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Article

4,6-Dichloro-5-Nitrobenzofuroxan: Different Polymorphisms and DFT Investigation of Its Reactivity with Nucleophiles

by
Elena Chugunova
1,2,*,
Nurgali Akylbekov
3,
Alexey Dobrynin
1,4,
Alexander Burilov
1,2,
Carla Boga
5,
Gabriele Micheletti
5,*,
Vincenzo Frenna
6,
Edoardo Jun Mattioli
7,
Matteo Calvaresi
7 and
Domenico Spinelli
7,*
1
Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Akad. Arbuzov st. 8, 420088 Kazan, Russia
2
Laboratory of Plant Infectious Diseases, FRC Kazan Scientific Center of Russian Academy of Sciences, Lobachevskogo st. 2/31, 420111 Kazan, Russia
3
Laboratory of Engineering Profile “Physical and Chemical Methods of Analysis”, Korkyt Ata Kyzylorda University, Aitekebie str. 29A, Kyzylorda 120014, Kazakhstan
4
Institute of Radio Electronics, Photonics and Digital Technologies, Kazan National Research Technical University, 10 Karl Marx Str., 420111 Kazan, Russia
5
Department of Industrial Chemistry ‘Toso Montanari’ ALMA MATER STUDIORUM, Università di Bologna, Viale del Risorgimento 4, 40136 Bologna, Italy
6
Department STEBICEF, University of Palermo, Ed.17, Viale delle Scienze, 90128 Palermo, Italy
7
Department of Chemistry ‘G. Ciamician’ ALMA MATER STUDIORUM, Università di Bologna, Via Selmi 2, 40126 Bologna, Italy
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(24), 13460; https://doi.org/10.3390/ijms222413460
Submission received: 25 October 2021 / Revised: 9 December 2021 / Accepted: 12 December 2021 / Published: 15 December 2021
(This article belongs to the Section Biochemistry)
Browse Figures
Versions Notes

Abstract

:
This research focuses on the X-ray structure of 4,6-dichloro-5-nitrobenzofuroxan 1 and of some of its amino derivatives (4a, 4e, 4g, and 4l) and on DFT calculations concerning the nucleophilic reactivity of 1. We have found that by changing the solvent used for crystallization, it is possible to obtain 4,6-dichloro-5-nitrobenzofuroxan (1) in different polymorphic structures. Moreover, the different torsional angles observed for the nitro group in 1 and in its amino derivatives (4a, 4e, 4g, and 4l) are strictly dependent on the steric hindrance of the substituent at C-4. DFT calculations on the course of the nucleophilic substitution confirm the role of the condensed furoxan ring in altering the aromaticity of the carbocyclic frame, while chlorine atoms strongly influence the dihedral angle and the rotational barrier of the nitro group. These results corroborate previous observations based on experimental kinetic data and give a deep picture of the reaction with amines, which proceeds via a “non-aromatic” nucleophilic substitution.

1. Introduction

In line with our interest in the study of the reactivity/activity of heterocyclic compounds, we thoroughly investigated the chemical/biological behavior of several classes of heterocycles containing nitrogen, oxygen, and sulphur atoms. Thus, we examined ring-into-ring rearrangements [1,2,3,4], reactivity with nucleophiles [5,6,7], ring-opening [8,9], and so on [10,11,12]. Moreover, considering that in the last few decades, the interest of chemists has been deeply focused on the pharmaceutical/pharmacological activities of several heterocyclic compounds [13,14,15], we evaluated some of their cardiovascular [16], antitumor [17], or anti-MDR1 [18] effects.
The study of biologically active compounds is one of the most interesting and rapidly developing branches of organic chemistry. The range of synthetic chemical compounds used in medicine and agriculture is constantly expanding, and this requires a continuous search for new substances with potential biological activity, and, consequently, the development of convenient, fresh methods for their synthesis [19,20,21,22].
Benzofuroxans (benzo[c][1,2,5]oxadiazole 1-oxides) occupy a relevant place in the variety of synthetic biological active compounds and are also of interest from a mechanistic point of view [23,24,25,26,27]. Benzofuroxans exhibit a wide spectrum of biological activities: they behave as UV-protective [28], antituberculosis [29], antileukemic, immunosuppressive [30], anti-infective [31], antibacterial [32], antifungal [33], insecticidal [34], and antiparasitic (antiplasmodial and trypanocidal) agents [35], calcium channel modulators [36], and monoamine oxidase inhibitors [37]. Benzofuroxans also find applications in different fields, such as pharmaceuticals, veterinary medicine, agricultural chemistry, and dyes [28,38,39,40,41].
Moreover, since the discovery of the physiological role of nitric oxide as a second messenger, the issue of identifying new ways to stimulate its formation in the body has become a relevant target [42,43,44,45]. The presence of the N-oxide fragment in the molecule of benzofuroxans has undoubtedly caused interest in the study of this class of compounds as a probable nitric oxide donor agent [46,47,48].
Derivatives of benzofuroxan can also be used as high-energy materials [49]. The benzofuroxan scaffold is moreover a promising starting point for the synthesis of different heteroaromatic and polycyclic heterocyclic compounds [50].
Accordingly, some of us are conducting a long-term study of new syntheses of benzofuroxan derivatives, their chemical reactivity, biological activity, and the possibility of their use in the biological/pharmacological fields [7,23,27,28,51]. Among the benzofuroxans used in our previous works, 4,6-dichloro-5-nitro-benzofuroxan (1) (Figure 1) is one of the most interesting chemical platforms because it easily reacts with various nucleophiles, leading to the formation of products with very interesting antimicrobial activity. Over the years, some researchers have synthesized, described, and studied the biological activity of more than 80 compounds deriving from it [52,53]. However, as some recent results have shown, this compound is of interest not only for its ability to give biologically active substances, but also for its chemistry, showing interesting reactivity with some nucleophiles [7,23,53] and also giving polymorphic forms of crystals during crystallization.
We recently investigated the nucleophilic reactivity of 4,6-dichloro-5-nitrobenzofuroxan (1) carrying out a kinetic study of its behavior in methanol and in toluene with a “fan” of amines (Scheme 1: 3a–k; aliphatic, primary and secondary, with low or high steric requirements; aromatic) [7], thus covering a wide range of basicity/nucleophilicity and steric requirements [54,55,56,57,58] and also gaining interesting information on the course of the reaction.
Interestingly, the compound 1, which can be considered as deriving from 1,3-dichloro-2-nitrobenzene (2) by condensation of a furoxan ring at a C4–C5 bond, shows chemical behavior that is quite different from that exhibited by 2 [59,60]. If we compare the structures of 1 and 2, we can observe some resemblances, but also some significant differences.
In both, the presence of two chlorine atoms in the 1,3-relationship constrains the nitro group at C2 out of the carbocyclic plane, greatly lowering its electron-withdrawing power. That means a kind of secondary steric effect will also occur [61], thus lowering the ability of the nitro group and activating a nucleophilic substitution process. This event causes a very low reactivity of 2 with nucleophiles.
Moreover, we can observe that in 2, the carbocyclic ring has an aromatic character and that the two chlorine atoms are chemically equivalent (this means that one of them can be indifferently substituted by the action of a nucleophile), while in 1, the carbocyclic ring (because of the condensation with the furoxan ring at the C4–C5 bond of 2) does not have an aromatic character and the two chlorine atoms are not chemically equivalent; accordingly, we have observed that only the chlorine at C4 can be substituted by nitrogen nucleophiles [7]. Finally, the condensed furoxan ring strongly affects the global electrophilic character of 1 and then its ability to react with nucleophiles.
As a matter of fact, while 2 shows a very low reactivity with nitrogen nucleophiles (aliphatic, as well as aromatic amines) [59,60], 1, in contrast, shows high reactivity [7] with the same amines, comparable to that of 2,4-dinitrochlorobenzene (5, Figure 2) [62].
This peculiar behavior of 4,6-dichloro-5-nitrobenzofuroxan (1) can be explained by taking into account two factors: (1) the strong electron-attracting effect of the condensed furoxan ring (which behaves as a strong electron-attracting group); and (2) the low aromatic character of the benzofuroxan ring, as indicated by its relatively low value of the Bird aromaticity index (81.0, perhaps the lowest IA reported for a benzocondensed aromatic system) [63,64,65].
To confirm the above considerations and gain further information on the structural characteristics of 4,6-dichloro-5-nitrobenzofuroxan (1) and of some of its amino derivatives, we have now collected new data concerning the X-ray structure of 1 and of some of its products of substitution with amines (4a, 4e, 4g, and 4l). The literature reports examples of polymorphism for some benzofuroxan derivatives (Figure 3).
For example, three different polymorphs (A, B, and C) were observed for 5,6-dichlorobenzofuroxan (6) [66]. All had disorders about a two-fold or pseudo-two-fold axis and were packed in ribbons in a head-to-tail fashion, such that the chlorine atoms of one molecule are close to the oxygen atoms of the next molecule.
Then, in 2001, it was firstly shown that at low temperatures, 5-bromobenzofuroxan (7) transformed into a second polymorph with a unit cell that was twice as large, but with essentially the same packing [67].
Moreover, 4,7-dichlorobenzofuroxan (8) and 5-iodobenzofuroxan (9) occur in two polymorphic forms [68,69].
At last, it was found that 5,6-dimethylbenzofuroxan (10) exists in four polymorphic forms that are polytypes of each other [70]. Each polymorph of 5,6-dimethylbenzofuroxan contains molecules disordered about pseudo-two-fold axes and arranged head-to-tail in ribbons, with the ribbons forming approximate planar layers held together by weak C—H···N and C—H···O interactions.
In addition, by using DFT computations, we collected data concerning the rotational barrier of the investigated compounds in solution, their electronic distribution, and the nucleophilic reactivity of 1.

