Halogen Bonding in N -Alkyl-3-halogenopyridinium Salts

: We performed a structural study of N -alkylated halogenopyridinium cations to examine whether choice of the N -substituent has any considerable effect on the halogen bonding capability of the cations. For that purpose, we prepared a series of N -ethyl-3-halopyridinium iodides and compared them with their N -methyl-3-halopyridinium analogues. Structural analysis revealed that N -ethylated halogenopyridinium cations form slightly shorter C − X · · · I − halogen bonds with iodide anion. We have also attempted synthesis of ditopic symmetric bis-(3-iodopyridinium) dications. Although successful in only one case, the syntheses have afforded two novel ditopic asymmetric monocations with an iodine atom bonded to the pyridine ring and another on the aliphatic N -substituent. Here, the C − I · · · I − halogen bond lengths involving pyridine iodine atom were notably shorter than those involving an aliphatic iodine atom as a halogen bond donor. This trend in halogen bond lengths is in line with the charge distribution on the Hirshfeld surfaces of the cations—the positive charge is predominantly located in the pyridine ring making the pyridine iodine atom σ -hole more positive than the one on the alkyl chan.


Solution and Single Crystal Synthesis of Cocrystals
N-ethyl-3-chloropyridinium iodide [N-Et-3-ClPy]I and was obtained by dissolving halogenopyridine (1 mmol) in hot acetone and adding ethyl iodide in excess (ca 1.2 mmol) whereupon the solutions were left to cool and evaporate. Yellow crystals suitable for single-crystal X-ray diffraction experiments appeared in one day. Yield: 213 mg (79%).
N-ethyl-3-bromopyridinium iodide [N-Et-3-BrPy]I was obtained by dissolving halogenopyridine (1 mmol) in hot dichloromethane and adding ethyl iodide in excess (ca 1.2 mmol) whereupon the solution was left to cool and evaporate. Brown crystals suitable for single-crystal X-ray diffraction experiments appeared in three days. Yield: 183 mg (58%).
N-ethyl-3-iodopyridinium iodide [N-Et-3-IPy]I was obtained by dissolving halogenopyridine (1 mmol) in hot dichloromethane and adding ethyl iodide in excess (ca 1.2 mmol) whereupon the solution was left to cool and evaporate. Yellow crystals suitable for single-crystal X-ray diffraction experiments appeared in three days. Yield: 297 mg (82%).
Single crystals (suitable for single crystal X-ray diffraction experiment) of [3-ClPyMe]I,

Powder X-ray Diffraction Measurements
Powder X-ray diffraction experiments on the samples were performed on an Aeris X-ray diffractometer (Malvern Panalytical, Malvern Worcestershire, UK) with CuKα1 (λ = 1.54056 Å) radiation. The scattered intensities were measured with a PIXcel-1D-Medipix3 detector. The angular range was from 5 • to 40 • (2θ) with a continuous step size of 0.02 • and measuring a time of 0.5 s per step.
Data collection methods were created using the program package START XRDMP CREATOR (Malvern Panalytical, Malvern Worcestershire, UK) while the data were analysed using X'Pert HighScore Plus (Version 2.2, Malvern Panalytical, Malvern Worcestershire, UK) [105]. Comparison of measured and calculated PXRD patterns of the prepared compounds are shown in Figures S9-S14 in Supplementary Materials.

