.

The ESP of the sildenafil saccharinate acetonitrile complex (III) is displayed in Fig. 9 in representations of the cation only (Fig. 9, left) and the complete complex (Fig. 9, right). The color bar scale (Fig. 9, left) shows that in the cation the ESP surface is completely positive with the strongest positive region above the hydrogen of the protonated nitrogen in the piperazine ring facing the saccharinate anion. In the representation of the complete complex (Fig. 9, right), the charge separation and hence the polarization between cation and anion is nicely visible with positive and negative surfaces, whereas the neutral acetonitrile solvent has an ESP surface close to zero.