Short X···N Halogen Bonds With Hexamethylenetetraamine as the Acceptor

Hexamethylenetetramine (HMTA) and N-haloimides form two types of short (imide)X···N and X–X···N (X = Br, I) halogen bonds. Nucleophilic substitution or ligand-exchange reaction on the peripheral X of X–X···N with the chloride of N-chlorosuccinimide lead to Cl–X···N halogen-bonded complexes. The 1:1 complexation of HMTA and ICl manifests the shortest I···N halogen bond [2.272(5) Å] yet reported for an HMTA acceptor. Two halogen-bonded organic frameworks are prepared using 1:4 molar ratio of HMTA and N-bromosuccinimide, each with a distinct channel shape, one possessing oval and the other square grid. The variations in channel shapes are due to tridentate and tetradentate (imide)Br···N coordination modes of HMTA. Density Functional Theory (DFT) studies are performed to gain insights into (imide)X···N interaction strengths (ΔEint). The calculated ΔEint values for (imide)Br···N (−11.2 to −12.5 kcal/mol) are smaller than the values for (imide)I···N (−8.4 to −29.0 kcal/mol). The DFT additivity analysis of (imide)Br···N motifs demonstrates Br···N interaction strength gradually decreasing from 1:1 to 1:3 HMTA:N-bromosuccinimide complexes. Exceptionally similar charge density values ρ(r) for N–I covalent bond and I···N non-covalent bond of a (saccharin)N–I···N motif signify the covalent character for I···N halogen bonding.


INTRODUCTION
Halogen bonding, an attractive interaction between the electrophilic region associated with a halogen [X] and a nucleophile [B] forming X···B non-covalent interaction (Desiraju et al., 2013), was recognized by Colin over one and a half centuries ago (Colin, 1814). However, the first Xray crystal structure evidence of a Br···O halogen bond (XB) in a co-crystal (dioxane)·Br 2 (Hassel et al., 1954) is considered as a ′′ turning point ′′ in subsequent research, development, and application of X···N/O/S motifs in more than one area (Metrangolo et al., 2008;Ho, 2015;Metrangolo and Resnati, 2015). The profound interest in X···N interactions is due to N-heteroaromatics widespread structures in nature (Gilday et al., 2015;Cavallo et al., 2016;Lim and Beer, 2018). Crystal engineering studies help promote a better understanding of the X···N(sp 2 ) X-bonding, and their structures have applications ranging from chemical and optical (Christopherson et al., 2018;Zhuo et al., 2018;Huang et al., 2019;Li et al., 2020) to the preparation of intriguing topologies (Turunen et al., 2017a,b;Vanderkooy et al., 2019). Equally important is the role of NMR (Erdelyi, 2012;Beale et al., 2013;Carlsson et al., 2015) and Density Functional Theory (DFT) (Clark et al., 2007;Politzer et al., 2013Politzer et al., , 2017Riley et al., 2013) studies in efforts to understand the properties of structures in solution.
The precedented yet unique formation route of X-X···N halogen bonds inspired us to prepare 2, 4, and 6. The Cl-Br···N of 2 and Cl-I···N of 4 and 6 were obtained by using trios HMTA, NCS, and NBS, and HMTA, NCS, and NIS, respectively. A two-step sequential ligand-exchange reaction can be attributed to the formation of Cl-Br/I···N motifs. For example, in the synthesis of 2, step one involves mixing HMTA and NBS. During this step, the initially formed (CO) 2 N-Br···N gradually converts to Br-Br···N motif by N-Br bond cleavage reaction followed by the exchange of (CO) 2 N and Br anions. In the second step, NCS, a chloride anion source, was added to replace the terminal bromide anion to give 2.
Single-crystals of 7-13 were obtained by slow evaporation of the corresponding HMTA and N-haloimide solutions (for more details, see SI). The 1:4 HMTA:NBS and 1:4 HMTA:NBP molar ratio reactions only gave the corresponding bidentate complexes 7 and 8 as the main products for structural analysis. Single-crystals isolated from different 1:4 HMTA:NBS experiments carried out by using various solvents also revealed the bidentate coordination for HMTA (for more details, see SI). Using a 1:4 HMTA:NBS molar ratio, complexes 9 and 10 were obtained employing different crystallization techniques. Complex 9, which contains a tridentate Br···N HMTA, was obtained using solvent-assisted grinding followed by solution crystallization, while 10, determined to be tetradentate Br···N HMTA, was crystallized by using the layering technique. Under the crystallization method of 9, the other HMTAimide combinations produced crystals of either HMTA or corresponding imide. Even 9 is not reproducible and yields crystals of succinimide and bidentate complex 7. The lack of reproducibility is due to the influence of several SCHEME 1 | (A-C) List of halogen-bonded complexes. uncontrolled factors in the crystallization process, such as N-X bond cleavage reactions and complex hydrogen bonding patterns.
Experiments conducted using 1:4 molar ratio of HMTA and NIS in different solvents all exclusively produced crystals of 11. A 1:2 HMTA:NISac molar ratio gives a monodentate complex 12. However, treating HMTA with an excess of NISac (12.5 eq) leads to the formation of unknown quantities of iodine-oriented ions consequently resulting in an iodonium complex [bis(HMTA)I] + I − 3 13. A related method to prepare [bis(HMTA)I] + I − 3 in the presence of concentrated iodine ethanol solution previously reported by Bowmaker et al. and Pritzkow (Bowmaker and Hannan, 1971;Pritzkow, 1975a) supports our hypothesis. Our attempts to crystallize the 1:4 ratio complexes of HMTA and iodopentafluorobenzene (Ipfb), HMTA and 1,4-diodotetrafluorobenzene (Ditfb), were unsuccessful and only yielded bidentate [HMTA]·[Ipfb] 2 and [HMTA]·[Ditfb] 2 , respectively. The corresponding XB parameters are used for discussions here and their structural data is included in the Supporting Information.
1.925 (4) 2.398 (5) 4.317 (7) 173.90 (14) Table 1 footnotes for R XB definition. c The structure has been previously reported but the bond parameters are from the current report.   Figure 3C) (Eia et al., 1956). The average Br···N distance of 2 is 0.145 Å shorter than [HMTA]·[Br 2 ] 2 due to the electron-withdrawing chloride. The donor σ -hole strength enhancement by a covalently bonded electron-withdrawing atom and the consequent XB distance shortening is in agreement with the literature (Politzer et al., 2017).

