Crystal structures, Hirshfeld surface analysis and Pixel energy calculations of three trifluoromethylquinoline derivatives: further analyses of fluorine close contacts in trifluoromethylated derivatives

2.1 Synthesis of mefloquine derivatives, 1–3

Compounds 1–3 were prepared as reported [15], [16]: all had physical and spectral data in agreement with those published. Each was recrystallized for the crystallographic study by the slow evaporation of a methanol solution at room temperature.

2.2 Crystallography

Crystal data, data collection and structure refinement details are summarized in Table 1 [26], [33], [34], [35], [36], [37], [38], [39], [40].

2.3 Hirshfeld surface analyses

The Hirshfeld surfaces and two-dimensional fingerprint (FP) plots [27] were generated using CrystalExplorer 3.1 [28]. The Hirshfeld surfaces mapped over d_norm were scaled between −0.140 and 1.600 arbitrary units.

2.4 Lattice energy and intermolecular interaction energy calculations

Lattice energies and intermolecular interaction energies were calculated using the Pixel code implemented in the CLP package [41], [42]. The program Pixel calculates intermolecular energies by a distributed charge description on the basis of a preliminary evaluation of charge density from Gaussian at MP2/6-311G** level of theory (CUBE option). The Pixel mode calculates the total stabilization energies of the packing of the molecules, E_tot, distributed as Coulombic (E_coul), polarization (E_pol), dispersion (E_disp), and repulsion (E_rep) terms between separate, rigid molecules: results are listed in Table 2. Coulombic terms are treated on the basis of Coulomb’s law, polarization terms are calculated as a linear dipole approximation, dispersion terms are based on London’s inverse six-power approximation involving ionisation potentials and polarizabilities, and the repulsion term is derived from the wave function overlap.

Partial analysis of the Pixel calculations allowed the identification of the pairs of molecules, which contribute most to the total energy of the packing. The results for the important pairs are provided in Table 3: such energy values pertain to both molecules in the pair, the reference molecule at x, y, z and its partner in the pair: the energies associated with the reference molecule at x, y, z are half of these sums.

3.1 General

The asymmetric units of the crystals of compounds 1–3 contain each a single molecule. Compound 1 crystallizes in the triclinic space group, P1̅, with Z=2. Compound 2 crystallizes in the monoclinic space group, P2₁/c, with Z=4. Compound 3 crystallizes in the monoclinic space group, C2/c, with Z=8. Figure 1 illustrates the atom arrangements and numbering schemes. The quinoline rings are nearly planar in all cases: outliers for 1 are C8 and C2 at +0.029(2) and 0.030(2) Å, respectively, for 2 C2 and C8A at +0.013(1) and –0.017(1) Å, respectively and for 3, C3 and N1 at +0.051(2) and −0.156(1) Å, respectively. Molecules of compound 1 exists in the quinolinone form. Such a form has been reported for several crystalline 4-hydroxyquinoline derivatives, including the parent compound [43]. Compound 3 exhibits an intramolecular hydrogen bond, namely C7–H7⋯F813.

Fig. 1:

Views of the asymmetric units of 1–3 with the numbering schemes. Displacement ellipsoids are drawn at the 50% probability level, hydrogen atoms as spheres with arbitrary radii.

Details of the hydrogen bonding and other intermolecular interactions are provided in Table 4. There the π⋯π and X–Y⋯π interactions, obtained from the Platon analyses, are listed for a specific ring, either the phenyl or the pyridyl ring, of the quinoline system. However, in the subsequent Figures and discussion in this article, such π interactions are normally referenced to the centre of the quinoline system, Cg, taken as the midpoint of the C–C bond common to both rings. Thus, for example the Cg⋯Cg distance in a π⋯π interaction involving two quinoline moieties is the distance between the two mid points. This has been done for two reasons, (i) one, the major one, the quinoline π system involves both rings, and (ii) it simplifies the diagrams.

