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Thiol-induced nitric oxide donation mechanisms in substituted dinitrobenzofuroxans
Nitric Oxide 62 (2017) 44e51
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Thiol-induced nitric oxide donation mechanisms in substituted dinitrobenzofuroxans Mikhail E. Kletskii, Oleg N. Burov*, Nikita S. Fedik, Sergey V. Kurbatov Department of Chemistry, Southern Federal University, 7, Zorge St., Rostov-on-Don, 344090, Russia
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 September 2016 Received in revised form 3 December 2016 Accepted 15 December 2016 Available online 15 December 2016
The goal of present work is the quantum chemical study of NO donation mechanism in dinitrobenzofuroxan aryl derivative. Mechanisms of its structural non-rigidity (1,3-N-oxidic and BoultonKatritzky rearrangements) and minimum energy pathways of NO donation under the action of sulfanyl radical SH$ were considered in details. DFT calculations were performed using B3LYP and UB3LYP functionals in the 6e311þþG(d,p) basis set. Obtained results showed that a high experimentally proven NO-donor activity of dinitrobenzofuroxan aryl derivative is connected with its existence in the form of mixture of 1-N-oxide and 3-N-oxide, where the 3-N-oxide is more reactive towards SH$. The thiolinduced low-barrier mechanism of NO-donation is a result of para-aminophenyl substituent availability in position 7 of dinitrobenzofuroxan. © 2016 Elsevier Inc. All rights reserved.
Keywords: Furoxan Nitrogen(II) oxide DFT calculations Thiol-induced NO donation mechanism
One of the priority tasks of medicinal chemistry is the development of new exogenic donors of nitric oxide NO. According to the World Health Organization, cardiovascular diseases are the major death cause [1,2], and one of the most important antianginal agents are coronarodilatators (for example, organic nitrates) whose therapeutic effect is caused by their ability to allocate NO. Nitric oxide is also a multimodal regulator of many physiological processes (vessels relaxation, platelets aggregation inhibition, functioning of both immune and nervous systems) and pathological conditions of the organism (infectious, inflammatory, tumor diseases) [3e10]. There are two major factors limiting targeted synthesis of new compounds able to produce NO molecule in the course of metabolism. The first one is the limitation of experimental methods allowing quick and quantitative registration of in vivo NO molecule formation for 10e20 s [11e13]. The second factor is incomplete knowledge about non-enzymatic (primarily thiol-induced) ways of nitric oxide generating in vivo [14e16]. Earlier we synthesized and studied a number of benzofuroxan derivatives (structures 1e6) known by their NO-donor properties [17]. The benzofuroxan fragment in these substances is coupled with p-excessive carbo- and heterocycles (Scheme 1). *Compound 4 was first described in the work [18]. NO-induction of compounds 3e6 was estimated according to
* Corresponding author. E-mail address: [email protected] (O.N. Burov). http://dx.doi.org/10.1016/j.niox.2016.12.004 1089-8603/© 2016 Elsevier Inc. All rights reserved.
biosensors luminescence on the basis of the MG 1655 strain of E. Coli [17,19]. Herewith, it turned out that compound 4 demonstrates 10-fold induction in comparison with nitroglycerine when using in the minimum effective concentration (Table 1). Nevertheless, for systems of type 4 the transformation mechanism leading to NO release is not known. Previously published data testify that furoxan-containing systems are transformed with the formation of NO under the action of various thiols. Earlier it was suggested that thiolate-anions (nucleophiles) are the main reactive forms of thiols. However our quantum chemical calculations of benzofuroxan (BF) and 4,6dinitrobenzofuroxan (DNBF) showed that this was energetically impossible [16] (Scheme 2; here and further relative changes of the Gibbs free energy are given in kcal/mol). The quantitative “structure-properties” analysis for 36 nitrobenzofuroxan derivatives synthesized and studied by us showed that the increased ability to generate NO symbatically correlates with the structural non-rigidity of the nitrobenzofuroxan fragment allowing coexistence of different isomers with similar energy on potential energy surface (PES). It is known that the main isomerization channels of nitrobenzofuroxans [18,20e22] are BoultonKatritzky rearrangement (BKR, Scheme 3) and 1,3-N-oxidic tautomery (Scheme 4). A possible increase of NO-donor activity for the systems, disposed to intramolecular isomerization, can be associated with different electron distribution (and, consequently, the reactivity of the intermediates on the PES) and/or existence of minor tautomeric
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Scheme 3. BKR in the substituted benzofuroxans.
Scheme 1. Simplified representation of structures 3e6 synthesis.
forms often not even registered experimentally. It is obvious that the study of mechanisms of such intramolecular nitrobenzofuroxans transformations will also allow us to predict the ways of nitric oxide formation. The aim of this work is the quantum chemical study of the mechanism of NO formation in the experimentally known aryl derivative of nitrobenzofuroxan. To solve this problem the structural non-rigidity of the system under investigation (the mechanisms of 1,3-N-oxidic rearrangement and the BKR) and minimum energy pathways (MEPs) of thiol-induced NO donation were considered. In the present work the quantum chemical DFT calculations were performed using B3LYP and UB3LYP functionals in the 6e311þþG(d,p) basis set. 1. Isomerization of system 4 We chose N,N-dimethylaniline derivative 4 as a model for the following reasons:
Scheme 4. Synchronous 1,3-N-oxidic rearrangements in system 4.
