Ortho‐Substituent Effects on Halogen Bond Geometry for N‐Haloimide⋯2‐Substituted Pyridine Complexes

Abstract The nature of (imide)N–X⋯N(pyridine) halogen‐bonded complexes formed by six N‐haloimides and sixteen 2‐substituted pyridines are studied using X‐ray crystallography (68 crystal structures), Density Functional Theory (DFT) (86 complexation energies), and NMR spectroscopy (90 association constants). Strong halogen bond (XB) donors such as N‐iodosuccinimide form only 1:1 haloimide:pyridine crystalline complexes, but even stronger N‐iodosaccharin forms 1:1 haloimide:pyridine and three other distinct complexes. In 1:1 haloimide:pyridine crystalline complexes, the haloimide's N─X bond exhibits an unusual bond bending feature that is larger for stronger N‐haloimides. DFT complexation energies (ΔE XB) for iodoimide–pyridine complexes range from −44 to −99 kJ mol−1, while for N‐bromoimide–pyridine, they are between −31 and −77 kJ mol−1. The ΔE XB of I⋯N XBs in 1:1 iodosaccharin:pyridine complexes are the largest of their kind, but they are substantially smaller than those in [bis(saccharinato)iodine(I)]pyridinium salts (−576 kJ mol−1), formed by N‐iodosaccharin and pyridines. The NMR association constants and ΔE XB energies of 1:1 haloimide:pyridine complexes do not correlate as these complexes in solution are heavily influenced by secondary interactions, which DFT studies do not account for. Association constants follow the σ‐hole strengths of N‐haloimides, which agree with DFT and crystallography data. The haloimide:2‐(N,N‐dimethylamino)pyridine complex undergoes a halogenation reaction resulting in 5‐iodo‐2‐dimethylaminopyridine.


Introduction
Non-covalent interactions (NCIs) are ubiquitous and pivotal in controlling the structural integrity, dynamics, stability, and properties of functional materials [1,2] as well as chemical [3] and biological systems. [4]Despite having lower strengths and being less that the directionality of the halogen bond (XB) interaction is determined by the size of the -hole. [8]Clark and Heßelmann explained this preference by performing natural bond order analysis on alkyl halides and proposing an approximate s 2 p x 2 p y 2 p z 1 configuration (where z is the direction of the R─X bond) for a head-on interaction of a halogen's deficient electron density site or -hole with nucleophiles. [9]ver the past few decades, XB crystal engineering has focused on using a variety of XB donors to interact with N/O/S-heterocycles, which has been extremely beneficial in the rational design of functional materials. [10,11]Previously studied XB complexes can be broadly divided into three classes: 1) R─X⋯Y, where the halogen is bound to a non-fluorinated organic backbone, 2) R F ─X⋯Y, where the halogen is bound to a fluorinated organic structure, and 3) Y⋯X + ⋯Y complexes, where the halogen carrying a positive charge is trapped between two Lewis bases.The utility of these three classes is well-known.For instance, class 1 neutral C─I•••N halogen-bonded systems have been used in the synthesis of phosphorescent materials, [12,13] the reversible nature and fluorine content of the class 2 C F ─I•••N XBs make them suitable for liquid crystals [14] and functional materials, [15] and class 3 [N•••I•••N] + XBs are used in the preparation of supramolecular capsules, [16][17][18] helicates, [19] and porous structures [20] as well as halogenating reagents due to the reactivity of iodine in them. [21]aloimides are a unique class of XB donors with N─X functionality situated between two electron withdrawing C═O or C═O and SO 2 groups, and their complexes belong to class 1.
A growing interest in haloimide complexes is fueled by the work of Fourmigué and co-workers, who has shown that the very strongly polarized N─I bond of N-iodosaccharin (NISac) will dissociate when combined with a highly nucleophilic 4-(N,N-dimethylamino)pyridine (DMAP), resulting in an iodopyridinium cation and an N-saccharinate anion, that is, formation of a salt. [22]In contrast, when mixed with a simple pyridine, the NISac produces a co-crystal with a modestly polarized N─I bond.Since then, studies on the N─I bond lengthening and I⋯N bond shortening features in (imide)N─I⋯N complexes using different pyridines have gained a lot of attention.From the viewpoint of haloimides, only three XB complex types have been studied: N-haloimide-p-substituted pyridines, [23─25] bis(N-imidato)halogen(I) cationic salts, [26] and N-haloimide pyridine N-oxide complexes, [27] all aiming to examine N─I and I⋯N lengthening and shortening features in (imide)N─I⋯N motifs.
Some of the most fundamental questions in this line of research were: when combined with ortho-substituted pyridines, how does changing the identity of the X-atom in the N─X group affect the XB strengths?What geometry variations would these donor-acceptor partners exhibit when made using analogous 2-substituted pyridines?What is the sensitivity of the N─X bond with respect to the donor and acceptor?The answers to these questions may not be apparent from an evaluation of a limited number of XB complexes since some donor-acceptor partners may produce small changes to bond parameters while others may have significant influence.The systematic investigation of the XB parameters and structural changes of donors and acceptors in 96 complexes formed by two N-halosuccinimides, two N-halophthalimides, and two N-halosaccharins against sixteen 2-substituted pyridines are shown in Figure 1.X-ray crystallography, computational studies, and solution NMR are used to explain these findings.

