An ortho­rhom­bic polymorph of isavuconazole

Ben, A.; Chęcińska, L.

doi:10.1107/S2056989025008886

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ISSN: 2056-9890

Volume 81| Part 11| November 2025| Pages 1018-1022

https://doi.org/10.1107/S2056989025008886

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An orthorhombic polymorph of isavuconazole

Anna Ben ^a,^b ^* and Lilianna Chęcińska ^b

^aUniversity of Lodz Doctoral School of Exact and Natural Sciences, Narutowicza 68, 90-136 Łódź, Poland, and ^bUniversity of Lodz, Faculty of Chemistry, Pomorska 163/165, 90-236 Łódź, Poland
^*Correspondence e-mail: [email protected]

Edited by L. Van Meervelt, Katholieke Universiteit Leuven, Belgium (Received 10 October 2025; accepted 13 October 2025; online 17 October 2025)

The title compound C₂₂H₁₇F₂N₅OS (systematic name: 4-{2-[(2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1,2,4-triazol-1-yl)butan-2-yl]-1,3-thiazol-4-yl}benzonitrile), represents a new orthorhombic polymorph of isavuconazole. The two stereogenic centers adopt the R,R configuration. In the crystal structure of the orthorhombic form, a mono-periodic chain motif is formed by a strong O—H⋯N hydrogen bond, while three additional C—H⋯N interactions propagate these chains into a tri-periodic supramolecular network. A comparison with the previously reported monoclinic polymorph [Voronin et al. (2021 ). CrystEngComm 23, 8513] is provided, supported by Hirshfeld surface and energy framework analyses.

Keywords: isavuconazole; crystal structure; polymorph; energy frameworks.

CCDC reference: 2495049

1. Chemical context

Heterocyclic compounds have long attracted considerable attention due to their importance as structural intermediates in many biologically active substances (Raman et al., 2025 ). For over a century, they have been one of the key areas of research in organic chemistry. Nitrogen-containing heterocycles, in particular, exhibit a wide range of applications, from pharmaceuticals and agriculture, through materials science and coordination chemistry, to the dye and pigment industry (Salma et al., 2024 ). Among these, triazole derivatives have drawn significant interest in recent decades due to their diverse chemical and biological activities, including antifungal (Li et al., 2019 ), anticancer (Slaihim et al., 2019 ), and antibacterial properties (Hussain et al., 2019 ).

Isavuconazole is a novel and promising broad-spectrum triazole used to treat invasive fungal infections in humans (Shirley & Scott, 2016 ). This drug is available in both intravenous and oral formulations (Lewis II et al., 2022 ) and demonstrates activity against yeasts, molds, and dimorphic fungi. Moreover, it has been approved for the treatment of invasive aspergillosis and mucormycosis (Miceli & Kauffman, 2015 ).

Only four crystal structures of isavuconazole have been reported to date: the pure form, a monohydrate, and two salts (Voronin et al., 2021). In this article a crystal structure of a new orthorhombic form of pure isavuconazole (ISV-ortho) is reported, and compared with its monoclinic form (ISV-mono) (Voronin et al., 2021).

2. Structural commentary

The title compound is orthorhombic, crystallizing in space group P2₁2₁2₁. The molecule (Fig. 1) consists of four rings (1,2,4-triazole, 2,5-difluorophenyl, 1,3-thiazole and benzonitrile) and a hydroxyl group connected to each other by a flexible chain. In both polymorphs of isavuconazole, ISV-ortho and ISV-mono, the stereogenic centers at C1 and C11 adopt an R,R configuration.

Figure 1
The molecular structure of ISV-ortho with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small spheres of arbitrary radii.

The superposition of the two polymorphs reveals clear conformational differences (Fig. 2). The main distinction lies in the orientation of the 4-(thiazol-4-yl)benzonitrile fragment, which is rotated by approximately 180°. Differences are also evident in the torsion angles: in the orthorhombic form, the torsion angles are −81.6 (2)° (C1—C11—C13—S1) and −37.3 (2)° (C2—C1—C11—C13), whereas in the monoclinic form the corresponding torsion angles are −118.4 (1) and −58.5 (2)°, respectively. Additionally, the dihedral angle between the triazole ring and the 2,5-difluorophenyl ring is 40.14 (8)° in ISV-ortho and 67.6 (1)° in ISV-mono.

Figure 2
Overlay of the title molecule (ISV-ortho) and the monoclinic polymorph (ISV-mono) with carbon atoms shown in brown.