1) NO-donor properties of system 4 were experimentally proven; 2) formation of two isomeric forms for this system was experimentally discovered in our studies as well as in the pioneer work [18] that established the foundations of dinitrochlorobenzofuroxan chemistry. In the model furoxan and benzofuroxan the N-oxide tautomerism obviously could not be considered because of indistinguishability of 1- and 3-N-oxides. For DNBF the approaches of the
Table 1 Results of biological testing of some benzoxazoles. Induction factor is a degree of the sensor luminescence amplification as a result of the inductor action [17]. Substance
Concentrations (in mg/ml) of the investigated substances which correspond to the maximum values of the induction factor
The maximum value of the induction factor
Nitroglycerine NOC-5 3 4 5 6
100.00 100.00 0.01 0.10 0.01 0.01
1.900 1.750 0.221 0.507 0.459 1.040
± ± ± ± ± ±
1.154 0.184 0.041 0.114 0.034 0.066
The minimum effective concentration, mg/ml
The values of the induction factor which correspond to the minimal effective concentrations
1.00 0.01 0.01 0.10 0.01 0.01
0.048 0.977 0.033 0.507 0.459 1.040
Scheme 2. Anionic thiol-induced ways of BF and DNBF destruction.
± ± ± ± ± ±
0.009 0.029 0.030 0.114 0.034 0.066
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Fig. 1. MEPs of 1,3-N-oxidic rearrangements in the system 4, according to B3LYP/6e31þþG(d,p) calculations. Blue (dotted) line corresponds to the one-step mechanism, purple (solid) line e to the three-step mechanism. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
attacking particle from different sides of the molecule plane are obviously equivalent. At the same time, in system 4 tautomeric isomerization can lead at once to two geometrically non-equivalent and NO-active forms: 1-N-oxide 4 and 3-N-oxide 4'. Generally, 1,3-N-oxidic tautomery is one of the fundamental and thoroughly experimentally investigated properties of the furoxan cycle [23]. It is known that the ratio of tautomers both in the gas and liquid phases is mainly determined by the “steric pressure” of substituents in the positions close to the oxadiazole cycle at the Noxide oxygen atom. For example, DNBF exists in solutions exclusively as the isomer of 1-oxide type due to the “steric pressure” of the nitro group [23]. The introduction of the dimethylanilinic substituent affects on the tautomer populations apparently comparable to the one of nitro group. System 4 can be rearranged, like any other furoxan, in two different ways - either synchronously or stepwise through the formation of ortho-dinitroso derivatives. The concerted rearrangement of 1-N-oxide 4 into 3-N-oxide 4′ proceeds through the sole transition state TS1 with a barrier of 18.3 kcal/mol and leads to the less thermodynamically stable product (Scheme 4, Fig. 1). Lower stability of 3-N-oxide 4 correlates with the fact that according to 1H NMR spectra its amount is only 8%. The concerted rearrangement process in substituted furoxans had been noted earlier [24]. The stepwise 1,3-N-oxidic rearrangement in system 4 (Scheme 5) proceeds in three stages through ortho-dinitroso form 7, isomer 7′ and ends with the formation of 3-N-oxide 4’. The highest activation barrier (TS3) is 18.7 kcal/mol, and activation barriers corresponded to TS2 and TS4 are 18.4 and 1.0 kcal/mol, respectively. It is interesting that none of the ortho-dinitroso forms (7 and 7′) is not planar. For 1,3-N-oxidic isomerizations transition states TS2, TS3 and TS4 separating 4, 7, 7′ and 40 from each other also have non-planar geometry (Scheme 5, Fig. S2 in Supplementary materials). Similar results had previously been obtained in the quantum chemical calculations of isomerizations in a number of furoxans [25]. Also note that in one of the early theoretical study of benzofuroxan isomerizations the inconsistency of the rearrangement with the least motion principle (implying planar intermediate forms) was substantiated [26]. It is obvious that basing on DFT calculations one cannot make an unambiguous conclusion on the mechanism of the systems 4#4′ rearrangement which is characterized by the proximity of the
activation barriers for both processes e concerted and stepwise. Moreover, there are only signals of protons of systems 4 and 4′ in NMR spectra [18]. Even having these data one cannot make a simple conclusion about the rearrangement mechanism, since ortho-dinitroso forms 7 and 7′ are kinetically unstable (Fig. 1), and their lifetime can be less than the characteristic time of the NMR method. In the work [18] for system 4 a conclusion was made about the existence of isomers formed as a result of the BKR, and the possibility itself of 1,3-N-oxidic rearrangement was not considered at all. Moreover, there do not exist nor experimental nor theoretical evidences of passing the rearrangement of this type. We believe that authors made this conclusion basing on the fact that they were first in the synthesis of 4,6-dinitro-7-chlorobenzofuroxan, which consists of one-pot 5-chlorobenzofuroxan nitration and the subsequent thermally induced BKR. Nevertheless, in numerous studies of nitrobenzofuroxans and nitrobenzodifuroxans, carried out over the last 20 years, nobody has been able to register the rearrangement of the BoultonKatritzky type. All the rearrangements of nitrobenzofuroxans were solely conditioned by 1,3-N-oxidic tautomery (e.g., reviews [27e29]). Similar rearrangements of the furoxan cycle were registed also in nitrobenzodifuroxans [24]. The BKR, as known, is a single-stage process allowed under thermal conditions. Previously it had been studied in detail [21,22,30,31], and its principal possibility has been shown experimentally for 5-chloro-6-dinitrobenzofuroxan [18],1. According to our data, the activation energy for such a process in the structure 4 is 26.1 kcal/mol, which is consistent with previously published for similar systems (Scheme 6, Fig. S3, Table S3 in Supplementary materials). According to our calculations, system 8 is 2.7 kcal/mol less stable than the original 1-N-oxidic form 4. It shows that BKR cannot compete with low-barrier 1,3-N-oxidic tautomery, and system 8 can exist in product mixture only in trace amounts, if it exists at all. Besides, this is consistent with the empirical rule according to
1 Note that formally the BKR can occur as a multistage process. However ab initio and DFT calculations [30,31], showed that this path is significantly hindered kinetically in comparison with single-stage.