Results and Discussion
As a preliminary approach to gauging the XB donor strengths of the N-bonded halogens their -hole sizes can be illustrated by plotting the molecular electrostatic potentials of N-haloimides and calculating their V s,max values.The comparison allows observation of the -hole dependence on the halogen as well as the imide structure (Figure 2).In general, iodines have larger -hole size than bromines, and halosaccharins have the largest V s,max values, decreasing in the order NISac > NIS ≥ NIP for N-iodoimides and NBSac > NBS ≥ NBP for N-bromoimides. Figure 2 provides some useful insights: i) although succinimides and phthalimides have very different electronic ring structures, there is no big difference in their -hole sizes.Note that in their structures the N─X group is situated between the two C═O groups.ii) The V s,max difference between NBP and NBSac is 14 kJmol −1 and between NIP and NISac is 21 kJmol −1 .Both phthalimide and saccharin have aromatic rings, but the former has N─X group between C═O groups, and the latter between C═O and SO 2 groups.These findings may suggest that the magnitude of V s,max values are significantly influenced by the type of the groups present adjacent to the N─X group rather than the aromatic ring.

X-Ray Crystallography
Sixty-eight crystal structures were crystallized from acetone using a 1:1 equivalent donor:acceptor ratio.Crystallization experiments resulted in five distinct types of complexes: the desired 1:1 halogen-bonded (58 structures, type 1), [bis(Nimidato)halogen(I)]pyridinium (4 structures, type 2), the neutral (1 structure, type 3) and salt (4 structures, type 4) hydrogenbonded co-crystals, and a halogenated derivative (1 structure, type 5).NIS, NIP, NBS, and NBP only form type 1 complexes, while NISac and NBSac produce types 1-4.The four types of saccharin complexes can be used to provide a general explanation of how the type 1 parent complex transforms during the crystallization processes.Type 2 is the ligand exchange reaction of a pyridine with an in situ formed saccharinate anion; analogous type 2 complexes with different pyridinium cations have been reported in the literature. [26]Type 3 is the consequence of iodine exchange with hydrogen, or proton abstraction by an in situ formed saccharinate anion that leads to the hydrogen-bonded complex.Type 4 formation could be mediated by one or more pathways; for instance, one pathway is type 2 N-X bonds breaking to give saccharinate anions, and saccharinate then hydrogen bonding with the protonated pyridinic nitrogen. [28]The second pathway is proton abstraction by pyridine from saccharin, that is, via type 3 to type 2. Note that i) types 1 and 3 are co-crystals while types 2 and 4 are salts, and ii) only NISac produces type 2 structures, which can be attributed to a strong -hole.However, considering that a type 3 with NIS has been reported, [29] the large -hole explanation appears less feasible, implying that the complexation outcome is influenced by packing and crystallization factors.Nevertheless, Figure 3 demonstrates the potential of haloimides and Lewis bases, when combined, to generate halogen(I) ions for halogenation in organic reactions. [30]Combining NISac and 2-(N,N-dimethylamino)pyridine produced the type 5 crystal structure, and the results of these findings are discussed with the help of further solution NMR studies.