3. Supramolecular features

The monoclinic polymorph of isavuconazole features only C—H⋯X (X =N/O/F) hydrogen bonds along with interactions involving π-electrons, such as C—H⋯π and aromatic π–π stacking interactions (Voronin et al., 2021). A quantum topology analysis revealed that the strongest individual intermolecular interaction in pure ISV-mono does not exceed 11 kJ mol⁻¹. This was taken to indicate a tendency of the API to exhibit amorphization or polymorphism due to the absence of persistent packing motifs (Voronin et al., 2016 , 2021).

In this study, we compare the supramolecular architectures of both polymorphs of ISV based on the analysis of interactions energies using the pairwise model implemented in CrystalExplorer (Spackman et al., 2021 ).

In the crystal structure of the orthorhombic form of ISV, the most important O1—H1⋯N3 hydrogen bond forms a mono-periodic chain substructure running along the crystallographic b-axis direction (Table 1, Fig. 3). This interaction is the strongest with a total energy estimated as −57.80 kJ mol⁻¹ and the largest contribution arising from Coulombic forces (–66.8 kJ mol⁻¹; Table 2). Three additional C—H⋯N interactions propagate these chains into a tri-periodic supramolecular network (Fig. 4). Among them, the molecular pair connected by C4—H4⋯N4 and C11—H11⋯N2 exhibits the second highest total energy (–40.10 kJ mol⁻¹) with a significant dispersive contribution (–45.3 kJ mol⁻¹), likely due to supporting close contacts between the (difluoro)phenyl ring and the thiazole group. Dispersion effects are also significant for molecular pairs involving contacts between triazole and benzene rings (–36.5 kJ mol⁻¹). The C12—H12B⋯N5 interaction leads to the formation of another sub-chain motif with a total pairwise energy of −32.0 kJ mol⁻¹.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O1—H1⋯N3ⁱ	0.83 (2)	1.99 (3)	2.7889 (16)	164 (3)
C4—H4⋯N4ⁱⁱ	0.95	2.65	3.277 (2)	124
C11—H11⋯F1	1.00	2.24	2.9815 (17)	130
C11—H11⋯N2ⁱⁱⁱ	1.00	2.51	3.317 (2)	138
C12—H12B⋯N5^iv	0.98	2.53	3.403 (2)	149
Symmetry codes: (i) $[-x, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]$ ; (ii) $[-x+1, y+{\script{1\over 2}}, -z+{\script{3\over 2}}]$ ; (iii) $[-x+1, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]$ ; (iv) $[-x+{\script{3\over 2}}, -y+1, z+{\script{1\over 2}}]$ .

Table 2
Interaction energies (kJ mol⁻¹) for the cluster of molecules with a radius of 3.8 Å for ISV-ortho and ISV-mono

N is the number of molecular pairs. R is the distance (Å) between molecular centroids. E_tot is the total energy and E_ele is the electrostatic (k = 1.057), E_pol is the polarization (k = 0.740), E_dis is the dispersion (k = 0.871) and E_rep is the repulsion (k = 0.618) component.

N	R	kE_ele	kE_pol	kE_dis	kE_rep	E_tot
ISV-ortho
2	10.15	−66.8	−13.8	−24.8	47.7	−57.8
2	15.18	−3.8	−1.0	−2.4	0.0	−7.1
2	8.95	−8.0	−1.6	−18.6	10.3	−18.0
2	11.06	−1.1	−1.3	−16.4	7.5	−11.2
2	14.04	−3.2	−0.4	−5.0	0.0	−8.5
2	8.38	−13.4	−2.4	−36.5	16.1	−36.3
2	6.79	−15.1	−3.3	−45.3	23.7	−40.1
2	12.06	−11.2	−2.4	−18.4	0.0	−32.0
2	11.70	−1.3	−0.1	−1.7	0.0	−3.0
ISV-mono
2	9.75	2.1	−2.1	−34.3	14.4	−19.9
2	5.83	−26.1	−5.7	−70.9	42.8	−59.9
2	8.98	−9.6	−2.4	−26.1	9.0	−29.3
2	11.96	−4.5	−0.7	−5.9	2.3	−8.9
2	10.73	−2.0	−1.0	−13.3	5.1	−11.4
2	9.6	−23.1	−4.1	−24.0	19.6	−31.8
2	12.33	−0.7	−3.4	−17.9	0.0	−22.0
2	14.74	−2.2	−1.0	−2.9	0.0	−6.1

Figure 3
A part of the crystal structure of ISV-ortho showing a mono-periodic chain motif running along the b-axis direction. Hydrogen bonds are drawn as dashed lines, and for the sake of clarity, the H atoms bonded to C atoms have been omitted. Symmetry code: (i) −x, y − $[{1\over 2}]$ , −z + $[{3\over 2}]$ .