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Scheme 5. Stepwise rearrangements in system 4.
Table 2 Parr's electrophilicity indices u according to the data of DFT calculations.
Scheme 6. BKR in system 4.
which the BKR effectively proceeds only in benzofuroxan derivatives containing a p-donor substituents in position 5 [18,31]. It is obvious as well that the location of p-donor groups in position 7 blocks the ability of such rearrangement2. The major importance of p-donor effect of the substituent can be explained by Parr's global electrophilicity indices u for two pairs of systems (Table 2, Schemes 6 and 7). It is obvious that the increase of donors will facilitates the BKR, while the electrophilicity will be reduced. Indeed, the rearrangement occurs only in the isomer characterized by smaller u index. Thus the equilibrium in the isomerization 4#4′ is shifted toward the original 1-N-oxide. It follows that for mechanisms of thiol-induced NO donation, one needs to consider both 1-N-oxide and 3-N-oxide, but excluding less stable and kinetically accessible isomer 8.
2 The electronic effect of the aminophenyl group was evaluated basing on the quantity of the charge transfer in the direction of the benzofuroxan fragment: it . was 0.22 e
System
4
8
9
10
u, eV
4.86
4.52
4.80
5.38
For the simplest earlier considered systems, MEPs in gas phase and in water at 37 C are contiguous: the difference of the kinetic and thermodynamic parameters does not exceed 2.0 kcal/mol [16]. In the present work we also compared the thermodynamic stability of experimentally known systems 4, 4′ and 8 both in the gas phase and considering solvatation effects (data in parentheses in Fig. 2). Additional ab initio gas phase calculations in the same basis set were carried out (data in square brackets in Fig. 2). As expected, during the transition from one phase or one method to another the relative stability of the isomers is qualitatively preserved although is changed somewhat quantitatively. That is why we considered for isomers 4 and 4′ the mechanism of thiol-induced NO donation in the gas phase. 2. Mechanisms of thiol-induced NO donation in system 4 As mentioned above, the radical attack of furoxans with sulfanyl SH was theoretically substantiated (Scheme 8) [16]. At the same
Scheme 7. BKR in 5-chloro-6-dinitrobenzofuroxan.
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Fig. 2. Relative stability of isomers 4, 4′ and 8 in the gas phase and in water at 310 K.
Scheme 8. Radical thiol-induced ways of BF and DNBF destruction.
time it turned out that the processes of NO-decomposition of furoxans and their annelated derivatives (BF and DNBF) proceed with activation energies that are achievable in the conditions of human organism and lead to the release of nitric oxide with a significant gain of energy. The systems considered earlier represent simplified models of nitric oxide donors [16]. An issue arises, is the extrapolation of these mechanisms on the real systems valid? To figure this out we studied MEPs of the destruction of real system 4 under the action of sulfanyl radical on both isomers of NO-donor. Due to the fact that in system 4 the aminophenyl fragment forms the angle ~49 with the plane of DNBF (~41 in system 4′), there is a possibility of the radical attack on the same carbon atom from two non-equivalent directions (Fig. 3, Schemes 9 and 10 and Supplementary materials). First, let us consider the attack on Scheme 9. The approaching of sulfanyl radical to 1-N-oxide 4 proceeds with a barrier of 17.4 kcal/ mol (TS 6) and leads to intermediate 11. Next, system 11 is
rearranged into acyclic dinitroso form 12 overcoming the barrier of 2.4 kcal/mol (TS 7). The last one turns into the final product 14 with the radical NO elimination and decrease of Gibbs free energy for 24.7 kcal/mol through two low-energy transition states (TS8, TS9, responsible for the conformational transformations) and intermediate 13. An attack on 3-N-oxide 4′ has a lower activation energy of the limiting stage (14.5 kcal/mol, TS 10) and leads to the adduct 15, which transforms into open dinitroso form 16. The last one decomposes into the thiolnitroso derivative 17 and NO, spending 1.5 kcal/mol (TS 12). The attack on structures 4 and 4′ according to Scheme 10 does not have fundamental differences in the mechanism, but is described in general by the MEP with higher activation energies. In this case, the attack on 1-N-oxide 4 proceeds through the transition state TS14 spending 19.3 kcal/mol. The resulting radical adduct 18 is transformed into intermediate 19 through transition state TS15. Further, structure 19 is decomposed with the minimum energy
Fig. 3. Molecular structures of substances 4 and 4′ (for more information see Supplementary materials, Fig. S1).
