Origins of the ANRORC reactivity in nitroimidazole derivatives

Abstract

The mechanism of the ANRORC-like ring transformation of nitroimidazole derivatives towards aniline has been studied by fully exploring the potential energy surface (PES). For this purpose the reaction of some aniline derivatives towards 1,4-dinitro-1H-imidazole, 2-methyl-1,4-dinitro-1H-imidazole and 5-methyl-1,4-dinitro-1H-imidazole and have been employed as model reactions. The study reveals that the most favorable path involves an initial amine attack at the C(5)–C(4) bond of the imidazole moiety, where the imidazole distortion appears to be the main factor for the favored nucleophilic attack on the C(5) site. We further show that the reaction regioselectivity is independent of the substitution patterns on the aryl moiety. Next, we highlight the key role of the proton transfer along the reaction pathway of the title reactions to allow a successful connection between two energetically lower regions along the PES: an electrophilically activated ring-opening step followed by the favored 5-exo-trig cyclization. Additionally, we show that this 5-exo-trig cyclization step is the rate determining step. Finally the tether strain and steric effects present in the rate determining TS structure are evaluated by means of the distortion/interaction model.

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1 Introduction

In the field of five-membered heterocycle chemistry, the ANRORC-like reaction (consisting of the addition of a nucleophile followed by ring-opening and ring-closure steps)¹ has become a powerful tool allowing a wide number of structures with potential biological activity to be obtained.^2–6 In this line, it has been shown that 1,4-dinitro-1H-imidazole reacts with anilines according to an ANRORC-like mechanism to yield 1-phenyl-1H-4-nitroimidazoles.^2,7,8 These structures, which have a well-recognized antibacterial activity,^9,10 are not readily available from classical synthetic routes. For instance, the nitration of 1-phenyl-1H-imidazole is not selective. Also, the 1-arylation of 4-nitro-1H-imidazole anions (which takes place via an S_NAr mechanism), is limited to phenyl derivatives containing strong electron-withdrawing substituents, such as the NO₂ group. However, from a mechanistic viewpoint, these compounds can be generated via a mechanism involving initial nucleophilic attack onto the imidazole ring (either the C(5) or C(2) sites), followed by a ring cleavage step to give a ring opened intermediate. The cyclization of this intermediate and elimination of nitramide close the set of steps needed to give the desired product. A general picture is depicted in Fig. 1.

Fig. 1 Plausible reaction mechanisms for the ANRORC-like reaction between 1,4-dinitro-1H-imidazole and aniline.

On the other hand, although some mechanistic aspects of the title reactions have been described,² it is not possible with the current state of the art to provide enough evidence to unequivocally assign the mechanism of these transformations. In other words, despite its importance in organic synthesis, a more accurate mechanism for this elegant ring transformation is still an open question. For instance, the role of the proton transfer mechanism from the nucleophile moiety along the reaction path remains unclear. Also, the reactivity patterns of the generated open-chain intermediates are as yet unknown. In this sense, the description of the cyclization step involved in this transformation is often misleading since it is commonly suggested in the literature that the cyclization step proceeds via a disfavored 5-endo-trig process.²

The present study represents a significant contribution along this line. In this work, we present an in depth theoretical study devoted to elucidate the mechanism of the title reactions, identifying the origins of the ANRORC reactivity in these compounds. For this purpose, we carried out a full exploration of the potential energy surface (PES) for the reaction between aniline and 1,4-dinitro-1H-imidazole as a model reaction. Substituent and torsional effects were evaluated to compare the reactivity of substituted anilines towards 2-methyl-1,4-dinitro-1H-imidazole.² The article is organized as follows: first we elucidate the origins of regioselectivity patterns present at the initial nucleophilic addition step. Next we focus on the electronic factors that determine the ANRORC reactivity in these compounds. Finally the substituent and tether strain effects present at the rate determining step are elucidated by means of a distortion/interaction model.

2 Results and discussion

2.1 Origins of regioselectivity: the role of imidazole distortion

The first task is to explore the regioselectivity patterns arising at the initial nucleophilic addition step in order to establish the preferred reaction pathway for this reaction. For this step, two scenarios are possible: the first one, involves nucleophilic attack onto the C(5) site, whilst a second scenario considers an initial amine attack step on the C(2) atom of the imidazole ring (see Fig. 1). The corresponding regioselective transition state structures were located for the nucleophilic attack of aniline towards a variety of 1,4-dinitro-1H-imidazole derivatives. These structures are depicted in Fig. 2.

