*3.4. Theoretical Study of Di*ff*erent Non-covalent Interactions in ASZ*·*1.5(1,4-FIB)*

*d*(H···N)/(RvdW(H) + RvdW(N)).

Table 4 and visualized in Figure 7.

*3.4. Theoretical Study of Different Non-covalent Interactions in ASZ·1.5(1,4-FIB)*  The supramolecular structure of **ASZ**·1.5(**1,4-FIB**) is formed by various non-covalent contacts (viz. lp-π interactions, hydrogen, and halogen bonding). We performed quantum chemical calculations and QTAIM analysis [32] to study the nature and energies of these non-covalent contacts in a model supramolecular cluster (**ASZ**)3·(**1,4-FIB**)4 based on the appropriate X-ray diffraction data (Supporting Information, Table S4). This approach depends very slightly on the basis set [81,82] or method [83,84] used and it was already successfully used by us previously for similar chemical systems [14,15,79,85,86] and upon studies of different non-covalent interactions (e.g., hydrogen/chalcogen/halogen bonds, stacking interactions, metallophilic interactions) in other The supramolecular structure of **ASZ**·1.5(**1,4-FIB**) is formed by various non-covalent contacts (viz. lp-π interactions, hydrogen, and halogen bonding). We performed quantum chemical calculations and QTAIM analysis [32] to study the nature and energies of these non-covalent contacts in a model supramolecular cluster (**ASZ**)3·(**1,4-FIB**)<sup>4</sup> based on the appropriate X-ray diffraction data (Supporting Information, Table S4). This approach depends very slightly on the basis set [81,82] or method [83,84] used and it was already successfully used by us previously for similar chemical systems [14,15,79,85,86] and upon studies of different non-covalent interactions (e.g., hydrogen/chalcogen/halogen bonds, stacking interactions, metallophilic interactions) in other organic and inorganic compounds [14,15,87–92]. The results of QTAIM analysis are presented in Table 4 and visualized in Figure 7.

organic and inorganic compounds [14,15,87–92]. The results of QTAIM analysis are presented in

**Table 4.** Values of the density of all electrons—ρ(**r**), Laplacian of electron density—∇ <sup>2</sup>ρ(**r**), energy density—Hb, potential energy density—V(**r**), and Lagrangian kinetic energy—G(**r**) (a.u.) at the bond critical points (3, −1), corresponding to different non-covalent interactions in (**ASZ**)<sup>3</sup> ·(**1,4-FIB**)<sup>4</sup> , bond lengths—*l* (Å), as well as energies for these contacts Eint (kcal/mol), defined by two approaches.\*. critical points (3, −1), corresponding to different non-covalent interactions in (**ASZ**)3·(**1,4-FIB**)4, bond lengths—*l* (Å), as well as energies for these contacts Eint (kcal/mol), defined by two approaches.\*. **Contact** ρ**(r)** ∇**2**ρ**(r) Hb V(r) G(r) Einta Eintb** *l* 

*Crystals* **2020**, *10*, 371 7 of 13

density—Hb, potential energy density—V(**r**), and Lagrangian kinetic energy—G(**r**) (a.u.) at the bond


<sup>a</sup> Eint = −V(**r**)/2 [93] <sup>b</sup> Eint = 0.429G(**r**) [94] \* Note that Tsirelson et al. [95] also proposed alternative correlations developed exclusively for non-covalent interactions involving iodine atoms, viz. Eint = 0.68(−V(**r**)) or Eint = 0.67G(**r**). correlations developed exclusively for non-covalent interactions involving iodine atoms, viz. Eint = 0.68(−V(**r**)) or Eint = 0.67G(**r**).

**Figure 7.** Contour line diagrams of the Laplacian distribution ∇2ρ(**r**), bond paths and selected zero-flux surfaces referring to the C–I···X (X = N, F, I) halogen bonding (left) and lp(I)···π(triazole) (right) interactions in (**ASZ**)3·(**1,4-FIB**)4. Bond critical points (3, −1) are shown in blue, nuclear critical points (3, −3) in pale brown, ring critical points (3, +1) in orange, cage critical points (3, +3) in light green. Length units—Å. **Figure 7.** Contour line diagrams of the Laplacian distribution ∇ <sup>2</sup>ρ(**r**), bond paths and selected zero-flux surfaces referring to the C–I· · ·X (X = N, F, I) halogen bonding (left) and lp(I)· · · π(triazole) (right) interactions in (**ASZ**)<sup>3</sup> ·(**1,4-FIB**)<sup>4</sup> . Bond critical points (3, −1) are shown in blue, nuclear critical points (3, −3) in pale brown, ring critical points (3, +1) in orange, cage critical points (3, +3) in light green. Length units—Å.

