The Batch Nature of Continuous Flow Production via Natural-Abundance Stable Isotopes

Abstract By definition, continuous flow (CF) production implies continuity in the products; however, virtually all CF products are derived from batched reactants. Consequently, virtually all aliquots of CF production should retain certain batch characteristics.Roncone, A.; et al. ( Trends Analyt. Chem.2024, 174, 117666., and references therein) demonstrated the highly specific nature of natural-abundance stable isotopes in individual batches of pharmaceutical and chemical materials. Here, we employ elemental analysis/isotope-ratio mass spectrometry (EA-IRMS) to quantify the natural-abundance stable-isotopic variations in CF production of products. We show that the batch nature of the reactants (6-bromonaphth-2-ol and methyl iodide) is transmitted to the product (6-bromonaphth-2-yl methyl ether). Instead of maintaining a smooth, continuous isotopic composition during CF production, the episodically batch-varying isotopic values (δ13C, δD, δ18O) of the reactant batches are transmitted downstream to the products. Although the batch nature of CF production is evident, only an initial evaluation of using isotope effects to parametrize yield (via fraction remaining of the starting material) is possible with the present relatively narrow range of yields. These early observations open new areas for process research. Beyond demonstrating the batch nature of CF production, there are at least two additional utilities in measuring isotopic compositions during CF production: (i) product authentication (batch/aliquot auditing) and (ii) process understanding (monitoring the continuity of the continuous flow reaction).