Intermolecular Halogen Bond Detected in Racemic and Optically Pure N-C Axially Chiral 3-(2-Halophenyl)quinazoline-4-thione Derivatives

The halogen bond has been widely used as an important supramolecular tool in various research areas. However, there are relatively few studies on halogen bonding related to molecular chirality. 3-(2-Halophenyl)quinazoline-4-thione derivatives have stable atropisomeric structures due to the rotational restriction around an N-C single bond. In X-ray single crystal structures of the racemic and optically pure N-C axially chiral quinazoline-4-thiones, we found that different types of intermolecular halogen bonds (C=S⋯X) are formed. That is, in the racemic crystals, the intermolecular halogen bond between the ortho-halogen atom and sulfur atom was found to be oriented in a periplanar conformation toward the thiocarbonyl plane, leading to a syndiotactic zig-zag array. On the other hand, the halogen bond in the enantiomerically pure crystals was oriented orthogonally toward the thiocarbonyl plane, resulting in the formation of a homochiral dimer. These results indicate that the corresponding racemic and optically pure forms in chiral molecules are expected to display different halogen bonding properties, respectively, and should be separately studied as different chemical entities.


Introduction
Atropisomers arising from the rotational restriction around a biaryl bond are key structural components in chiral catalysts, natural products, biologically active compounds and chiral functional materials [1][2][3][4], and their enantioselective construction has been studied by many groups [5,6]. In contrast to well-known atropisomeric biaryls, atropisomers that emerge due to the rotational restriction around an N-C single bond, namely, N-C axially chiral compounds have attracted scant attention until recently [7]. In 2005 and 2010, we reported highly enantioselective syntheses of ortho-tert-butyl anilides (N-C axially chiral amides) and N-(ortho-tert-butylphenyl)-2-arylindoles (N-C axially chiral nitrogencontaining aromatic heterocycles) through chiral Pd-catalyzed N-C bond forming reactions [8,9]. Since the publication of these reactions, N-C axially chiral compounds have been widely accepted as new target molecules for catalytic asymmetric reactions, and highly enantioselective catalytic syntheses of diverse N-C axially chiral compounds have been achieved (more than one hundred original papers on the catalytic enantioselective synthesis of N-C axially chiral compounds have been published to date) [10][11][12]. Furthermore, the synthetic utility of N-C axially chiral products has been demonstrated through their application in various asymmetric reactions [10][11][12]. At the present time, N-C axially chiral chemistry has become a hot research topic in the field of synthetic organic chemistry.
These N-C axially chiral derivatives are also pharmaceutically attractive compounds. For example, 3-(2-halophenyl)quinazolin-4-one derivatives 1a and 1b, which are also known as mebroqualone and mecloqualone, are stable atropisomeric compounds due to the rotational restriction around an N-Ar bond (the rotational barriers = ∆G ‡ = ≥31.5 kcal mol −1 ) and they possess a tranquilizing effect based on GABA receptor agonist activity (Figure 1 and Scheme 1) [13,14]. In 2016, we succeeded in the catalytic asymmetric synthesis of axially chiral mebroqualone 1a and its derivatives [15]. In the course of this study, a unique property of a halogen bond (chirality-dependent halogen bond) was found in the crystals of 1a and 1b [16]. As shown in Figure 1, in the crystal of racemic 1a (and 1b), an intermolecular halogen bond (C=O· · · X) between the ortho-halogen and carbonyl oxygen atoms was formed, leading to the syndiotactic zig-zag array in which molecules of opposite absolute configuration were alternately connected. In contrast, the analogous formation of a halogen bond was not found in the crystals of optically pure 1a and 1b. Over the last two decades, halogen bonding (X· · · B) has aroused great interest as a new type of noncovalent interaction and has been widely used as an important supramolecular tool in various fields such as crystal engineering, liquid crystals, material science, and biological systems [17][18][19][20][21][22][23][24]. On the other hand, although halogen bondmediated chiral recognitions and chiral catalysts with halogen bond donor functionality have also been reported, there are relatively few studies on halogen bonding related to molecular chirality such as those shown in Figure 1 [25][26][27][28][29][30]. The halogen bond observed in axially chiral quinazolinones 1a and 1b suggests that in the case of chiral compounds, the corresponding racemic and optically active forms, ought to have different halogen bonding properties, and should be explored as different chemical entities. In addition, since homo-and hetero-chiral associations sometimes affect the pharmacokinetics and drug efficacy [31], the chirality-dependent halogen bond may offer meaningful information to contemplate the difference in pharmacological activity between the optically pure forms and the racemates.
It has been reported that the conversion of quinazolinones to quinazolinone-thione analogues significantly increased their pharmacological activity [32][33][34]. Quite recently, we found that optically pure mebroqualone 1a and mecloqualone 1b can be converted to the corresponding thione analogues, i.e. 3-(2-bromophenyl)-2-methylquinazoline-4-thione (2a) and 3-(2-chlorophenyl)-2-methylquinazoline-4-thione (2b), respectively, without a decrease in enantiomeric excess through the reaction with Lawesson's reagent (Scheme 1) [35]. The obtained thione derivatives 2a and 2b have higher rotational barriers than the corresponding quinazolinones 1a and 1b. The reaction in Scheme 1 is the first example of the conversion of optically active N-C axially chiral amides to thioamide analogues. The sulfur atom of the C=S group is also known to work as a Lewis base in the halogen bond [36][37][38][39][40][41], while it is less commonly studied in comparison with halogen bonding with C=O and C=N functional groups. We were curious about whether the chirality-dependent halogen bond detected in 1a and 1b is also observed in crystals of the thione analogues 2a and 2b.
In this article, we report the crystal structure and intermolecular halogen bonds (C=S· · · X) which were detected in the crystals of racemic and optically pure N-C axially chiral 3-(2-halophenyl)quinazoline-4-thione derivatives. In contrast to quinazolin-4-one derivatives, in quinazoline-4-thione analogues, the intermolecular halogen bond was detected in not only racemic crystals but also in optically pure crystals. Meanwhile, the halogen bonds in the racemate and optically pure form were found to be oriented in a different direction (angle) toward thiocarbonyl plane.