Table 2 shows the interaction energies calculated by the program Pixel for the three compounds. In all cases, the dispersion term contributes the majority of the stabilization suggesting that the π⋯π and X–Y⋯π interactions are important for the structural stability. These interactions seem to assume special relevance for 2, when compared with 1 and 3, as the dispersive energy of the structure contributes 67.5% of the total stabilization energy. As discussed later, although to a lesser extent, the F⋯F and F⋯H contacts also contribute significantly to the total dispersion energy.

3.2 Compound 1

The intermolecular interactions in compound 1 are a strong classical N1–H1⋯O4 hydrogen bond, weaker C8–H8⋯O4 and C7–H7⋯F21 hydrogen bonds, and a π⋯π stacking interaction. In addition, there are F23⋯F23 close contacts at 2.819(3) Å, well within the sum of the contact radii of 2×1.47 Å. Table 5 lists the symmetry operations. The Hirshfeld surface and fingerprint (FP) plots [28], [29] are shown in Fig. 2. Percentages of atom⋯atom close contacts, obtained from the FP plots, are listed in Table 2. As can be seen the highest percentage of any atom⋯atom close contact is clearly that for F⋯F at 40.4%: the next highest percentage is that of H⋯O/O⋯H at only 14.2%. Including other F⋯atom contacts, the total fluorine atom contacts are almost a half of all the contacts at 47%.

Fig. 2:

Compound 1. (a) A view of the Hirshfeld surface, with designated contacts on the surface indicated for N1–H1⋯O4, C8–H8⋯O4 and C7–H7⋯F21 hydrogen bonds and a π⋯π stacking interaction, (b) the FP plot: the blue spikes ending at d_e; d_i=(1.4; 1.1) and (1.1; 1.4) relate to F⋯H/H⋯F contacts, the blue spike at the middle of the FP relates to H⋯N/N⋯H contacts, and the high intensity of pixels, green and red areas relate to C⋯C contacts.

The majority of the stabilization energy of the structure, according to Pixel calculations, arise from six distinct pairs of molecules, see Fig. 3. Table 3 lists the calculated energies for each pair of molecules.

Fig. 3:

Compound 1. Pairs of molecules, calculated by the Pixel approach to be the most significant contributors to the stabilization: in each case the green reference molecule is at x, y, z and its paired molecule is in element colours, at a designated site: other molecules are drawn in grey, (a) pairs, Ia and Ib, with partner molecules at −1+x, y, z and 1+x, 1–y, 1–z, respectively: molecules are linked by C–H⋯O and N–H⋯O interactions, (b) pair, II: there are no close contacts between the molecules in the pair: the grey coloured molecules provide the conduits for the stabilization: partner molecule is at 1–x, −y, 1–z, (c) two views of pair III, formed from π⋯π interactions: partner molecule at 1–x, 1–y, 1–z, (d) pairs IV, again there is no close contacts between the molecules in the pair: partner molecule is at 2–x, −y, 1–z, (e) pair V showing F⋯F contacts between molecules at x, y, z and −x, 1–y, 1–z.

These six pairs are:

1. Pairs composed of Ia and Ib, derived from molecules at x, y, z and 1–x, y, z, for Ia and x, y, z and 1+ x, y, z, for Ib, are formed from the linkage of the molecules by the N1–H1⋯O4 and C8–H8⋯O4 hydrogen bonds in an overall C6 chain, see Fig. 3a. With the carbonyl oxygen atoms active as bi-acceptors, this chain contains a R21(6) ring.

2. Pair II: there are no direct close contacts between the molecules in this pair: the grey coloured molecules provide the conduits for the stabilization: the partner molecule is at 1–x, –y, 1–z, see Fig. 3b.

3. Pair III: two views, one side-on and the other one looking down the stack show this pair, formed from a π⋯π interaction: partner molecule at 1–x, 1–y, 1–z. The extent of overlap of the π systems in this interaction is high (Fig. 3c); in addition, the perpendicular distance between the best planes though the two molecules is 3.346(13) Å with a Cg⋯Cg separation of 4.777 Å.

4. Pair IV: again there is no direct close contact between the molecules in this pair: the partner molecule is at 2–x, –y, 1–z (Fig. 3d).

5. Pair V shows F23⋯F23 contacts between molecules at x, y, z and –x, 1–y, 1–z (Fig. 3e); the F23⋯F23 distance is 2.819(3) Å.