Figure 4
Crystal packing of ISV-ortho showing the formation of a tri-periodic supramolecular network.

In the crystal structure of the monoclinic form of ISV, the hydroxyl group participates in an intramolecular O—H⋯N hydrogen bond, thus only the C—H donors contribute to intermolecular interactions, supported by aromatic contacts. The most significant total energies of molecular pairs are summarized in Table 2. It is seen that the highest total pairwise energies are comparable in both polymorphs; however, the interactions responsible for them are completely different. Furthermore, the electrostatic-to-dispersive contribution ratio differs: 25:75 for the monoclinic and 42:58 for the orthorhombic form. This clearly demonstrates that the monoclinic polymorph is dominated by non-directional dispersion interactions, whereas the orthorhombic polymorph shows an increased contribution from Coulombic forces.

4. Hirshfeld surface analysis

Hirshfeld surface analysis (Spackman & McKinnon, 2002 ; Spackman & Jayatilaka, 2009 ) was performed using CrystalExplorer (Spackman et al., 2021) to visualize and quantify intermolecular interactions in both polymorphs of isavuconazole. As shown in the breakdown diagram (Fig. 5), the major contributions to the Hirshfeld surface in both forms arise from H⋯H, N⋯H/H⋯N, and C⋯H/H⋯C contacts. The dominant share of H⋯H contacts is comparable between the two forms, whereas the proportions of N⋯H/H⋯N and C⋯H/H⋯C contacts appear complementary. Comparison of 2D fingerprint plots reveals that the main differences originate from N⋯H/H⋯N interactions. In the ISV-ortho form, these contacts appear as sharp, long spikes (shorter distances), while in the ISV-mono form, they are much shorter and less pronounced (longer distances). The contribution of F⋯H/H⋯F contacts is also higher in the orthorhombic form (14.4%) compared with the monoclinic one (8%). The S⋯H/H⋯S interactions show the opposite trend, contributing 3% in ISV-ortho versus 5.9% in ISV-mono, likely due to conformational differences that allow additional close contacts with the thiazole ring in ISV-mono. In ISV-ortho, the smaller contribution of S⋯H interactions seem to be compensated by S⋯C contacts. Each of the other contact types contributes less than 10% in both forms.

Figure 5
Hirshfeld surface contact contributions and two-dimensional fingerprint plots for ISV-ortho (left) and ISV-mono (right). The d_i and d_e values are the closest internal and external distances (in Å) from given points on the Hirshfeld surface.

5. Database survey

A search of the Cambridge Structural Database (CSD version 5.46, November 2024, Groom et al., 2016 ) revealed four structures of isavuconazole (Voronin et al., 2021): an anhydrous monoclinic form (GALJUC), a monohydrate form (GALJIQ), and two salts with phosphoric acid (GALJOW) and p-toluenesulfonic acid (GALJEM).

6. Synthesis and crystallization

The isavuconazole (purity 98%) used in this study was purchased from BLD Pharmatech GmbH (Germany). A pure crystalline form of isavuconazole was obtained unexpectedly from cocrystallization of the drug with pyrazinedicarboxylic acid; all substances (0.05 mmol) were used with a fixed stoichiometric ratio of 1:1, dissolved in ethanol (3 ml EtOH) and the mixture was heated to 346 K.

7. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 3. All hydrogen atoms bonded to carbon atoms were placed geometrically and refined as riding, with U_iso(H) = 1.2 U_eq(C) for the methylene, methine and aromatic groups or U_iso(H) = 1.5 U_eq(C) for the methyl group. The hydrogen atom of the hydroxyl group was found in a difference-Fourier map.

Table 3
Experimental details

Crystal data
Chemical formula	C₂₂H₁₇F₂N₅OS
M_r	437.46
Crystal system, space group	Orthorhombic, P2₁2₁2₁
Temperature (K)	100
a, b, c (Å)	8.9485 (1), 11.6975 (1), 19.8730 (1)
V (Å³)	2080.21 (3)
Z	4
Radiation type	Cu Kα
μ (mm⁻¹)	1.75
Crystal size (mm)	0.22 × 0.20 × 0.05

Data collection
Diffractometer	Rigaku XtaLAB Synergy, Dualflex, HyPix
Absorption correction	Gaussian (CrysAlis PRO; Rigaku OD, 2024 )
T_min, T_max	0.228, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	32125, 4184, 4132
R_int	0.028
(sin θ/λ)_max (Å⁻¹)	0.633

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.021, 0.055, 1.03
No. of reflections	4184
No. of parameters	285
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.21, −0.19
Absolute structure	Flack x determined using 1711 quotients [(I⁺)−(I⁻)]/[(I⁺)+(I⁻)] (Parsons et al., 2013 )
Absolute structure parameter	0.002 (4)
Computer programs: CrysAlis PRO (Rigaku OD, 2024), SHELXT (Sheldrick, 2015a ), SHELXL2019/3 (Sheldrick, 2015b ), Mercury (Macrae et al., 2020 ), PLATON (Spek, 2020 ) and publCIF (Westrip, 2010 ).