A detailed structure analysis for type 1 structures was carried out to investigate the bond parameters.All complexes have short X•••N distances that are smaller than the sum of the X-and Natom van der Waals radii (Br + N = 3.40 Å, I + N = 3.53 Å), and ∠N-X•••N that range from 169°to 180°(see Tables S1-S6, Supporting Information).The examination of the asymmetric unit cells reveals that 51 out of 58 structures contain one 1:1 XB complex, while the others deviate from the 1:1 stoichiometry.The X•••N distances in these seven additional structures are essentially identical, differing just by a maximum of ≈0.07 Å.    2) Å], which is surprising given that nitrogen in simple pyridine is less nucleophilic than, for instance, 2-ethylpyridine [31] in NISac-9, which has a longer I•••N distance of 2.325(18) Å.Two different N-bromoimide complexes were identified for NBSac-5; the first has a Br•••N distance of 2.392(2) Å and the second of
The optimized structures do not exhibit large deviations of the N─X bond linearity.The Δ values for halosuccinimides and halophthalimides are all below 1.1°.For halosaccharins, the Δ values are slightly larger but remain below 3.0°, with an exception for NBSac-13 (7.3°) and NBSac-14 (5.1°), which contain the bulky substituents that can result in steric strain on the XB and subsequent bond bending.This additional evidence demonstrates that the large Δ values are caused by packing forces and secondary interactions to other XB complexes in the solid-state crystals.
The gas-phase DFT XB complexation energies (ΔE XB ) are summarized in Figure 7.In general, for the same XB acceptor, the energy trend follows the -hole strength, that is, halosaccharin >> halosuccinimide ≥ halophthalimide (Table S9, Supporting Information).Pyridines with electron withdrawing trifluoromethyl group have the smallest ΔE XB values while those with bulky ─CH(Ph) 2 and ─SiMe 3 groups have the largest ΔE XB values.Overall, the X•••N energies are in the range of −28 kJ mol −1 to −99 kJ mol −1 , and they are 8 kJ mol −1 to 39 kJ mol −1 larger than those values reported for halosuccinimide-para-substituted pyridines. [24]The ΔE XB energies of negatively charged DFT data of iodoimide complexes of type I crystal structures are compiled in Figure 8 to examine the influence of the imide scaffold and pyridinic substituents on I•••N distances and ΔE XB values.This analysis reveals interesting trends and insightful conclusions: i) in succinimide-, phthalimide-and saccharin-2halopyridine series, that is along the x-axis, the overall ΔE XB values follow the order F < Cl ≤ Br < I < Et.For iodoimide-2-halopyridines, the ΔE XB differences from complex-to-complex are not greater than 4.1 kJ mol −1 .The maximum ΔE XB difference is observed between NISac-2 and NISac-3.The ΔE XB values of iodoimide-2-ethylpyridine are 15.3-18.4,15.3-18.2,and 19.4-23 kJ mol −1 larger than their iodoimide-2-halopyridines. Smaller variations in ΔE XB values between iodoimide-2-halopyridines can be related to the pyridinic nitrogen's weak nucleophilicity, which is caused by the electron-withdrawing halogen substituents and the sudden "jump" in ΔE XB values for iodoimide-2-ethylpyridine to the electron donating ethyl substituent.ii) Iodine's electron accepting capability is significantly impacted by the imide scaffold and ΔE XB values follow the -hole strength.The ΔE XB differences between succinimide and phthalimide complexes are less than 0.6 kJ mol −1 along the y-axis, but they are ≈11-18 kJ mol −1 between phthalimide and saccharin complexes.This comparison demonstrates that while tuning XBs is possible, tuning XBs with N-haloimides is more reliable than tuning XBs with pyridines and is especially not effective with electron withdrawing groups.

