Monodentate halogen bond activation of aziridines in formal [3 + 2] cycloadditions

Abstract

The ring opening of aziridines to produce various N-heterocycles traditionally requires strong Lewis acids or transition metal catalysts, with non-covalent organocatalytic approaches remaining largely unexplored. Herein, we demonstrate that N-heterocyclic iodonium salts can effectively catalyze [3 + 2] cycloadditions of aziridines through a monodentate halogen bond (XB) activation. Using 1–5 mol% of the iodolium catalyst, a wide range of aziridines undergo an efficient cycloaddition with a variety of dipolarophiles (carbonyls, alkynes, and alkenes) to furnish oxazolidines, pyrrolines, and pyrrolidines. DFT calculations revealed a previously underexplored N-activation mode, with detailed non-covalent interaction analysis showing that the N-heterocyclic iodonium salt's exceptional performance stems from combined I–N and I–π interactions.

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Introduction

Non-covalent interactions have been demonstrated to play a hitherto unparalleled role in the supramolecular assembly of proteins,^1–4 in enzymatic reactions,^5–7 as well as in drug design and material science.^8–15 Among the extensive array of non-covalent interactions, hydrogen bond donors have shown notable efficacy in their role as organocatalysts, facilitating a diverse spectrum of reactions.^16–21 In recent years, halogen bond (XB)^22,23 and chalcogen bond (ChB)²⁴ donors have emerged as significant contributors to the field of organocatalysis.^25–32 Also, these compounds have been recognized for their substantial contributions in crystal engineering,^33,34 molecular recognition,^35,36 and in medicinal applications.^37,38 The restriction of reactivity imposed by non-covalent interactions delineates the constraints of this catalysis discipline, particularly regarding the limitations of activation targets and reaction patterns. Despite the capacity of halogen or chalcogen bond donors to activate a variety of molecules, including carbonyl compounds,^39–42 imines,⁴³ and nitroolefins,^44–46 their application has recently been extended to more challenging substrates such as esters,⁴⁷ alkenes,⁴⁸ alkynes,⁴⁹ and even carbene precursors.^50,51 Nevertheless, the activation of strained heterocycles such as aziridines remains a formidable challenge, as these transformations have historically relied on strong Lewis acids, transition metals, or high temperatures (Scheme 1A).^52–55 In 2022, Wang and co-workers presented the first example of a bidentate selenium(II) catalyst for the non-covalent activation of aziridines in a [3 + 2] cycloaddition (Scheme 1B).⁵⁶ They demonstrated the ability to obtain different N-heterocycles by altering the dipolarophile from alkenes to alkynes and carbonyls in good yields. Further NMR experiments demonstrated that a cooperative Se–O and Se–N activation, facilitating the bidentate mode, in conjunction with the precise distance between the two selenium units, was instrumental in achieving the desired outcome. In a recent study, Tan and co-workers introduced a novel class of bidentate organotellurium catalysts, which demonstrated remarkable efficacy in the activation of various azetidines and aziridines for the cycloaddition with alkenes and alkynes.⁵⁷

Scheme 1 (A) Typical approach for the activation of aziridines by strong Lewis acids, transition metals, or elevated temperatures. (B) First example of non-covalent organocatalysis for the ring opening of aziridines by a bidentate chalcogen bond catalyst by Wang and co-workers. (C) This work: XB-catalyzed [3 + 2] cycloaddition of aziridines with carbonyls, alkynes, and alkenes.

Given the well-established fact that XB-donors facilitate significantly more robust activation than their chalcogen analogs, our research group was intrigued by the question of whether hypercoordinated iodine compounds,^58–64 especially our previously developed N-heterocyclic iodonium salt XB catalysts,^65–67 would also allow an effective activation of aziridines for [3 + 2]-cycloadditions.

In the present work, we demonstrate that such an activation by a monodentate XB catalyst is a straightforward process that allows the synthesis of a variety of oxazolidine, pyrroline, and pyrrolidine scaffolds from N-sulfonyl aziridines.

Results and discussion

Reaction development

Initially, the reactivity of this activation process by halogen bonding was evaluated through the investigation of the well-established monodentate XB catalysts 1a–e in the ring opening of N-tosyl-protected aziridine 2a with cyclohexanone (3a) to obtain oxazolidine 4a (Scheme 2). Initial preoptimizations with catalyst 1a (see SI) revealed that a catalyst loading of only 1 mol% of the XB-donor in DCM was sufficient to successfully synthesize the target compound 4a in a nearly quantitative yield after 2 h.