The calculated energies for each of these significant pairs of molecules in 1 are listed in Table 3.

The summation of the E_tot energies of pairs I–V is −184.9 kJ mol⁻¹, of which one half, −92.45 kJ mol⁻¹, is associated with the common reference molecule at x, y, z. This value is 87.6% of the total stabilization energy (−105.5 kJ mol⁻¹). The contribution of pair V to the stabilization energy of the structure is ca. 3.5%. Electrostatic repulsion between fluorine atoms is compensated by the dispersive effect provided by the complete structure.

3.2.1 Overall structure of 1

The overall structure of 1 is readily conceived to be composed of chains of molecules, formed from the N1–H1⋯O4 and C8–H8⋯O4 hydrogen bonds, which are linked into nearly planar sheets by C7–H7⋯F21 hydrogen bonds. These sheets, or layers, are then linked by F23⋯F23 and π⋯π interactions into a layered 3-dimensional structure (Fig. 4).

Fig. 4:

The packing of the molecules of 1. Alternating layers of molecules, formed from N1–H1⋯O4, C8–H8⋯O4 and C7–H7⋯F21 hydrogen bonds are by linked by F⋯F contacts and by π⋯π interactions. Only a few of the linkages of the layers have been drawn.

3.3 Compound 2

The intermolecular interactions in crystals of compound 2 are C7–H7⋯N1 and C42–H42A⋯F21 hydrogen bonds, along with C41–H41A⋯π and π⋯π interactions. The symmetry operations for these interactions are listed in Table 4. A view of the Hirshfeld surface is shown in Fig. 5a: the contacts indicated by the red areas on the surface have been designated. The FP plot is shown in Fig. 5b. Percentages of atom⋯atom close contacts, obtained from analyses of the FP plots are shown in Table 2. As with compound 1, the highest percentage atom-atom contacts are the H⋯F/F⋯H contacts at 37.2%, which is slightly lower than that for compound 1, as is also the sum of the percentages of all fluorine contacts. Significantly, the second highest contacts in 2 are H⋯H at 29.0%, much higher than that in compound 1: the next highest percentage in 2 is that for H⋯O/O⋯H at 14.2%.

Fig. 5:

Compound 2. (a) View of the Hirshfeld surface showing the various contact sites, (b) FP plot: the inner spikes are due to F⋯H/H⋯F contacts and the outer ones due to the N⋯H/H⋯N contacts.

The majority of the stabilization energy of the structure, according to Pixel calculations, comes from six distinct pairs of molecules (Fig. 6). Table 2 lists the calculated energies. These pairs are:

Fig. 6:

Compound 2. Pairs of molecules calculated by the Pixel approach to be the most significant contributors to the energy: in each case the green reference molecule is at x, y, z and the paired molecules in element colours is at a designated site: other molecules are drawn in grey. (a) pair, I, is a C41–H41A⋯π linked dimer: partner molecule at 1–x, −y, 1–z, (b) pair II; there are no close contacts between the pairs, the grey coloured molecules act as conduits: the partner molecule is at −x, 1–y, 1–z, (c) pairs IIIa and IIIb are within a C6 chain involving C7–H7⋯N1 hydrogen bonds: partner molecules at −x, 0.5+y, 0.5–z and −x, −0.5+y, 0.5–z for IIIa and IIIb, respectively, (d) pairs, IVa and IVb are within a C9 chain involving C42–H42A⋯F21 hydrogen bonds: partner molecules are at 1–x, 0.5+y, 1.5–z and 1–x, −0.5+y, 1.5–z, respectively.

1. Pair I is a C41–H41A⋯π linked dimer (Fig. 6a), with molecules at x, y, z (green coloured molecule) and 1–x, –y, 1–z (atom coloured molecule).

2. Pair II is illustrated in Fig. 6b: the two molecules involved are at x, y, z (green coloured molecule) and −x, 1–y, 1–z (element coloured molecule). Although these molecules do not exhibit direct atom···atom close contacts, each pair provides a significant contribution to the overall structural stabilization energy of −39.5 kJ mol⁻¹. The Pixel calculations can indicate two molecules, that are not “connected” by such interactions as H bonds, π⋯π, C–H⋯π, but still make a significant contribution to the stabilization of the structure, due to the electronic stabilization that arises from the possibility of delocalization via another molecule (i.e. the grey coloured molecule) that acts as a bridge between the pairs that are not virtually in contact.