Fig. 2 Transition state structures for the regioselective addition of the nucleophile onto the imidazole ring. The computed Gibbs free energy (in kcal mol⁻¹) corresponds to 1 M and 298 K standard state. The C(2)–N(3)–C(4)–C(5) dihedral angle of the imidazole moiety (green) is given in degrees.

The results obtained reveal that the nucleophilic attack of the NH₂ moiety at the C(5) atom of the azole ring lies between 8.1 kcal mol⁻¹ and 11.0 kcal mol⁻¹ lower than the corresponding nucleophilic attack on the C(2) site. It must be stressed that the intramolecular hydrogen bond (HB) interaction between the acidic hydrogen of aniline and the nitro group was originally given a key role in the mechanism in other related reactions.^11–13 However, the optimized transition state structure for the amine attack step in the water/methanol cavity, suggests that this interaction is weak at best. Following this hypothesis, we carried out a second-order perturbation energy analysis within the framework of the NBO procedure.¹⁴ In this approach, the second-order perturbation energies of interaction are calculated as:

where q_i is the ith donor orbital occupancy, ε_i and ε_j are diagonal elements (orbital energies) and F_ij are the off diagonal elements of the Fock matrix, respectively. ΔE_ij measures the strength of the donor–acceptor interaction between orbitals φ_i and φ_j. This analysis has been suggested to be well suited for examining HB interactions in some related organic reactions. The NBO analysis for TS-1a, TS-1c and TS-1e reveals that this HB interaction is less than 0.5 kcal mol⁻¹. These results reinforce the hypothesis previously advanced and show that the preference for the nucleophilic addition onto the C(5) site cannot be attributed to intramolecular HB effects.

In order to achieve a better understanding of the origin of the regioselectivity patterns, we interpret the activation barriers for both reaction paths by using the distortion/interaction model.¹⁵ In this model, the activation energy is related to the energy required for the geometrical deformation that leads to the right TS structure, and that stimulates favorable interactions between the two distorted reactants. Rather recently, Houk and Garg successfully explained the regioselectivities of some nucleophilic reactions through the distortion/interaction model.^16–19 Herein, we relate the distortion energy to the deformation of the C(2)–N(3)–C(4)–C(5) dihedral angle of the imidazole moiety at the transition state as a measure of imidazole distortion (see Fig. 2). The corresponding imidazole and nucleophile distortion energies are depicted in Fig. 3. The results obtained herein by using Houk’s model reveal that the imidazole distortion appears to be the main factor favoring the nucleophilic attack on the C(5) site, whereas the nucleophile displays a marginal effect on the computed transition-state distortion energies (see Fig. 3). This response may be attributed to two main factors: (i) the late nature of the transition structure associated with the amine attack on C(2) site which entails a significant distortion at the reaction center, arising as a response to the re-hybridization of the C(2) atom and (ii) the distortion at the immediate neighborhood of the reaction center that results from the reorganization of the electron density during the bond forming/bond breaking processes. The key role of imidazole distortion in the control of regioselectivity is also highlighted by comparing the interaction energies which are quite similar (see Fig. 3). This response can be conveniently rationalized in terms of chemical reactivity descriptors, as the Fukui function, or in a better way, by analyzing the frontier molecular orbital of the heterocyclic rings. From Fig. 4 it is possible to note that the LUMO coefficients of C(2) and C(5) for imidazole derivatives are roughly similar and exhibit low values for the electrophilic Fukui function.

Fig. 3 Distortion/interaction analysis for nucleophile–addition transition states. Black: imidazole distortion, red: amine distortion, blue: interaction energy and green: activation energy. All of the values are given in kcal mol⁻¹.

Fig. 4 LUMO for heterocyclic rings considered in the present study: 1,4-dinitro-1H-imidazole (left), 2-methyl-1,4-dinitro-1H-imidazole (center) and 5-methyl-1,4-dinitro-1H-imidazole (right). Values presented are the electrophilic Fukui function.