Scheme 2 ¹H-NMR kinetic studies for the cycloaddition of aziridine 2a with cyclohexanone (3a) employing various iodine(III) XB-donors 1a–e. General reaction conditions: 2a (0.100 mmol, 1.0 eq.), 3a (3.0 eq.), XB catalyst 1 (1 mol%), DCM (0.1 M), rt.

After implementing the aforementioned conditions, a ¹H-NMR kinetic study was conducted with all well-established catalysts 1a–e.^42,65–67 This kinetic study revealed that catalyst 1a exhibited the highest level of activity, surpassing all the other iodonium salt catalysts. It should be noted that the N-heterocyclic iodonium salt catalysts 1b and 1d have shown comparable conversion rates to each other and provided good yields of about 80% after 4 h reaction time. It is also noteworthy that the C-bound pyrazole 1c exhibited a significant decrease in activity, with a yield of only 22% after the specified time, while using the simple iodolium salt catalyst 1e resulted in almost negligible product formation.

The observed effectiveness of these catalysts in activating aziridines aligns with the relative Lewis acidity strength of the tested monodentate iodonium salts, with higher acidity generally producing better results.⁶⁸ This observation suggests that the efficiency of the halogen bond-catalyzed reaction depends heavily on the strength of the catalyst's Lewis acid properties. To further verify the relevance of the XB for the catalytic activation, the reaction was carried out with catalyst 1a in the presence of 10 mol% NBu₄Br. This experiment resulted in no product formation, indicating an XB-mediated activation of the aziridine 2a.

After establishing the aforementioned conditions, other substrates were investigated. Through time-dependent ¹H-NMR spectroscopy, we could prove that when utilizing benzaldehyde (3b) as a coupling partner, a complete conversion to oxazolidine 4b could be obtained after a reaction time of approximately 30 min (Scheme 3A).

Scheme 3 XB-catalyzed cycloaddition between aziridine 2a and benzaldehyde (3b) with 1a as the XB donor. General reaction conditions: 2a (0.100 mmol, 1.0 equiv.), 3b (3.0 equiv.), 1a (1 mol%), DCM (0.1 M), rt. (A) Kinetic investigation of diastereoselectivity. (B) Kinetic investigation with the addition of NBu₄Br (10 mol%) after 15 min.

This reaction exhibited a diastereomeric ratio (dr) of 92 : 8, in favor of the cis-isomer (cis-4b).⁶⁹ We also observed that as the reaction continued, the diastereomeric ratio underwent a shift. After a reaction time of 1 h, a commendable dr of 90 : 10 was obtained; however, after 2 h, a ratio of 78 : 22 was already observed, which resulted after 4 h in a final dr of 45 : 55, with the trans-4b isomer being slightly favored. The experiment provided clear evidence that the initial kinetic preference is gradually overridden as the catalyst continues to mediate reversible ring-opening/ring-closing sequences, ultimately approaching thermodynamic equilibrium where the slightly more stable trans-4b isomer marginally predominates. To further verify the observed behavior, we repeated the reaction but added NBu₄Br (10 mol%) after an initial reaction time of 15 min (Scheme 3B). Analysis of the ¹H-NMR spectra over a 3-hour period clearly showed that addition of the Lewis base completely halted the reaction. This confirms our hypothesis that catalyst 1a causes the observed time-dependent conversion between diastereomers. It also highlights the importance of continuous reaction monitoring to properly determine the scope of suitable substrates.