3. Pairs IIIa and IIIb are within a zig-zag C6 chain, propagated in the direction of the b axis derived from C7–H7⋯N1 hydrogen bonds (Fig. 6c): symmetry operations: x, y, z (green sticks) and −x, 0.5+y, 0.5–z and −x, −0.5+y, 0.5–z (atom coloured molecules) for pairs IIIa and IIIb, respectively.

4. Pairs IVa and IVb are also within a zig-zag C6 chain, propagated in the direction of the b axis, generated from C42–H42A hydrogen bonds (Fig. 6d): partner molecules are at x, y, z (green coloured) and at 1–x, 0.5+y, 1.5–z and 1–x, −0.5+y, 1.5–z (atom coloured molecules), respectively.

The calculated energy for each of these important pairs of molecules is listed in Table 3. The sum of the E_tot energies of these pairs is −132.2 kJ mol⁻¹, of which one half, −66.1 kJ mol⁻¹, is associated with the common reference molecule at x, y, z. This value can be compared with the total calculated value by the program Pixel 3.1 of −93.7 kJ mol⁻¹ (Table 2). The identified pairs contribute 70.5% of the total energy of the structure, of which 7.7% arise from contacts involving fluorine atoms, which are assumed to be predominately of a dispersive nature.

3.3.1 Overall structure of 2

The chains formed from the C7–H7⋯N1 and the C42–H42A⋯F211 hydrogen bonds shown in Fig. 6c and d, respectively, are linked to form planar sheets composed entirely of R44(28) rings. The sheets are linked into a 3-dimensional array by combinations of π⋯π and C41–H41A⋯π interactions. A slice through the three dimensional structure is shown in Fig. 7.

Fig. 7:

A view of part of a slice though the 3-dimensional structure of 2, illustrating the connection of the sheets formed from C42–H42A⋯F211 and C7–H7⋯N1 hydrogen bonds by C41–H41A⋯π and π⋯π interactions.

3.4 Compound 3

The intermolecular interactions in crystals of compound 3 are N–H⋯X (X=N, F) and C–H⋯X (X=N, F) hydrogen bonds and two distinct π⋯π interactions (Fig. 8). The π⋯π interaction, termed a, is stronger than the other one of this type, b, as shown by the greater overlap of the π systems of the molecules (Fig. 8) and by the shorter Cg⋯Cg separation: 3.770 and 3.94 Å, respectively, in a and b.

Fig. 8:

Compound 3. Overlap of the molecules in the π⋯π interactions, a and b.

Views of the Hirshfeld surface and the FP plot are shown in Fig. 9. Percentages of atom⋯atom close contacts, obtained from analyses of the FP plots are provided in Table 2. As with compound 1, the highest percentage atom-atom contact is of the H⋯F/F⋯H type at 47.2%. Considering that there are two trifluoromethyl groups, it is not surprising that this compound shows the highest percentage of all three compounds studied here. All the fluorine close contacts sum to 60.7%. Interestingly, the percentage of F⋯F contacts is calculated to be 12.2%, despite there being no F⋯F contacts within the accepted sum of the contact radii, although a number of these contacts appear just outside this sum. It does suggest that distances out of this sum must still have some significance. For an organic molecule like 3 the percentage of H⋯H close contacts is low, as in 1.

Fig. 9:

Compound 3. (a)–(c) Three views of the Hirshfeld surface of 3 with sites of close contact indicated by red areas, (d) The FP plot: the blue spikes ending at d_e; d_i (1.4; 1.1) and (1.1; 1.4) are due to the F⋯H/H⋯F contacts and the outer blue spikes ending at d_e; d_i (1.2; 0.8) and (0.8; 1.2) are due to the H⋯N/N⋯H contacts.

The total energy of the structure of 3 is shown in Table 2. The majority of the stabilization energy of the structure, according to Pixel calculations, comes from eight distinct pairs of molecules, listed in Table 3.