These results are consistent with the nearly identical interaction energies predicted above reinforcing the crucial role of imidazole distortion on the regioselectivity patterns. During the review process of this article, a referee called our attention to consider exploring the role of the substitution patterns at the aryl moiety on the reaction regioselectivity. In this line, the reviewer suggested exploring the effect of ortho, meta and para substitution on the regioselectivity patterns. As expected, our calculation reveals that the stereoelectronic effect exerted by these nucleophiles does not change the regioselectivity patterns. In other words our calculation shows that the reaction regioselectivity is not dependent on to the substitution pattern on the aryl moiety (see Table S1 in ESI†). So, these results are in line with the experimental data provided by Suwiński and co-workers: these authors point out that nucleophilic addition on the C(5)–C(4) bond is the dominant mechanism for the nucleophilic attack step.^7,20

2.2 Potential energy surface analysis

Having established the most favorable reaction path for the initial nucleophilic attack step, we now evaluate the electronic factors that determine the ANRORC reactivity in these systems. For this purpose we investigate the ring opening and ring closure steps in these compounds by fully exploring the PES for the reaction between aniline and 1,4-dinitro-1H-imidazole as a model reaction. As mentioned in the preceding section, the second step along the proposed reaction mechanism involves C(5)–N(1) bond cleavage to give an open-chain intermediate. Based on the feasibility of a solvent-assisted proton transfer, three reaction paths were considered for this ring-opening process. It is worth mentioning at this point that efforts to locate a transition structure involving a N(1)–H intermediate were unsuccessful in the water/methanol cavity. However, the gas phase PES reveals that this mechanism is highly disfavored (see ESI†). The resulting transition structures for the considered ring-cleavage mechanism are depicted in Fig. 5. As can be seen, the favored reaction path proceeds via the zwitterionic TS-2a transition structure. Even though the participation of the unshared electron pair of the amine moiety is achieved in nearly every bond-breaking transition structure (see for instance TS-2a and TS-2c in Fig. 5), the TS-2a structure is significantly lower in energy. In this context, the prevalence of TS-2a could be related to the better ability of the N(1)–C(2)–N(3) fragment to accommodate the electron density which is developed at the transition state. In this sense, we propose that the protonation of the N(3) site allows an electrophilic activation at the heterocyclic ring, thereby causing a better charge transfer at the TS region. In order to test this hypothesis, we carried out reactivity indices profile analysis oriented to obtain further information on the electrophilic activation pattern at the heterocyclic fragment. For this purpose, we evaluated the group electrophilicity condensed over the N(1)–C(2)–N(3) fragment along the reaction coordinate for all ring-opening transition structures. Global (ω⁺) and condensed to atom k (ω⁺_k) electrophilicity indexes may be readily obtained as follows:^21,22

ω⁺_k = ω⁺f⁺_k

Fig. 5 M06-2X/6-31+G(d,p) transition state structures for the proposed ring-cleavage mechanism of the title reactions. Free activation energies are given in kcal mol⁻¹. Distances are given in Å.

The global electrophilicity index is expressed in terms of the electronic chemical potential (μ, the negative of electronegativity) and the chemical hardness (η) which may be approached in terms of the one-electron energies of the frontier molecular orbital HOMO and LUMO. The regional electrophilicity is projected onto atoms or groups by using the appropriate electrophilic Fukui function f⁺_k, using a method described elsewhere.^23,24 The results obtained are presented in Fig. 6.

Fig. 6 Group electrophilicity condensed over the N(1)–C(2)–N(3) fragment along the reaction coordinate of the three ring opening processes.

From Fig. 6, it is possible to note that the highest electrophilic activation at the imidazole moiety is achieved in TS-2a whereas a marginal electrophilic activation is observed at the same fragment for TS-2b. These results are in good agreement with the trends obtained in the computed activation barriers of these three processes (see Fig. 5). Furthermore, a key result can be extracted by comparing the charge transfer patterns for TS-2a and TS-2c: when the N(1)–C(2)–N(3) fragment is protonated it enhances by nearly a factor of two their group electrophilicity. This electrophilic activation elicits a significant energy barrier lowering of 6.1 kcal mol⁻¹. These results are relevant because they emphasize the following aspects: (i) the importance of a protic media for the reaction outcome, favoring a proton transfer from the nucleophile to the N(3) site in the imidazole moiety. This result is consistent with the experimental findings that the reaction does not occur in aprotic media and (ii) that position N(3) must be free for proton transfer allowing the system to become electrophilically activated, thereby facilitating the ring opening process. The latter idea can be used as a key piece of information to elucidate the reaction mechanism of some related systems, namely imidazolium salts, whose reactivity patterns still remain in controversy.²⁵ For instance, recently Génisson and co-workers pointed out the non-occurrence of a ring degenerate transformation in the reaction of 3-methylimidazolium salts with primary amines. A mechanistic approach to unravel the mechanism of this interesting ring transformation is currently ongoing in our group.

