DFT Mechanistic Study on the Reaction of Benzenesulfonyl Azides with Oxabicyclic Alkenes

The reaction of benzenesulfonyl azides with oxabicyclic alkenes to form aziridines, reported by Chen et al (J. Org. Chem. 2019, 84, 18, 11863-11872), could proceed via initial [3+2] cycloaddition to form triazoline intermediates followed by dinitrogen cleavage or via initial dinitrogen cleavage of the benzenesulfonyl azide to afford a nitrene intermediate followed by insertion of this species into the olefinic bond of the oxabicyclic alkene. Calculations at the DFT M06-2X/6-311G+(d,p) level show that the initial [3+2] cycloaddition has barriers of 17.3 kcal/mol (endo) and 10.2 kcal/mol (exo) while the initial nitrogen extrusion step has a barrier of 38.9 kcal/mol. The rate-determining step along the former pathway is the dinitrogen cleavage from triazoline cycloadducts which has barriers of 32.3 kcal/mol (endo) and 38.6 kcal/mol (exo) and that along the latter pathway is dinitrogen cleavage from benzenesulfonyl azide with an activation of barrier of 38.9 kcal/mol. The [3+2] addition of benzenesulfonyl azide with oxabicyclic alkene to afford endo and exo triazoline intermediates is kinetically favored over the dinitrogen cleavage from benzenesulfonyl azide by 21.6 and 28.1 kcal/mol for endo and exo pathway respectively. Thus, the preferred pathway for the reaction of oxabicyclic alkene with benzenesulfonyl azide is via initial [3+2] addition followed by dinitrogen cleavage, contrary to the proposal by Chen et al. The lower activation barrier for the dinitrogen extrusion step leading to endo aziridine compared to exo isomer means that the endo product will be formed as the major product, confirming the


Introduction
Aziridines well-known three-membered heterocycles containing a nitrogen atom, and are among the most widely used intermediates in organic synthesis, where they act as precursors for the synthesis of complex molecules due to the strains incorporated in their skeletons. In addition to their importance as reactive intermediates, many biologically-active compounds have been found to possess these three-membered rings [1][2][3][4][5][6][7][8][9] . Over 130 biologically active aziridine-containing compounds have been confirmed to have pharmacological activity including antitumor, antibacterial, and antimicrobial effects 10 .
Even though aziridines have been synthesized by the reactions of nitrene precursor Ntosyliminobenzyliodinane with olefins, N-tosyliminobenzyliodinane has a short shelf-life and poor solubility in common solvents [11][12][13][14] . In 2019, Chen and co-workers successfully reported the synthesis of aziridines by employing a three-component cycloaddition of oxabicyclic alkene with NaN3 and arylsulfonyl chlorides under metal-free conditions with the aziridine products in good yield up to 82% yield (Scheme 1) 15 . Also, the endo-cycloadduct was obtained as the predominant product, although the cycloaddition of oxabicyclic alkenes have been known to generally produce the exo-product as the predominant product. Chen and co-workers reported that the group positon properties of the monosubstituted arylsulfonyl chlorides had little effect on product yield, but had a large effect on the endo/exo diasterioselectivities of the product; 4-benzenesulfonyl azides gave the endo-cycloadduct as the predominant product whiles 2 or 3-nitrobenzenesulfonyl chloride gave 3 the exo-cycloadduct as the predominant product. Moreover, electron-withdrawing groups on the oxabicyclic alkene had reduced the product yield but with improved endo-selectively whiles electron-donating groups on the oxabicyclic alkene had slightly higher yields but with decreased endo-selectivity. Scheme 1. Three-component cycloaddition of oxabicyclic alkene in the presence of NaN3 and arylsulfonyl chloride to afford endo (P_Endo) and exo (P_Exo) aziridines 15 .
Although the products from Chen and co-workers are known, the mechanistic rationale for the observed diasterioselectivities has not been established. After the arylsulfonyl azide has been generated from the reaction of NaN3 with arylsulfonyl chloride, the plausible mechanism for the reaction of arylsulfonyl azide with oxabicyclic alkene to afford the aziridine products are depicted in Scheme 2 and 3. Chen et al. have proposed that the reaction could proceed via an initial dinitrogen cleavage from arylsulfonyl azide to form a nitrene species and subsequent insertion of this species into the olefinic bond of oxabicyclic alkene to afford the aziridine products 15 .
However, the reaction could also proceed via [3+2] cycloaddition to afford triazoline intermediates and subsequent dinitrogen cleavage from this intermediate to form the final aziridine products.
Which pathway is preferred? Computational chemistry methods are often employed in the 4 prediction and rationalization of reactivity trends in order to provide theoretical guidance for correlative experiments.
Herein, density functional theory (DFT) calculations are employed to elucidate the mechanism of the reaction of arylsulfonyl azides with oxabicyclic alkene toward the formation of aziridines. The aim of this study is to provide a detailed mechanistic insight into the reaction of arylsulfonyl azides with oxabicyclic alkene by examining the energetics of the various elementary steps leading to the formation of the observed exo/endo products in the experimental work of Chen et al 15 . The effect of different substituents on the benzene group of the benzenesulfonyl azide and on the oxabicyclic alkene on the energetics of the reaction is also investigated. In addition, the effect of solvent on the energetics of the reaction is also explored. An in-depth understanding of the mechanism of the reaction will provide chemical insights into the reactivity of the reaction which is crucial for the control and development of better synthetic methods to influence product outcomes. 7