The QTAIM analysis reveals the existence of bond critical points (3, −1) (BCPs) for all non-covalent interactions listed in Table 4. The properties of electron density, Laplacian of electron density and energy density in these BCPs are common for non-covalent interactions. Energies for these non-covalent contacts (vary from 0.9 to 6.0 kcal/mol) were defined according to the procedures developed by Espinosa et al. [93] and Vener et al. [94] using the equations Eint = 0.5(−V(**r**)) or Eint = 0.429G(r), respectively. The balance between the potential energy density V(**r**) and Lagrangian kinetic energy G(**r**) at the BCPs reveals that a covalent contribution is absent in all supramolecular contacts listed in Table 4, except I1S···N3 halogen bonding [96]. The QTAIM analysis reveals the existence of bond critical points (3, −1) (BCPs) for all non-covalent interactions listed in Table 4. The properties of electron density, Laplacian of electron density and energy density in these BCPs are common for non-covalent interactions. Energies for these non-covalent contacts (vary from 0.9 to 6.0 kcal/mol) were defined according to the procedures developed by Espinosa et al. [93] and Vener et al. [94] using the equations Eint = 0.5(−V(**r**)) or Eint = 0.429G(r), respectively. The balance between the potential energy density V(**r**) and Lagrangian kinetic energy G(**r**) at the BCPs reveals that a covalent contribution is absent in all supramolecular contacts listed in Table 4, except I1S· · · N3 halogen bonding [96].

#### **4. Conclusions 4. Conclusions**

In combination with 1,2,4,5-tetrafluoro-3,6-diiodobenzene, a classical XB donor, we have identified a new halogen-bonded solid for anastrozole, an anticancer aromatase inhibitor drug. These findings continue to provide proof-of-principle for the productive employment of halogen bonds in the design and discovery of stable crystalline forms of important drug substances. Moreover, these results suggest that the range of potential XB donors for co-crystallization with basic nitrogen-rich molecular frameworks can potentially be expanded beyond the classical ones. The distinctive features of the crystal structures obtained and characterized in detail in this work are the presence of XBs with both triazole N atoms, firstly found for anastrazole. Apart from that, In combination with 1,2,4,5-tetrafluoro-3,6-diiodobenzene, a classical XB donor, we have identified a new halogen-bonded solid for anastrozole, an anticancer aromatase inhibitor drug. These findings continue to provide proof-of-principle for the productive employment of halogen bonds in the design and discovery of stable crystalline forms of important drug substances. Moreover, these results suggest that the range of potential XB donors for co-crystallization with basic nitrogen-rich molecular frameworks can potentially be expanded beyond the classical ones. The distinctive features of the crystal structures obtained and characterized in detail in this work are the presence of XBs with both triazole N atoms, firstly found for anastrazole. Apart from that, the adduct structure demonstrates the lp(I)· · · π(triazole) attractive interactions, which may also be important for the adduct

formation. The findings encourage us to continue searching for yet novel opportunities to detect XBs as indispensable forces leading to the formation of a new crystal. The results of these studies will be reported in due course.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/2073-4352/10/5/371/s1, Figure S1: Structural motifs around the C–I· · · N XBs including 1,2,4-triazole moiety in CCDC structures; Figure S2: Structural motifs around the lp(I)· · · C interactions including 1,2,4-triazole moiety in CCDC structures; Figure S3: Powder X-ray diffraction data (blue line) of mixture, obtained by mechanical grinding of 2**ASZ** + 3(**1,4-FIB**) mixture with MeOH additions; Figure S4: Powder X-ray diffraction data (blue line) of mixture, obtained by grinding of crystalline material grown from 2**ASZ** + 3(**1,4-FIB**) solution in methanol; Table S1: Parameters of the C–I· · · N XBs including 1,2,4-triazole moiety in CCDC structures; Table S2: Parameters of the lp(I)· · · C interactions including 1,2,4-triazole moiety in CCDC structures; Table S3: Crystal data and structure refinement for **ASZ**·1.5(**1,4-FIB**); Table S4: Cartesian atomic coordinates of model supramolecular cluster.

**Author Contributions:** Conceptualization, M.K., A.V.S., and D.M.I.; data curation, D.M.I.; formal analysis, A.S.N. and D.M.I.; funding acquisition, A.V.S.; investigation, M.A.K.; methodology, D.M.I.; project administration, D.M.I.; resources, A.V.S.; software, A.S.N.; supervision, M.K. and D.M.I.; validation, M.A.K.; visualization, A.S.N. and D.M.I.; writing—original draft, A.S.N. and D.M.I.; writing—review & editing, M.K. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was funded by Russian Science Foundation, grant number 17-73-20185.

**Acknowledgments:** Physicochemical studies were performed at the Center for X-ray Diffraction Studies belonging to Saint Petersburg State University.

**Conflicts of Interest:** The authors declare no conflict of interest.