Scope of the reaction with carbonyls

With this information in hand, the reaction of aziridine 2a with benzaldehyde (3b) was terminated after 30 min with an excellent yield of 93% and 92 : 8 dr for the target oxazolidine 4b (Scheme 4). With sterically hindered 2-methylbenzaldehyde (3c), we observed a significant decrease in the conversion rate. After 24 h, oxazolidine 4c could still be obtained in 85% yield with an improved diastereoselectivity of >95 : 5. The cycloaddition of 2a with the electron-donating 4-methoxybenzaldehyde (3d) yielded the desired oxazolidine 4d after 30 min in nearly quantitative yield of 96% but with no diastereoselectivity. The electron-withdrawing nitro-substituted oxazolidine 4e was also accessible under the investigated reaction conditions with 90% yield and 95 : 5 dr after 2 h. Next, we focused on aromatic carbonyl compounds. Acetophenone, indanone, and benzophenone proved to be suitable coupling partners for the cycloaddition of aziridine 2a, with yields of up to 97% and up to 75 : 25 dr for the oxazolidines 4f–4h. We also conducted the cycloaddition with acetone, which resulted in a comparable and nearly quantitative yield of 99% for 4i. Using N-methylisatin (3j) as the substrate, the reaction time increased to 24 h with a moderate yield of 62% and 3.5 : 1 dr for the desired spirocycle 4j.

Scheme 4 Substrate scope for the XB-catalyzed cycloaddition of aziridines 2 and carbonyls 3 toward oxazolidines 4. General reaction conditions: 2 (0.100 mmol, 1.0 equiv.), 3 (3.0 equiv.), 1a (1 mol%), DCM (0.1 M), rt. ^a Reaction time: 30 min. ^b Reaction time: 24 h. ^c Reaction time: 6 h.

Next, a variety of aziridines were investigated under our reaction conditions with cyclohexanone as the coupling reagent. First, various protecting groups on the aziridine moiety were compared, and it was found that both the Nosyl (Ns) and Mesyl (Ms) protecting groups could be used, although significantly longer reaction times were required compared to the Tosyl protecting group, and lower yields for 4k and 4l of 64% and 91% were observed. Other protecting groups, such as Acetyl or Boc, did not show any reactivity under the reaction conditions investigated. Concerning the substitution on the aromatic skeleton of the aziridine, electron-rich, electron-poor or slightly sterically demanding derivatives 4o–s were accessible in yields of up to 96%.

Aliphatic aziridines, such as 2t and 2u, could also be converted via XB-catalysis in the cycloaddition, but yielded oxazolidines 4t and 4u in significantly lower yields of 44% and 73%. Herein, we observed the formation of several by-products, including the ring-opening of the oxazolidine, which are likely attributable to the extended reaction times of 6 h and 24 h. The indene-derived aziridine 2v could again be converted to oxazolidine 4v in a short reaction time with a high yield of 95%, which indicates the requirement of the aromatic functionality of the aziridine for a fast and effective reaction outcome. The more activated aziridines 4w and 4x were unsuitable substrates. In both cases, known Lewis acid-mediated rearrangements occurred (see SI). Even adjusting the reaction conditions, such as lower temperatures or an increased catalyst loading, did not allow a successful reaction. To gain deeper insights into this reaction's regioselectivity, we conducted the cycloaddition of aziridine 2y. We were able to separate the two resulting regioisomers 4y and 4z in 31% and 19% yield, respectively, with the higher substituted one as the expected major regioisomer.

Notably, our reaction protocol also worked well for opening the four-membered ring compound azetidine 5. When combined with benzaldehyde, this reaction produced oxazinane 6 with good stereoselectivity (single diastereomer) and yield (75%).

Scope of the reaction with alkynes

Beyond creating oxazolidines 4 from aziridines 2 and carbonyls 3, we found that our established reaction conditions also effectively promoted the cycloaddition between aziridines and alkynes 7 to form pyrrolines 8 (Scheme 5). Indeed, the reaction with phenylacetylene with 2a afforded the desired pyrroline 8a in an excellent yield of 91%. To further extend the range of aryl alkynes, various substituents on the aryl skeleton were investigated under the reaction conditions. While slightly sterically-hindered or electron-donating alkynes could be efficiently converted to the desired pyrrolines 8b–d in yields of up to 92%, the use of electron-deficient alkynes afforded only traces of the target compounds 8e and 8f. Furthermore, diphenylacetylene and 1-phenylpropyne were identified as suitable coupling reagents, yielding the corresponding pyrrolines 8g and 8h in 79% and 88% yield, respectively. The limitations of the method could be demonstrated through the utilization of alkyl or TMS-substituted derivatives, which are less activated or sterically hindered. Using these alkyne derivatives to potentially give pyrrolines 8i–k resulted either in complete absence of product formation or yielded inseparable mixtures of compounds, demonstrating the limitations of this methodology with sterically hindered or electronically deactivated substrates. In the context of the aziridine scope, the evaluation of various aromatic substituents on the aziridine skeleton was conducted. The employment of the slightly sterically-hindered 2-methyl-substituted aziridine proved to be efficient within the reaction conditions, and the product 8l could be obtained in a yield of 89%.