2. Results

Looking at 4,6-dichloro-5-nitrobenzofuroxan (1) its structure was confirmed by X-rays analysis, evidencing that it exists in two different polymorphs (1a and 1b; see Figure 4) depending on the solvent used for the crystallization. 1a (Figure 4, left) crystallizes from chloroform/hexane in the triclinic space group P-1 with one molecule of 1a per asymmetric unit. In contrast, polymorph 1b (Figure 4, right) obtained by crystallization from acetone/pentane is an orthorhombic one. It crystallizes in space group P212121 with one molecule of 1b per asymmetric unit.
The substituted benzofuroxan fragment is planar in both structures, and nitro groups largely deviate from the molecule’s plane on slightly different angles, between −84° and −93° (Figure 5). Interestingly, this datum well confirms our hypothesis [7] that because of the presence of the two adjacent chlorine atoms, the nitro group of 1 “suffers” a kind of secondary steric effect [61], and then it is not able to activate the process of nucleophilic substitution to the best of its ability. Moreover, looking at the C–C bond lengths in the carbocyclic ring of 1, we received confirmation on our hypothesis [7] that this ring does not have a “real” aromatic character. As a matter of fact, their lengths range from 1.351 Å (for the C4–C5 bond) to 1.439 Å (for the C5–C6 bond) in 1a, and from 1.363 Å (for the C4–C5 bond) to 1.429 Å (for the C5–C6 bond) in 1b. Interestingly, the length variations in the two polymorphs show similar trends (see Figure 5).
Dimer is formed in 1a due to intermolecular hydrogen bonds of C–H···O-type between the hydrogen at C7 and the oxygen at N1 (Figure 6), while an infinite chain along the crystallographic 0α axis is formed in the 1b (Figure 6).
Concerning compounds 4a, 4e, 4g [7], and 4l [23], the relevant results of X-ray structure determinations are summarized in Figure 7.
The examination of the structures obtained for 4a, 4e, 4g, and 4l, compared with that of 1, requires some comments. Of course, we can anticipate that the entity of the rotation of the nitro group in 1 and in the relevant amines shall depend on the different steric hindrances exerted by the substituents present at C4. In fact, we have observed that in all of them, the rotation of the nitro group with respect to the carbocyclic ring is significantly lower than in 1, and this datum is well in line with provisions. In fact, looking at the substituents at C4, ongoing from a chlorine atom (in 1) to a secondary (in 4e and in 4g) and then to a primary amino group (in 4a and in 4l), a significant decrease of the steric hindrance occurs, and then a lowering of the out-of-plane rotation of the nitro group must be (and has been) observed. This result depends on the lower steric effect exerted by the three classes of substituents, which causes a lowering of the rotation of the nitro group from −84° or −93° (in 1a and 1b) to −64° and −103° (in 4e and 4g) and to −41° and 39° (in 4a and 4l).
The presence of a hydrogen atom linked to the amino nitrogen one in 4a and in 4l makes the formation of hydrogen bonds possible with the oxygen atoms of the adjacent nitro group. We have observed different behaviors in the two compounds—in 4l, we only observed the occurrence of an intramolecular hydrogen bond (Figure 8 and Figure 9), while we noted both an intramolecular and an intermolecular hydrogen bond in 4a (Figure 10 and Figure 11). This different behavior could be associated to the appearance of electrostatic repulsion between the nitro group and the acceptor carboxyl group, which prevents the approach of two molecules and the occurrence of a multicenter hydrogen bond.
To investigate the structural characteristics of the 4,6-dichloro-5-nitrobenzofuroxan molecule in solution, we carried out DFT calculations. Starting from the coordinates of the two polymorphs 1a and 1b, and optimizing their structure in solution, they converge toward four degenerate minima (Figure 12). The torsional angles of the nitro group in the minima are 75.2°, 104.8°, 255.2°, and 284.8°. In these geometries, the nitro group is very close to an orthogonal arrangement with respect to the aromatic plane of the molecule. Additionally, in solution, the nitro group of 1 “suffers” a kind of secondary steric effect, because of the presence of the two adjacent chlorine atoms.
The energy necessary to pass from the minima to the conformations assumed by the molecules in the polymorph 1a and 1b is minimal (0.15 kcal mol−1 for 1a and 0.04 kcal mol−1) due to the flatness of this region of the potential energy surface. The calculated rotational barrier of the nitro group in (1) is 9.15 kcal mol−1.
To shed light on the role of chlorine substituents in exerting secondary steric effect toward the nitro group, we also calculated the potential energy profiles, related to the torsional angle of the nitro group, on the monochlorinated compounds 6-chloro-5-nitrobenzofuroxan (11) and 4-chloro-5-nitrobenzofuroxan (12) and on 1,3-dichloro-2-nitrobenzene (2) (Figure S1).
Interestingly, in 2, the dihedral angles of the nitro group in the minima are 74.4°, 105.6°, 254.4°, and 285.6°. These torsional angles are very close to the value observed in 1. Additionally, the value of the rotational barrier of the nitro group (7.8 kcal mol−1) in 2 is in line with the value obtained for 1. On the contrary, the equilibrium value of the torsional angles of the nitro group, in absence of the second chlorine atom, shifts toward planarity for 11 (52.6°, 129.4°, 232.6°; 309.4°), and even more for 12 (43.5°, 136.1°, 223.5°, 316.1°). More importantly, the absence of the second chlorine atom greatly lowers the rotational barrier of the nitro group (2.6 and 1.3 kcal mol−1 for 11 and 12, respectively). This result confirms the role of the “couple” of chlorine atoms to hinder the rotation of the nitro group.
To investigate how the “condensed” furoxan ring affects the aromaticity of the benzene ring, we analyzed the bond lengths of the optimized structures in (1), (2), (11), and (12).
The lack of a second chlorine atom does not affect the low aromatic character of (1). In fact, in (11) and (12), the bond lengths that characterize the carbocyclic moiety do not vary significantly upon removal of the second chlorine atom (Figure 13). We can conclude that the number of chlorine atoms in the ring does not influence its aromaticity.
On the contrary, when the condensed furoxan ring is lacking, as in (2) (Figure 13), a clear aromatic character of the benzene moiety also appears when the two chlorines are present as substituents.
In conclusion, DFT calculations confirm the role of the condensed furoxan ring in altering the aromaticity of the carbocyclic frame, while chlorine atoms strongly influence the dihedral angle and the rotational barrier of the nitro group. These results corroborate previous observations based on experimental kinetic data [7].
Moving from structure to reactivity, when we investigated the nucleophilic substitution of 4,6-dichloro-5-nitrobenzofuroxan [7], we observed that in 1, only the selective substitution of chlorine at C4 by nitrogen nucleophiles occurred.
The calculated Mulliken charges (Figure 14) well explain the regioselectivity of the nucleophilic substitution reaction between 1 and the nucleophilic amines. The reactive carbon atom C4 is characterized by the largest positive charge (2.01 au). The charge at C6 is smaller (1.53 au). The strong electron-withdrawing effect, exerted by the condensed furoxan ring, is clear by comparing the values of the charges in 1 with those of 11 and 12, and that of 1 with that of 2.
In addition, our previous work [7] showed that 1 is much more reactive with nitrogen nucleophiles than 2 and had a reactivity similar to that of 2,4-dinitroclorobenzene (5) [62].
The Frontier Molecular Orbital (FMO) theory provides support for this evidence. The calculated HOMO-LUMO gap between the HOMO of the nucleophile (pyrrolidine) and the LUMO of the electrophilic compounds 1, 2, and 5 is 5.48, 6.61, and 5.89 eV. These gaps agree with experimental reactivity observations where compounds 1 and 5 show similar reactivity (small HOMO-LUMO gap), while compound 2 is characterized by much lower reactivity (large HOMO-LUMO gap).
To gain a quantitative description of the reaction mechanism, we calculated the energy profile of the selective nucleophilic substitution of 1 with pyrrolidine. Figure 15 depicts the reaction mechanism, which is a two-step process involving a nucleophilic attack of a pyrrolidine molecule on the reactive C4 centre of 1 at the first reversible stage, leading to the formation of the intermediate IC, and then at the second stage, the elimination of the chlorine anion with a concerted proton transfer to a second pyrrolidine molecule leading to the formation of the product PC and pyrrolidinium chloride.
The first step is characterized by an energy barrier of 17.8 kcal mol−1, in excellent agreement with experimental kinetic data where the measured activation free energy is 17.7 kcal mol−1. The formation of the intermediate IC is a slightly endoergonic process (+2.0 kcal mol−1), but the barrierless elimination of the chlorine atom with the concerted proton transfer rapidly leads to the stable product PC (4g) that is strongly exoergonic (−36.7 kcal mol−1), making the reactive process irreversible in agreement with experimental data.
The addition/elimination process of the pyrrolidine molecule to the 4,6-dichloro-5-nitrobenzofuroxan (1) resembles an aza-Michael addition to nitro alkenes, where the nitro group exerts the typical push/pull effect [71]. In fact, during the addition process, an incipient electron flow from the pyrrolidine nitrogen (NPYR1) is directed toward the C4–Cl bond (see RC in Figure 15a), also involving the conjugated nitro group, as clearly observed from data in Table 1, particularly looking at the C4–C5 and C5–NNO2 bond lengths. Two-dimensional and three-dimensional representations of the various critical points are given in the SI.
This observation explains how the nitro group supports the addition step of the nucleophilic substitution (pulling effect). This process is additionally enhanced by the fused furoxan ring. In fact, the furoxan ring, as described previously, breaks the aromaticity in the carbocyclic ring, and the C4–C5 double bond becomes similar to an electron-poor olefin bond. The other bond lengths that characterize the compound 1 are substantially unchanged during the reaction, evidencing the localization of the reactive process.
In TS2 the reaction coordinate is dominated by the proton transfer from IC to a pyrrolidine molecule: NPYR13–H (1.19 Å) and H–NPYR21 (1.44 Å). The proton transfer involves a second pyrrolidine molecule and triggers the barrierless exit of the chloride anion. Again, this reactive process is facilitated by the nitro group (pushing effect) that makes the leaving of the chloride anion a highly favoured process (see IC in Figure 15a). The elimination process restores the geometries of the C4–C5 and C5–NNO2 bonds similarly to the reactant, as expected in a substitution process.