I-I· · ·N and Cl-I· · ·N Halogen Bonds
Complexes 3 and 4 reveal monodentate coordination manner for HMTA (see Supplementary Figures 3, 4) (Supplementary Figure 3). The bidentate structures 5 and 6 are isomorphous (Supplementary Figures 5, 6). The two I···N distances in corresponding structures are comparable to each other. The average I···N distance of 5 is 0.136 Å longer than 6 owing to the stronger e-withdrawing power of chlorine in the latter structure. The average I···N distances of HMTA-I 2 complexes increase with the increase of HMTA denticity, 3 [2.402 (5)   suggesting either reduced electrostatic attractive interaction between iodine and nitrogen or simply a consequence of packing forces. Interesting observations were made when I···N distances of HMTA-dihalogen and the pyridine-dihalogens were compared (Figure 4, Table 1, and Supplementary Tables 8-10). The average I···N distances of HMTA-dihalogens follow the order I-I···N HMTA > Cl-I···N HMTA similar to pyridinedihalogens, I-I···N py > Br-I···N py > Cl-I···N py . Unlike HMTA-ICl, pyridine-ICl structures exhibit a broad spectrum of I···N distances ( Figure 4B vs. Figure 4E). In Cl-I···N py systems, the substituents' potential to alter the pyridine π-character and Natom nucleophilicity are responsible factors that can be attributed to the broad range of I···N py distances. This substituent mediated π-electron tunability is not possible in non-aromatic systems such as HMTA.