Scheme 5 Substrate scope for the XB-catalyzed cycloaddition of aziridines 2 and alkynes 7 toward pyrrolines 8. General reaction conditions: 2 (0.100 mmol, 1.0 equiv.), 7 (3.0 equiv.), 1a (1 mol%), DCM (0.1 M), rt. ^a 1a (5 mol%) was used. ^b Reaction time: 30 min. ^c Reaction time: 24 h. ^d Reaction time: 1 h. ^e Reaction temperature: 50 °C.

The formation of the highly activated pyrroline 8m was unsuccessful due to product decomposition in the purification process. Pyrrolines 8n and 8o, containing OAc- or Br-substitutions, were obtained in yields of 85% and 88%. In contrast, the electron-deficient NO₂-substituted derivative could only be accomplished in a yield of 29%. After an extended reaction time of 24 h. The efficacy of alternative protective groups was also demonstrated, exhibiting a reaction behavior analogous to that observed with carbonyl derivatives. The Ns-protected pyrroline 8q and the Ms-protected derivative 8r could be isolated in yields of 47% and 88%. The pyrroline 8s was accessible under the developed reaction conditions, but only in a moderate yield of 50%. Our method showed clear limitations when applied to aliphatic aziridines like the cyclohexene-derived compound, as we detected no formation of the target pyrroline 8t. Similar to our earlier findings with carbonyl compounds, we found that azetidine 5 (the four-membered ring analog) could react with phenylacetylene to produce tetrahydropyridine 9, though with only 35% yield.

Scope of the reaction with alkenes

Inspired by the study conducted by Wang and co-workers,⁵⁶ we also investigated the ring opening of aziridines with alkene compounds to obtain pyrrolidines. Initial experiments conducted under the previously utilized reaction conditions with aziridine 2a and styrene (10a) yielded low yields of the desired compound, accompanied by long reaction times and the formation of multiple side products. Increasing the catalyst loading to 5 mol% effectively addressed the aforementioned issues, thereby enabling the exploration of a substrate scope for the cycloaddition of aziridines with alkene derivatives. Unlike the cycloadditions with carbonyl compounds, we found that diastereoselectivity could not be controlled in these reactions. ¹H-NMR monitoring revealed that both diastereomers formed in nearly equal amounts right at the beginning of the reaction. For example, the initial reaction of aziridine 2a with styrene (10a) afforded a promising yield of 87% and 1 : 1 dr for the desired pyrrolidine 11a after 1 h reaction time (Scheme 6).

Scheme 6 Substrate scope for the XB-catalyzed cycloaddition of aziridines 2 and alkenes 10 toward pyrrolidines 11. General reaction conditions: 2 (0.100 mmol, 1.0 equiv.), 10 (3.0 equiv.), 1a (5 mol%), DCM (0.1 M), rt. ^a Reaction time: 24 h. ^b Reaction time: 2 h. ^c Reaction temperature: 50 °C. ^d Reaction time: 4 h. ^e Reaction time: 8 h.

In the following, we started our investigation by examining various aromatic substituents on the styrene derivative to induce a potential diastereoselectivity characterized by electronic or steric properties. Using the sterically-hindered 2-methylstyrene, pyrrolidine 11b was obtained in 63% yield with 1.3 : 1 dr, indicating a negligible impact of steric substituents on diastereoselectivity. Furthermore, para-alkyl substituted pyrrolidines 11c,d were generated in high yields of up to 90%, while the strong electron-donating methoxy substituted derivative 11e was unsuitable due to its rapid polymerization. Other para substituents such as Ph, OAc or Br afforded the desired products 11f–h in up to 72% and up to 1.2 : 1 dr. The strong electron-deficient pyrrolidine 11i could only be detected in traces after an extended reaction time of 24 h. Subsequently, the focus shifted to the investigation of substitutions on the exocyclic double bond of styrene. For trisubstituted pyrrolidines 11j–l, yields ranged from 42% to 91%. In case of indene as the dipolarophile, an inseparable mixture of the product 11m and the non-cyclized derivative was obtained (see SI). As an example of alkyl substitution, the reaction with isobutene yielded dimethylpyrrolidine 11n in 85% yield. It was also possible to convert 1,3-dimethylindole as an alkene source under the developed conditions, leading to hexahydropyrrolo[2,3-b]indole 11o in 37% yield and with 1 : 1 dr, whose core structure plays a relevant role in biology and pharmacology.⁷⁰