3. Materials and Methods

3.1. General

The following compounds were prepared according with the literature procedures indicated: 4,6-dichloro-5-nitrobenzo[c][1,2,5]oxadiazole 1-oxide (1) [53], and 4-aminobenzo[c][1,2,5]oxadiazole 1-oxides 4a, 4e, 4g [7], and 4l [23].

3.2. Crystallographic Analyses

The X-ray diffraction experiments for compounds 1a, 1b, 4a, 4e, 4g, and 4l were carried out on a Bruker KAPPA APEX II CCD diffractometer (graphite-monochromated Mo Kα (0.71073 Å) radiation). Data collection: images were indexed, integrated, and scaled using the APEX2 [72] data reduction package and corrected for absorption using SADABS [73]. The structures of compounds were solved by the direct methods and refined by the anisotropic (isotropic for all H atoms) full-matrix least-squares method against F2 of all reflections using SHELX [74]. The positions of the hydrogen were calculated geometrically and refined in the riding model.

3.2.1. Crystallographic Data for 4,6-dichloro-5-nitrobenzo[c][1,2,5]oxadiazole 1-oxide (1a)

C6HCl2N3O4, M 250.00, triclinic, P-1, a 7.124(5), b 7.359(5), c 8.614(6) Å, α 91.478(8), β 95.886(8), γ 105.257(8)°, V 432.7(5) Å3, Z 2, Dcalcd 1.919g·cm−3, μ(Mo-Kα) 0.746 mm−1, F(000) 248, (θ 2.4–28.0°, completeness 99.9%), T 150(2) K, orange prism, (0.05 × 0.1 × 0.1) mm3, 5691 measured reflections in index range −9 ≤ h ≤ 9, −9 ≤ k ≤ 9, −11 ≤ l ≤ 11, 2082 independent (Rint 0.036), 136 parameters, R1 = 0.0320 (for 1627 observed I > 2σ(I)), wR2 = 0.0823 (all data), GOOF 1.00, largest diff. peak and hole 0.40 and −0.28 e.A−3.

3.2.2. Crystallographic Data for 4,6-dichloro-5-nitrobenzo[c][1,2,5]oxadiazole 1-oxide (1b)

C6HCl2N3O4, M 250.00, orthorhombic, P212121, a 6.3259(18), b 6.4507(18), c 21.315(6) Å, V 869.8(4) Å3, Z 4, Dcalcd 1.909 g·cm−3, μ(Mo-Kα) 0.742 mm−1, F(000) 496, (θ 1.9–27.0°, completeness 100.0%), T 150(2) K, colorless prism, (0.07 × 0.09 × 0.28) mm3, 5420 measured reflections in index range −8 ≤ h ≤ 8, −8 ≤ k ≤ 6, −27 ≤ l ≤ 27, 1893 independent (Rint 0.036), 136 parameters, R1 = 0.0326 (for 1684 observed I > 2σ(I)), wR2 = 0.0652 (all data), GOOF 1.06, largest diff. peak and hole 0.25 and −0.25 e.A−3.

3.2.3. Crystallographic Data for 4-(butylamino)-6-chloro-5-nitrobenzo[c][1,2,5]oxadiazole 1-oxide (4a)

C10H11ClN4O4, M 286.68, triclinic, P-1, a 7.4066(8), b 8.4714(11), c 10.2782(13) Å, α 94.214(6), β 93.778(5), γ 111.867(5)°, V 593.84(13) Å3, Z 2, Dcalcd 1.603g·cm−3, μ(Mo-Kα) 0.340 mm−1, F(000) 296, (θ 3.1–26.0°, completeness 99.3%), T 296(2) K, orange prism, (0.17 × 0.28 × 0.61) mm3, transmission 0.6687–0.7454, 4954 measured reflections in the index range −6 ≤ h ≤ 9, −10 ≤ k ≤ 10, −12 ≤ l ≤ 12, 2316 independent (Rint 0.038), 173 parameters, R1 = 0.0421 (for 1416 observed I > 2σ(I)), wR2 = 0.0893 (all data), GOOF 0.92, largest diff. peak and hole 0.23 and −0.26 e.A−3.