(imide)N-Br···N Halogen Bonds
HMTA is bidentate in 7 and 8, tridentate in 9, and tetradentate in 10. The asymmetric unit of 7 contains one HMTA, two NBS donors, and a chloroform molecule (Supplementary Figure 7) (Raatikainen and Rissanen, 2011), suggesting packing forces influence XB parameters in solid-state structures. The average of Br···N distances in 7 is longer by 0.03 Å than the distance in 8 [2.388(7) Å, Supplementary Figure 8] implying the bromine of NBS and NBP have comparable e-accepting power in crystals.
Complex 9 prepared by solvent-assisted manual grinding, contains four crystallographically independent NBS donors of which one NBS does not participate in the X-bonding. Three Br···N distances vary from 2.371(8) to 2.411(9) Å ( Table 2). The fourth HMTA nitrogen and the non-halogen-bonded NBS stabilize via N···C interaction [ca. 3.16 Å] as shown in Figure 5 and Supplementary Figure 9. Overall, the 1:4 acceptor:donor units effectively pack through numerous HB interactions to a framework possessing oval shape channels. The channels occupy a total volume of 181 Å 3 /unit cell. The relative channel volume (rcv) (Raatikainen and Rissanen, 2012) of 9 is 8.3%, and is the smallest when compared to our earlier XBOF structures (Raatikainen and Rissanen, 2012). Single-crystals of 10 were obtained by hexane diffusion into CCl 4 , which is layered on top of the CHCl 3 solution containing a 1:4 molar ratio of HMTA:NBS. The white solids at the CCl 4 -CHCl 3 interface indicate [HMTA]·[NBS] n complexation, and the gradual disappearance suggests potential inclusion of CCl 4 or CHCl 3 in crystals. Complex 10 crystallizes in the tetragonal P4 2 /nmc and the packing structure contains an extended square-grid like channels filled with CCl 4 molecules (Figure 6) (Raatikainen and Rissanen, 2012).     (Figures 7B,D). Complex 13 bond parameters are similar to the reported structure (Pritzkow, 1975a). The two + I-N bond distances of 13 are 2.288(14) and 2.299(15) Å, and appear within 0.02 Å of the corresponding distances in the reported structure (Supplementary Figure 15).

Molecular Electrostatic Potentials (MEP)
In order to evaluate the donor-acceptor abilities of HMTA and N-haloimides, MEP were mapped onto their respective Van der Waals surfaces as depicted in Figure 8. The most negative potential, located at the HMTA N-atoms (V S,min , −30 kcal/mol), is comparable to values estimated at the O-atoms of NBS (−31 kcal/mol) and NBP (−29 kcal/mol). A V S,max of magnitude +16 kcal/mol is associated with the -CH 2 -protons adjacent to the sp 3 N-atom. In NBS, the V S,max at the bromine σhole and the five-member ring-centroid are similar ( Figure 8B). The V S,max of NBP bromine σ-hole is the same as the NBS; however, the V S,max values over its five-and six-membered ring centroids are significantly smaller (Figure 8C, +17 and +2 kcal/mol). Compared to the aforementioned donor σ-hole strengths, the NIS and NISac iodine σ-holes V S,max values +42 and +50 kcal/mol are significantly larger. The NIS fivemembered ring-centroid V S,max value (+30 kcal/mol) is slightly smaller than in NBS but larger than in NBP. To our surprise, the electron-withdrawing -SO 2 group of NISac could only render a positive potential of +7 kcal/mol at the six-membered ringcentroid. The global MEP analysis suggests that the nucleophilic and electrophilic sites of HMTA and NBS/NIS molecules have equal propensity to form Br···N, C-H···N, and C-H···O=C interactions, which is in good agreement with packing forces discussed in the XBOF structures (Raatikainen and Rissanen, 2012).

Additivity Interaction Energy
The additivity interaction energy, defined as the interaction energy enhancement or reduction of a (imide)X···N motif in a 1:1 complex when donors are successively added to HMTA, are estimated for complexes [HTMA]·[NBS] 1−3 . The RI-MP2/def2-TZVP optimized bond distances and interaction energies of the 1:1, 1:2, and 1:3 complexes of [HTMA]·[NBS] n are shown in Figure 9. The XB interaction energy in the 1:1 complex is −12.2 kcal/mol and has progressively reduced to −11.45 kcal/mol in 1:2 complex to −10.97 kcal/mol in 1:3 complex. The energy analysis is consistent with the N···Br equilibrium distance that gradually increases from 1:1 to 1:3 complex.