Next, we focused on the conversion of various aziridines. Both electron-donating and electron-withdrawing aromatic substituents have shown good performance with yields ranging from 68% to 87% and up to 1.6 : 1 dr for pyrrolidines 11p–11t, indicating a minor influence on the diastereoselectivity by these substituents. Regarding the protecting groups, the Nosyl-protected pyrrolidine 11u was accessible in a moderate yield of 58%, while the Mesyl-protected derivative 11v was unstable during the purification process. Trisubstituted pyrrolidine 11w was synthesized in 62% yield with 4 : 1 dr, whereas the cyclohexene-derived aziridine showed no conversion toward 11x. As with the other coupling reagents, styrene could also be converted with azetidine 5 in a formal cycloaddition to piperidine 12 in a yield of 61% and 1.8 : 1 dr.

Computational investigation

To gain insight into the coordination of the N-heterocyclic iodolium catalyst 1a (N- vs. O-coordination) to the substrate and the origin of the high activity of this catalyst, DFT calculations were performed on the halogen-bond catalyzed formal cycloaddition between aziridine 2a and acetone (Fig. 1). Free energies obtained at the ωB97X-D3BJ/def-2 TZVP (SMD18, DCM)//ωB97X-D3BJ/def-2 SVP (SMD18, DCM) level of theory at 298 K were used for the discussion (see SI for further details). The coordination of the catalyst 1a²⁺ to the aziridine 2a results in the formation of two complexes, N-I and O-I, that were found to be energetically very close, with a slight preference for the O-coordination of 0.6 kcal mol⁻¹ (Fig. 1A).

Fig. 1 DFT computations of the key intermediates for O- and N-activation at the ωB97X-D3BJ/def-2 TZVP (SMD18, DCM)//ωB97X-D3BJ/def-2 SVP (SMD18, DCM) level of theory at 298 K. (A) Free energy profile (in kcal mol⁻¹) for the cycloaddition between aziridine 2a and acetone to oxazolidine 4i. (B) Non-covalent interaction analysis of the key transition states. Color code for NCI plots: red = repulsion, green = van der Waals attraction/weak interaction (e.g., hydrogen bonding, halogen bonding), blue = strong interaction (e.g., hydrogen bonding, halogen bonding).

Following the incorporation of acetone into the activation complex, the disparity between the two intermediates, N-II and O-II, diminishes to 0.2 kcal mol⁻¹. The XB-catalyzed bond-breaking process then occurs via N-TS1 (19.6 kcal mol⁻¹) or O-TS1 (25.5 kcal mol⁻¹) to yield the dipole intermediates N-III (1.4 kcal mol⁻¹) and O-III (13.2 kcal mol⁻¹). This substantial discrepancy in the transition state energies prompted further investigation into the behavior, which was subsequently analyzed in detail using the non-covalent interaction analysis (NCIPlot) method (Fig. 1B). This analysis clearly demonstrates that O-TS1 interacts through an I–O interaction (2.38 Å), as well as a pronounced π–π interaction between the aromatic part of the iodonium salt and the aromatic unit of the aziridine. In contrast, N-TS1 exhibits, in addition to these interactions, a further I–π interaction (3.43 Å) with the second σ-hole of the catalyst toward the aromatic skeleton of the aziridine. This interaction, in combination with the presumably better stability between the negative charge on the nitrogen and the positive one on the catalyst (ion pair), clearly favors the latter transition state (ΔΔG^‡ = 5.9 kcal mol⁻¹). This hypothesis is further substantiated by the resulting dipole intermediates, where the observed difference increased to 11.8 kcal mol⁻¹. A comparison with iodolium salt 1e, which is experimentally inactive, reveals endergonic activation energies and significantly higher transition states (see SI for further discussion), yet the interaction behavior is the same for both pathways.