Single Crystal X-ray Diffraction Measurements
Single crystal X-ray diffraction experiments were performed using an Oxford Diffraction Xcalibur Kappa CCD X-ray diffractometer (Oxford Diffraction Ltd., Abingdon, UK) with graphite-monochromated MoKα (λ = 0.71073 Å) radiation. The data sets were collected using the ω-scan mode over the 2θ-range up to 54 • . Programs CrysAlis PRO CCD and CrysAlis PRO RED were employed for data collection, cell refinement, and data reduction [106,107]. The structures were solved and refined using SHELXS (Version 2013, Göttingen, Germany), SHELXL programs (Version 2013, Göttingen, Germany), SHELXT programs (Version 2013, Göttingen, Germany), respectively [108,109]. The structural refinement was performed on F 2 using all data. The hydrogen atoms were placed in calculated positions and treated as riding on their parent atoms (C-H = 0.93 Å and U iso (H) = 1.2 U eq (C) for aromatic and methine hydrogen atoms; C-H = 0.96 Å and U iso (H) = 1.5 U eq (C) for methyl hydrogen atoms, C-H = 0.97 Å and U iso (H) = 1.2 U eq (C) for methylene hydrogen atoms). The position of the proton in [4-IPy···H···4-IPy] + cation could not be reliably located from the electron difference map, and it was modelled as disordered over two positions on the nitrogen atoms of both 4-IPy molecules with Crystals 2021, 11, 1240 4 of 17 0.5 occupancy. All calculations were performed using the WinGX or Olex2 1.3-ac4 crystallographic suite of programs [110,111]. The figures were prepared using Mercury 2020.2.0 (CCDC, Cambridge, UK) [112]. Crystallographic data of the prepared compounds are shown in Table S2 in Supplementary Materials. ORTEP plots of the obtained compounds are shown in Figures S1-S8 in Supplementary Materials. CCDC No. 2109490-2109497, contain crystallographic data for this paper.
Data collection and analysis were performed using the program package STARe Software (Version 15.00, Mettler Toledo, Greifensee, Switzerland) [113]. TG and DSC thermograms of the prepared compounds are shown in Figures S15-S20 in the Supplementary Materials.
Substitution of chlorine on the pyridine ring with bromine leads to a significant difference in the structural arrangement of the cations and anions. The main difference is the presence of a C−Br· · · I − halogen bond shorter by ca. 6% than the sum of the corresponding van der Waals radii (d(Br1· · · I1) = 3.611(7) Å, ∠ (C2-Br1··· I1) = 169.2(2) • ). A methylene hydrogen atom of the ethyl group participates in a C−H· · · I − hydrogen bond with the iodide anion (d(C6· · · I1) = 4.013(6) Å). This combination of halogen and hydrogen bonds connects bromopyridinium cations and iodide anions in helical chains extending along the crystallographic b axis. The iodide anions also participate in anion-π contacts (d(C1· · · I1) = 3.575(5) Å) with cations from the neighbouring chains, which leads to formation of layers perpendicular to the c axis in the structure of [N-Et-3-BrPy]I ( Figure 2).
In the structure of [N-Et-3-Ipy]I the cations and the anions are also connected in chains (along the crystallographic b axis) with combinations of C−I· · · I − halogen bonds (d(I1· · · I2) = 3.473(3) Å, ∠ (C2-I1··· I2) = 178.25(7) • ) shorter by ca. 12% than the sum of the corresponding van der Waals radii, and C−H· · · I − hydrogen bonds (d(C1· · · I2) = 3.778(3) Å), but here the hydrogen bond is formed by an aromatic hydrogen atom in ortho position to the pyridine nitrogen. The chains are connected into layers via C−H· · · I − hydrogen bonds (d(C7· · · I2) = 4.094(3) Å) with a methyl hydrogen atom ( Figure 3). Substitution of chlorine on the pyridine ring with bromine leads to a significant difference in the structural arrangement of the cations and anions. The main difference is the presence of a C−Br⋯I − halogen bond shorter by ca. 6% than the sum of the corresponding van der Waals radii (d(Br1⋯I1) = 3.611 (7)      If one is to compare halogen bonding in N-ethylated 3-halogenopyridinium iodides to those in N-methylated 3-halogenopyridinium iodides, one can see that in both series cations derived from 3-bromopyridine and 3-iodopyridine participate in C−X· · · I − halogen bonds. Conversely, in N-ethyl-3-chloropyridinium iodide, cations do not participate in halogen bonding, while in N-methyl-3-chloropyridinium iodide some of symmetrically independent cations participate in the C−Cl· · · I − halogen bonds with iodide anion, but these halogen bonds are longer than the sum of the corresponding van der Waals radii. When comparing the lengths of the halogen bonds in the two series of iodides, both the C−Br· · · I − and the C−I· · · I − halogen bonds are shorter in the N-ethylated salts than in the N-methylated salts ( Table 1). The ESP values plotted on the Hirshfeld surface of cations are similar in 3-bromopyridinium cations while in case of 3-iodopyridinium