Interaction Energies
All interaction energies ( E int ) were estimated by using their corresponding X-ray crystal structure coordinates. The calculated E int values range from −11.2 to −12.5 kcal/mol for Br···N motifs. The E int values decrease when the HMTA denticity increases, −12.5 kcal/mol for 7, −12.1 kcal/mol for 9, and −11.2 kcal/mol for 10, and the results are in good agreement with the additivity analysis. The E int value of 7 is stronger than NBS···N Py (−9.2 kcal/mol) (Stilinović et al., 2017), and Br···N interactions between NBS and substituted pyridines (−6.7 to 11.3 kcal/mol) (Stilinović et al., 2017). These results indicate that the sp 3 N-atom lone-pair overlaps better with NBS bromine σhole compared to the aromatic sp 2 nitrogen. In all the Br···N motifs, the charge density values ρ(r) for N-Br covalent bond and Br···N non-covalent bond are significantly different, indicating the absence of a shared-shell character (see Figure 10). Similarly, a contrary covalent character has been recently described for NBSac···N Py structures (Aubert et al., 2017). Similar to the interaction energies, a decreasing trend for charge density ρ(r) at the bond critical point (BCP) was observed for 7, 9, and 10 complexes.
In contrast to the same σ -hole strengths of NBS and NBP, the Br···N halogen bonds interaction strengths of 8 (−14.0 kcal/mol) are slightly larger than in 7 (−12.5 kcal/mol). This agrees with the well-known fact that the fused six-membered ring in NBP removes electron density from the five-membered ring, consequently making the bromine more electrophilic. The E int values of ancillary interactions, for example, N···π(ring-centroid) and C-H···N hydrogen bond contacts in 7, are estimated to understand their interaction strengths relative to Br···N motifs (see Figure 10). The E int of N···π (−6.6 kcal/mol) and C-H···N (−3.1 kcal/mol) contacts are weaker than XBs (−12.5 kcal/mol). The presence of the BCPs and bond paths of their connecting atoms are other evidences for N···π and C-H···N contacts. This suggests that weak and moderately strong HBs, that originate from donor-acceptor components' electron-rich and deficient sites, are inevitable and may contribute to the XB stabilization energy.
The I···N interaction energies of 11 (−19.1 kcal/mol) and [HMTA]·[NIS] 4 (−16.7 kcal/mol) are larger than corresponding bromine structures, and twice the energy of C-I···N contacts (−8.4 kcal/mol) in [HMTA]·[Iodopentafluorobenzene] 2 (see Supplementary Figure 16). The E int and the ρ(r) values at the BCP of 11 are somewhat larger than [HMTA]·[NIS] 4 , which agrees with the additivity analysis. Complex 12 involving NISac has the largest interaction energy of all the (imide)I···N HMTA halogen bonds (−29.0 kcal/mol) owing to larger iodine σhole strength in NISac (+50 kcal/mol). The ρ(r) values at the BCPs of I···N halogen bond, similar to N-I covalent indicating a degree of covalency with shared-shell character, is remarkable. This agrees with the N-I and I···N bonds covalent character discussion in [DMAP]·[NISac] (Makhotkina et al., 2015). In order to evaluate ancillary interactions in the packing structure, E int values are estimated of representative C-H···O=S and C-H···π dimers shown in Figure 11. The E int values of the lp-π and C-H···π interactions are −4.7 and −2.8 kcal/mol. The C-H···π interactions exhibit a modest interaction energy (−2.8 kcal/mol) and are comparable to HB energies observed in 7. The AIM analysis reveals that C-H···O=S

CONCLUSION
In summary, we investigated Y-X···N (X = Br, I and Y = N, Cl, Br, I) halogen bonds in 13 X-ray crystal structures obtained from HMTA and N-haloimides. Two complexes of HMTA with iodoperfluorobenzene and 1,4-diiodotetrafluorobenzene consisting of C-I···N halogen bonds were also prepared, and their solid-state structures were studied for comparison purposes. The Y-X···N distances depend on the nature of Y-atom and the donor scaffold. DFT based MEPs provided us with important experimental insights into the nature of donor-donor and donor-acceptor interactions. Donors, such as NBS/NIS possessing σ -hole (V S,max ) and C-H acidic proton (V S,min ) values, have high probabilities to form XBOFs via (imide) X···N halogen bonds and orthogonal C-H···O=C hydrogen bonds. The lack of acidic sp 3 C-H protons, like in NBP, encourage π-π and other hydrogen bond interactions obstructing the formation of the desired 1:4 ratio [HMTA]:[NBP] and eventually affect XBOFs' self-assembly processes. In terms of DFT interactions energies, the (imide)N-X···N(HMTA) halogen bonds varying from −11.2 to −12.5 kcal/mol for X = Br, and −8.4 to −29.0 kcal/mol for X = I, are stronger than corresponding (imide)N-X···N(pyridines) halogen bonds. A comprehensive solution NMR study on [HMTA]·[N-haloimide] n complexes, optimization of crystallization conditions to synthesize XBOFs using other HMTA-imide combinations, and post-synthetic solvent exchange process of (imide)N-Br···N XBOFs are currently under investigation in our laboratory.

DATA AVAILABILITY STATEMENT
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material.

AUTHOR CONTRIBUTIONS
RP was responsible for supervision, methodology development, manuscript preparation, and SCXRD analysis. All halogen bond complexes, except 12, for X-ray crystallography, done in JYU, were prepared by GA, 12 was prepared by LG. Both JR and GP were external thesis supervisors for GA and LG, respectively. AF and AB were responsible for computational studies. KR was responsible for proofreading the final manuscript version.