In the last step, the formed open-chain intermediate can undergo a ring-closure step to yield the desired reaction product. For this ring-closing process, two scenarios are possible. Their associated transition structures are depicted in Fig. 7. According to this figure, the first reaction path considered involves the cyclization of the intermediate Int-2a, through a 5-exo-trig process. The second scenario implies a ring-closing mechanism that begins from Int-2b and takes place via a 5-endo-trig arrangement. Note that, although the most favored channel for the ring-cleavage step suggests the preferential formation of the Int-2a intermediate, in a protic media both tautomers can be in equilibrium. In this sense, the favored reaction path can be determined in the light of the Curtin–Hammett principle.²⁶ As shown in Fig. 7, the energetically lowest reaction path for this cyclization step proceeds via the TS-3a transition structure. The computed activation barrier for these competitive channels shows that TS-3a lies 10.5 kcal mol⁻¹ lower than the corresponding 5-endo-trig transition structure (TS-3b), results in line with the empirical Baldwin rules for the ring-closure reactions.^27,28 Note that the analysis of the overall process reveals that this cyclization mechanism appears to be the rate determining step. The corresponding free energy profile is depicted in Fig. 8.

Fig. 7 M06-2X/6-31+G(d,p) optimized transition state structures for the competitive cyclization mechanism. Relative free energies are given in kcal mol⁻¹. Distances are given in Å.

Fig. 8 Relative Gibbs free energies (in kcal mol⁻¹) for the favored reaction path of the title reaction. The computed Gibbs free energy corresponds to 1 M and 298 K standard state.

These results highlight the key role of the proton transfer step towards the N(3) site of the imidazole moiety prior to the ring-opening step. In this context, the occurrence of the proton shift prior to the ring-cleavage step allows a successful connection between two energetically lower regions along the PES, namely an electrophilically activated ring-opening step and the favored 5-exo-trig cyclization. Also, the presence of the N(3)–H functionality allows a significant energy barrier lowering at the rate determining TS, brought about by an intramolecular HB interaction at the TS structure. With the aid of a NBO procedure, we predict that this intramolecular HB interaction elicits an energy barrier lowering of about 4.0 kcal mol⁻¹. On the other hand, it is important to stress at this point that the achievement of the required Bürgi–Dunitz trajectory²⁹ to get a favored orbital overlap between the nucleophilic and electrophilic fragments at the 5-exo-trig transition state, entails significant tether strain effects. Indeed, at the rate determining TS the nucleophile moiety and the imine functionality (the trigonal unsaturated electrophilic center) are connected by a tether which is settled in a 1,3-allylic fashion.³⁰ The key role of tether strain effects present at the rate determining step will be further discussed using the distortion/interaction model.

2.3 Substituent and tether strain effects

The main results discussed in the preceding section for the model reaction point out that the reaction proceeds via a 5-exo-trig cyclization as the rate determining step. These results are in good agreement with the kinetic data recorded elsewhere for the reaction between anilines and 2-methyl-1,4-dinitro-1H-imidazole. In other words, whereas the experimental data suggest a mechanism where the ring opening is a facile process and the rate determining step involves the intramolecular nucleophilic attack, the PES analysis correctly assesses this response. However, an interesting question that arises is: why the substituents at the amine moiety exert a marginal effect at the rate determining step? Fig. 9 illustrates the kinetic results obtained for the rate determining step for the reaction between anilines and 2-methyl-1,4-dinitro-1H-imidazole.

Fig. 9 Rate determining step for the ANRORC-like reaction between aniline derivatives and 2-methyl-1,4-dinitro-1H-imidazole. Rate constants are taken from ref. 2.