8. Pairwise model energies and their energy frameworks

Pairwise model energies (Turner et al., 2014 ) were estimated and visualized (Turner et al., 2015 ; Mackenzie et al., 2017 ) between molecules within a cluster with a radius of 3.8 Å, using CrystalExplorer software (Spackman et al., 2021). The computational approach uses a B3LYP/6-31G(d,p) molecular wave function calculated for the respective molecular arrangement in the crystal. The total interaction energy between any nearest-neighbour molecular pairs was estimated in terms of four components: electrostatic, polarization, dispersion and exchange–repulsion, with scale factors (k) of 1.057, 0.740, 0.871 and 0.618, respectively.

Supporting information

CCDC reference: 2495049

Crystal structure: contains datablocks I, global. DOI: https://doi.org/10.1107/S2056989025008886/vm2317sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989025008886/vm2317Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989025008886/vm2317Isup3.cml

checkCIF report

Computing details top

4-{2-[(2R,3R)-3-(2,5-Difluorophenyl)-3-hydroxy-4-(1,2,4-triazol-1-yl)butan-2-yl]-1,3-thiazol-4-yl}benzonitrile top

Crystal data top

C₂₂H₁₇F₂N₅OS	D_x = 1.397 Mg m⁻³
M_r = 437.46	Cu Kα radiation, λ = 1.54184 Å
Orthorhombic, P2₁2₁2₁	Cell parameters from 28179 reflections
a = 8.9485 (1) Å	θ = 4.4–77.0°
b = 11.6975 (1) Å	µ = 1.75 mm⁻¹
c = 19.8730 (1) Å	T = 100 K
V = 2080.21 (3) Å³	Plate, colourless
Z = 4	0.22 × 0.20 × 0.05 mm
F(000) = 904

Data collection top

Rigaku XtaLAB Synergy, Dualflex, HyPix diffractometer	4184 independent reflections
Radiation source: micro-focus sealed X-ray tube, PhotonJet (Cu) X-ray Source	4132 reflections with I > 2σ(I)
Mirror monochromator	R_int = 0.028
Detector resolution: 10.0000 pixels mm^-1	θ_max = 77.3°, θ_min = 4.4°
ω scans	h = −10→10
Absorption correction: gaussian (CrysAlisPro; Rigaku OD, 2024)	k = −11→14
T_min = 0.228, T_max = 1.000	l = −24→25
32125 measured reflections

Refinement top

Refinement on F²	Hydrogen site location: mixed
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F² > 2σ(F²)] = 0.021	w = 1/[σ²(F_o²) + (0.030P)² + 0.3775P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.055	(Δ/σ)_max = 0.001
S = 1.03	Δρ_max = 0.21 e Å⁻³
4184 reflections	Δρ_min = −0.19 e Å⁻³
285 parameters	Absolute structure: Flack x determined using 1711 quotients [(I⁺)-(I^-)]/[(I⁺)+(I^-)] (Parsons et al., 2013)
0 restraints	Absolute structure parameter: 0.002 (4)
Primary atom site location: structure-invariant direct methods

Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
S1	0.27613 (4)	0.47460 (4)	0.57074 (2)	0.03016 (10)
F1	0.51741 (10)	0.68366 (8)	0.79865 (5)	0.0253 (2)
F2	−0.00623 (12)	0.75217 (9)	0.92935 (5)	0.0362 (2)
O1	0.10049 (12)	0.63322 (9)	0.69664 (5)	0.0192 (2)
N1	0.25015 (13)	0.85359 (10)	0.70417 (6)	0.0178 (2)
N2	0.33567 (15)	0.92245 (11)	0.74385 (7)	0.0219 (3)
N3	0.09947 (14)	0.98951 (11)	0.73679 (6)	0.0224 (3)
N4	0.52605 (14)	0.55185 (11)	0.61439 (6)	0.0208 (3)
N5	1.22751 (19)	0.61588 (15)	0.39819 (8)	0.0391 (4)
C1	0.24879 (16)	0.64444 (12)	0.72044 (7)	0.0174 (3)
C2	0.31189 (16)	0.74593 (12)	0.67995 (7)	0.0189 (3)
H2A	0.422088	0.747449	0.684257	0.023*
H2B	0.286951	0.736175	0.631761	0.023*
C3	0.11079 (17)	0.89399 (12)	0.70097 (8)	0.0202 (3)
H3	0.031324	0.859480	0.676635	0.024*
C4	0.24030 (17)	1.00243 (13)	0.76200 (8)	0.0228 (3)
H4	0.267423	1.064314	0.790447	0.027*
C5	0.25190 (16)	0.67557 (11)	0.79592 (7)	0.0183 (3)
C6	0.38393 (17)	0.69634 (13)	0.83090 (8)	0.0210 (3)
C7	0.3890 (2)	0.73257 (13)	0.89697 (8)	0.0258 (3)
H7	0.482322	0.744423	0.918691	0.031*
C8	0.2569 (2)	0.75139 (13)	0.93113 (7)	0.0284 (3)
H8	0.256705	0.776037	0.976678	0.034*
C9	0.12582 (19)	0.73321 (14)	0.89692 (8)	0.0255 (3)
C10	0.11984 (17)	0.69603 (13)	0.83093 (8)	0.0210 (3)
H10	0.026052	0.684490	0.809584	0.025*
C11	0.34188 (16)	0.53393 (12)	0.70649 (7)	0.0196 (3)
H11	0.434223	0.539147	0.734658	0.023*
C12	0.25850 (19)	0.42638 (13)	0.72888 (8)	0.0257 (3)
H12A	0.169462	0.415987	0.700824	0.038*
H12B	0.228474	0.434422	0.776063	0.038*
H12C	0.324116	0.359800	0.724093	0.038*
C13	0.39205 (17)	0.52523 (13)	0.63439 (7)	0.0208 (3)
C14	0.42004 (19)	0.49034 (15)	0.51479 (8)	0.0292 (3)
H14	0.414034	0.473052	0.468164	0.035*
C15	0.54393 (18)	0.53089 (13)	0.54615 (7)	0.0234 (3)
C16	0.69074 (18)	0.54990 (13)	0.51454 (8)	0.0244 (3)
C17	0.7979 (2)	0.61881 (15)	0.54546 (8)	0.0306 (4)
H17	0.775707	0.654112	0.587329	0.037*
C18	0.9363 (2)	0.63651 (17)	0.51599 (9)	0.0341 (4)
H18	1.008092	0.684119	0.537319	0.041*
C19	0.9696 (2)	0.58388 (15)	0.45471 (8)	0.0291 (4)
C20	0.86455 (19)	0.51375 (14)	0.42361 (8)	0.0275 (3)
H20	0.887849	0.477219	0.382228	0.033*
C21	0.7261 (2)	0.49738 (13)	0.45314 (7)	0.0262 (3)
H21	0.654342	0.450069	0.431590	0.031*
C22	1.1127 (2)	0.60168 (16)	0.42323 (9)	0.0326 (4)
H1	0.056 (3)	0.584 (2)	0.7187 (12)	0.040 (6)*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
S1	0.02487 (18)	0.0387 (2)	0.02694 (18)	0.00058 (17)	−0.00362 (15)	−0.01020 (16)
F1	0.0180 (4)	0.0266 (5)	0.0312 (5)	−0.0017 (4)	−0.0013 (4)	−0.0015 (4)
F2	0.0370 (5)	0.0408 (5)	0.0306 (5)	0.0009 (5)	0.0150 (4)	−0.0053 (4)
O1	0.0168 (5)	0.0170 (5)	0.0238 (5)	−0.0015 (4)	−0.0019 (4)	0.0011 (4)
N1	0.0182 (6)	0.0153 (5)	0.0198 (5)	−0.0005 (5)	0.0003 (5)	0.0009 (4)
N2	0.0202 (6)	0.0190 (6)	0.0266 (6)	−0.0021 (5)	−0.0020 (5)	−0.0023 (5)
N3	0.0204 (6)	0.0182 (6)	0.0286 (6)	0.0016 (5)	−0.0009 (5)	−0.0011 (5)
N4	0.0245 (6)	0.0174 (6)	0.0204 (6)	0.0047 (5)	0.0004 (5)	−0.0008 (5)
N5	0.0384 (9)	0.0498 (9)	0.0293 (7)	0.0012 (8)	0.0074 (7)	0.0022 (7)
C1	0.0165 (7)	0.0157 (6)	0.0199 (6)	0.0003 (5)	−0.0001 (5)	−0.0004 (5)
C2	0.0191 (7)	0.0163 (7)	0.0214 (6)	0.0016 (5)	0.0021 (5)	0.0002 (6)
C3	0.0188 (7)	0.0179 (7)	0.0238 (7)	0.0000 (6)	−0.0009 (6)	0.0007 (6)
C4	0.0222 (7)	0.0184 (7)	0.0279 (7)	−0.0009 (6)	−0.0022 (6)	−0.0028 (5)
C5	0.0212 (7)	0.0134 (6)	0.0205 (6)	−0.0005 (5)	0.0000 (6)	0.0013 (5)
C6	0.0215 (7)	0.0166 (7)	0.0249 (7)	−0.0003 (6)	0.0010 (6)	0.0010 (6)
C7	0.0310 (8)	0.0207 (8)	0.0257 (7)	−0.0034 (7)	−0.0069 (7)	0.0000 (6)
C8	0.0422 (9)	0.0229 (7)	0.0202 (6)	−0.0021 (7)	0.0006 (7)	−0.0019 (6)
C9	0.0298 (8)	0.0217 (8)	0.0251 (7)	0.0008 (6)	0.0085 (6)	−0.0002 (6)
C10	0.0219 (7)	0.0171 (7)	0.0240 (7)	−0.0009 (6)	0.0017 (6)	0.0007 (6)
C11	0.0197 (6)	0.0172 (7)	0.0218 (7)	0.0022 (6)	−0.0012 (5)	−0.0008 (6)
C12	0.0277 (8)	0.0166 (7)	0.0327 (8)	0.0036 (6)	0.0021 (7)	0.0026 (6)
C13	0.0218 (7)	0.0166 (7)	0.0239 (7)	0.0039 (6)	−0.0022 (6)	−0.0030 (6)
C14	0.0313 (8)	0.0332 (9)	0.0231 (7)	0.0064 (7)	−0.0030 (6)	−0.0064 (7)
C15	0.0303 (8)	0.0197 (7)	0.0203 (7)	0.0068 (6)	−0.0001 (6)	−0.0016 (6)
C16	0.0307 (8)	0.0226 (7)	0.0200 (7)	0.0077 (6)	0.0011 (6)	0.0023 (6)
C17	0.0348 (9)	0.0330 (9)	0.0240 (7)	0.0021 (7)	0.0039 (7)	−0.0056 (7)
C18	0.0341 (9)	0.0384 (10)	0.0297 (8)	−0.0004 (8)	0.0037 (7)	−0.0041 (7)
C19	0.0337 (9)	0.0300 (8)	0.0237 (7)	0.0079 (7)	0.0050 (7)	0.0049 (6)
C20	0.0382 (9)	0.0248 (7)	0.0195 (7)	0.0110 (7)	0.0023 (6)	0.0024 (6)
C21	0.0358 (8)	0.0223 (7)	0.0203 (6)	0.0062 (7)	−0.0007 (6)	0.0007 (5)
C22	0.0378 (9)	0.0362 (9)	0.0238 (7)	0.0083 (8)	0.0034 (7)	0.0019 (7)