Computational details and methodology
All the quantum chemical calculations were carried out with the Spartan'14 16 and Gaussian 09 17 computational chemistry software suites at the M06-2X/6-311+G(d,p) levels of theory. The Minnesota functional M06-2X, developed by Zhao and Truhlar 18 , is a hybrid meta-generalized gradient approximation (meta-GGA) functional that has been shown to be effective at geometry optimizations and computing thermochemical and kinetic parameters of chemical reactions 19,20 .
Using the polarizable continuum model (PCM), 1,4-dioxane was employed to compute solvation effects in the reactions 21 .
The guess geometries of the molecules were constructed with the Spartan's graphical model builder and minimized interactively using the molecular mechanics force field 22 . Transition state structures were computed by first obtaining guess input structures. This was achieved by constraining specific internal coordinates of the molecules (bond lengths, bond angles, dihedral angles) while fully optimizing the remaining internal coordinates. This procedure gives appropriate guess transition state input geometries which are then submitted for full transition state calculations without any geometry or symmetry constraints.
Full harmonic vibrational frequency calculations were carried out to verify that each transition state structure had a Hessian matrix with only a single negative eigen value, characterized by an imaginary vibrational frequency along the respective reaction coordinates. Intrinsic reaction coordinate calculations were then performed to ensure that each transition state smoothly connects the reactants and products along the reaction coordinate 23,24 .
The global electrophilicities (ω), and maximum electronic charge (ΔNmax) of the various benzenesulfonyl azide derivatives were calculated using equations (1) and (2). The electrophilicity index measures the ability of a reactant to accept electrons 25 and it has been found to be a function of the electronic chemical potential, μ = (EHOMO + ELUMO)/2 and chemical hardness, η = (ELUMO -EHOMO) as defined by Pearson's acid-base concept 26 . Hence, species with large electrophilicity 8 values are more reactive towards nucleophiles. These equations are based on the Koopmans theory 27 originally established for calculating ionization energies from closed-shell Hartree-Fock wavefunctions, but have since been adopted as acceptable approximations for computing electronic chemical potential and chemical hardness.
The maximum electronic charge transfer (ΔNmax) measures the maximum electronic charge that the electrophile may accept. Thus, species with large ΔNmax index would be best electrophile and hence poor nucleophile given a series of compounds.

Reaction of oxabicyclic alkene and benzenesulfonyl azide to afford aziridines P_Endo and P_Exo
The relative energies of the reactants, intermediates, transition states and products as well as

Product distribution in the reaction of oxabicyclic alkene with benzenesulfonyl azide
The Boltzmann distribution has been applied to rationalize the amount of P_Exo and P_Endo that will be formed in the reaction of benzenesulfonyl azide with oxabicyclic alkene using the energetics obtained. Here, the activation barrier for the rate-determining step is employed. The ratio of endo to exo products can be written as: Since

Substituent effects on the reaction of oxabicyclic alkene with benzenesulfonyl azide
To investigate the effects of substituents on the energetics of the reaction and products outcomes, electron-donating groups and electron-withdrawing groups are introduced at the position R1 of the benzene group on the benzenesulfonyl azide. The aim of this section of the study is to predict the type of substituents that the benzenesulfonyl azide substrate must contain to influence products yield. The results obtained under this section of the study are reported in Table 3 to 7.