Crystallization and Structure of 2
Single crystals of quinazoline-4-thiones 2a and 2b (racemic and optically pure forms) were prepared through recrystallization by natural evaporation from a solution of hexane and chloroform (1:1) which yielded yellow prismatic crystals suitable for X-ray crystallographic studies. Racemates 2a and 2b have an isomorphic relationship with the same Orthorhombic Pbca space group and have quite similar molecular structures. The structure of 2a in the racemic crystals is shown in Figure 2b with the corresponding numbering schemes (the structure of quinazolinone 1a is also shown in Figure 2a for comparison). Selected intramolecular bond distances and angles of racemic 1a,b and 2a,b are summarized in Table 1, showing their similar structure; the bond lengths of C1-S1 for 2a and 2b are 1.659(2) and 1.6587(14) Å, respectively. Most of the molecular structural details are similar, but when oxygen is converted to sulfur, the dihedral angle between ring-A and ring-B of the molecules in the racemic crystals 2a and 2b increases to become orthogonal.

Supramolecular Association of 2a
The crystal packing and remarkable halogen bond of racemic mebroqualone thione analogue 2a are shown in Figure 3. The structure of racemic 2a is very similar to that of racemic mebroqualone 1a shown in Figure 1. That is, syndiotactic zig-zag arrays, in which molecules of opposite absolute configuration are alternately connected [· · · (P)-2a· · · (M)-2a· · · ], are formed by the intermolecular interaction between the sulfur and ortho-bromine atoms. The intermolecular distance of S· · · Br is 3.4143(6) Å and is 6.5% shorter than the sum of van der Waals radii of bromine and sulfur atoms, which is 3.65 Å. The arrangement of C11-Br1· · · S1 i (i: 1/2 − x, 1/2 + y, z) is nearly linear [the bond angle = 172.04(6) • ] and this strongly supports the formation of the halogen bond (C=S· · · Br).
In the crystal of optically pure (P)-2b, similar to (P)-2a, the formation of a homochiral dimer through the intermolecular interaction between the sulfur and ortho-chloro atoms was found (Figure 5b). The intermolecular distance of S· · · Cl is 3.464(1) Å and is 2.4% shorter than the sum of van der Waals radii of chlorine and sulfur atoms, which is 3.55 Å [In optically pure (P)-1b, no intermolecular O· · · Cl interaction was observed]. The bond angles of C11-Cl1· · · S2 iii (iii: x, y, 1 + z) and the torsion angle of C-C=S· · · Cl are 158.2(6) • and 112.3(2) • , respectively. This torsion angle indicates that the halogen bond of (P)-2b is directed orthogonally toward the thiocarbonyl plane, as observed for (P)-2a.
Since the magnitudes of the shortening of the halogen bonds of ortho-chloro derivatives 2b and (P)-2b (1.8% and 2.4%, respectively) are smaller than those of ortho-bromo derivatives 2a and (P)-2a (6.5% and 6.2%, respectively), it is obvious that the S· · · Br interaction is stronger in comparison with the S· · · Cl interaction.