cations N-methylated one have somewhat smaller ESP value than the N-ethylated one. All in all, there is no significant difference in halogen bonding between the N-ethylated and the N-methylated halogenopyridinium cations with iodide anions. In order to expand the series of N-ethylated iodopyridinium salts, we have attempted to synthesize N-ethyl-4-iodopyridinium iodide from 4-iodopyridine and ethyl iodide. However, despite numerous attempts of synthesis, we were not able to isolate the desired product. Instead, when the reaction was performed in a mixture of hot acetone and dichloromethane, a minute amount (two single crystals) of solid product was obtained, which was identified as 4-iodopyridinium hemihydroiodide ((4-IPy)2HI). It was presumably formed by a reaction of 4-IPy and the traces of hydroiodic acid produced by hydrolysis of ethyl iodide with water absorbed from the atmosphere over time. Although in the structure of (4-IPy)2HI the position of the HI hydrogen atom could not be ascertained from the electron difference map, it is evident that it is placed between the nitrogen atoms of a pair of molecules, interconnecting them by a charge assisted [119] Figure 5). It is interesting to note that this structure presents an excellent illustration of the HSAB principle in supramolecular chemistry [120,121]-the iodine atom of the [(4-IPy)2H] + complex is the softer Lewis acid and therefore preferentially binds to the softer Lewis base, i.e., iodide. In contrast, the proton is the hardest Lewis acid and preferentially bind to the harder Lewis base, i.e., pyridine nitrogen. In the structure of [N-Ace-3-Brpy]I, the bromine atom again forms a halogen bond with the iodide anion (d(Br1· · · I1) = 3.694(7) Å, ∠ (C2-Br1··· I1) = 166.4(1) • ). Iodide anion also binds [N-Ace-3-Brpy] + cation through C−H· · · I − hydrogen bonds (d(C1· · · I1) = 3.754(4) Å) with an aromatic hydrogen atom in ortho position to the pyridine nitrogen which lead to the formation of helical chains extending along the crystallographic b axis (Figure 4b). A different set of C−H· · · I − hydrogen bonds (d(C3· · · I1) = 3.847(5) Å) leads to the formation of the 2D structure (Figure 4c).
In order to expand the series of N-ethylated iodopyridinium salts, we have attempted to synthesize N-ethyl-4-iodopyridinium iodide from 4-iodopyridine and ethyl iodide. However, despite numerous attempts of synthesis, we were not able to isolate the desired product. Instead, when the reaction was performed in a mixture of hot acetone and dichloromethane, a minute amount (two single crystals) of solid product was obtained, which was identified as 4-iodopyridinium hemihydroiodide ((4-IPy) 2 HI). It was presumably formed by a reaction of 4-IPy and the traces of hydroiodic acid produced by hydrolysis of ethyl iodide with water absorbed from the atmosphere over time. Although in the structure of (4-IPy) 2 HI the position of the HI hydrogen atom could not be ascertained from the electron difference map, it is evident that it is placed between the nitrogen atoms of a pair of molecules, interconnecting them by a charge assisted [119] (probably symmetrical) N· · · H· · · N hydrogen bond (d(N· · · N) = 3.202(8) Å) into a [(4-IPy) 2 H] + complex. The iodide anion participates in two C−I· · · I − halogen bonds (d(I1· · · I3) = 3.502(7) Å, ∠ (C3-I1···I3) = 173.8(2) • ; d(I2· · · I3) = 3.533(7) Å, ∠ (C8-I2···I3) = 172.7(2) • ), with two neighbouring [(4-IPy) 2 H] + hydrogen-bonded complexes. This combination of hydrogen and halogen bonds forms supramolecular chains which are further connected into double chains through C−H· · · I − hydrogen bonds (d(C6· · · I1) = 4.028(7) Å) ( Figure 5). It is interesting to note that this structure presents an excellent illustration of the HSAB principle in supramolecular chemistry [120,121]-the iodine atom of the [(4-IPy) 2 H] + complex is the softer Lewis acid and therefore preferentially binds to the softer Lewis base, i.e., iodide. In contrast, the proton is the hardest Lewis acid and preferentially bind to the harder Lewis base, i.e., pyridine nitrogen. As shown above, the hydrogen bonded [(4-IPy)2H] + complex acts in the crystal structure of (4-IPy)2HI as a linear ditopic cationic halogen bond donor. This observation inspired us to attempt deliberate synthesis of ditopic cationic halogen bond donors by linking a pair of iodinated pyridine rings with different hydrocarbon linkers. For this purpose, we selected 3-IPy (which has shown to be a more reliable substrate for N-alkylation) as the iodopyridine, and propylene and (E)-buta-2-enylene chains as linkers. These linkers were selected as the latter was expected to result in a linear ditopic donor (due to the constricted rotation about the double bond), while the former would result in a bent molecule (the linker being an odd-numbered hydrocarbon chain).