These pairs are:

1. Pair I (Fig. 10a) is a strong π⋯π-linked dimer, A (Fig. 8a) with additional linkages via C5–H5⋯N44 and C41–H41⋯N44 hydrogen bonds: symmetry operations of the two participating molecules are x, y, z and 1–x, y, 0.5–z (atom coloured molecule).

2. Pair II (Fig. 10b) involves molecules at x, y, z and 0.5–x, 0.5–y, −z (atom coloured molecule). The weaker π⋯π interaction, b (Fig. 8b) is a weak link between these molecules. However, a significant contribution to the overall lattice stabilization energy arises via the grey molecules, which as mentioned above provides pathways for electronic stabilization. The links between the pair and the grey coloured molecules involve C44–H44A⋯F811, C44–H44A⋯N1, C44–H44A⋯F213, C5–H5⋯N44 and N41–H41⋯N44 hydrogen bonds.

3. Pairs IIIa and IIIb with molecules involved in pair IIIA located at x, y, z and 0.5+x, 0.5–y, 0.5+z, and those in pair IIIb at x, y, z and −0.5+x, 0.5–y, −0.5+z. The pairs IIIa and IIIb are located within a zig-zag chain of molecules linked by N4–H44A⋯N1 and potentially three N44–H44A⋯F213, N44–H44A⋯F811 and N44–H44B⋯F811 hydrogen bonds (Fig. 10c). The strongest hydrogen bond involved in the chain is N44–H44A⋯N1, which on its own generates a C(9) chain. The three N–H⋯F hydrogen interactions are, at best, weak due to H⋯F separations of 2.66, 2.61 and 2.67 Å, respectively, close to or at the sum of the contact radii of 2.67 Å. Furthermore the N–H⋯F angles of the latter two are both less than 107°. If all four interactions are considered, then the chain can be designated a R21(4), R21(5), R21(6),  C(10), C(10), C(11), C(11) chain.

4. Pair IV does not have close contacts, but as in pair II, adjacent molecules, drawn in grey in Fig. 10d are considered to act as conduits for the electron delocalisation (see above). As shown in Fig. 10d, there are many connections between the grey coloured molecules and each of the molecules in pair IV.

5. Pair V, a symmetric dimer, with a R22(10) ring, is directly connected by pairs of C7–H7⋯F813 interactions. Symmetry operations for the pair of molecules are x, y, z (green sticks) and 1–x, 1–y, −z (atom coloured molecule).

6. Pairs VIa and VIb appear in a C10 chain formed from C43–H43B⋯F811 hydrogen bonds: reference molecule at x, y, z, partner molecules at 0.5–x, 0.5+y, 0.5–z and 0.5–x, −0.5–y, 0.5–z, for VIa and VIb, respectively.

Fig. 10:

Compound 3. Pairs of molecuels calculated by the Pixel approach to be the most significant contributors to the energy: in each case the green reference molecule is at x, y, z and the paired molecule in element colours at the designated site: additional molecules are drawn grey, (a) pair I, incorporating a π⋯π interaction, and N41–H41⋯N44 and C5–C5⋯N44 hydrogen bonds and paired molecule at 1–x, y, 0.5–z, (b) pair II, paired molecule at 0.5–x, 0.5–y, –z, (c) pairs IIIA and IIIB: paired molecules at 0.5+x, 0.5–y, 0.5+z (IIIA) and −0.5+x, 0.5–y, –0.5+z (IIIB), (d) pair IV, with paired molecule at 0.5–x, 0.5–y, −1–z, (e) pair V, a symmetric dimer, with a R22(10) ring, formed from a pair of C7–H7⋯F813 interactions: paired molecule at 1–x, 1–y, –z, (f) pairs VIa and VIb, within a C10 chain formed from C43–H43B⋯F811 contacts, interactions of the molecule placed at x, y, z (green stick) with molecules at 0.5–x, 0.5+y, 0.5–z and 0.5–x, –0.5–y, 0.5–z for VIa and VIb, respectively.