M.E. Kletskii et al. / Nitric Oxide 62 (2017) 44e51
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Scheme 9. Calculated first direction for the radical thiol-induced ways of the NO formation. UB3LYP functional and 6-311þþG(d,p) basis set.
Scheme 10. Calculated second direction for the radical thiol-induced ways of the NO formation. UB3LYP functional and 6-311þþG(d,p) basis set.
consumptions (TS16) to product 20 and nitric oxide. Isomer 4′ is more reactive, and MEP of its decomposition passes through the transition state TS17 with a lower activation energy leading to the local minimum 21. Further, acyclic system 22 is formed with a barrier (TS18) of only 1.6 kcal/mol. Then structure 22 transforms into product 23 and NO through the transition state TS19 with an energy gain of 28.0 kcal/mol. Thus, we showed that the destruction of the considered furoxan under the action of sulfanyl radical proceeded easier in the 3-oxide form 4’. Let's note some of the features. The first radical adducts 11 and 15 are stable on the PES as pairs of atropisomers (Scheme 9). The same is true for system 18 and 21 (Scheme 10). Moreover, the difficulty of the substituent rotation around a CeC bond in system 4
correlates with the activation energy for the complete rotation that amounts 10.4 kcal/mol. Like in papers [14,15] and in order to close the discussion about the anionic mechanism of the nitric oxide donating we also checked the thermodynamic effects of system 4 destruction under SH attack3. The results show that formation of products 14, 17, 20, 23 and NO leads to significant raising of the Gibbs free energy: 49.7, 46.2, 49.6 and 46.4 kcal/mol, respectively (Scheme 11). As expected, such processes are thermodynamically highly
3 Substitution products were considered in the conformations which were obtained in the MEPs calculations for radical attack.
50
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Scheme 11. Anionic thiol-induced ways. Grel values are in kcal/mol. B3LYP functional and 6-311þþG(d,p) basis set.
unfavorable; therefore the mechanism of radical attack studied in the present work seems as the most realistic. 3. Conclusions Obtained results show that a high experimentally proven NOdonor activity of dinitrobenzofuroxan 4 is related to its existence as a mixture of 1,3-N-oxidic isomers, where the 3-N-oxide 4′ is more reactive towards SH. The thiol-induced low-barrier mechanism of NO-donation is the result of para-aminophenyl substituent availability in position 7 of DNBF.
Also the program of reactive indices calculations, kindly provided by E. Chamorro (Departamento de Ciencias Químicas, Facultad de Ecología y Recursos Naturales, Universidad Nacional s Bello, Santiago, Chile) [43], was used in the present work. In Andre all cases the electrophilicity index u (which is a measure of the energetic stabilization of the system when it receives an additional electric charge from the nucleophile) was calculated according to the formula
.
u ¼ m2 2h; where m ¼ ðEHOMO þ ELUMO Þ=2 and h ¼ ELUMO EHOMO
4. Experimental All quantum chemical calculations were performed using the software package Gaussian 09 [32] running on the Silver cluster at the Institute of Physical and Organic Chemistry of the Southern Federal University. Calculations were carried out using DFT approximations, B3LYP exchange-correlation functional [33e35] for closed electron shells, UB3LYP exchange-correlation functional for open electron shells and triple-zeta quality basis set 6e311þþG(d,p) [36]. The triple zeta basis set was previously shown to be appropriate for the reproduction of vibrational frequencies, geometry and MEPs of reactions involving furoxan derivatives [16,37,38]. Ab initio RHF calculations were carried out in the same basis set. The complete geometry optimization of molecular structures corresponding to stationary points on the PESs was accomplished to gradient value of 107 hartree/bohr using analytical calculations of gradients according to the scheme of Berny [39]. The nature of stationary points was studied by the calculations of Hessian matrix. The MEPs of reactions were obtained using a gradient descent from the transition states in the forward and backward directions of the transition vectors. The search of transition states was based on the approaches of linear and quadratic synchronous transits [40,41]. The solvation effects were accounted for by using the polarized continuum model (PCM) [42] in H2O at 310 K.