Similar to racemic ortho-bromo and chloro derivatives 2a,b, the crystal lattice in racemic 2c is constructed by four (P)-and (M)-molecules (total eight molecules) as shown in Figure 7. The molecular structures of 2a-c are similar but the dihedral angle between ring-A and ring-B of the molecules in the crystal 2c is slightly small, 82.64 • in comparison with those in the crystals 2a,b (86.93 • and 87.84 • , respectively). In the packing structure, the intermolecular π· · · π stackings between quinazolinone rings were found to give the dimer between (P)-and (M)-2c. Typically, the intermolecular distance between two ring-C centroids is 3.5335(13) Å [the corresponding perpendicular distance is 3.3672(8) Å], showing the strong stacked structure, and the dimer further interacts between two ring-A centroids with a distance of 4.2843(12) Å [the corresponding perpendicular distance is 3.4393(7) Å] to give columnar stacking along the a axis. The weak C-H· · · π and CH· · · F interactions were also observed in the packing. Unfortunately, the intermolecular halogen bond (C=S· · · F) between ortho-fluoro and sulfur atoms was not detected. It is well known that the order of strength of the halogen bond is I· · · B > Br· · · B > Cl· · · B >> F· · · B and that halogen bonds (F· · · B) between fluorine atoms and a Lewis base are uncommon. To understand all the intermolecular interactions, the Hirshfeld surface (HS) analysis [45] was carried out for the crystals of 2a-c using Crystal Explorer 17.5 and the results are summarized in Supplementary Materials. The main interactions for the whole structure of racemic 2a are H(inside)· · · H(outside) and C· · · H/H· · · C contributing 36.5% and 24.7%, respectively, to the overall crystal packing due to the high surface area of the aromatic. The presence of two halogen bonds are found to be the contributions of the S· · · Br (1.2%) and Br· · · S (1.2%) contacts with the sharp finger plots, indicating the 1D alternate zig-zag arrangement. No contribution of the C· · · C (1.0%), Br· · · Br (0%), and S· · · S (0%) shows the predominant halogen bonds. The N· · · H/H· · · N contribution is also observed 5.3% between the quinazoline rings. On the other hand, the results of (P)-2a shows only one-way halogen bonds and the corresponding contributions of the S· · · Br/Br· · · S is 1.0% with the sharp finger plot. The contributions of H· · · H, C· · · H/H· · · C, C· · · C, Br· · · Br, S· · · S, and N· · · H/H· · · N are 35.6%, 27.8%, 0.8%, 1.1%, 0%, and 4.7%, respectively. The characteristics of the interaction of racemic 2a and (P)-2a are also reflected well in chloro-derivatives 2b, but the halogen bonds of 2a are more effective; the S· · · Cl/Cl· · · S for racemic 2b and (P)-2b are 2.1% and 0.9%, respectively. The HS analysis of 2c shows the weak intermolecular interactions and the corresponding contribution of π· · · π, C-H· · · π, and H· · · F interactions through C· · · C (5.4%), C· · · H/H· · · C (23.4%), and H· · · F/F· · · H (9.4%), respectively. The contributions of S· · · F/F· · · S and N· · · H/H· · · N are 1.8% and 7.1%, respectively, on the HS but no direct halogen bonds were detected from the finger plots.
We also succeeded in the synthesis of optically pure 2-methylquinazoline-4-thione bearing an ortho-iodophenyl group, through the reaction shown in Scheme 1. However, since the ortho-iodo derivative is extremely unstable, gradual decomposition occurs during the crystallization and the preparation of a single crystal was not possible.