Subsequent rotations to N-IV and O-IV enable the following ring closure step. In the case of O-coordination, this intermediate can be converted barrierless into the stable catalyst-product complex O-V (−7.8 kcal mol⁻¹). In the case of the N-coordinated reaction pathway, the barrier for bond formation is predominantly attributable to the increased stability of the dipole intermediate due to the previously mentioned ion pair. This bond formation transition state N-TS2 with a free energy of 18.0 kcal mol⁻¹, subsequently results in a stable catalyst-product complex N-V (1.0 kcal mol⁻¹). Decomplexation yields the oxazolidine 4i (−5.3 kcal mol⁻¹) and regenerates the catalyst 1a²⁺. In summary, the favored N-coordination pathway demonstrates a rate-determining step (RDS) barrier of 19.6 kcal mol⁻¹ and is exergonic by 5.3 kcal mol⁻¹.

Conclusions

In conclusion, a straightforward method for the synthesis of various five-membered N-heterocycles from aziridines via XB-catalyzed [3 + 2] cycloadditions through monodentate activation is presented. N-Sulfonyl-protected aziridines have been shown to efficiently react in a formal [3 + 2] cycloaddition with carbonyls, alkynes, or alkenes as dipolarophiles in high yields and partially controllable diastereoselectivity. The exceptional performance of the N-heterocyclic iodonium salt catalyst as the XB-donor was ascertained through DFT calculations of the reaction pathway and an examination of the non-covalent interactions in the bond-breaking process. The monodentate N-coordination pathway, which has emerged as the favored reaction mode for this specific catalyst type, is still underexplored and presents opportunities for addressing additional activation targets through XB-catalysis in the future.

Methods

General procedure for cycloaddition of aziridines with various dipolarophiles

Under an argon atmosphere, a dry 10 mL tube (screw cap with septum) was charged with 1a (1.6 mg, 1.00 μmol, 1 mol% or 8.2 mg, 5.00 μmol, 5 mol% in case of alkenes as substrates) and aziridine 2 (0.100 mmol, 1.0 equiv.), evacuated three times, and backfilled with argon. Subsequently, DCM (1.0 mL) and the corresponding carbonyl 3 or alkyne 7 or alkene 10 (0.300 mmol, 3.0 equiv.) were added to the reaction mixture. The reaction was stirred until completion of the reaction (¹H-NMR analysis), nBu₄NBr (3.2 mg, 10.0 μmol, 10 mol%) was added, and the solvent was evaporated. The residue was purified by column chromatography to give the desired N-heterocycles.

Computational details

All structures were preoptimized using a combination of XTB⁷¹ and CREST^72,73 to evaluate the lowest energy conformers. The optimization and frequency analysis of these conformers were calculated using ORCA 6.0.1^74–78 with the ωB97X-D3BJ/def2-SVP^78–83 level of theory at room temperature (298 K). This combination was selected due to the complex binding nature of the σ-hole interactions, and its performance has been demonstrated with analogous systems.^84–87 The solvent effects, utilizing DCM as the solvent, were incorporated into the optimization through the implemented solvation model based on the density approach (SMD)⁸⁸ in ORCA 6.0.1 in its slightly modified version (SMD18)⁸⁹ with a corrected radius for iodine atoms. Single point energies were performed on the lowest energy small basis set calculations using ωb97X-D3BJ/def2-TZVP. Relative free energies (ΔG) were calculated as the energy difference between the complexes or the transition states (TS) and the sum of the energies of the reactants and the catalyst. Transition states were verified by the intrinsic reaction coordinate (IRC)⁹⁰ method as implemented in ORCA 6.0.1. The reaction energy diagram was initially created using EveRplot⁹¹ and then modified with ChemDraw. The structures were visualized with CYLView⁹² and the hydrogen atoms were omitted for clarity. The analysis of non-covalent interactions (NCI) was performed with NCIPlot^93–95 and visualized by VMD.⁹⁶ The coordinates of all calculated structures are given in the SI.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this study, including detailed experimental procedures, spectroscopic data, and additional information, are available in the supplementary information (SI). Supplementary information: experimental procedures and the analytical data, including the corresponding NMR-spectra for unknown compounds and the Cartesian coordinates of the optimized structures from the DFT calculations. See DOI: https://doi.org/10.1039/d5qo01119a.

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