Symmetrical Noncovalent Interactions Br ··· Br Observed in Crystal Structure of Exotic Primary Peroxide Symmetrical Noncovalent Interactions Br···Br Observed in Crystal Structure of Exotic Primary Peroxide

: 4-Bromobenzamidrazone reacts with cyclopentanone giving 3-(4-bromophenyl)-5-(4-peroxobutyl)-1,2,4-triazole, which precipitated as pale-yellow crystals during the reaction. The intermolecular noncovalent interactions Br ··· Br in the single-crystal XRD structure of the peroxo compound were studied theoretically using quantum chemical calculations ( ω B97XD / x2c-TZVPPall) and quantum theory of atoms in molecules (QTAIM) analysis. These attractive intermolecular noncovalent interactions Br ··· Br is type I halogen ··· halogen contacts and their estimated energy is 2.2–2.5 kcal / mol. These weak interactions are suggested to be one of the driving forces (albeit surely not the main one) for crystallization of the peroxo compound during the reaction and thus its stabilization in the solid state. Abstract: 4-Bromobenzamidrazone reacts with cyclopentanone giving 3-(4-bromophenyl)-5-(4-peroxobutyl)-1,2,4-triazole, which precipitated as pale-yellow crystals during the reaction. The intermolecular noncovalent interactions Br···Br in the single-crystal XRD structure of the peroxo compound were studied theoretically using quantum chemical calculations (ωB97XD/x2c-TZVPPall) and quantum theory of atoms in molecules (QTAIM) analysis. These attractive intermolecular noncovalent interactions Br···Br is type I halogen···halogen contacts and their estimated energy is 2.2–2.5 kcal/mol. These weak interactions are suggested to be one of the driving forces (albeit surely not the main one) for crystallization of the peroxo compound during the reaction and thus its stabilization in the solid state.


Introduction
Short halogen···halogen contacts can be classified on two types ( Figure 1) [1]. Type I is simply due to crystal packing effects, while type II (halogen bonding) is directed noncovalent interactions [2] formed between the σ-hole (electrophilic region) on the halogen (Hal) atom and a nucleophile.

Introduction
Short halogen···halogen contacts can be classified on two types ( Figure 1) [1]. Type I is simply due to crystal packing effects, while type II (halogen bonding) is directed noncovalent interactions [2] formed between the σ-hole (electrophilic region) on the halogen (Hal) atom and a nucleophile. Although both types of Hal···Hal contacts have similar abundance, today halogen bond (type II) has drawn significantly higher attention and similarly to hydrogen bonds, metallophilic contacts, Although both types of Hal···Hal contacts have similar abundance, today halogen bond (type II) has drawn significantly higher attention and similarly to hydrogen bonds, metallophilic contacts, and stacking interactions, halogen bonding is now widely used in crystal growth and design and in and stacking interactions, halogen bonding is now widely used in crystal growth and design and in supramolecular engineering [1,[3][4][5]. The recently published relevant reviews are devoted to theoretical approaches to Hal···Hal contacts [6,7] and also application of Hal···Hal contacts in supramolecular engineering [8][9][10][11][12], catalytic reactions [13], organometallic and coordination chemistry [14][15][16][17][18], polymer science [19], medical chemistry and drug discovery [20][21][22][23], and to the involvement of Hal···Hal contacts in human function [24].
In this communication, we describe symmetrical type I noncovalent interactions observed between two bromine atoms, which allow isolation of primary peroxide formed in the reaction of amidrazone and cyclopentanone (along with different hydrogen bonds and other crystal packing effects dominating in this respect).

Results and Discussion
Reaction of 4-bromobenzamidrazone 1 with cyclopentanone 2 (1.2 equiv.) in methanol at 60 °C for 96 h in air results in unpredictable formation of 1,2,4-triazole 3 featuring aliphatic peroxide chain as several pale-yellow crystals, which were studied by single-crystal XRD (Scheme 1a and Figure 2), among the formation of 1,4-di(4-bromophenyl)tetrazine as a major product of the reaction [25]. Reaction of other para-substituted aromatic amidrazones, i.e., 4-RC6H4C(NH2)=NNH2 (R = CF3, H, MeO) under the same conditions resulted in formation of only the corresponding tetrazines [25], whereas generation of the peroxide substrates was not observed even by HRESI + -MS. Ar = 4-BrC 6 H 4 Scheme 1. Reaction scheme of the formation of primary aliphatic peroxide (a) and the plausible mechanism of its generation (b-g). Plausible mechanism of this reaction includes an acid catalyzed reversible Schiff condensation (b). 1 H NMR reaction monitoring in CD3OD reveals that the reaction mixture approached an equilibrium (molar ratio 1:3 ≈ 1:9) at 60 °C for ca. 1 h. The reaction stops at this step in the case of utilization of an argon atmosphere, but under air it proceeds further and the next plausible step includes tautomerization (c) and oxidation of the enamine by molecular oxygen giving secondary Scheme 1. Reaction scheme of the formation of primary aliphatic peroxide (a) and the plausible mechanism of its generation (b-g).
In this communication, we describe symmetrical type I noncovalent interactions observed between two bromine atoms, which allow isolation of primary peroxide formed in the reaction of amidrazone and cyclopentanone (along with different hydrogen bonds and other crystal packing effects dominating in this respect).