Geometric parameters (Å, º) top

S1—C14	1.7112 (17)	C7—H7	0.9500
S1—C13	1.7398 (15)	C8—C9	1.372 (2)
F1—C6	1.3636 (18)	C8—H8	0.9500
F2—C9	1.3642 (18)	C9—C10	1.383 (2)
O1—C1	1.4149 (17)	C10—H10	0.9500
O1—H1	0.83 (3)	C11—C13	1.505 (2)
N1—C3	1.335 (2)	C11—C12	1.529 (2)
N1—N2	1.3625 (18)	C11—H11	1.0000
N1—C2	1.4570 (18)	C12—H12A	0.9800
N2—C4	1.317 (2)	C12—H12B	0.9800
N3—C3	1.329 (2)	C12—H12C	0.9800
N3—C4	1.3645 (19)	C14—C15	1.357 (2)
N4—C13	1.301 (2)	C14—H14	0.9500
N4—C15	1.3875 (19)	C15—C16	1.473 (2)
N5—C22	1.154 (2)	C16—C17	1.396 (2)
C1—C2	1.5412 (19)	C16—C21	1.402 (2)
C1—C5	1.5438 (19)	C17—C18	1.385 (3)
C1—C11	1.5627 (19)	C17—H17	0.9500
C2—H2A	0.9900	C18—C19	1.397 (2)
C2—H2B	0.9900	C18—H18	0.9500
C3—H3	0.9500	C19—C20	1.392 (3)
C4—H4	0.9500	C19—C22	1.441 (2)
C5—C10	1.392 (2)	C20—C21	1.384 (2)
C5—C6	1.392 (2)	C20—H20	0.9500
C6—C7	1.380 (2)	C21—H21	0.9500
C7—C8	1.381 (2)