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Nitric Oxide journal homepage: www.elsevier.com/locate/yniox
Thiol-induced nitric oxide donation mechanisms in substituted dinitrobenzofuroxans Mikhail E. Kletskii, Oleg N. Burov*, Nikita S. Fedik, Sergey V. Kurbatov Department of Chemistry, Southern Federal University, 7, Zorge St., Rostov-on-Don, 344090, Russia
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 September 2016 Received in revised form 3 December 2016 Accepted 15 December 2016 Available online 15 December 2016
The goal of present work is the quantum chemical study of NO donation mechanism in dinitrobenzofuroxan aryl derivative. Mechanisms of its structural non-rigidity (1,3-N-oxidic and BoultonKatritzky rearrangements) and minimum energy pathways of NO donation under the action of sulfanyl radical SH$ were considered in details. DFT calculations were performed using B3LYP and UB3LYP functionals in the 6e311þþG(d,p) basis set. Obtained results showed that a high experimentally proven NO-donor activity of dinitrobenzofuroxan aryl derivative is connected with its existence in the form of mixture of 1-N-oxide and 3-N-oxide, where the 3-N-oxide is more reactive towards SH$. The thiolinduced low-barrier mechanism of NO-donation is a result of para-aminophenyl substituent availability in position 7 of dinitrobenzofuroxan. © 2016 Elsevier Inc. All rights reserved.
Keywords: Furoxan Nitrogen(II) oxide DFT calculations Thiol-induced NO donation mechanism
One of the priority tasks of medicinal chemistry is the development of new exogenic donors of nitric oxide NO. According to the World Health Organization, cardiovascular diseases are the major death cause [1,2], and one of the most important antianginal agents are coronarodilatators (for example, organic nitrates) whose therapeutic effect is caused by their ability to allocate NO. Nitric oxide is also a multimodal regulator of many physiological processes (vessels relaxation, platelets aggregation inhibition, functioning of both immune and nervous systems) and pathological conditions of the organism (infectious, inflammatory, tumor diseases) [3e10]. There are two major factors limiting targeted synthesis of new compounds able to produce NO molecule in the course of metabolism. The first one is the limitation of experimental methods allowing quick and quantitative registration of in vivo NO molecule formation for 10e20 s [11e13]. The second factor is incomplete knowledge about non-enzymatic (primarily thiol-induced) ways of nitric oxide generating in vivo [14e16]. Earlier we synthesized and studied a number of benzofuroxan derivatives (structures 1e6) known by their NO-donor properties [17]. The benzofuroxan fragment in these substances is coupled with p-excessive carbo- and heterocycles (Scheme 1). *Compound 4 was first described in the work [18]. NO-induction of compounds 3e6 was estimated according to
* Corresponding author. E-mail address: [email protected] (O.N. Burov). http://dx.doi.org/10.1016/j.niox.2016.12.004 1089-8603/© 2016 Elsevier Inc. All rights reserved.
biosensors luminescence on the basis of the MG 1655 strain of E. Coli [17,19]. Herewith, it turned out that compound 4 demonstrates 10-fold induction in comparison with nitroglycerine when using in the minimum effective concentration (Table 1). Nevertheless, for systems of type 4 the transformation mechanism leading to NO release is not known. Previously published data testify that furoxan-containing systems are transformed with the formation of NO under the action of various thiols. Earlier it was suggested that thiolate-anions (nucleophiles) are the main reactive forms of thiols. However our quantum chemical calculations of benzofuroxan (BF) and 4,6dinitrobenzofuroxan (DNBF) showed that this was energetically impossible [16] (Scheme 2; here and further relative changes of the Gibbs free energy are given in kcal/mol). The quantitative “structure-properties” analysis for 36 nitrobenzofuroxan derivatives synthesized and studied by us showed that the increased ability to generate NO symbatically correlates with the structural non-rigidity of the nitrobenzofuroxan fragment allowing coexistence of different isomers with similar energy on potential energy surface (PES). It is known that the main isomerization channels of nitrobenzofuroxans [18,20e22] are BoultonKatritzky rearrangement (BKR, Scheme 3) and 1,3-N-oxidic tautomery (Scheme 4). A possible increase of NO-donor activity for the systems, disposed to intramolecular isomerization, can be associated with different electron distribution (and, consequently, the reactivity of the intermediates on the PES) and/or existence of minor tautomeric
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45
Scheme 3. BKR in the substituted benzofuroxans.
Scheme 1. Simplified representation of structures 3e6 synthesis.
forms often not even registered experimentally. It is obvious that the study of mechanisms of such intramolecular nitrobenzofuroxans transformations will also allow us to predict the ways of nitric oxide formation. The aim of this work is the quantum chemical study of the mechanism of NO formation in the experimentally known aryl derivative of nitrobenzofuroxan. To solve this problem the structural non-rigidity of the system under investigation (the mechanisms of 1,3-N-oxidic rearrangement and the BKR) and minimum energy pathways (MEPs) of thiol-induced NO donation were considered. In the present work the quantum chemical DFT calculations were performed using B3LYP and UB3LYP functionals in the 6e311þþG(d,p) basis set. 1. Isomerization of system 4 We chose N,N-dimethylaniline derivative 4 as a model for the following reasons:
Scheme 4. Synchronous 1,3-N-oxidic rearrangements in system 4.