Results and Discussion
Reaction of 4-bromobenzamidrazone 1 with cyclopentanone 2 (1.2 equiv.) in methanol at 60 °C for 96 h in air results in unpredictable formation of 1,2,4-triazole 3 featuring aliphatic peroxide chain as several pale-yellow crystals, which were studied by single-crystal XRD (Scheme 1a and Figure 2), among the formation of 1,4-di(4-bromophenyl)tetrazine as a major product of the reaction [25]. Reaction of other para-substituted aromatic amidrazones, i.e., 4-RC6H4C(NH2)=NNH2 (R = CF3, H, MeO) under the same conditions resulted in formation of only the corresponding tetrazines [25], whereas generation of the peroxide substrates was not observed even by HRESI + -MS.   Plausible mechanism of this reaction includes an acid catalyzed reversible Schiff condensation (b). 1 H NMR reaction monitoring in CD3OD reveals that the reaction mixture approached an equilibrium (molar ratio 1:3 ≈ 1:9) at 60 °C for ca. 1 h. The reaction stops at this step in the case of utilization of an argon atmosphere, but under air it proceeds further and the next plausible step includes tautomerization (c) and oxidation of the enamine by molecular oxygen giving secondary Plausible mechanism of this reaction includes an acid catalyzed reversible Schiff condensation (b). 1 H NMR reaction monitoring in CD 3 OD reveals that the reaction mixture approached an equilibrium (molar ratio 1:3 ≈ 1:9) at 60 • C for ca. 1 h. The reaction stops at this step in the case of utilization of an argon atmosphere, but under air it proceeds further and the next plausible step includes tautomerization (c) and oxidation of the enamine by molecular oxygen giving secondary peroxide (d). Availability of electron-withdrawing peroxo group close to the imine C atom provides intramolecular nucleophilic attack by the NH 2 moiety giving spiro intermediate (e). The last step includes heterolytic C-C bond splitting, which accompanied by aromatization of the 1,2,4-triazole cycle and stabilization of the carbanion by the electron-withdrawing peroxo group (f). Proton transfer from the N atom to the C atom terminates the reaction (g). Further experimental or computational studies are needed to confirm the suggested mechanism.
Because precipitation of the peroxo compound 3 has been observed only in the case of amidrazone 1 featuring bromine atom in the structure, which (i) has intermediate electronic effects in the row of R's: CF 3 , Br, H, MeO, and (ii) cannot sterically affect the reaction proceeding, we suggested that weak halogen···halogen intermolecular interactions (along with different hydrogen bonds and other crystal packing effects dominating in this respect) provide precipitation of 3 during the reaction progress and thus stabilization the peroxide 3 in the solid state. Based upon this observation and our interest in unusual noncovalent interactions involving halogen atoms, we studied theoretically the origin of the symmetrical intermolecular Br···Br contacts (type I, Figure 1), which were detected in the single-crystal XRD structure of 3.
Indeed, the intermolecular distance Br···Br in the crystal structure of 3 is 3.414 Å, which is shorter than the sum of van der Waals radii [26] of two bromine atoms (3.66 Å). In order to confirm from a theoretical viewpoint the existence of these intermolecular short contacts Br···Br in the crystal under study, we carried out quantum chemical calculations (ωB97XD/x2c-TZVPPall level) and quantum theory of atoms in molecules (QTAIM) analysis [27] for model dimeric associate (Table 1). The visualization of intermolecular noncovalent interactions Br···Br in the crystal structure of 3 are shown in Figures 3 and 4. Table 1. Results of quantum theory of atoms in molecules (QTAIM) analysis: ρ(r), ∇ 2 ρ(r), λ 2 , H b , V(r), and G(r) values (in a.u.) at the bond critical point, corresponding to intermolecular noncovalent interactions Br···Br in the single-crystal XRD structure of 3 and estimated energy for these contacts defined by two approaches-E int (kcal/mol).  [28]; b E int = 0.57G(r) [28].