The reaction of 3-IPy with 1,3-diiodopropane in 2:1 ratio, which was expected to produce the bent dication did not yield the desired product. Instead, we obtained N- (3- Halogen bonds involving the pyridine iodine atom as halogen bond donor are ca. 10% and 12% shorter than the sum of the corresponding van der Waals radii. On the other hand, one of the two halogen bonds involving an alkyl iodine atom as a halogen bond donor is ca. 2% shorter, while the other one is ca. 2% longer than the sum of the corresponding van der Waals radii. The neighbouring chains are further interconnected by a network of C−H⋯I − and C−H⋯I contacts in a 3D structure ( Figure 6). As shown above, the hydrogen bonded [(4-IPy) 2 H] + complex acts in the crystal structure of (4-IPy) 2 HI as a linear ditopic cationic halogen bond donor. This observation inspired us to attempt deliberate synthesis of ditopic cationic halogen bond donors by linking a pair of iodinated pyridine rings with different hydrocarbon linkers. For this purpose, we selected 3-IPy (which has shown to be a more reliable substrate for N-alkylation) as the iodopyridine, and propylene and (E)-buta-2-enylene chains as linkers. These linkers were selected as the latter was expected to result in a linear ditopic donor (due to the constricted rotation about the double bond), while the former would result in a bent molecule (the linker being an odd-numbered hydrocarbon chain).

Conclusions
Introducing various (aliphatic) N-substituents on the pyridine ring of 3-bromo-and 3-iodopyridine appears to be a viable method for preparation of an entire class of cationic halogen bond donors. Using aliphatic dihalogenides to produce bis-(halogenopyridinium) dications capable of acting as ditopic halogen bond donors has proven to be somewhat less successful-of the two attempted target cations, only one was isolated, and it decomposed during an attempted ion exchange. However, this opened the possibility of the synthesis of potentially ditopic asymmetric aliphatic-aromatic mono-

Conclusions
Introducing various (aliphatic) N-substituents on the pyridine ring of 3-bromo-and 3-iodopyridine appears to be a viable method for preparation of an entire class of cationic halogen bond donors. Using aliphatic dihalogenides to produce bis-(halogenopyridinium) dications capable of acting as ditopic halogen bond donors has proven to be somewhat less successful-of the two attempted target cations, only one was isolated, and it decomposed during an attempted ion exchange. However, this opened the possibility of the synthesis of potentially ditopic asymmetric aliphatic-aromatic monocationic halogen bond donors, with two halogens which greatly differ in ESP values corresponding to the halogen σ-hole, and therefore in halogen bonding potential.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/cryst11101240/s1, Figure S1. Molecular structure of [N-Et-3-ClPy]I showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level, and H atoms are shown as small spheres of arbitrary radius; Figure S2. Molecular structure of [N-Et-3-BrPy]I showing the atomlabelling scheme. Displacement ellipsoids are drawn at the 50% probability level, and H atoms are shown as small spheres of arbitrary radius; Figure S3. Molecular structure of [N-Et-3-IPy]I showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level, and H atoms are shown as small spheres of arbitrary radius; Figure S4. Molecular structure of [N-Ace-3-ClPy]I showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level, and H atoms are shown as small spheres of arbitrary radius; Figure S5. Molecular structure of   2 HI showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level, and H atoms are shown as small spheres of arbitrary radius; Figure S6 Table S1. An overview and crystallographic data of the prepared compounds. CCDC 2109490-2109497 contain crystallographic data for this paper. These data can be obtained free of charge from the Director, CCDC, 12 Union Road, Cambridge, CBZ 1EZ, UK (Fax: +44-1223-336033; email: deposit@ccdc.cam.ac.uk or www: http://www.ccdc.cam.ac.uk accessed on 25 August 2021).