Modulation of Rotational Dynamics in Halogen-Bonded Cocrystalline Solids.

Dynamic processes are responsible for the functionality of a range of materials, biomolecules, and catalysts. We report a detailed systematic study of the modulation of methyl rotational dynamics via the direct and the indirect influence of noncovalent halogen bonds. For this purpose, a novel series of cocrystalline architectures featuring halogen bonds (XB) to tetramethylpyrazine (TMP) is designed and prepared using gas-phase, solution, and solid-state mechanochemical methods. Single-crystal X-ray diffraction reveals the capacity of molecular bromine as well as weak chloro-XB donors to act as robust directional structure-directing elements. Methyl rotational barriers (Ea) measured using variable-temperature deuterium solid-state NMR range from 3.75 ± 0.04 kJ mol-1 in 1,3,5-trichloro-2,4,6-trifluorobenzene·TMP to 7.08 ± 0.15 kJ mol-1 in 1,4-dichlorotetrafluorobenzene·TMP. Ea data for a larger series of TMP cocrystals featuring chloro-, bromo-, and iodo-XB donors are shown to be governed by a combination of steric and electronic factors. The average number of carbon-carbon close contacts to the methyl group is found to be a key steric metric capable of rationalizing the observed trends within each of the Cl, Br, and I series. Differences between each series are accounted for by considering the strength of the σ-hole on the XB donor. One possible route to modulating dynamics is therefore via designer cocrystals of variable stoichiometry, maintaining the core chemical features of interest between a given donor and acceptor while simultaneously modifying the number of carbon close contacts affecting dynamics. These principles may provide design opportunities to modulate more complex geared or cascade dynamics involving larger functional groups.

Highly regio- and diastereoselective [3 + 2]-cycloadditions involving indolediones and α,ß-disubstituted nitroethylenes.

A highly diastereoselective [3 + 2]-cycloaddition strategy involving multiple oxindoles and several α,ß-disubstituted nitroethylenes is developed to access tetra-substituted α-spiropyrrolidine frameworks. A variety of α-amino acids were employed for the first time in order to generate azomethine ylides under thermal conditions, affording regioisomers 13 and 14 merely by changing the α-substituents (R = H and substituted carbons) of the α-amino acids. The reaction tolerates various sterically demanding, electron-rich and electron-deficient aryl and nitrogen substituents on glycines, oxindoles and nitroethylenes. The operational simplicity, such as the use of a metal-free and non-inert environment, the utilization of non-halogenated solvents and the ease of isolation, adhering to the principles of green chemistry, makes this process attractive for scale-up opportunities. The reaction delivers good yields (80-94%) and diastereoselectivities (up to 98 : 2) in favor of (cis,cis)-spirooxindoles, with opposite regioselectivity compared to ß-nitrostyrenes under identical conditions. Two spiropyrrolidine cycloadducts with unprotected amides exhibited significant activity against Gram-positive MRSA.