General Information
The melting points were uncorrected. The 1 H and 13 C NMR spectra were recorded on a 400 MHz spectrometer. In the 1 H and 13 C NMR spectra, chemical shifts were expressed in δ (ppm) downfield from CHCl 3 (7.26 ppm) and CDCl 3 (77.0 ppm), respectively. HRMS were recorded on a double focusing magnetic sector mass spectrometer using electron impact ionization. Column chromatography was performed on silica gel (75-150 µm). Mediumpressure liquid chromatography (MPLC) was performed on a 25 × 4 cm i.d. prepacked column (silica gel, 10 µm) with a UV detector. High-performance liquid chromatography (HPLC) was performed on a 25 × 0.4 cm i.d. chiral column with a UV detector.

X-ray Single Crystal Structural Analysis
The single crystal X-ray structures were determined by a Bruker D8 Quest with MoKα radiation (λ = 0.71073 Å) generated at 50 kV and 1 mA. All the crystals were coated with paratone-N oil and measured at 100 K. SHELXT program was used for solving the structures [46]. Refinement and further calculations were carried out using SHELXL [47]. The crystal data and structure refinement of four crystals are summarized in Table 3. H atoms were placed in geometrically idealized positions and refined as riding, with aromatic C-H = 0.95 Å and U iso (H) = 1.2U eq (C). The chiral crystal (P)-2b shows the correct absolute structure and the flack parameter is −0.02 (3). CCDC 2153821 (rac-2a), 2153822 (rac-2b), 2153823 [(P)-2b], and 2153825 (rac-2c) contain the Supplementary Materials for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving. html, accessed on 3 February 2022. The structural information of CCDC1561609 (rac-1a), 1897963 (rac-1b), and 2032428 [(P)-2a] was used [16,35].

Conclusions
We found that in the crystals of racemic and optically pure N-C axially chiral 3-(2bromo-and 2-chloro-phenyl)-2-methylquinazoline-4-thiones, different types of intermolecular halogen bonds between ortho-halogens and sulfur atoms are formed. The halogen bonds detected in the racemic crystals are located in the periplanar region of the thiocarbonyl plane, leading to the syndiotactic zig-zag array in which molecules of opposite absolute configuration are alternately connected. The modes of halogen bonding and association are very similar to those detected in the corresponding racemic carbonyl analogues (mebroqualone and mecroqualone). On the other hand, the halogen bonds in the optically pure crystals are oriented orthogonally toward the thiocarbonyl plane, resulting in the formation of a homochiral dimer. This is in remarkable contrast to the optically pure carbonyl analogues in which no intermolecular interaction between carbonyl oxygen and ortho-halogen atoms was detected. Although it is well known that the different types of hydrogen bonding are formed in racemic and enantiomerically pure crystals [48,49], homoand hetero-chirality dependent halogen bonds mentioned in this paper are quite rare [16]. These results clearly expose the fact that the corresponding racemic and enantiomerically pure forms of chiral substances are expected to display different halogen bonding properties and should be separately studied as different chemical entities.

Conflicts of Interest:
The authors declare no conflict of interest.
Sample Availability: Samples of the compounds are available from the authors.