C14—S1—C13	89.26 (7)	C9—C10—H10	120.2
C1—O1—H1	110.0 (16)	C5—C10—H10	120.2
C3—N1—N2	110.06 (12)	C13—C11—C12	111.54 (12)
C3—N1—C2	130.12 (12)	C13—C11—C1	112.57 (12)
N2—N1—C2	119.29 (12)	C12—C11—C1	111.65 (11)
C4—N2—N1	102.39 (12)	C13—C11—H11	106.9
C3—N3—C4	102.67 (12)	C12—C11—H11	106.9
C13—N4—C15	111.26 (13)	C1—C11—H11	106.9
O1—C1—C2	103.92 (11)	C11—C12—H12A	109.5
O1—C1—C5	111.32 (11)	C11—C12—H12B	109.5
C2—C1—C5	108.60 (11)	H12A—C12—H12B	109.5
O1—C1—C11	111.34 (11)	C11—C12—H12C	109.5
C2—C1—C11	110.44 (11)	H12A—C12—H12C	109.5
C5—C1—C11	110.97 (11)	H12B—C12—H12C	109.5
N1—C2—C1	110.76 (11)	N4—C13—C11	123.34 (13)
N1—C2—H2A	109.5	N4—C13—S1	114.13 (11)
C1—C2—H2A	109.5	C11—C13—S1	122.51 (11)
N1—C2—H2B	109.5	C15—C14—S1	110.73 (11)
C1—C2—H2B	109.5	C15—C14—H14	124.6
H2A—C2—H2B	108.1	S1—C14—H14	124.6
N3—C3—N1	110.08 (13)	C14—C15—N4	114.60 (14)
N3—C3—H3	125.0	C14—C15—C16	125.84 (14)
N1—C3—H3	125.0	N4—C15—C16	119.53 (14)
N2—C4—N3	114.79 (13)	C17—C16—C21	118.74 (15)
N2—C4—H4	122.6	C17—C16—C15	120.84 (14)
N3—C4—H4	122.6	C21—C16—C15	120.41 (15)
C10—C5—C6	116.15 (13)	C18—C17—C16	120.97 (15)
C10—C5—C1	120.72 (13)	C18—C17—H17	119.5
C6—C5—C1	122.80 (13)	C16—C17—H17	119.5
F1—C6—C7	116.84 (14)	C17—C18—C19	119.56 (17)
F1—C6—C5	119.31 (13)	C17—C18—H18	120.2
C7—C6—C5	123.82 (15)	C19—C18—H18	120.2
C6—C7—C8	119.22 (15)	C20—C19—C18	120.19 (16)
C6—C7—H7	120.4	C20—C19—C22	119.51 (15)
C8—C7—H7	120.4	C18—C19—C22	120.30 (17)
C9—C8—C7	117.61 (13)	C21—C20—C19	119.83 (15)
C9—C8—H8	121.2	C21—C20—H20	120.1
C7—C8—H8	121.2	C19—C20—H20	120.1
F2—C9—C8	118.75 (14)	C20—C21—C16	120.70 (15)
F2—C9—C10	117.76 (15)	C20—C21—H21	119.7
C8—C9—C10	123.49 (15)	C16—C21—H21	119.7
C9—C10—C5	119.69 (14)	N5—C22—C19	179.8 (2)

