Pyridine-4-thiol as halogen-bond (HaB) acceptor: influence of the noncovalent interaction in its reactivity

Pyridine-4-thiol has been explored as an acceptor for a halogen-bond (HaB) interaction. For this compound, it is the S atom instead of the pyridine group that is the moiety of choice for establishing the interactions, producing a betaine-type structure. Interestingly, when left in solution, this compound forms a methylene-bridged sulfide that implies the activation of the CH2Cl2 solvent. The pre-organization imposed by the HaB seems to have a clear influence on the outcome.


Introduction
Halogen bonding (HaB) is a noncovalent interaction that has attracted increasing attention during the last few decades, due to its role in crystal engineering, molecular recognition processes, as a structure-directing tool and for the modulation of some physical properties (Politzer et al., 2007;Brammer et al., 2001;Aakerö y et al., 2013;Cavallo et al., 2016). Also, its influence in reactivity and catalysis is increasingly acknowledged (Bulfield & Huber, 2016;Bamberger et al., 2019;Jó nsson et al., 2022).
In our group, we have explored this interaction in metallic complexes, both for main group and transition metals, and have observed the influence of HaB in the structural arrangement and reactivity (Dorté z et al., 2020;Mosquera et al., 2016Mosquera et al., , 2017Vidal et al., 2013). In this work, we are interested in exploring pyridine-4-thiol as a HaB acceptor since there are two possible sites able to act as such, namely, the pyridine group and the S atom. Pyridines are one of the most popular types of HaB acceptor, a search in the Cambridge Structural Database (CSD; Version 5.42, with updates to September 2021; Groom et al., 2016) for HaB interactions with C-X (X = Br or I) gives over 1000 hits. On the other hand, sulfur has two available lone pairs and can be a potent HaB acceptor since it can interact with more than one HaB donor, which can lead to interesting topologies. However, it has been less studied, although in a search in the CSD, there is a significant number of structures that display S atoms as a HaB acceptor; a search for C-X� � �S (X = Br or I) interactions in the angle range 160-180 � gave 715 hits.
We have explored the interaction of pyridine-4-thiol with the iconic IC 6 F 4 I molecule as HaB donor. Interestingly, for this molecule, it is not the pyridine group but the S atom that acts as the HaB acceptor, which is surprising since in the related compound Py-S-Py, it is the pyridine group that acts as the HaB acceptor (Arman et al., 2010). Furthermore, the presence of C-S� � �I interactions in this cocrystal favours the stabilization of the zwitterionic form for pyridine-4-thiol (namely, pyridin-1-ium-4-ylsulfanide), which has important implications in the reactivity of the molecule, and in fact an unusual C-Cl activation of the dichloromethane solvent is observed to give the bis[(pyridin-1-ium-4-yl)sulfanyl]methane dication.

General considerations
All manipulations were carried out under an inert atmosphere of argon using standard Schlenk techniques. All solvents were dried prior to use following standard methods. All reagents were commercially obtained and were used without further purification.

Figure 1
The synthetic scheme for the preparation of cocrystal 1.

Synthesis of (HPy-CH 2 -PyH)Cl 2 (2).
To pyridine-4thiol (50 mg, 0.45 mmol) in a Schlenk flask was added CH 2 Cl 2 (10 ml). To this suspension, C 6 F 4 I 2 (180 mg, 0.45 mmol) was added and, to dissolve the mixture completely, tetrahydrofuran (10 ml) were added. The solution was left to stir for 48 h. A clear solution was formed, to which a layer of hexane (16 ml) was added. After the solution had diffused into the hexane, brown crystals of 2 of good enough quality for analysis by X-ray diffraction were isolated (yield: 32%, 22 mg).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 1. H atoms were placed geometrically and left riding on their parent atoms, except for the H atoms bonded to N1 in cocrystal 1, and C10 and N1 in salt 2, which were found in a Fourier map.