3.2.4. Crystallographic Data for 4-(benzyl(methyl)amino)-6-chloro-5-nitrobenzo[c][1,2,5]oxadiazole 1-oxide (4e)

C14H11ClN4O4, M 334.72, monoclinic, P21/c, a 11.53(2), b 10.599(9), c 12.047(15) Å, β 90.68(12)°, V 1472(3) Å3, Z 4, Dcalcd 1.510 g·cm−3, μ(Mo-Kα) 0.286 mm−1, F(000) 688, (θ 2.6-30.0°, completeness 76.4%), T 296(2) K, orange prism, (0.12 × 0.20 × 0.31) mm3, transmission 0.3945–0.7455, 6389 measured reflections in the index range −16 ≤ h ≤ 15, −13 ≤ k ≤ 15, −13 ≤ l ≤ 15, 3378 independent (Rint 0.340), 210 parameters, R1 = 0.1330 (for 541 observed I> 2σ(i)), wR2 = 0.1479 (all data), GOOF 0.89, largest diff. peak and hole 0.19 and −0.20 e.A−3.

3.2.5. Crystallographic Data for 6-chloro-5-nitro-4-(pyrrolidin-1-yl)benzo[c][1,2,5]oxadiazole 1-oxide (4g)

C10H9ClN4O4, M 284.66, triclinic, P-1, a 8.8447(11), b 10.8450(15), c 13.5532(18) Å, α 93.052(3), β 104.591(3), γ 108.750(3)°, V 1178.5(3) Å3, Z 4 (2 independent molecules), Dcalcd 1.604g·cm−3, μ(Mo-Kα) 0.342 mm−1, F(000) 584, (θ 2.5–27.0°, completeness 98.7%), T 296(2) K, orange prism, (0.18 × 0.31 × 0.61) mm3, transmission 0.6865–0.7463, 10088 measured reflections in index range −11 ≤ h ≤ 7, −13 ≤ k ≤ 13, −17 ≤ l ≤ 17, 5056 independent (Rint 0.030), 343 parameters, R1 = 0.0486 (for 3439 observed I > 2σ(I)), wR2 = 0.1546 (all data), GOOF 1.02, largest diff. peak and hole 0.46 and −0.36 e.A−3.

3.2.6. Crystallographic Data for 4-(3-carboxypropylamino)-6-chloro-5-nitrobenzo[c][1,2,5]oxadiazole 1-oxide (4l)

C10H9ClN4O6, M 316.66, monoclinic, P21/n, a 11.800(6), b 7.300(4), c 15.081(7) Å, β 110.697(5)°, V 1215.2(11)Å3, Z 4, Dcalcd 1.731 g·cm−3, μ(Mo-Kα) 0.353 mm−1, F(000) 648, (θ 1.9-28.7°, completeness 99.0%), T 150(2) K, red-orange prism, (0.1 × 0.01 × 0.15) mm3, transmission 0.6572–0.7458, 10997 measured reflections in index range: −15 ≤ h ≤ 15, −9 ≤ k ≤ 9, −20 ≤ l ≤ 20, 3118 independent (Rint 0.053), 193 parameters, R1 = 0.0423 (for 2070 observed I > 2σ(I)), wR2 = 0.1453 (all data), GOOF 0.86, largest diff. peak and hole 0.32 and −0.25 e.A−3.
Crystallographic data for the structures of compounds 1a, 1b, 4a, 4e, 4g, and 4l have been deposited at the Cambridge Crystallographic Data Centre (CCDC) where the supplementary publication no. is CCDC 2112027-2112032, accordingly. A copy of the data can be obtained, free of charge, on application to the CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax: +44 122 3336033 or e-mail: [email protected]; internet: www.ccdc.cam.ac.uk (accessed on 1 March 2021)).

3.3. Computational Details

All reported DFT computations were performed with the Gaussian 16 series of programs [75] using the M06-2X functional [76] and the 6-311++G** basis set [77]. The geometries of the various critical points on the potential energy surface were fully optimized with the gradient method available in Gaussian 16, and harmonic vibrational frequencies were computed to evaluate the nature of all critical points. The solvent effect was considered during optimization and frequency calculations using the Polarizable Continuum Model (PCM) employing the integral equation formalism variant (IEFPCM) [78] and using methanol (ε = 32.613) [78] was used as a solvent for the calculation of the energetic.

4. Conclusions

Starting from some kinetic results collected studying the reactivity of 4,6-dichloro-5-ntrobenzofuroxan (1) with several nitrogen nucleophiles [7], we enlarged our interest to the study of the X-ray structure of 1 and of some of its amino derivatives (4a, 4e, 4g, and 4l), gaining interesting results concerning their geometry.
As expected, different torsional angles were observed for the nitro group in 1 and in the amino derivatives (4a, 4e, 4g, and 4l) strictly depending on the steric hindrance of the substituent at C4. Moreover, the results concerning the structure of 1 (that exists in two different polymorphs (1a and 1b) as a function of the solvent used for the crystallization) were also confirmed: (a) the role of the two chlorine atoms in determining the out-of-plane rotation of the nitro group (so causing a sort of secondary steric effect) [61] and (b) the non-aromatic character of the “benzene” ring in 1 caused by the condensed furoxan ring.
Finally, the calculations of the energy profile concerning the nucleophilic substitution of 1 with pyrrolidine (giving 4g) furnished a calculated profile of reaction strictly recalling the experimental kinetic results collected by some of us [7], giving a further confirmation of the “non-aromatic” character of the nucleophilic substitution occurring in 1.
On the whole, we can say that X-rays and DFT calculations provided a nice confirmation to the hypotheses that we had previously advanced on the basis of kinetic results [7].

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/ijms222413460/s1.

Author Contributions

Writing—original draft preparation and funding acquisition D.S.; writing—review and editing, funding acquisition C.B. and G.M.; writing—review and editing, E.C.; investigation (chemistry), N.A.; supervision (chemistry), A.B.; investigation (X-ray study), A.D.; investigation (chemistry) V.F., investigation (DFT Calculation), E.J.M. and M.C. All authors have read and agreed to the published version of the manuscript.