The calculated energies for each of these important pairs of molecules are listed in Table 3. The sum of the E_tot energies is −309.9 kJ mol⁻¹, of which one half, −154.95 kJ mol⁻¹, is associated with the common reference molecule at x, y, z. This value can be compared with the total value of −156.6 kJ mol⁻¹ listed in Table 2 as calculated by the program Pixel 3.1. In this structure, the amount of fluorine contacts is higher than in 1 and 2, due to the presence of an additional CF₃ group. The energy associated with the fluorine close contacts sum to −55.6 kJ mol⁻¹, which is ca. 35% of the total energy.

3.4.1 Overall structure of 3

The structure of 3 can be considered to be composed of one-molecule wide columns, linked by a series of N–H⋯F interactions into a three dimensional array (Fig. 11). The columns of molecules are formed from both π⋯π interactions, a and b, in combination with N44–H44B⋯N1, N41–H41⋯N44, C5–H5⋯N44, N44–H44A⋯F811, N44–H44B⋯F811 and N44–H44A⋯F213 hydrogen bonds, i.e. utilizing pairs I and II. A side-on view of the column is shown in Fig. 11a, while Fig. 11b gives the view looking down the column. Such columns are linked by C3–H3⋯F211, C7–H7⋯F813 and C43–H43B⋯F2213 hydrogen bonds (Fig. 11c).

Fig. 11:

Compound 3. (a) A side-on view of a part of a one-molecule wide column formed from linking the pairs I and II shown in Fig. 10a and b, (b) view looking down a column, (c) view of the packing of the columns connected by fluorine close contacts.

3.5 Fluorine close contacts in other trifluoromethylated compounds

To provide further data on fluorine close contacts in trifluoromethylated compounds, Hirshfeld surface analyses were conducted on a number of compounds, whose crystal structures had been reported by us [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56] in earlier structural/biological studies. The Hirshfeld surface analyses utilized the previously reported cifs. In addition, fluorine close-contacts in four mefloquinium salts, already published [30], [31], [32], [57], have also been considered, as have the data for compounds, 1–3. Data for mono- and bis(trifluoromethyl) derivatives is listed in Tables 6 and 7, respectively. These tables list the percentages of all fluorine ⋯atom close contacts as well as a selected number of common atom⋯atom contacts found generally in organic molecules. While we acknowledge that the basis for the choice of these compounds is a selective one, i.e. trifluoromethylated compounds we had previously worked with, we feel that a good cross section of trifluoromethylated compounds are covered in this survey. The range of total fluorine⋯atom contacts in Tables 6 and 7 extends from 20 to 62%. With a limited number of samples covering a wide range of molecule types, and a differing number of other acceptor/donor atoms present in these molecules, a detailed analysis of the range of fluorine⋯atom contacts of 20–62% is somewhat premature. However, looking at the values for the mono-trifluoromethyl compounds in Table 6, it appears, superficially at least, that the number of hydrogen atoms of all types, i.e. alkyl, aryl, hydroxyl, amino, etc. present in the molecules has an influence. Thus MOKNES with 30 hydrogen atoms has the lowest fluorine⋯atom contacts at 21.0%, while MAZZIX, with just two hydrogen atoms, has the highest percentage of fluorine⋯atom contacts at 64.9%. In between MOKNES and MAZZIX in Table 6, there are 12 compounds, having between 3 and 12 hydrogens, exhibiting a range of fluorine close contacts from 29.5 to 50.9%, but without an obvious correlation.

Table 6:

Fluorine close contacts in mono(trifluoromethylated) compounds: comparisons with selected atom⋯atom contacts.