Solution NMR Studies
The 15 N NMR coordination shift, Δ 15 N coord , is a useful tool for measuring the strengths of coordination [43] and halogenbonded [44][45][46][47] complexes.It is defined as the difference between the  15 N chemical shift of a halogen-bonded complex and that of its free ligand.[46][47] In this study, we were able to successfully determine the Δ 15 N coord for NIS and NBS, but for other XB donors, it was not viable due to absence of protons at the 3-position.Instead, the coordination shifts of the pyridinic nitrogen atoms were used to compare the strengths of X•••N XBs, with a larger Δ 15 N coord value indicating a stronger X•••N interaction.The Δ 15 N coord magnitudes of pyridinic nitrogens followed the halogen's hole strength order: NISac > NIS ≥ NIP for I•••N halogen bonds and NBSac > NBS ≥ NBP.Note that despite the same -hole strengths of N-iodosuccinimide (165 kJ mol −1 ) and Niodophthalimide (165 kJ mol −1 ) donors, the Δ 15 N coord of pyridinic nitrogen atoms in iodosuccinimide complexes are significantly larger than iodophthalimide (Table S10, Supporting Information).For example, |Δ 15 N coord | of NIS-1 is 41.5 ppm and that of NIP-1 is 0.7 ppm.The Δ 15 N coord values of bromosuccinimide and bromophthalimide complexes are smaller, ranging from 0.4 to 6 ppm and 0.1 to 4.5 ppm, respectively.Overall, the Δ 15 N coord values of iodoimide complexes are larger than bromoimide, which is consistent with the fact that as the halogen size decreases (I > Br > Cl > F), the XB donating properties decrease.
Association constants (K XB ) are determined in CDCl 3 from changes in haloimide proton resonances caused by the XB complexation.A 6-10 mm N-haloimide solutions were titrated using ≈0.15 m pyridine stock solutions (for details, see Supporting Information).The K XB values for a 1:1 donor:acceptor binding model were established using the online Bindfit program [48] (Tables S11, Supporting Information).The K XB values range from 4 to 3494 m −1 for NIS, 7 to 2790 m −1 for NIP, 236 to 144 459 m −1 for NISac, and 1 to 394 m −1 for NBSac.For NBS and NBP complexes K XB values are small (≈1-5 m −1 ) and are within in the fitting errors due to weak binding (for details, see Table S11, Supporting Information).The concentration of pyridines has an impact on K XB values.For instance, K XB values of NBS-8, NBP-8, and NBSac-8 titrated by using ≈0.15 m 2-methylpyridine (8) solutions are 5, 4, and 332 m −1 , respectively, while those titrated with 1 m 2-methylpyridine (8) solutions are 21, 19, and 423 m −1 , respectively.Estimation of K XB values for haloimide-2dimethylaminopyridine complexes were unsuccessful due to signal broadening.Single crystals formed from the NISac-16 titration sample were characterized by X-ray diffraction to be a halogenated product, 5-iodo-2-dimethylaminopyridine (16-I).Note that in their crystallization studies, Fourmigué and co-workers also obtained protonated 3-bromo-4-dimethylaminopyridine and saccharinate as co-crystals by mixing DMAP and NBSac. [25] 1:1 equivalent of NISac-16 was monitored by 1 H and 1 H─ 15 N HMBC NMR spectroscopy at 298 K conditions.The halogenated product begins to form as soon as the donor and acceptor components are mixed, as seen in The calculated ΔE XB and experimental association constants logarithmic K XB values of NIS, NIP, NISac, and NBSac complexes were examined for correlation (Figure S5a, Supporting Information).While the correlation exhibits a rough trend, the data points are significantly scattered around the trendline resulting in a weak linear correlation (R 2 = 0.760).The strongest measured association constants, such as NISac-5 (log K XB measured 4.65 versus predicted 2.5) and NISac-12 (log K XB measured 5.10 versus predicted 3.5), are those with the largest deviations from the overall trend.Since the calculated ΔE XB show largest deviations for the NISac-Z series, the complexation was also modelled by calculating free energies of complexation, ΔG PCM XB in chloroform solution using the Polarizable Continuum Model (PCM) method (Table S4, Supporting Information).However, the comparison of log K XB and ΔG PCM XB (Figure S5b, Supporting Information) did not show any correlation (R 2 = 0.189).The deviations indicate that the simple computational 1:1 model is unable to accurately describe the complex binding situations that arise in solution.
The logarithmic K XB values of NIS, NIP, NISac, and NB-Sac complexes were plotted in the stack mode as shown in Figure 10 and their average K XB values follow the computed XB donor's -hole strength.Note that the K XB values of haloimide-2-dimethylaminopyridine complexes are not included in the average, and their dummy data points in the chart are included for reference.Large K XB values of iodosaccharin complexes clearly suggest that it's iodine has a stronger electron accepting power among the iodoimide donors.The distribution of K XB values for NBSac, NIP, and NIS complexes is steady, whereas the pattern for NISac complexes exhibits abrupt changes, which could be combinedly attributed to the strong XB complexation ability of NISac and secondary interactions.Within in the electron withdrawing groups panel, K XB values of pyridines with electron withdrawing groups are small with an exception for 2-iodopyridine.