In order to gain insight about the substituent effects, we located the transition state for the reaction between 2-methyl-1,4-dinitro-1H-imidazole and substituted anilines. It is worth mentioning at this point that the analysis of all possible steps for this reaction displays the same response as for the model reaction (see ESI†), thereby reinforcing the key role of proton transfer towards the N(3) site proposed herein. Transition structures for the rate determining step of the reaction between 2-methyl-1,4-dinitro-1H-imidazole and substituted anilines are shown in Fig. 10. From Fig. 10 it is possible to note that the ΔG^‡ values calculated for the intramolecular nucleophilic attack are in line with the experimental reactivity displayed by these compounds. These results suggest that the tether strain and steric hindrance effects present at the rate determining step are clearly more important than the electronic effects. Indeed, whereas substituent effects play a key role at the initial nucleophilic attack (see ESI†) a marginal effect is observed at the rate determining step. In this sense, we suggest that the cyclization step is controlled by torsional strain effects. Thus, in order to evaluate the tether strain and steric hindrance effects present at the rate determining TS-structure, we computed the distortion energy for the tether fragment and for the electrophilic moiety according to the previously reported model by Houk and co-workers.^31,32 The models employed to estimate the tether strain and distortion energy of imine fragment are depicted in Fig. 11.

Fig. 10 M06-2X/6-31+G(d,p) transition state structures for the rate determining step for the reaction between 2-methyl-1,4-dinitro-1H-imidazole and aniline derivatives. Free activation energies are given in kcal mol⁻¹. Distances are given in Å.

Fig. 11 Models to estimate both tether strain and distortion energy present at the rate determining-TS.

The computed tether distortion energy and imine distortion energy for the 5-exo-trig transition structure (ΔE^‡_d(tether) = 23.0 kcal mol⁻¹ and ΔE^‡_d(imine) = 25.2 kcal mol⁻¹), strongly suggest that tether strain arising from a 1,3-allylic arrangement at the TS region and steric hindrance effects, plays a crucial role in the ANRORC mechanism in this processes. This result agrees well with the reactivity patterns observed in other five-membered heterocycles involved in this ANRORC-type process where the rate determining transition state is arranged in a 1,3-allylic mode.³³

3 Conclusions

The transition states for the ANRORC-like reaction between aniline and 1,4-dinitro-1H-imidazole have been located. The first step involves the regioselective addition of the nucleophile onto the C(5)–C(4) bond, where the imidazole distortion appears to be the main factor for the favored nucleophilic attack onto the C(5) site. We suggest that proton transfer towards the N(3) site of imidazole moiety, plays a key role on the reaction outcome allowing a successful connection between two energetically lower regions along the PES, namely, an electrophilically activated ring-opening step and the favored 5-exo-trig cyclization. Finally, we highlight the key role of tether strain effects present in the rate determining TS structure which are clearly more important that the electronic effects. These results are in line with the kinetic data reported elsewhere and appear as a key piece of information to understand the ring transformation of other related systems whose reaction mechanism remains in controversy.

4 Computational details

Full optimization of all structures were carried out with the hybrid meta-GGA M06-2X functional³⁴ in conjunction with the 6-31+G(d,p) basis set. All of the TS structures were optimized with SMD³⁵ corrections to mimic solvation effects by water/methanol mixture used as reaction medium in the experimental study.^1,7 The parameters required to describe the water/methanol cavity were obtained from the Minnesota Solvent Descriptor Database.³⁶ Harmonic analysis and intrinsic reaction coordinate (IRC) calculations were performed to confirm the nature of the proposed transition state geometries.³⁷ Computed free activation energies in solution reported herein are referenced to 298 K and 1 M standard state.^38,39 All calculations were carried using Gaussian 09 software.⁴⁰ 3D structures were generated by using CYLView program.⁴¹

Acknowledgements

This work was supported by Project ICM-RC-130006-CILIS, granted by Fondo de Innovación para la Competitividad del Ministerio de Economía, Fomento y Turismo, Chile, Conicyt grant 21120876 and Fondecyt Postdoctoral grant 3140525.

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Footnote

† Electronic supplementary information (ESI) available: Cartesian coordinates of all optimized structures, energies and their thermal free energy corrections. Gas phase IRC for alternative ring-opening mechanism. See DOI: 10.1039/c6ra00199h

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