Results and discussion
In order to achieve the crystallization of pyridine-4-thiol and IC 6 F 4 I, both compounds were dissolved in a mixture of CH 2 Cl 2 and tetrahydrofuran under argon. The suspension was heated briefly to obtain a clear solution (Fig. 2). From this, orange crystals were isolated after three weeks by slow evaporation and the structure was determined by X-ray diffraction analysis.
As shown in Fig. 2, a cocrystal has been formed incorporating two molecules of pyridine-4-thiol and one of IC 6 F 4 I. This compound crystallized in the monoclinic space group P2 1 /c. In this case, it is the S atom that acts as the HaB acceptor, which stabilizes the zwitterionic form of pyridine-4-thiol and, at the same time, the pyridine group is blocked by the proton. It should be noted that pyridine-4-thiol has been used frequently as a ligand for d-and f-block metals, and in those cases most often the zwitterionic form is the one present (CSD; Groom et al., 2016).

Figure 3
Histograms of the S� � �I distances for the S� � �I-C interaction for (a) an S atom with a À 1 charge (149 hits) and (b) an S atom with no charge (339 hits). In salt 2, the S� � �I distance is 3.158 (7) Å .  Zuluaga et al., 2020;Postnikov et al., 2015;Bozopoulos & Rentzeperis, 1986;Hirschberg et al., 2014). Sulfur can form bifurcated interactions and in this case behaves as such; on one side it interacts with the I atom and on the other side with the pyridinium N-H proton. This behaviour as a dual acceptor for both a halogen and a H atom has been observed previously; however, there are not many examples (Ding et al., 2020).
The perfluorinated unit, p-C 6 F 4 I 2 , interacts from both sides to give discrete units formed by the interaction of two molecules of pyridine-4-thiol. These units are linked via weaker N-H� � �I and C-H� � �F interactions to give layers. As mentioned before, for the related Py-S-Py derivative, the interaction is established between the pyridine group and the I atom to give an N Py � � �I-C contact (N Py � � �I = 2.838 Å and N Py � � �I-C = 177.93 � ) (Arman et al., 2010). Hence, the preference for one group or the other is not very strong and may even be governed by kinetics and, if there is a competing aceptor, such is in the case of the proton, may direct the choice of the donor. In fact, for the thiocyanate, which can also act as a dual donor, the formation of both HaB interactions with the N or the S atom has also been oberved for the same donors (Soldatova et al., 2020).
When the reaction is performed on a larger scale and left stirring for 48 h, the solution changes colour to brown. It was possible to obtain crystals from this solution by diffusion into a hexane layer. The isolated brown crystals were of good enough quality to be determined by single-crystal X-ray diffraction. Interestingly, a methylene-bridged sulfide resulting from the displacement of both Cl atoms from dichloromethane by two molecules of pyridine-4-thiol, i.e. an [L 2 CH 2 ] 2+ dication, is formed. The displaced Cl atoms are still present as chloride counter-ions of the dication generated. The activation of the C-Cl bond has been observed previously, most often via a radical mechanism and less frequently via a nucleophilic mechanism. In fact, in our group, we have observed a similar reactivity when a zwitterionic betaine derivative composed of a nucleophilic carbene and a carbodimide (CDI-NHC) is left stirring for a long time in a dichloromethane solution (Sá nchez-Roa et al., 2018). As in this case, the activation of the C-Cl bond is promoted by the presence of zwitterionic species. As mentioned before, the zwitterionic form of pyridine-4-thiol is stabilized by the presence of the HaB interaction, which implies a pre-organization that influences the outcome of the reaction. A similar behaviour has been described previously for isocyanates (Soldatova et al., 2020).
Moreover, the evolution of pyridine-4-thiol in solution when it is left stirring in solution at 67 � C for 15 h gives the [HS-Py-Py] + derivative, as has been reported previously (Ding et al., 2020). In our case, the presence of IC 6 F 4 I favours the competitive reaction that implies the CH 2 Cl 2 activation.  The proposed mechanism for the formation of salt 2.