Conclusion
In conclusion, the N─X⋯N (X = I, Br) halogen-bonded complexes formed by three N-bromoimide and three N-iodoimide halogen bond (XB) donors and sixteen 2-susbstituted pyridines were investigated through experimental and DFT studies.The large data set (68 crystal structures, 86 gas-phase DFT optimized structures, and 90 NMR association constants) was used to investigate XB properties methodically based on XB donors and acceptors.These donor-acceptor partners produced essentially three types of crystalline complexes: fifty-eight 1:1 haloimide:pyridine, four [bis(N-imidato)iodine(I)]pyridinium and five hydrogen-bonded complexes.In the solid-state structures, the I⋯N distances of 1:1 N-iodoimide-pyridine complexes varied from 2.279 (11)   the halogen sigma-hole on N-haloimides governs the tunability and overrides the weaker electronic properties of pyridinic substituents.Even though the N−X⋯N monodentate halogen bond is the potent and major non-covalent interaction, secondary bonding characteristics of XB donor structures, as revealed by crystal structures, and solvation may be even higher in solution which could explain the lack of correlation between DFT energies and solution data.The trends of NMR association constants have been calculated independently for each of the N-haloimide-PyNO and their average association constants follow the -hole strengths of XB donors, which is in agreement with DFT and solid-state X-ray crystallography data.Statistical Analysis: Olex 2 [49] and Mercury [50] were employed for data extraction of XB parameters from 68 X-ray crystal structures.Microsoft Excel was used for the correlation analysis of Figures 6 and 10.The means of N−X bond distances are 2.008 ± 0.003 Å, X⋯N are 2.472 ± 0.003 Å, and bond bending angles are 6.6 ± 0.1°.There are 102 DFT energies (86 gasphase and 16 with solvent model).The DFT linear correlation tests have been carried out by least squares fits using the OriginPro 2017 program.There are 90 binding constants in Figure 10.At least 20 1 H NMR experiments were performed to estimate the 1:1 binding model of each halogenbonded complex.Titration data was fitted into a 1:1 binding model using the Nelder-Mead (Simplex) method with the "subtract initial values" option ticked available in the online Bindfit software. [48]We employed a minimum of 40 data points of phthalimide and saccharin complexes, and a minimum of 20 data points of succinimide complexes to determine whether or not the binding model is 1:1 donor:acceptor.The mean of association constant values is 11 205 M −1 (for SDs, see Table S11, Supporting Information).The outliers are not excluded from the analysis because they are a part of the study.