Funding

N.A. is grateful for the financial support of research to the Science Committee of the Ministry of Education and Science of Republic of Kazakhstan (Grant No.AP09562322) and the Ministry of Agriculture of the Republic of Kazakhstan (BR10764960). RSA research was carried out by E.C., A.B., A.D. at the Arbuzov Institute of Organic and Physical Chemistry, and was funded by the government assignment for the FRC Kazan Scientific Center of RAS. The synthetic part was carried out by E.C. and A.B. at the Laboratory of Plant Infectious Diseases and was supported by the Ministry of Science and Higher Education of the Russian Federation (grant no. 075-15-2019-1881). Bologna group authors thank Alma Mater Studiorum–Università di Bologna (RFO funds).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are contained within the article or in Supplementary Materials, or are available on request from the corresponding author Elena Chugunova.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Cosimelli, B.; Guernelli, S.; Spinelli, D.; Buscemi, S.; Frenna, V.; Macaluso, G. On the Synthesis and Reactivity of the Z-2,4-Dinitrophenylhydrazone of 5-Amino-3-Benzoyl-1,2,4-Oxadiazole. J. Org. Chem. 2001, 66, 6124–6129. [Google Scholar] [CrossRef]
  2. D’Anna, F.; Frenna, V.; Macaluso, G.; Marullo, S.; Morganti, S.; Pace, V.; Spinelli, D.; Spisani, R.; Tavani, C. On the Rearrangement in Dioxane/water of (Z)-Arylhydrazones of 5-Amino-3-Benzoyl-1,2,4-Oxadiazole into (2-Aryl-5-Phenyl-2H-1,2,3-Triazol-4-yl)ureas: Substituent Effects on the Different Reaction Pathways. J. Org. Chem. 2006, 71, 5616–5624. [Google Scholar] [CrossRef]
  3. Micheletti, G.; Frenna, V.; Macaluso, G.; Boga, C.; Spinelli, D. Mononuclear Rearrangement of the Z-Phenylhydrazones of Some 3-Acyl-1,2,4-Oxadiazoles: Effect of Substituents on the Nucleophilic Character of the >C═N-NH-C6H5 Chain and on the Charge Density of N-2 of the 1,2,4-Oxadiazole Ring (Electrophilic Counterpart). J. Org. Chem. 2019, 84, 2462–2469. [Google Scholar] [CrossRef]
  4. Spinelli, D.; Mugnoli, A.; Andreani, A.; Rambaldi, M.; Frascari, S. A New Ring Transformation: Conversion of 6-p-Chlorophenyl-3-methyl-5-nitrosoimidazo[2,1-b]thiazole into 6-p-Chlorophenyl-8-Hydroxy-5-Methyl-3-Oxo-1,2,4-oxadiazolo[3,4-c][1,4-c]thiazine by the Action of Mineral Acids. J. Chem. Soc. Chem. Commun. 1992, 15, 1394–1395. [Google Scholar] [CrossRef]
  5. Dell’Erba, C.; Spinelli, D. Thiophene series—VI: Substituent Effect on the Rate of Nucleophilic Substitution: Kinetics of the Reaction between 2-Bromo-3-Nitro-5-X-Thiophenes and Piperidine in Ethanol. Tetrahedron 1965, 21, 1061–1066. [Google Scholar] [CrossRef]
  6. Spinelli, D.; Guanti, G.; Dell’Erba, C. Transmission of Substituent Effects in Systems with Bonds of Different Order. Kinetics of the Reactions of 3-Bromo-2-Nitro-4-X-Thiophens and 3-Bromo-4-Nitro-2-X-Thiophens with Sodium Benzenethiolate in Methanol. J. Chem. Soc. Perkin Trans. 1972, 2, 441–445. [Google Scholar] [CrossRef]
  7. Chugunova, E.; Frenna, V.; Consiglio, G.; Micheletti, G.; Boga, C.; Akylbekov, N.; Burilov, A.; Spinelli, D. On the Nucleophilic Reactivity of 4,6-Dichloro-5-Nitrobenzofuroxan with Some Aliphatic and Aromatic Amines: Selective Nucleophilic Substitution. J. Org. Chem. 2020, 85, 13472–13480. [Google Scholar] [CrossRef]
  8. Dell’Erba, C.; Spinelli, D.; Leandri, G. Ring-Opening Reaction in the Thiophen Series: Reaction between 3,4-Dinitrothiophen and Secondary Amines. J. Chem. Soc. D Chem. Commun. 1969, 9, 549. [Google Scholar] [CrossRef]
  9. Petrillo, G.; Benzi, A.; Bianchi, L.; Maccagno, M.; Pagano, A.; Tavani, C.; Spinelli, D. Recent advances in the use of conjugated nitro or dinitro-1,3-butadienes for the synthesis of heterocycles. Tetrahedron Lett. 2020, 61, 152297. [Google Scholar] [CrossRef]
  10. Spinelli, D.; Zanirato, P. On the Chemical, NMR and Kinetic Properties of 2-Azido- and 3-Azidothiophene. J. Chem. Soc. Perkin Trans. 1993, 2, 1129–1133. [Google Scholar] [CrossRef]
  11. Attanasi, O.A.; Favi, G.; Filippone, P.; Giorgi, G.; Mantellini, F.; Moscatelli, G.; Spinelli, D. Flexible Protocol for the Chemo- and Regioselecive Building of Pyrroles and Pyrazoles by Reactions of Dianishefsky’s Dienes with 1,2-Diaza-1,3-butadienes. Org. Lett. 2008, 10, 1983–1986. [Google Scholar] [CrossRef]
  12. Rakib, E.M.; Boga, C.; Calvaresi, M.; Chigr, M.; Franchi, P.; Gualandi, I.; Ihammi, A.; Lucarini, M.; Micheletti, G.; Spinelli, D.; et al. A Multidisciplinary Study of Chemico-Physical Properties of Different Classes of 2-Aryl-5(or 6)-Nitrobenzimidazoles: NMR, Electrochemical Behavior, ESR, and DFT Calculations. Arab. J. Chem. 2021, 14, 103179. [Google Scholar] [CrossRef]
  13. Deplano, A.; Karlsson, J.; Svensson, M.; Moraca, F.; Catalanotti, B.; Fowler, C.J.; Onnis, V. Exploring the fatty acid amide hydrolase and cyclooxygenase inhibitory properties of novel amide derivatives of ibuprofen. J. Enzyme Inhib. Med. Chem. 2020, 35, 815–823. [Google Scholar] [CrossRef] [Green Version]
  14. Baldisserotto, A.; Demurtas, M.; Lampronti, I.; Tacchini, M.; Moi, D.; Balboni, G.; Vertuani, S.; Manfredini, S.; Onnis, V. In-Vitro Evaluation of Antioxidant, Antiproliferative and Photo-Protective Activities of Benzimidazolehydrazone Derivatives. Pharmaceuticals 2020, 13, 68. [Google Scholar] [CrossRef] [Green Version]
  15. Clemente, F.; Matassini, C.; Giachetti, S.; Goti, A.; Morrone, A.; Martínez-Bailén, M.; Orta, S.; Merino, P.; Cardona, F. Piperidine Azasugars Bearing Lipophilic Chains: Stereoselective Synthesis and Biological Activity as Inhibitors of Glucocerebrosidase (GCase). J. Org. Chem. 2021, 86, 12745–12761. [Google Scholar] [CrossRef]
  16. Carosati, E.; Cosimelli, B.; Ioan, P.; Severi, E.; Katneni, K.; Chiu, F.C.; Saponara, S.; Fusi, F.; Frosini, M.; Matucci, R.; et al. Understanding Oxadiazolothiazinone Biological Properties: Negative Inotropic Activity versus Cytochrome P450-Mediated Metabolism. J. Med. Chem. 2016, 59, 3340–3352. [Google Scholar] [CrossRef] [Green Version]
  17. Dell’Erba, C.; Chiavarina, B.; Fenoglio, C.; Petrillo, G.; Cordazzo, C.; Boncompagni, E.; Spinelli, D.; Ognio, E.; Aiello, C.; Mariggiò, M.A.; et al. Inhibition of Cell Proliferation, Cytotoxicity and Induction of Apoptosis of 1,4-bis(1-Naphthyl)-2,3-dinitro-1,3-butadiene in Gastrointestinal Tumor Cell Lines and Preliminary Evaluation of Its Toxicity in vivo. Pharmacol. Res. 2005, 52, 271–282. [Google Scholar] [CrossRef]