Effect of electron-donating groups on the reaction
To establish the effects of electron-donating groups (EDGs) on the energetics of the reaction, we Also, the effect of OH and OCH3 on the reaction via Path B was also investigated. A marginal decrease in activation barrier for initial dinitrogen extrusion is observed for both OH and OCH3 with OH and OCH3 having activation barriers of 37.1 kcal/mol and 37.0 kcal/mol respectively.

Also the activation barriers for the nitrene insertion into the olefinic bond for OH and OCH3
substituents are 3.1 kcal/mol (endo and exo) and 3.2 kcal/mol (endo and exo). With these results, distribution of endo and exo products is expected to be even if the reaction is to proceed via Path B but an even product distribution is not observed in experiment.

Effect of electron-withdrawing groups on the reaction
In order to establish the effect of electron-withdrawing groups (EWGs) on the energetics of the reaction, we employed F, Cl, CF3, CN, and NO2 substituted benzenesulfonyl azide. In all cases, a marginal decrease in activation barrier is observed for TS1_Endo and TS1_Exo (see table 3 which is the rate-determining step via Path B is higher than the barrier for dinitrogen extrusion via TS2_Endo and TS2_Exo which the rate-determining step via Path A. This results also indicate that, the most feasible pathway for the reaction of oxabicyclic alkene with arylsulfonyl azides is via Path A and not Path B. Table 3. Activation energies of the elementary steps involved in the reaction of Ph-, CH3-, OCH3-, OH-, and NH2-substituted benzenesulfonyl azide and oxabicyclic alkene, computed at the M06-2X/6-311+G(d,p) level of theory. Energies in kcal/mol. Table 4. Relative energies of intermediates and products involved in the reaction of Ph-, CH3-, OCH3-, OH-, and NH2-substituted benzenesulfonyl azide and oxabicyclic alkene, computed at the M06-2X/6-311+G(d,p) level of theory. Energies in kcal/mol. Table 5. Activation energies of the elementary steps involved in the reaction of F-, Cl-, CF3-, CN-, and NO2-substituted benzenesulfonyl azide and oxabicyclic alkene at the M06-2X/6-311+G(d,p) level of theory. Energies in kcal/mol.  Table 7. Activation energies of the elementary steps involved in the reaction of OH-, OCH3, F-, Cl-, CN-, and NO2-substituted benzenesulfonyl azide and oxabicyclic alkene via Path B at the M06-2X/6-311+G(d,p) level of theory. Energies in kcal/mol.

Reaction of di-substituted oxabicyclic alkenes with benzenesulfonyl azides
This section of the study investigates how substituents on the oxabicyclic alkene affect the  TS1_Endo may correspond to slight increase in product yield but with decreased selectivity since the exo-product is also favoured.
On the other hand, electron-withdrawing groups at the position 6 and 7 of the oxabicyclic alkene significantly decrease the activation barrier of the cycloaddition addition through TS1_Endo and increase the activation barrier for TS1_Exo, with NO2 having an activation barrier of 13.7 kcal/mol and 11.6 kcal/mol for TS1_Endo and TS1_Exo respectively. This corresponds to a decrease by respectively.
In the experimental work of Chen et al 15 , they observed that, when electron-withdrawing groups were substituted on the oxabicyclic alkene, the products yield decreased but with improved endo/exo selectivities (up to >99:1 endo/exo) and for the reaction of 4-nitrobenzenesulfonyl azide with di-substituted bromooxabicyclic alkene, only the endo product was isolated.
The decrease in product yield when electron-withdrawing groups are substituted at the position 6 and 7 of the oxabicyclic alkene can be attributed to the increase in activation barrier for TS2 which is the rate-determining step, and the decrease in yield of the exo product isolated under the same 22 conditions can also be attributed to the increase in activation barrier for the cycloaddition step through TS1_Exo.
Effects of substituents on the reaction of 4-methoxybenzenesulfonyl azide with di-substituted oxabicyclic alkene was also investigated. From the results, electron-donating groups marginally decrease the activation barriers for TS1_Endo and TS1_Exo whiles electron-withdrawing groups marginally increase the activation barriers for the cycloaddition step through TS1_Endo and