Figure 3 .
Figure 3.A summary of types of X-ray crystal structures of halogen-and hydrogen-bonded complexes presented using the saccharin donor.

Figure 4 .
Figure 4. Comparison of N─X and X•••N (X = Br, I) bond elongations and shortenings, a) in N-bromoimide and b) N-iodoimide complexes.Uncomplexed N-haloimide N─X bond lengths are shown in parentheses (color code: Br, gold, I, purple, and N, blue dots).Note: The data in the figure corresponds to 58 crystal structures.The mean of N−X bond distances is 2.008 ± 0.003 Å, and X⋯N is 2.472 ± 0.003 Å.

Figure 8 .
Figure 8. DFT optimized structural data of (top row) succinimide-pyridine, (middle row) phthalimide-pyridine, and (bottom row) saccharin-pyridine complexes.The bond parameters of crystal structures are shown in red italics for comparison.

Figure 9 .
The presence of broad 1 H NMR signals in the initial spectra indicates either the coexistence of multiple complexes or a rapid exchange of complexes on the NMR time scale.The 1 H NMR signals related to 5-iodo-2-dimethylaminopyridine and saccharin are separated after ≈12 h.The  15 N values of pyridinic and -NMe 2 nitrogen in 16 and the halogenated product are −110 and −319 ppm and −105 and −315 ppm, respectively (Figure S102, Supporting Information).
to 2.614(4) Å, whereas Br⋯N distances of N-bromoimide-pyridine complexes ranged from 2.266(2) to 2.631(2) Å.The 1:1 haloimide:pyridine halogen-bonded complexes form an intricate network of secondary interactions such as hydrogen bonds and - contacts, inducing (imide)N−X bond bending.The N─X distances plotted against X•••N distances of 1:1 haloimide:ortho-substituted pyridine complexes show lower correlation values than the literature meta-and para-substituted pyridine complexes, indicating the XB parameters in the former are more affected by packing forces than the latter.Packing analysis revealed that the C═O and SO 2 oxygen exhibits multidentate C─H•••O and C  •••O contacts, which are prevalent in succinimide complexes due to acidic ─CH 2 ─ protons, and ─ contacts in phthalimide and saccharin complexes due to their -system.DFT XB interaction energies for N-iodoimide-pyridine complexes range from −44 to −99 kJ mol −1 , while for Nbromoimide-pyridine complexes, they are between −31 and −77 kJ mol −1 .These bond energies are significantly smaller than N─I bond energies calculated for [N─I─N]ˉXBs (−576.3kJ mol −1 ) in [bis(N-imidato)halogen(I)]pyridinium complexes.The ΔE DFT energies of 1:1 haloimide:pyridine complexes follow the order: N-iodosaccharin > Niodosuccinimide ≧ N-iodophthalimide > N-bromosaccharin > Nbromosuccinimide ≧ N-bromophthalimide.DFT analysis revealed that while tuning of N−X•••N XBs is possible, tuning XBs with N-haloimides is more effective than tuning XBs with respect to substituents of pyridines and is notably ineffective with electron withdrawing groups.This discovery suggests that

Figure 10 .
Figure 10.Chart displaying K XB values trend of N-iodosaccharin-(cyan), N-iodosuccinimide-(fuchia-violet), N-iodophthalimide-(orange) and Nbromosaccharin-(marigold) complexes.Determinations of the K XB values of the haloimide-2-(N,N-dimethylamino)pyridine complexes were unsuccessful due to 1 H NMR signal broadening and arbitrary values are included in the chart for comparison purposes.Their K XB values are not included in the average.Note: There are 60 binding constants in the figure.Their mean value is 11 205 m −1 .Note that the standard deviations (SDs) of several NISac complex association constants exceed their association values due to large fitting errors, as a result SD values are not depicted in the figure.See TableS11(Supporting Information) for fitting errors.