1) NO-donor properties of system 4 were experimentally proven; 2) formation of two isomeric forms for this system was experimentally discovered in our studies as well as in the pioneer work [18] that established the foundations of dinitrochlorobenzofuroxan chemistry. In the model furoxan and benzofuroxan the N-oxide tautomerism obviously could not be considered because of indistinguishability of 1- and 3-N-oxides. For DNBF the approaches of the
Table 1 Results of biological testing of some benzoxazoles. Induction factor is a degree of the sensor luminescence amplification as a result of the inductor action [17]. Substance
Concentrations (in mg/ml) of the investigated substances which correspond to the maximum values of the induction factor
The maximum value of the induction factor
Nitroglycerine NOC-5 3 4 5 6
100.00 100.00 0.01 0.10 0.01 0.01
1.900 1.750 0.221 0.507 0.459 1.040
± ± ± ± ± ±
1.154 0.184 0.041 0.114 0.034 0.066
The minimum effective concentration, mg/ml
The values of the induction factor which correspond to the minimal effective concentrations
1.00 0.01 0.01 0.10 0.01 0.01
0.048 0.977 0.033 0.507 0.459 1.040
Scheme 2. Anionic thiol-induced ways of BF and DNBF destruction.
± ± ± ± ± ±
0.009 0.029 0.030 0.114 0.034 0.066
46
M.E. Kletskii et al. / Nitric Oxide 62 (2017) 44e51
Fig. 1. MEPs of 1,3-N-oxidic rearrangements in the system 4, according to B3LYP/6e31þþG(d,p) calculations. Blue (dotted) line corresponds to the one-step mechanism, purple (solid) line e to the three-step mechanism. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
attacking particle from different sides of the molecule plane are obviously equivalent. At the same time, in system 4 tautomeric isomerization can lead at once to two geometrically non-equivalent and NO-active forms: 1-N-oxide 4 and 3-N-oxide 4'. Generally, 1,3-N-oxidic tautomery is one of the fundamental and thoroughly experimentally investigated properties of the furoxan cycle [23]. It is known that the ratio of tautomers both in the gas and liquid phases is mainly determined by the “steric pressure” of substituents in the positions close to the oxadiazole cycle at the Noxide oxygen atom. For example, DNBF exists in solutions exclusively as the isomer of 1-oxide type due to the “steric pressure” of the nitro group [23]. The introduction of the dimethylanilinic substituent affects on the tautomer populations apparently comparable to the one of nitro group. System 4 can be rearranged, like any other furoxan, in two different ways - either synchronously or stepwise through the formation of ortho-dinitroso derivatives. The concerted rearrangement of 1-N-oxide 4 into 3-N-oxide 4′ proceeds through the sole transition state TS1 with a barrier of 18.3 kcal/mol and leads to the less thermodynamically stable product (Scheme 4, Fig. 1). Lower stability of 3-N-oxide 4 correlates with the fact that according to 1H NMR spectra its amount is only 8%. The concerted rearrangement process in substituted furoxans had been noted earlier [24]. The stepwise 1,3-N-oxidic rearrangement in system 4 (Scheme 5) proceeds in three stages through ortho-dinitroso form 7, isomer 7′ and ends with the formation of 3-N-oxide 4’. The highest activation barrier (TS3) is 18.7 kcal/mol, and activation barriers corresponded to TS2 and TS4 are 18.4 and 1.0 kcal/mol, respectively. It is interesting that none of the ortho-dinitroso forms (7 and 7′) is not planar. For 1,3-N-oxidic isomerizations transition states TS2, TS3 and TS4 separating 4, 7, 7′ and 40 from each other also have non-planar geometry (Scheme 5, Fig. S2 in Supplementary materials). Similar results had previously been obtained in the quantum chemical calculations of isomerizations in a number of furoxans [25]. Also note that in one of the early theoretical study of benzofuroxan isomerizations the inconsistency of the rearrangement with the least motion principle (implying planar intermediate forms) was substantiated [26]. It is obvious that basing on DFT calculations one cannot make an unambiguous conclusion on the mechanism of the systems 4#4′ rearrangement which is characterized by the proximity of the
activation barriers for both processes e concerted and stepwise. Moreover, there are only signals of protons of systems 4 and 4′ in NMR spectra [18]. Even having these data one cannot make a simple conclusion about the rearrangement mechanism, since ortho-dinitroso forms 7 and 7′ are kinetically unstable (Fig. 1), and their lifetime can be less than the characteristic time of the NMR method. In the work [18] for system 4 a conclusion was made about the existence of isomers formed as a result of the BKR, and the possibility itself of 1,3-N-oxidic rearrangement was not considered at all. Moreover, there do not exist nor experimental nor theoretical evidences of passing the rearrangement of this type. We believe that authors made this conclusion basing on the fact that they were first in the synthesis of 4,6-dinitro-7-chlorobenzofuroxan, which consists of one-pot 5-chlorobenzofuroxan nitration and the subsequent thermally induced BKR. Nevertheless, in numerous studies of nitrobenzofuroxans and nitrobenzodifuroxans, carried out over the last 20 years, nobody has been able to register the rearrangement of the BoultonKatritzky type. All the rearrangements of nitrobenzofuroxans were solely conditioned by 1,3-N-oxidic tautomery (e.g., reviews [27e29]). Similar rearrangements of the furoxan cycle were registed also in nitrobenzodifuroxans [24]. The BKR, as known, is a single-stage process allowed under thermal conditions. Previously it had been studied in detail [21,22,30,31], and its principal possibility has been shown experimentally for 5-chloro-6-dinitrobenzofuroxan [18],1. According to our data, the activation energy for such a process in the structure 4 is 26.1 kcal/mol, which is consistent with previously published for similar systems (Scheme 6, Fig. S3, Table S3 in Supplementary materials). According to our calculations, system 8 is 2.7 kcal/mol less stable than the original 1-N-oxidic form 4. It shows that BKR cannot compete with low-barrier 1,3-N-oxidic tautomery, and system 8 can exist in product mixture only in trace amounts, if it exists at all. Besides, this is consistent with the empirical rule according to
1 Note that formally the BKR can occur as a multistage process. However ab initio and DFT calculations [30,31], showed that this path is significantly hindered kinetically in comparison with single-stage.