  18. Viale, M.; Cordazzo, C.; de Totero, D.; Budriesi, R.; Rosano, C.; Leoni, A.; Ioan, P.; Aiello, C.; Croce, M.; Andreani, A.; et al. Inhibition of MDR1 Activity and Induction of Apoptosis by Analogues of Nifedipine and Diltiazem: An in vitro Analysis. Investig. New Drugs 2011, 29, 98–109. [Google Scholar] [CrossRef]
  19. Blakemore, D.C.; Castro, L.; Churcher, I.; Rees, D.C.; Thomas, A.W.; Wilson, D.M.; Wood, A. Organic synthesis provides opportunities to transform drug discovery. Nat. Chem. 2018, 10, 383–394. [Google Scholar] [CrossRef]
  20. Fedorowicz, J.; Sączewski, J.; Konopacka, A.; Waleron, K.; Lejnowski, D.; Ciura, K.; Tomašič, T.; Skok, Ž.; Savijoki, K.; Morawska, M.; et al. Synthesis and Biological Evaluation of Hybrid Quinolone-Based Quaternary Ammonium Antibacterial Agents. Eur. J. Med. Chem. 2019, 179, 576–590. [Google Scholar] [CrossRef]
  21. Dai, J.; Dan, W.; Zhang, Y.; Wang, J. Recent Developments on Synthesis and Biological Activities of γ-Carboline. Eur. J. Med. Chem. 2018, 157, 447–461. [Google Scholar] [CrossRef]
  22. Totobenazara, J.; Burke, A.J. New Click-Chemistry Methods for 1,2,3-Triazoles Synthesis: Recent Advances and Applications. Tetrahedron Lett. 2015, 56, 2853–2859. [Google Scholar] [CrossRef]
  23. Serkov, I.V.; Chugunova, E.A.; Burilov, A.R.; Bachurin, S.O. Synthesis of Amino Acid Derivatives of Benzofuroxan. Dokl. Chem. 2013, 450, 149–151. [Google Scholar] [CrossRef]
  24. Micheletti, G.; Iannuzzo, L.; Calvaresi, M.; Bordoni, S.; Telese, D.; Chugunova, E.; Boga, C. Intriguing Enigma of Nitrobenzofuroxan’s “Sphinx”: Boulton-Katritzky Rearrangement or Unusual Evidence of the N-1/N-3-Oxide Rearrangement? RSC Adv. 2020, 10, 34670–34680. [Google Scholar] [CrossRef]
  25. Micheletti, G.; Boga, C.; Pafundi, M.; Pollicino, S.; Zanna, N. New electron-donor and -acceptor architectures from benzofurazans and sym-triaminobenzenes: Intermediates, products and an unusual nitro group shift. Org. Biomol. Chem. 2016, 14, 768–776. [Google Scholar] [CrossRef]
  26. Micheletti, G.; Boga, C. Nucleophile/Electrophile Combinations in Aromatic Substitution: From Wheland to Wheland-Meisenheimer Intermediates Using Strongly Activated Arenes. Synthesis 2017, 49, 3347–3356. [Google Scholar] [CrossRef]
  27. Chugunova, E.; Boga, C.; Sazykin, I.; Cino, S.; Micheletti, G.; Mazzanti, A.; Sazykina, M.; Burilov, A.; Khmelevtsova, L.; Kostina, N. Synthesis and antimicrobial activity of novel structural hybrids of benzofuroxan and benzothiazole derivatives. Eur. J. Med. Chem. 2015, 93, 349–359. [Google Scholar] [CrossRef] [PubMed]
  28. Chugunova, E.A.; Sazykina, M.A.; Gibadullina, E.M.; Burilov, A.R.; Sazykin, I.S.; Chistyakov, V.A.; Timasheva, R.E.; Krivolapov, D.B.; Goumont, R. Synthesis, Genotoxicity and UV-Protective Ac-tivity of New Benzofuroxans Substituted by Aromatic Amines. Lett. Drug Des. Discov. 2013, 10, 145–154. [Google Scholar] [CrossRef]
  29. Fernandes, G.F.S.; Campos, D.L.; Da Silva, I.C.; Prates, J.L.B.; Pavan, A.R.; Pavan, F.R.; Dos Santos, J.L. Benzofuroxan Derivatives as Potent Agents against Multidrug-Resistant Mycobacterium Tuberculosis. ChemMedChem 2021, 16, 1268–1282. [Google Scholar] [CrossRef]
  30. Cerecetto, H.; Porcal, W. Pharmacological Properties of Furoxans and Benzofuroxans: Recent Developments. Mini Rev. Med. Chem. 2005, 5, 57–71. [Google Scholar] [CrossRef]
  31. Jorge, S.D.; Masunari, A.; Rangel-Yagui, C.O.; Pasqualoto, K.F.M.; Tavares, L.C. Design, Synthesis, Antimicrobial Activity and Molecular Modeling Studies of Novel Benzofuroxan Derivatives against Staphylococcus Aureus. Bioorg. Med. Chem. 2009, 17, 3028–3036. [Google Scholar] [CrossRef]
  32. Galkina, I.V.; Tudriy, E.V.; Bakhtiyarova, Y.V.; Usupova, L.M.; Shulaeva, M.P.; Pozdeev, O.K.; Egorova, S.N.; Galkin, V.I. Synthesis and Antimicrobial Activity of Bis-4,6-Sulfonamidated 5,7-Dinitrobenzofuroxans. J. Chem. 2014, 2014, 367351. [Google Scholar] [CrossRef]
  33. Wang, L.; Zhang, Y.-Y.; Wang, L.; Liu, F.; Cao, L.-L.; Yang, J.; Qiao, C.; Ye, Y. Benzofurazan Derivatives as Antifungal Agents against Phytopathogenic Fungi. Eur. J. Med. Chem. 2014, 80, 535–542. [Google Scholar] [CrossRef]
  34. Rosas-García, N.M.; Herrera-Mayorga, V.; Mireles-Martínez, M.; Villegas-Mendoza, J.M.; Rivera, G. Toxic Activity of N-Oxide Derivatives Against Three Mexican Populations of Spodoptera Frugiperda. Southwest. Entomol. 2014, 39, 717–726. [Google Scholar] [CrossRef]
  35. Dos Santos Petry, L.; Pillar Mayer, J.C.; de Giacommeti, M.; Teixeira de Oliveira, D.; Razia Garzon, L.; Martiele Engelmann, A.; Magalhães de Matos, A.F.I.; Dellaméa Baldissera, M.; Dornelles, L.; Melazzo de Andrade, C.; et al. In Vitro and In Vivo Trypanocidal Activity of a Benzofuroxan Derivative against Trypanosoma Cruzi. Exp. Parasitol. 2021, 226–227, 108125. [Google Scholar] [CrossRef]
  36. Visentin, S.; Amiel, P.; Fruttero, R.; Boschi, D.; Roussel, C.; Giusta, L.; Carbone, E.; Gasco, A. Synthesis and Voltage-Clamp Studies of Methyl Racemates and Enantiomers and of Their Benzofuroxanyl Analogues. J. Med. Chem. 1999, 42, 1422–1427. [Google Scholar] [CrossRef]
  37. Severina, I.S.; Axenova, L.N.; Veselovsky, A.V.; Pyatakova, N.V.; Buneeva, O.A.; Ivanov, A.S.; Medvedev, A.E. Nonselective Inhibition of Monoamine Oxidases A and B by Activators of Soluble Guanylate Cyclase. Biochemistry 2003, 68, 1048–1054. [Google Scholar] [CrossRef]
  38. Cerecetto, H.; Gonzalez, M. Benzofuroxan and Furoxan. Chemistry and Biology. In Bioactive Heterocycles IV. Topics in Heterocyclic Chemistry; Khan, M.T.H., Ed.; Springer: Berlin/Heidelberg, Germany, 2007; Volume 10, pp. 265–308. [Google Scholar] [CrossRef]
  39. Ferreira, A.K.; Pasqualoto, K.F.M.; Kruyt, F.A.E.; Palace-Berl, F.; Azevedo, R.A.; Turra, K.M.; Rodrigues, C.P.; Ferreira, A.C.F.; Salomon, M.A.C.; de Sa Junior, P.L.; et al. BFD-22 a New Potential Inhibitor of BRAF Inhibits the Metastasis of B16F10 Melanoma Cells and Simultaneously Increased the Tumor Immunogenicity. Toxicol. Appl. Pharmacol. 2016, 295, 56–67. [Google Scholar] [CrossRef]
  40. Smolobochkin, A.; Gazizov, A.; Sazykina, M.; Akylbekov, N.; Chugunova, E.; Sazykin, I.; Gildebrant, A.; Voronina, J.; Burilov, A.; Karchava, S.; et al. Synthesis of Novel 2-(Het)arylpyrrolidine Derivatives and Evaluation of Their Anticancer and Anti-Biofilm Activity. Molecules 2019, 24, 3086. [Google Scholar] [CrossRef] [Green Version]