Compound	CCDC codes [references]	Percentage of atom⋯atom contacts
		Individual fluorine-atom contacts						Total % of F contacts	Selected other atom-aton contacts
		F⋯F	F⋯O/O⋯F	F⋯C/C⋯F	F⋯H/H⋯F	N⋯F/F⋯N	F⋯X/X⋯F		O⋯H/H⋯O	H⋯H	C⋯C	C⋯H/H⋯C
	MOKZES 718159 [44]	1.3	0.2	2.5	17.0	0.0		21.0	10.7	51.0	0.7	11.5
	ZEFLII 1453086 [45]	3.4	0.8	0.2	25.1	–		29.5	18.3	22.1	6.1	18.6
	PAJCUZ 254943 [46]	0.9 0.0	3.1 3.1	2.0 1.5	26.8 27.0	0.0 0.0		32.8	15.3 16.5	22.4 22.7	10.1 9.2	13.8 14.7
	SASYAN 282187 [47]	7.1	0.0	7.0	19.5	0.0		33.6	7.8	13.0	6.9	6.3
	TITTUM 679958 [48]	5.9	0.0	1.7	24.3	2.8		34.7	7.1	21.8	9.6	8.7
	VENKEF 621462 [51]	9.4	3.7	5.6	18.0	1.1	0.3b	38.1	17.7	1.2	0.8	6.8
	EFAYAL 182032 Mol 1 Mol 2 [52]	13.6 15.2	1.3 1.2	0.2 0.2	24.1 22.9	0.0 0.0		39.2 39.5	26.5 24.5	9.5 11.4	8.3 8.3	6.6 6.6
	This study 1895507	3.5	0.1	0.7	37.2	0.0	–	41.5	0.2	29.0	7.0	12.9
	TERPAI 630053 [51]	2.0	0.7	3.9	28.8	6.1	2.0c	43.5	4.9	4.9	2.3	5.1
	TITTOG 679957 [48]	3.1	2.6	3.4	24.9	0.6		43.6	6.0	21.7	7.4	10.7
	GEHSIW 612451 [52]	23.7	8.2	1.1	9.6	2.1		44.7	23.6	4.0	7.0	8.5
	This study 1895504	4.6	0.3	1.7	40.4	0.0	–	47.0	14.2	13.3	9.6	10.6
	PAJBEI 254930 [53]	12.9	1.7	1.5	34.8	0.0		50.9	0.0	6.3	1.4	6.7
	MAZZIX 296350 [54]	18.1		5.8	14.1	11.4	15.5d	64.9	–	3.1	0.0	1.3

1. ^aX=Br; ^bX=I; ^cX=Cl; ^dX=S.

Table 7:

Percentages of fluorine-atom and selected other atom⋯atom close contacts in bis(trifluoromethylated) compounds.

Compound	CCDC codes [ref]	Percentage of atom⋯atom contacts
		Individual fluorine⋯atom contacts						Total % of F contacts	Selected other atom⋯atom contacts
		F⋯F	F⋯O/O⋯F	F⋯C/C⋯F	F⋯H/H⋯F	N⋯F/F⋯N	F⋯X/X⋯F		O⋯H/H⋯O	H⋯H	C⋯C	C⋯H/H⋯C
	FUQMEJ 153346 [55]	15.3	5.8	9.6	16.7	1.1	–	31.8	19.5	3.4	0.7	1.4
	ELAMAH 1436547 [56]	7.2	0.4	2.5	28.7	–	0.3b	39.0	14.4	29.3	0.8	7.6
	AYEPIF 1510084 [30]	7.6		4.6	23.1	1.4	4.6b	41.3	19.2	31.2	2.3	9.6
	HISFEX 1879700 [31]	7.7	–	5.4	25.4	1.0	2.7b	42.7	10.2	12.4	0.3	3.4
	XACQOO 1053234 9R*,10S*,17S*, N3R*-stereoisomer [57]	3.0	6.8	3.3	31.9	1.1	1.9a	48.0	13.1	20.1	2.5	8.7
	XAGQUU 1053712 9R*,10S*,17R*, N3S*-stereoisomer [57]	1.9	3.6	2.3	37.2	0.3	3.4a	48.7	16.3	16.3	3.0	7.5
	XAGREF 1063830 [57]	1.6	3.1	0.4	44.5	0.0	−	49.6	1.7	26.3	1.8	16.0
	1895506 COMPOUND, 3, This study 1895506	12.2	–	0.7	47.2	0.6		60.1	–	17.2	7.2	7.7
	VEZRAW 1844854 [32]	10.5		7.0	40.8	0.3	3.1b	61.7	11.2	11.9	0.6	3.5

1. ^aX=S; ^bX=Cl.