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47
Scheme 5. Stepwise rearrangements in system 4.
Table 2 Parr's electrophilicity indices u according to the data of DFT calculations.
Scheme 6. BKR in system 4.
which the BKR effectively proceeds only in benzofuroxan derivatives containing a p-donor substituents in position 5 [18,31]. It is obvious as well that the location of p-donor groups in position 7 blocks the ability of such rearrangement2. The major importance of p-donor effect of the substituent can be explained by Parr's global electrophilicity indices u for two pairs of systems (Table 2, Schemes 6 and 7). It is obvious that the increase of donors will facilitates the BKR, while the electrophilicity will be reduced. Indeed, the rearrangement occurs only in the isomer characterized by smaller u index. Thus the equilibrium in the isomerization 4#4′ is shifted toward the original 1-N-oxide. It follows that for mechanisms of thiol-induced NO donation, one needs to consider both 1-N-oxide and 3-N-oxide, but excluding less stable and kinetically accessible isomer 8.
2 The electronic effect of the aminophenyl group was evaluated basing on the quantity of the charge transfer in the direction of the benzofuroxan fragment: it . was 0.22 e
System
4
8
9
10
u, eV
4.86
4.52
4.80
5.38
For the simplest earlier considered systems, MEPs in gas phase and in water at 37 C are contiguous: the difference of the kinetic and thermodynamic parameters does not exceed 2.0 kcal/mol [16]. In the present work we also compared the thermodynamic stability of experimentally known systems 4, 4′ and 8 both in the gas phase and considering solvatation effects (data in parentheses in Fig. 2). Additional ab initio gas phase calculations in the same basis set were carried out (data in square brackets in Fig. 2). As expected, during the transition from one phase or one method to another the relative stability of the isomers is qualitatively preserved although is changed somewhat quantitatively. That is why we considered for isomers 4 and 4′ the mechanism of thiol-induced NO donation in the gas phase. 2. Mechanisms of thiol-induced NO donation in system 4 As mentioned above, the radical attack of furoxans with sulfanyl SH was theoretically substantiated (Scheme 8) [16]. At the same
Scheme 7. BKR in 5-chloro-6-dinitrobenzofuroxan.
48
M.E. Kletskii et al. / Nitric Oxide 62 (2017) 44e51
Fig. 2. Relative stability of isomers 4, 4′ and 8 in the gas phase and in water at 310 K.
Scheme 8. Radical thiol-induced ways of BF and DNBF destruction.
time it turned out that the processes of NO-decomposition of furoxans and their annelated derivatives (BF and DNBF) proceed with activation energies that are achievable in the conditions of human organism and lead to the release of nitric oxide with a significant gain of energy. The systems considered earlier represent simplified models of nitric oxide donors [16]. An issue arises, is the extrapolation of these mechanisms on the real systems valid? To figure this out we studied MEPs of the destruction of real system 4 under the action of sulfanyl radical on both isomers of NO-donor. Due to the fact that in system 4 the aminophenyl fragment forms the angle ~49 with the plane of DNBF (~41 in system 4′), there is a possibility of the radical attack on the same carbon atom from two non-equivalent directions (Fig. 3, Schemes 9 and 10 and Supplementary materials). First, let us consider the attack on Scheme 9. The approaching of sulfanyl radical to 1-N-oxide 4 proceeds with a barrier of 17.4 kcal/ mol (TS 6) and leads to intermediate 11. Next, system 11 is
rearranged into acyclic dinitroso form 12 overcoming the barrier of 2.4 kcal/mol (TS 7). The last one turns into the final product 14 with the radical NO elimination and decrease of Gibbs free energy for 24.7 kcal/mol through two low-energy transition states (TS8, TS9, responsible for the conformational transformations) and intermediate 13. An attack on 3-N-oxide 4′ has a lower activation energy of the limiting stage (14.5 kcal/mol, TS 10) and leads to the adduct 15, which transforms into open dinitroso form 16. The last one decomposes into the thiolnitroso derivative 17 and NO, spending 1.5 kcal/mol (TS 12). The attack on structures 4 and 4′ according to Scheme 10 does not have fundamental differences in the mechanism, but is described in general by the MEP with higher activation energies. In this case, the attack on 1-N-oxide 4 proceeds through the transition state TS14 spending 19.3 kcal/mol. The resulting radical adduct 18 is transformed into intermediate 19 through transition state TS15. Further, structure 19 is decomposed with the minimum energy
Fig. 3. Molecular structures of substances 4 and 4′ (for more information see Supplementary materials, Fig. S1).