  41. Chugunova, E.A.; Voloshina, A.D.; Mukhamatdinova, R.E.; Serkov, I.V.; Proshin, A.N.; Gibadullina, E.M.; Burilov, A.R.; Kulik, N.V.; Zobov, V.V.; Krivolapov, D.B.; et al. The Study of the Biological Activity of Amino-Substituted Benzofuroxans. Lett. Drug Des. Discov. 2014, 11, 502–512. [Google Scholar] [CrossRef]
  42. Murad, F. Nitric Oxide: The Coming of the Second Messenger. Rambam Maimonides Med. J. 2011, 2, e0038. [Google Scholar] [CrossRef] [Green Version]
  43. Bryan, N.S. Nitric Oxide Enhancement Strategies. Futur. Sci. OA 2015, 1, FSO48. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Serafim, R.A.M.; Primi, M.C.; Trossini, G.H.G.; Ferreira, E.I. Nitric Oxide: State of the Art in Drug Design. Curr. Med. Chem. 2012, 19, 386–405. [Google Scholar] [CrossRef]
  45. Miller, M.R.; Megson, I.L. Recent Developments in Nitric Oxide Donor Drugs. Br. J. Pharmacol. 2007, 151, 305–321. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Zhang, H.; Wang, X.; Mao, J.; Huang, Y.; Xu, W.; Duan, Y.; Zhang, J. Synthesis and Biological Evaluation of Novel Benzofuroxan-Based Pyrrolidine Hydroxamates as Matrix Metalloproteinase Inhibitors with Nitric Oxide Releasing Activity. Bioorg. Med. Chem. 2018, 26, 4363–4374. [Google Scholar] [CrossRef]
  47. Medana, C.; Di Stilo, A.; Visentin, S.; Fruttero, R.; Gasco, A.; Ghigo, D.; Bosia, A. NO Donor and Biological Properties of Different Benzofuroxans. Pharm. Res. 1999, 16, 956–960. [Google Scholar] [CrossRef]
  48. Schiefer, I.T.; VandeVrede, L.; Fa’, M.; Arancio, O.; Thatcher, G.R.J. Furoxans (1,2,5 Oxadiazole-N-Oxides) as Novel NO Mimetic Neuroprotective and Procognitive Agents. J. Med. Chem. 2012, 55, 3076–3087. [Google Scholar] [CrossRef] [Green Version]
  49. Sarlauskas, J.; Anusevicius, Z.; Misiūnas, A. Benzofuroxan (Benzo[1,2-c]1,2,5-Oxadiazole N-Oxide) Derivatives as Potential Energetic Materials: Studies on Their Synthesis and Properties. Cent. Eur. J. Energ. Mater. 2012, 9, 365–385. [Google Scholar] [CrossRef]
  50. Lima, L.M.; Amaral, D.N.D. Beirut Reaction and Its Application in the Synthesis of Quinoxaline-N,N’-Dioxides Bioactive Compounds. Rev. Virtual Química 2013, 5, 1075–1100. [Google Scholar] [CrossRef]
  51. Chugunova, E.; Samsonov, V.; Gerasimova, T.; Rybalova, T.; Bagryanskaya, I. Synthesis and Some Properties of 2H-Benzimidazole 1,3-Dioxides. Tetrahedron 2015, 71, 7233–7244. [Google Scholar] [CrossRef]
  52. Chugunova, E.A.; Akylbekov, N.I.; Appazov, N.O.; Makhrus, E.M.; Burilov, A.R. Synthesis of the First Tertiary Ammonium Derivative of 6-Chloro-5-Nitrobenzofuroxan. Russ. J. Org. Chem. 2016, 52, 920–921. [Google Scholar] [CrossRef]
  53. Gibadullina, E.M.; Chugunova, E.A.; Mironova, E.V.; Krivolapov, D.B.; Burilov, A.; Yusupova, L.M.; Pudovik, M.A. Reaction of 4,6-Dichloro-5-Nitrobenzofuroxan with Aromatic Amines and Nitrogen-Containing Heterocycles. Chem. Heterocycl. Compd. 2012, 48, 1228–1234. [Google Scholar] [CrossRef]
  54. Frenna, V.; Vivona, N.; Spinelli, D.; Consiglio, G. Amine Basicities in Benzene and in Water. J. Chem. Soc. Perkin Trans. 1985, 2, 1865–1868. [Google Scholar] [CrossRef]
  55. Hall, N.F.; Marshall, R.; Sprinkle, M.R. Relations between the Structure and Strength of Certain Organic Bases in Aqueous Solution. J. Am. Chem. Soc. 1932, 54, 3469–3485. [Google Scholar] [CrossRef]
  56. Graham Solomon, T.W.; Fryhle, C.B. Organic Chemistry, 7th ed.; John Wiley & Sons: New York, NY, USA, 2000; p. 946. [Google Scholar]
  57. Hall, H.K., Jr. Correlations of the Base Strengths of Amines. J. Am. Chem. Soc. 1957, 79, 5441–5444. [Google Scholar] [CrossRef]
  58. Mayr, H.; Patz, M. Scales of Nucleophilicity and Electrophilicity: A System for Ordering Polar Organic and Organometallic Reactions. Angew. Chem. Int. Ed. Engl. 1994, 33, 938–957. [Google Scholar] [CrossRef]
  59. Ito, M.; Ikumi, A. Diphenylamine Compound and Method for Producing Same. EU Patent EP2792667A1, 22 October 2014. [Google Scholar]
  60. Matsuo, M.; Taniguchi, K.; Katsura, Y.; Kamitani, T.; Ueda, I. New 2-aryliminoimidazolidines. I. Synthesis and antihypertensive properties of 2-(2-phenoxyphenylimino) imidazolidines and related compounds. Chem. Pharm. Bull. 1985, 33, 4409–4421. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  61. Capon, B.; Chapman, N.B. 122. Nucleophilic displacement reactions in aromatic systems. Part VI. Influence of nuclear alkyl groups in the aromatic system. Kinetic of the reactions of chlorodinitrotoluenes and related compounds with piperidine, aniline and ethoxide ions in ethanol, and with methoxide ions in methanol. J. Chem. Soc. 1957, 74, 600–609. [Google Scholar] [CrossRef]
  62. Bunnett, J.F.; Garbisch, E.W., Jr.; Pruitt, K.M. The “Element Effect” as a Criterion of Mechanism in Activated Aromatic Nucleophilic Substitution Reactions. J. Am. Chem. Soc. 1957, 79, 385–391. [Google Scholar] [CrossRef]
  63. Bird, C.W. A New Aromaticity Index and its Application to Five-membered Ring Heterocycles. Tetrahedron 1985, 41, 1409–1414. [Google Scholar] [CrossRef]
  64. Bird, C.W. Heteroaromaticity. 5. A Unified Aromaticity Index. Tetrahedron 1992, 48, 335–340. [Google Scholar] [CrossRef]
  65. Bird, C.W. Heteroaromaticity. 8. The influence of N-oxide formation on heterocyclic aromaticity. Tetrahedron 1993, 49, 8441–8448. [Google Scholar] [CrossRef]
  66. Ojala, C.R.; Ojala, W.H.; Britton, D.; Gougoutas, J.Z. Packing Similarities of Three Isosteric Molecules: 4,5-Dichlorophthalic Anhydride, 4,5-Dibromophthalic Anhydride and 5,6-Dichlorobenzfurazan 1-Oxide, Including Three Polymorphs of 5,6-Dichlorobenzfurazan 1-Oxide. Acta Crystallogr. B 1999, 55, 530–542. [Google Scholar] [CrossRef] [Green Version]
  67. Pink, M.; Britton, D. 5-Chloro- and 5-Bromobenzofurazan 1-Oxide Revisited. Acta Cryst. B 2002, 58, 116–124. [Google Scholar] [CrossRef] [PubMed]
  68. Britton, D.; Mallory, F.B.; Mallory, C.W. The Crystal Packing of 4,7-Dichloro- and 4,7-Dibromobenzo[c]furazan 1-Oxide. Acta Cryst. Commun. 2002, 58, O235–O238. [Google Scholar] [CrossRef] [Green Version]
  69. Britton, D.; Noland, W.E.; Clark, C.M. 5-Iodobenzofurazan 1-Oxide: Polymorphs, Pseudosymmetry and Disorder. Acta Cryst. Commun. 2008, 64, o187–o190. [Google Scholar] [CrossRef]
  70. Britton, D.; Young, V.G.J.; Noland, W.E.; Pinnow, M.J.; Clark, C.M. Four Polymorphs (Polytypes) of 5,6-Dimethylbenzofurazan 1-Oxide. Acta Cryst. B 2012, 68, 536–542. [Google Scholar] [CrossRef]
