Disentangling the effect of pressure on a mechanochemical bromination reaction by solid-state NMR spectroscopy

Abstract

Mechanical forces, including compressive stresses as one of the most important consequences, have a significant impact on chemical reactions. Besides the preparative opportunities, mechanochemical conditions benefit from the absence of any organic solvent, the possibility of a significant synthetic acceleration and unique reaction pathways. Together with an accurate characterization of ball-milling products, the development of a deeper mechanistic understanding of the occurring transformations at a molecular level is critical for fully grasping the potential of organic mechanosynthesis. In this vein, we studied a bromination of a cyclic sulfoximine in a mixer mill and used solid-state nuclear magnetic resonance (NMR) spectroscopy for structural characterization of the reaction products. Magic-angle spinning (MAS) NMR was applied for elucidating the product mixtures taken from the milling jar without introducing any further post-processing on the sample-of-interest. Ex-situ 13C-detected NMR spectra of ball-milling products showed the formation of a rather crystalline solid phase with the regioselective bromination of the S-aryl group of the heterocycle in position 4. Completion is reached in less than 30 minutes as deduced from the NMR spectra. The bromination can also be achieved by magnetic stirring, but then, a longer reaction time is required. Mixing the solid educts in the NMR rotor allows to get in-situ insights into the reaction and enables the detection of a reaction intermediate. The pressure alone induced in the rotor by MAS is not sufficient to lead to full conversion and the reaction occurs on slower time scales than in the ball mill, which is crucial for analysing mixtures taken from the milling jar by solid-state NMR. Our data suggest that on top of centrifugal forces, an efficient mixing of the starting materials is required for reaching a complete reaction.

Opportunities and Challenges in Applying Solid‐State NMR Spectroscopy in Organic Mechanochemistry

“…[16] This compound is known for its unusually high sublimation tendency, which can lead to a rapid alternation in the enantiomer composition of a scalemic sample. [62] Direct analyses of TFL mixtures by ex situ solid-state NMR pro-vides reliable data, since the optical pure phases can be distinguished from the racemic compound, [63] whereas solution-based NMR techniques cannot differentiate between those phases and come with the danger of losing parts of the product by sublimation, thereby changing the enantiomer ratio of the sample to be analyzed.…”

Opportunities and Challenges in Applying Solid-State NMR Spectroscopy in Organic Mechanochemistry

“…[16] This compound is known for its unusually high sublimation tendency, which can lead to a rapid alternation in the enantiomer composition of a scalemic sample. [55] Direct analyses of TFL mixtures by ex-situ solid-state NMR provides reliable data, since the optical pure phases can be distinguished from the racemic compound, [56] whereas solution-based NMR techniques cannot differentiate between those phases and come with the danger of losing parts of the product by sublimation, thereby changing the enantiomer ratio of the sample to be analyzed.…”