M.E. Kletskii et al. / Nitric Oxide 62 (2017) 44e51
49
Scheme 9. Calculated first direction for the radical thiol-induced ways of the NO formation. UB3LYP functional and 6-311þþG(d,p) basis set.
Scheme 10. Calculated second direction for the radical thiol-induced ways of the NO formation. UB3LYP functional and 6-311þþG(d,p) basis set.
consumptions (TS16) to product 20 and nitric oxide. Isomer 4′ is more reactive, and MEP of its decomposition passes through the transition state TS17 with a lower activation energy leading to the local minimum 21. Further, acyclic system 22 is formed with a barrier (TS18) of only 1.6 kcal/mol. Then structure 22 transforms into product 23 and NO through the transition state TS19 with an energy gain of 28.0 kcal/mol. Thus, we showed that the destruction of the considered furoxan under the action of sulfanyl radical proceeded easier in the 3-oxide form 4’. Let's note some of the features. The first radical adducts 11 and 15 are stable on the PES as pairs of atropisomers (Scheme 9). The same is true for system 18 and 21 (Scheme 10). Moreover, the difficulty of the substituent rotation around a CeC bond in system 4
correlates with the activation energy for the complete rotation that amounts 10.4 kcal/mol. Like in papers [14,15] and in order to close the discussion about the anionic mechanism of the nitric oxide donating we also checked the thermodynamic effects of system 4 destruction under SH attack3. The results show that formation of products 14, 17, 20, 23 and NO leads to significant raising of the Gibbs free energy: 49.7, 46.2, 49.6 and 46.4 kcal/mol, respectively (Scheme 11). As expected, such processes are thermodynamically highly
3 Substitution products were considered in the conformations which were obtained in the MEPs calculations for radical attack.
50
M.E. Kletskii et al. / Nitric Oxide 62 (2017) 44e51
Scheme 11. Anionic thiol-induced ways. Grel values are in kcal/mol. B3LYP functional and 6-311þþG(d,p) basis set.
unfavorable; therefore the mechanism of radical attack studied in the present work seems as the most realistic. 3. Conclusions Obtained results show that a high experimentally proven NOdonor activity of dinitrobenzofuroxan 4 is related to its existence as a mixture of 1,3-N-oxidic isomers, where the 3-N-oxide 4′ is more reactive towards SH. The thiol-induced low-barrier mechanism of NO-donation is the result of para-aminophenyl substituent availability in position 7 of DNBF.
Also the program of reactive indices calculations, kindly provided by E. Chamorro (Departamento de Ciencias Químicas, Facultad de Ecología y Recursos Naturales, Universidad Nacional s Bello, Santiago, Chile) [43], was used in the present work. In Andre all cases the electrophilicity index u (which is a measure of the energetic stabilization of the system when it receives an additional electric charge from the nucleophile) was calculated according to the formula
.
u ¼ m2 2h; where m ¼ ðEHOMO þ ELUMO Þ=2 and h ¼ ELUMO EHOMO
4. Experimental All quantum chemical calculations were performed using the software package Gaussian 09 [32] running on the Silver cluster at the Institute of Physical and Organic Chemistry of the Southern Federal University. Calculations were carried out using DFT approximations, B3LYP exchange-correlation functional [33e35] for closed electron shells, UB3LYP exchange-correlation functional for open electron shells and triple-zeta quality basis set 6e311þþG(d,p) [36]. The triple zeta basis set was previously shown to be appropriate for the reproduction of vibrational frequencies, geometry and MEPs of reactions involving furoxan derivatives [16,37,38]. Ab initio RHF calculations were carried out in the same basis set. The complete geometry optimization of molecular structures corresponding to stationary points on the PESs was accomplished to gradient value of 107 hartree/bohr using analytical calculations of gradients according to the scheme of Berny [39]. The nature of stationary points was studied by the calculations of Hessian matrix. The MEPs of reactions were obtained using a gradient descent from the transition states in the forward and backward directions of the transition vectors. The search of transition states was based on the approaches of linear and quadratic synchronous transits [40,41]. The solvation effects were accounted for by using the polarized continuum model (PCM) [42] in H2O at 310 K.
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