TS1_Exo. Also a marginal decrease in activation barrier is observed for TS2_Endo and
TS2_Endo when electron-donating groups are substituted at the position 6 and 7 of the oxabicyclic alkene. However, electron-withdrawing groups increase the activation barrier for the dinitrogen extrusion step via TS2_Endo and TS2_Exo respectively. Table 8. Activation energies of the elementary steps involved in the reaction of 4-nitrobenzenesulfonyl azide and several disubstituted oxabicyclic alkene, computed at the M06-2X/6-311+G(d,p) level of theory. Energies in kcal/mol  Table 10. Activation energies of the elementary steps involved in the reaction of 4methoxybenzenesulfonyl azide and several disubstituted oxabicyclic alkene, computed at the M06-2X/6-311+G(d,p) level of theory. Energies in kcal/mol Table 11. Relative energies of intermediates and products involved in the reaction of 4methoxybenzenesulfonyl azide and several disubstituted oxabicyclic alkene, computed at the M06-2X/6-311+G(d,p) level of theory. Energies in kcal/mol

Reaction of oxabicyclic alkene with 2-nitrobenzenesulfonyl azide
Chen and co-workers observed that when 2 or 3-nitrobenzenesulfonyl chloride was used to generate the azide, the exo-cycloadducts were obtained as the predominant products whiles 4nitrobenzenesulfonyl chloride gave the endo-cycloadducts as the predominant products. To provide insight into this varying selectivity when position of the substituent is varied, we employed 2-nitrobenzenesulfonyl azide and 2-methoxybenzenesulfonyl azide in our study.
The optimized geometries of the transition state structures as well as the relative energies of the reactants, intermediates, transition states and products involved in the reaction of 2- nitrobenzenesulfonyl azide with oxabicyclic alkene are shown in Figure 3. In 2nitrobenzenesulfonyl azide, the nitro group is substituted at the ortho position of the benzene.
There appears to be no

Analysis of the global reactivity indices
The electrophilicity indices is used as a parameter for predicting the chemical reactivity of electrophilic molecules. Molecules with the largest ω value will be the best nucleophile in a given series of molecules. Also, species with large ω values will be more reactive towards nucleophiles. From

Conclusion
Two different pathways for the reaction of benzenesulfonyl azides with oxabicyclic alkenes have been investigated. The results of the study show that the most plausible pathway for the formation of the endo and exo aziridine products is through the initial [3+2] cycloaddition of the benzenesulfonyl azide with oxabicyclic alkene to form triazoline cycloadducts followed by dinitrogen extrusion instead of an initial dinitrogen cleavage from the benzenesulfonyl azide to form a nitrene species and subsequent insertion of this species into the olefinic bond of the oxabicyclic alkene proposed by Chen et al. 15 The initial [3+2] addition of benzenesulfonyl azide with oxabicyclic alkene to afford triazoline intermediates is kinetically favored over the dinitrogen cleavage from benzenesulfonyl azide by 21.6 and 28.1 kcal/mol for endo and exo products respectively. Also the formation of intermediate aziridines is thermodynamically favored over the formation of the nitrene species by 54.3 (endo) and 55.3 (exo) kcal/mol. The dinitrogen extrusion step leading to the formation of endo aziridine isomer is kinetically favoured over that of exo isomer by 6.3 and 6.2 kcal/mol in gas phase and 1,4-dioxane respectively. Since the rate-determining step is the dinitrogen extrusion step, product endo aziridine isomer will be formed as the predominant product. Solvent 1,4-dioxane marginally decrease the activation barrier for dinitrogen extrusion step leading to the formation of both endo and exo aziridine product.
The ratio of endo aziridine product to exo product has been calculated using the Boltzmann product. Electron-donating groups on the oxabicyclic alkene decrease the activation barrier for the rate-determining step whiles electron-withdrawing groups increase the activation barrier for the rate-determining step. An FMO analysis shows an inverse electron demand nature for the reaction and results obtained are in complete agreement with experimental observation.