C3—N1—N2—C4	−0.52 (15)	C2—C1—C11—C13	−37.30 (16)
C2—N1—N2—C4	−172.96 (12)	C5—C1—C11—C13	−157.78 (12)
C3—N1—C2—C1	−67.54 (18)	O1—C1—C11—C12	−48.73 (15)
N2—N1—C2—C1	103.15 (14)	C2—C1—C11—C12	−163.64 (12)
O1—C1—C2—N1	73.99 (13)	C5—C1—C11—C12	75.87 (15)
C5—C1—C2—N1	−44.61 (15)	C15—N4—C13—C11	177.28 (13)
C11—C1—C2—N1	−166.50 (11)	C15—N4—C13—S1	−1.04 (16)
C4—N3—C3—N1	−0.67 (16)	C12—C11—C13—N4	−133.40 (15)
N2—N1—C3—N3	0.79 (16)	C1—C11—C13—N4	100.19 (16)
C2—N1—C3—N3	172.15 (13)	C12—C11—C13—S1	44.79 (17)
N1—N2—C4—N3	0.10 (17)	C1—C11—C13—S1	−81.62 (15)
C3—N3—C4—N2	0.35 (18)	C14—S1—C13—N4	0.40 (13)
O1—C1—C5—C10	−3.97 (18)	C14—S1—C13—C11	−177.93 (13)
C2—C1—C5—C10	109.85 (14)	C13—S1—C14—C15	0.37 (14)
C11—C1—C5—C10	−128.58 (14)	S1—C14—C15—N4	−1.05 (19)
O1—C1—C5—C6	−177.17 (12)	S1—C14—C15—C16	177.01 (12)
C2—C1—C5—C6	−63.35 (17)	C13—N4—C15—C14	1.36 (19)
C11—C1—C5—C6	58.23 (17)	C13—N4—C15—C16	−176.83 (13)
C10—C5—C6—F1	−176.72 (13)	C14—C15—C16—C17	162.90 (17)
C1—C5—C6—F1	−3.2 (2)	N4—C15—C16—C17	−19.1 (2)
C10—C5—C6—C7	1.5 (2)	C14—C15—C16—C21	−18.1 (2)
C1—C5—C6—C7	174.96 (14)	N4—C15—C16—C21	159.86 (14)
F1—C6—C7—C8	177.32 (13)	C21—C16—C17—C18	0.7 (2)
C5—C6—C7—C8	−0.9 (2)	C15—C16—C17—C18	179.76 (16)
C6—C7—C8—C9	−0.3 (2)	C16—C17—C18—C19	−0.5 (3)
C7—C8—C9—F2	−179.42 (14)	C17—C18—C19—C20	−0.3 (3)
C7—C8—C9—C10	0.8 (2)	C17—C18—C19—C22	179.77 (17)
F2—C9—C10—C5	−179.98 (13)	C18—C19—C20—C21	0.8 (2)
C8—C9—C10—C5	−0.2 (2)	C22—C19—C20—C21	−179.20 (15)
C6—C5—C10—C9	−0.9 (2)	C19—C20—C21—C16	−0.6 (2)
C1—C5—C10—C9	−174.52 (13)	C17—C16—C21—C20	−0.2 (2)
O1—C1—C11—C13	77.62 (14)	C15—C16—C21—C20	−179.18 (14)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···N3ⁱ	0.83 (2)	1.99 (3)	2.7889 (16)	164 (3)
C4—H4···N4ⁱⁱ	0.95	2.65	3.277 (2)	124
C11—H11···F1	1.00	2.24	2.9815 (17)	130
C11—H11···N2ⁱⁱⁱ	1.00	2.51	3.317 (2)	138
C12—H12B···N5^iv	0.98	2.53	3.403 (2)	149

Symmetry codes: (i) −x, y−1/2, −z+3/2; (ii) −x+1, y+1/2, −z+3/2; (iii) −x+1, y−1/2, −z+3/2; (iv) −x+3/2, −y+1, z+1/2.

Interaction energies (kJ mol^-1) for the cluster of molecules with a radius of 3.8 Å for ISV-ortho and ISV-mono top

N	R	kE_ele	kE_pol	kE_dis	kE_rep	E_tot
ISV-ortho
2	10.15	-66.8	-13.8	-24.8	47.7	-57.8
2	15.18	-3.8	-1.0	-2.4	0.0	-7.1
2	8.95	-8.0	-1.6	-18.6	10.3	-18.0
2	11.06	-1.1	-1.3	-16.4	7.5	-11.2
2	14.04	-3.2	-0.4	-5.0	0.0	-8.5
2	8.38	-13.4	-2.4	-36.5	16.1	-36.3
2	6.79	-15.1	-3.3	-45.3	23.7	-40.1
2	12.06	-11.2	-2.4	-18.4	0.0	-32.0
2	11.70	-1.3	-0.1	-1.7	0.0	-3.0
ISV-mono
2	9.75	2.1	-2.1	-34.3	14.4	-19.9
2	5.83	-26.1	-5.7	-70.9	42.8	-59.9
2	8.98	-9.6	-2.4	-26.1	9.0	-29.3
2	11.96	-4.5	-0.7	-5.9	2.3	-8.9
2	10.73	-2.0	-1.0	-13.3	5.1	-11.4
2	9.6	-23.1	-4.1	-24.0	19.6	-31.8
2	12.33	-0.7	-3.4	-17.9	0.0	-22.0
2	14.74	-2.2	-1.0	-2.9	0.0	-6.1

Acknowledgements

The financial support from University of Łodz Doctoral School of Exact and Natural Sciences is gratefully acknowledged.

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