Role of Water in the Reaction Mechanism and endo/exo Selectivity of 1,3‐Dipolar Cycloadditions Elucidated by Quantum Chemistry and Machine Learning

Abstract

Asymmetric 1,3-dipolar cycloadditionso fa zomethine ylides with activated olefins are among the mosti mportant and versatile methods fort he synthesis of enantioenrichedp yrroline and pyrrolidine derivatives. Despite both theoretical and practical importance, the role of water molecules in the reactivity and endo/exo selectivity remains unclear.T oe xplore how water accelerates the reactions and improves the endo/exo selectivity of the cycloadditionso f 1,3-dipole phthalazinium-2-dicyanomethanide (1)a nd two dipolarophiles,a na bi nitio-quality neuraln etwork potential that overcomes the computational bottleneck of explicitly considering water molecules was used. It is demonstrated that not only the nature of both the dipolarophile and the 1,3-dipole, but also the solvent medium, can perturb or even alter the reactionm echanism. An extreme case was found for the reaction of 1,3-dipole 1 with methyl vinyl ketone,i nw hicht he reaction mechanism changes from a concerted to as tepwise mode on going from MeCN to H 2 O as solvent, with formation of az witterionic intermediate that is av ery shallow minimum on the energy surface. Thus, high stereocontrol can still be expected despite the stepwise nature of the mechanism. The resultsindicate that water can induce globalp olarizationa long the reaction coordinate and highlight the role of microsolvation effects andb ulk-phase effects in reproducing the experimentallyo bserved aqueous acceleration and enhanced endo/exo selectivity.[a] Dr.Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.Figure 14. ESP-coloring intermolecular penetrationmap of A) TS1 MVK-(cis/endo) -8H 2 O and B) TS MAC-(cis/endo) -8H 2 O.P ositive and negative partsa re shown in red and blue,r espectively.

Reaction profiles for quantum chemistry-computed [3 + 2] cycloaddition reactions

“…A recent computational study by Yang and co-workers investigated the role of explicit water molecules on 1,3-cycloaddition reactions using DFT-quality neural network potentials and compared to experimental data. They concluded that even in the most extreme cases considered, aqueous cycloaddition reactions tended to retain a (quasi-)concerted mechanism and most qualitative solvation trends could already be successfully recovered through implicit modelling 34 . Our own benchmarking results also corroborate the adequacy of implicit solvent modelling to recover experimental trends (Fig.…”

Potential use of the Diels-Alder reaction in biomedical and nanomedicine applications

“…In contrast to this, water has also been shown to improve the reaction rate and promote the endo isomers formation [39,40]. It is thought that the presence of water stabilises the carbonyl group, which reduces the energy barrier for the forward reaction [39].…”

Modeling Chemical Processes in Explicit Solvents with Machine Learning Potentials

“…[25][26][27][28] However, the application of MLPs to study chemical processes in solution remains underexplored. The few reported examples include urea decomposition in water, 29 1,3-dipolar cycloadditions in water, 30 and reactions in alkali carbonate-hydroxide electrolytes, 31 with the NNPs being the state-of-the-art approach requiring thousands of AIMD configurations.…”

“…Other models only provide a point prediction for a given structure and are thus unable to utilise this metric. 41 Another approach widely used in NNPs, 30,[42][43][44] although not limited to, is query-by-committee, where uncertainty is quantified through the variance of predicted energies or forces among an ensemble of MLPs, referred to as committees. In the case of NNs, multiple potentials are trained with the same architecture but with different initial parameters.…”