Laplacian of Electron
Symmetry 2020, 12, x FOR PEER REVIEW 3 of 7 peroxide (d). Availability of electron-withdrawing peroxo group close to the imine C atom provides intramolecular nucleophilic attack by the NH2 moiety giving spiro intermediate (e). The last step includes heterolytic C-C bond splitting, which accompanied by aromatization of the 1,2,4-triazole cycle and stabilization of the carbanion by the electron-withdrawing peroxo group (f). Proton transfer from the N atom to the C atom terminates the reaction (g). Further experimental or computational studies are needed to confirm the suggested mechanism. Because precipitation of the peroxo compound 3 has been observed only in the case of amidrazone 1 featuring bromine atom in the structure, which (i) has intermediate electronic effects in the row of R's: CF3, Br, H, MeO, and (ii) cannot sterically affect the reaction proceeding, we suggested that weak halogen···halogen intermolecular interactions (along with different hydrogen bonds and other crystal packing effects dominating in this respect) provide precipitation of 3 during the reaction progress and thus stabilization the peroxide 3 in the solid state. Based upon this observation and our interest in unusual noncovalent interactions involving halogen atoms, we studied theoretically the origin of the symmetrical intermolecular Br···Br contacts (type I, Figure 1), which were detected in the single-crystal XRD structure of 3.
Indeed, the intermolecular distance Br···Br in the crystal structure of 3 is 3.414 Å, which is shorter than the sum of van der Waals radii [26] of two bromine atoms (3.66 Å). In order to confirm from a theoretical viewpoint the existence of these intermolecular short contacts Br···Br in the crystal under study, we carried out quantum chemical calculations (ωB97XD/x2c-TZVPPall level) and quantum theory of atoms in molecules (QTAIM) analysis [27] for model dimeric associate ( Table 1). The visualization of intermolecular noncovalent interactions Br···Br in the crystal structure of 3 are shown in Figures 3 and 4. Table 1. Results of quantum theory of atoms in molecules (QTAIM) analysis: ρ(r), ∇ 2 ρ(r), λ2, Hb, V(r), and G(r) values (in a.u.) at the bond critical point, corresponding to intermolecular noncovalent interactions Br···Br in the single-crystal XRD structure of 3 and estimated energy for these contacts defined by two approaches-Eint (kcal/mol).    The appropriate bond critical point for intermolecular noncovalent interactions Br···Br in the single-crystal XRD structure of 3 was found during the QTAIM analysis. The properties of electron density in this bond critical point are typical for noncovalent interactions [29,30] and, in particular, for similar weak contacts halogen···halogen [31][32][33]. Energy for these contacts (2.2-2.5 kcal/mol) was estimated using the procedures developed by Tsirelson et al. for non-covalent contacts involving bromine atoms using the equations Eint = 0.58(−V(r)) or Eint = 0.57G(r), respectively [28]. Note that estimated energy of these symmetrical intermolecular Br···Br contacts in the single-crystal XRD structure of 3 is very well consistent with the approximate dimerization energy of the appropriated model dimeric associate calculated at the ωB97XD/x2c-TZVPall level (stabilization amounts to 2.1 kcal/mol). The balance between G(r) and V(r) at the bond critical point reveals that a covalent contribution in the intermolecular noncovalent interactions Br···Br in the X-ray structure of 3 is negligible [34]. The sign of λ2 in appropriate bond critical point for intermolecular noncovalent interactions Br···Br in the X-ray structure of 3 reveals that these contacts are attractive [35,36].

X-Ray Diffraction Study
The Agilent Technologies «Xcalibur» diffractometer was used for X-ray diffraction experiment. X-ray diffraction experiment was collected at 100 K using monochromated MoKα radiation. The parameters of unit cell (Table S1) were refined by least square techniques in the 2θ range of 5-55° for MoKα. Structure was solved using Superflip [37,38] by the charge flipping method and refined using the SHELXL [39] program implemented in the OLEX2 [40] program package. The CrysAlisPro [41] program complex was used for empirical absorption correction using spherical harmonics in SCALE3 ABSPACK scaling algorithm. The crystallographic data have been deposited at Cambridge Crystallographic Data Centre (CCDC 1969513) and can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif. Also appropriated cif-file with single-crystal XRD structure of 3 is given in Supplementary Materials.

