The nanoreactor approach first introduced by the group of Martı́nez [Wang et al. Nat. Chem. 2014, 6, 1044–1048] has recently attracted much attention because of its ability to accelerate the discovery of reaction pathways. Here, we provide a comprehensive study of various simulation parameters and present an alternative implementation for the reactivity-enhancing spherical constraint function, as well as for the detection of reaction events. In this context, a fully automated postsimulation evaluation procedure based on RDKit and NetworkX analysis is introduced. The chemical and physical robustness of the procedure is examined by investigating the reactivity of selected homogeneous systems. The optimized procedure is applied at the GFN2-xTB level of theory to a system composed of HCN molecules and argon atoms, acting as a buffer, yielding prebiotically plausible primary and secondary precursors for the synthesis of RNA. Furthermore, the formose reaction network is explored leading to numerous sugar precursors. The discovered compounds reflect experimental findings; however, new synthetic routes and a large collection of exotic, highly reactive molecules are observed, highlighting the predictive power of the nanoreactor approach for unraveling the reactive manifold.

The kinetics of the ring-opening reactions of thiophenolates with geminal bis(acceptor)-substituted cyclopropanes in DMSO at 20 °C was monitored by photometric methods. The determined second-order rate constants of the S N 2 reactions followed linear relationships with Mayr nucleophilicity parameters (N/s N ) and Brønsted basicities (pK aH ) of the thiophenolates as well as with Hammett substituent parameters (σ) for groups attached to the thiophenolates. Phenyl-substituted cyclopropanes reacted by up to a factor of 15 faster than their unsubstituted analogues, in accord with the known activating effect of adjacent π-systems in S N 2 reactions. Variation of the electronic properties of substituents at the phenyl groups of the cyclopropanes gave rise to parabolic Hammett relationships. Thus, the inherent S N 2 reactivity of electrophilic cyclopropanes is activated by electron-rich π-systems because of the more advanced C1À C2 bond polarization in the transition state. On the other hand, electron-poor π-systems also lower the energetic barriers for the attack of anionic nucleophiles owing to attractive electrostatic interactions.

The kinetics of ring‐opening reactions with thiophenolates in DMSO were monitored to assess the inherent SN2 reactivity of electrophilic cyclopropanes. Phenyl‐substituted cyclopropanes reacted faster than their unsubstituted analogues. Variation in the electronic properties of substituents at the phenyl groups of the indandione‐derived cyclopropanes gave rise to parabolic Hammett relationships, which revealed variable electrophile‐dependent effects on the stabilization of the transition states. More information can be found in the Full Paper by A. R. Ofial et al. (DOI: 10.1002/chem.202103027). Artwork by A.S.