  71. Berner, O.M.; Tedeschi, L.; Enders, D. Asymmetric Michael Additions to Nitroalkenes. Eur. J. Org. Chem. 2002, 12, 1877–1894. [Google Scholar] [CrossRef]
  72. APEX2 (Version 2.1). SAINTPlus. Data Reduction and Correction Program (Version 7.31A); Bruker Advanced X-Ray Solutions; BrukerAXS Inc.: Madison, WI, USA, 2006. [Google Scholar]
  73. Sheldrick, G.M. Program for Empirical X-Ray Absorption Correction, Bruker-Nonius; SADABS: Madison, WI, USA, 1990. [Google Scholar]
  74. Sheldrick, G.M. SHELX Programs. Acta Cryst. 2015, C71, 3–8. [Google Scholar] [CrossRef]
  75. Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Petersson, G.A.; Nakatsuji, H.; et al. Gaussian 16, Revision, C.01; Gaussian Inc.: Wallingford, CT, USA, 2016. [Google Scholar]
  76. Zhao, Y.; Truhlar, D.G. The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Non-covalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Four M06-Class Functionals and 12 Other Functionals. Theor. Chem. Acc. 2008, 120, 215–241. [Google Scholar] [CrossRef] [Green Version]
  77. Frisch, M.J.; Pople, J.A.; Binkley, J.S. Self-Consistent Molecular-Orbital Methods. 25. Supplementary Functions for Gaussian-Basis Sets. J. Chem. Phys. 1984, 80, 3265–3269. [Google Scholar] [CrossRef]
  78. Tomasi, J.; Mennucci, B.; Cammi, R. Quantum Mechanical Continuum Solvation Models. Chem. Rev. 2005, 105, 2999–3093. [Google Scholar] [CrossRef] [PubMed]
Ijms 22 13460 g001 550
Figure 1. Structure of 4,6-dichloro-5-nitrobenzofuroxan (1) and of 1,3-dichloro-2-nitrobenzene (2).
Figure 1. Structure of 4,6-dichloro-5-nitrobenzofuroxan (1) and of 1,3-dichloro-2-nitrobenzene (2).
Ijms 22 13460 g001
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Scheme 1. Nucleophilic reactivity of 1 with amines.
Scheme 1. Nucleophilic reactivity of 1 with amines.
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Figure 2. 2,4-Dinitrochlorobenzene (5).
Figure 2. 2,4-Dinitrochlorobenzene (5).
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Figure 3. Representative benzofuroxans for which the phenomenon of crystal polymorphism was observed.
Figure 3. Representative benzofuroxans for which the phenomenon of crystal polymorphism was observed.
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Figure 4. Geometry of 1a (left) and 1b (right).
Figure 4. Geometry of 1a (left) and 1b (right).
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Figure 5. Overlay structures of 1a (green) and 1b (red).
Figure 5. Overlay structures of 1a (green) and 1b (red).
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Figure 6. Packing of 1a (left) and 1b (right).
Figure 6. Packing of 1a (left) and 1b (right).
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Figure 7. Geometry of 4a, 4e, 4g, and 4l.
Figure 7. Geometry of 4a, 4e, 4g, and 4l.
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Figure 8. Intramolecular H-bond in 4l.
Figure 8. Intramolecular H-bond in 4l.
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Figure 9. A packing of molecules in crystal of compound 4l. Only classical hydrogen bonds are observed.
Figure 9. A packing of molecules in crystal of compound 4l. Only classical hydrogen bonds are observed.
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Figure 10. A packing of molecules in crystal of compound 4a.
Figure 10. A packing of molecules in crystal of compound 4a.
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Figure 11. A packing of molecules in crystal of compound 4a.
Figure 11. A packing of molecules in crystal of compound 4a.
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Figure 12. (a) Rotational barrier of the nitro group in the 4,6-dichloro-5-nitrobenzofuroxan molecule (1) in solution. (b) Optimized structures of (1) in solution.
Figure 12. (a) Rotational barrier of the nitro group in the 4,6-dichloro-5-nitrobenzofuroxan molecule (1) in solution. (b) Optimized structures of (1) in solution.
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Figure 13. Optimized geometry of 11, 12, and 2 in solution.
Figure 13. Optimized geometry of 11, 12, and 2 in solution.
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Figure 14. Mulliken partial charges of compounds 1, 2, 11, and 12. Indicated in blue are the most positive electrophilic carbon atoms; in red are the second most positive electrophilic carbon atoms.
Figure 14. Mulliken partial charges of compounds 1, 2, 11, and 12. Indicated in blue are the most positive electrophilic carbon atoms; in red are the second most positive electrophilic carbon atoms.
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Figure 15. (a) Reaction mechanism and (b) energy profile (energies in kcal mol−1) of the reactions of 4,6-dichloro-5-nitrobenzofuroxan (1) with pyrrolidine.
Figure 15. (a) Reaction mechanism and (b) energy profile (energies in kcal mol−1) of the reactions of 4,6-dichloro-5-nitrobenzofuroxan (1) with pyrrolidine.
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Table
Table 1. C4–C5 and C5–NNO2 bond lengths (Angstrom) during the reactive process.
Table 1. C4–C5 and C5–NNO2 bond lengths (Angstrom) during the reactive process.
d(C4–C5) [Å]d(C5–NNO2) [Å]
RC1.361.48
TS11.391.46
IC1.491.38
TS21.501.39
PC1.411.45
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Chugunova, E.; Akylbekov, N.; Dobrynin, A.; Burilov, A.; Boga, C.; Micheletti, G.; Frenna, V.; Mattioli, E.J.; Calvaresi, M.; Spinelli, D. 4,6-Dichloro-5-Nitrobenzofuroxan: Different Polymorphisms and DFT Investigation of Its Reactivity with Nucleophiles. Int. J. Mol. Sci. 2021, 22, 13460. https://doi.org/10.3390/ijms222413460

AMA Style

Chugunova E, Akylbekov N, Dobrynin A, Burilov A, Boga C, Micheletti G, Frenna V, Mattioli EJ, Calvaresi M, Spinelli D. 4,6-Dichloro-5-Nitrobenzofuroxan: Different Polymorphisms and DFT Investigation of Its Reactivity with Nucleophiles. International Journal of Molecular Sciences. 2021; 22(24):13460. https://doi.org/10.3390/ijms222413460

Chicago/Turabian Style

Chugunova, Elena, Nurgali Akylbekov, Alexey Dobrynin, Alexander Burilov, Carla Boga, Gabriele Micheletti, Vincenzo Frenna, Edoardo Jun Mattioli, Matteo Calvaresi, and Domenico Spinelli. 2021. "4,6-Dichloro-5-Nitrobenzofuroxan: Different Polymorphisms and DFT Investigation of Its Reactivity with Nucleophiles" International Journal of Molecular Sciences 22, no. 24: 13460. https://doi.org/10.3390/ijms222413460

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