Computational Details
The single point DFT calculations based on the experimental X-ray geometry of model dimeric associate were carried out using the dispersion-corrected hybrid functional ωB97XD [42] in Gaussian-09 [43] program package. The segmented contracted all-electron relativistic triple-ζ valence quality basis sets x2c-TZVPPall [44] were used. The quantum theory of atoms in molecules (QTAIM) analysis [27] and independent gradient model analysis of noncovalent interactions based The appropriate bond critical point for intermolecular noncovalent interactions Br···Br in the single-crystal XRD structure of 3 was found during the QTAIM analysis. The properties of electron density in this bond critical point are typical for noncovalent interactions [29,30] and, in particular, for similar weak contacts halogen···halogen [31][32][33]. Energy for these contacts (2.2-2.5 kcal/mol) was estimated using the procedures developed by Tsirelson et al. for non-covalent contacts involving bromine atoms using the equations E int = 0.58(−V(r)) or E int = 0.57G(r), respectively [28]. Note that estimated energy of these symmetrical intermolecular Br···Br contacts in the single-crystal XRD structure of 3 is very well consistent with the approximate dimerization energy of the appropriated model dimeric associate calculated at the ωB97XD/x2c-TZVPall level (stabilization amounts to 2.1 kcal/mol). The balance between G(r) and V(r) at the bond critical point reveals that a covalent contribution in the intermolecular noncovalent interactions Br···Br in the X-ray structure of 3 is negligible [34]. The sign of λ 2 in appropriate bond critical point for intermolecular noncovalent interactions Br···Br in the X-ray structure of 3 reveals that these contacts are attractive [35,36].

Synthetic Procedure
A solution of amidrazone 1 (214 mg, 1 mmol), TsOH·H 2 O (10 mg, 0.05 mmol), and cyclopentanone 2 (100 mg, 1.2 mmol) in methanol (5 mL) was kept at 60 • C for 96 h. The crystals of 3 formed during the reaction were isolated from the reaction solution and were subjected to single-crystal XRD.

X-Ray Diffraction Study
The Agilent Technologies «Xcalibur» diffractometer was used for X-ray diffraction experiment. X-ray diffraction experiment was collected at 100 K using monochromated MoKαradiation. The parameters of unit cell (Table S1) were refined by least square techniques in the 2θ range of 5-55 • for MoKα. Structure was solved using Superflip [37,38] by the charge flipping method and refined using the SHELXL [39] program implemented in the OLEX2 [40] program package. The CrysAlisPro [41] program complex was used for empirical absorption correction using spherical harmonics in SCALE3 ABSPACK scaling algorithm. The crystallographic data have been deposited at Cambridge Crystallographic Data Centre (CCDC 1969513) and can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif. Also appropriated cif-file with single-crystal XRD structure of 3 is given in Supplementary Materials.

Computational Details
The single point DFT calculations based on the experimental X-ray geometry of model dimeric associate were carried out using the dispersion-corrected hybrid functional ωB97XD [42] in Gaussian-09 [43] program package. The segmented contracted all-electron relativistic triple-ζ valence quality basis sets x2c-TZVPPall [44] were used. The quantum theory of atoms in molecules (QTAIM) analysis [27] and independent gradient model analysis of noncovalent interactions based on Symmetry 2020, 12, 637 5 of 7 promolecular density [45] were performed in Multiwfn program package (v. 3.6) [46]. The Cartesian atomic coordinates for model dimeric associate are presented in Table S2 (Supporting Information).

Conclusions
In this work, the formation of organic primary peroxide from amidrazone and cyclopentanone was described. The 3-(4-bromophenyl)-5-(4-peroxobutyl)-1,2,4-triazole precipitates as pale-yellow crystals during the reaction and the intermolecular noncovalent interactions Br···Br in the crystal structure were determined. Results of quantum chemical calculations indicated that these attractive intermolecular noncovalent interactions Br···Br is type I halogen···halogen contacts and their estimated energy is 2.2-2.5 kcal/mol. These symmetric weak interactions (along with different hydrogen bonds and other crystal packing effects) are suggested to be one of the driving forces for crystallization of the peroxo compound during the reaction and thus its stabilization in the solid state. Further studies of the found reaction are under investigation in our group.
Supplementary Materials: The following Supporting Information is available online at http://www.mdpi.com/ 2073-8994/12/4/637/s1, Table S1: Crystal data for 3, Table S2: Cartesian atomic coordinates for model dimeric associate of 3, cif-file with single-crystal XRD structure of 3.  Acknowledgments: Physicochemical studies were performed at the Center for X-ray Diffraction Studies belonging to Saint Petersburg State University. We thank the Reviewers of this communication for their valuable advices and comments.