sigma-hole interactions
Compound 2 crystallized in an orthorhombic noncentrosymmetric spatial group Fdd2. The central C atom shows an angle slightly wider [116.3 (4) � ] than that typical of sp 3 -hybridation, probably due to the presence of the S atoms; the value is similar to that previously reported for bis [(pyridin-4yl)sulfanyl]methane (Carballo et al., 2007(Carballo et al., , 2008a(Carballo et al., ,b, 2009Lago et al., 2013Lago et al., , 2014. The S-CH 2 -S plane forms an angle of 78.66 (8) � with the planes of the pyridine rings, which are placed in opposite directions relative to the central CH 2 unit; this arrangement is also observed in the reported derivatives where bis[(pyridin-4-yl)sulfanyl]methane behaves as a ligand (Carballo et al., 2007(Carballo et al., , 2008a(Carballo et al., ,b, 2009Lago et al., 2013Lago et al., , 2014. This arrangement is the origin of the conformational chirality shown by this compound (Fig. 4). In our case, this disposition is also influenced by the presence of a hydrogen bond involving one chloride anion and the proton bonded to atom C4 of the ring. This conformation is reinforced by a chalcogen bond established between the Cl and S atoms [S� � �Cl = 3.373 (4) Å and C-S� � �Cl = 156.94 (5) � ], which is significantly shorter than the van der Waals radii radius sum (3.55 Å ; Bondi, 1964). Although the S atom can present two �-holes, in this case, only one interaction is observed with the chloride anion.
As mentioned before, the formation of the cation in 2 is an unusual reaction. Although similar substitution reactions have been reported for some secondary aliphatic (Souquet et al., 1993), alicyclic (Matsumoto et al., 1984) or heteroaromatic amines (Juliá et al., 1982;Zhao et al., 2011), the process usually takes place under special conditions, such as very high pressures or in highly polar solvent mixtures. Futhermore, it should be noted that the formation of the neutral equivalent bis[(pyridin-4-yl)sulfanyl]methane from pyridine-4-thiol in the presence of CH 2 Cl 2 has been described previously in basic conditions, i.e. in an alcoholic solution with an excess of NaOH, the reaction taking several days to complete (Amoedo-Portela et al., 2005). In our case, the mechanism is different, as shown in the reaction pathway displayed in Fig. 5. Taking into account our previous studies, we have detected that the first step that implies the substitution of the chloride is the rate-determining step, and it proceeds via an S N 2 mechanism. This process leads to a reactive chloromethyl intermediate -CH 2 Cl + which evolves quickly to the final product where both Cl atoms have been displaced (Sá nchez- Roa et al., 2018). Hence, in this case, the IC 6 F 4 I role would be as a catalyst.

1,2,4,5-Tetrafluoro-3,6-diiodobenzene bis(pyridin-1-ium-4-ylsulfanide) (1)
Crystal data Special details 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. Refinement. Data collection was performed at 200 (2) K, with the crystals covered with perfluorinated ether oil. Single crystals were mounted on a Bruker-Nonius Kappa CCD single crystal diffractometer equipped with a graphitemonochromated Mo-Kα radiation (λ = 0.71073 Å). Multiscan absorption correction procedures were applied to the data (Blessing, 1995). The structure was solved using the WINGX package, (Farrugia, 2012) by direct methods (SHELXS-2013) and refined using full-matrix least-squares against F 2 (SHELXL-2016). (Sheldrick, 2015) All nonhydrogen atoms were anisotropically refined. Full-matrix least-squares refinements were carried out by minimizing w(Fo 2 -Fc 2 ) 2 with the SHELXL2014 weighting scheme and stopped at shift/err < 0.001. The final residual electron density maps showed no remarkable features.  (11) Special details 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. Refinement. Data collection was performed at 200 (2) K, with the crystals covered with perfluorinated ether oil. Single crystals were mounted on a Bruker-Nonius Kappa CCD single crystal diffractometer equipped with a graphitemonochromated Mo-Kα radiation (λ = 0.71073 Å). Multiscan absorption correction procedures were applied to the data (Blessing, 1995). The structure was solved using the WINGX package, (Farrugia, 2012) by direct methods (SHELXS-2013) and refined using full-matrix least-squares against F 2 (SHELXL-2016). (Sheldrick, 2015) All nonhydrogen atoms were anisotropically refined. Full-matrix least-squares refinements were carried out by minimizing w(Fo 2 -Fc 2 ) 2 with the SHELXL2014 weighting scheme and stopped at shift/err < 0.001. The final residual electron density maps showed no remarkable features. Crystallographic data for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no.