Flow-Enabled Deuteration of Saturated Fatty Acids over Platinum Group Metals: Mechanistic and Process Insights

Metal-catalyzed hydrothermal deuteration is a versatile approach for hydrogen–deuterium exchange (HDE) reactions, offering precise isotopic labeling of organic molecules. Here, we report the development of a scalable flow deuteration method that permits the tunable isotopic selectivity of saturated short-chain fatty acids over platinum group metal (PGM) catalysts. Benchmarking against conventional batch hydrothermal deuteration in pressurized vessels demonstrated that flow deuteration sustains high steady-state activity, improves single-pass yields, and provides mechanistic insights into isotopologue formation. Under optimized conditions, 10 wt % Pt/C achieved 93% D (deuterium incorporation) and 98% isolated yield of sodium butyrate-d7 in 90 min time-on-stream (TOS) under H2-free conditions (20 bar D2O, 220 °C) in a single pass. Notably, flow deuteration afforded high selectivity to -d7 (60%) and -d6 (32%) isotopologues and favored the formation of thermodynamically stable isotopologues at elevated temperatures, as confirmed by isotopologue analysis (MS) and isotopomer distribution (NMR). The intrinsic activity of Pt (TOF = 6 h–1) exceeds that of Pd metal (with similar loading) by an order of magnitude, determined at iso-conversion (<20% conversion under differential reactor conditions). In situ catalyst activation allowed for four consecutive reaction cycles without loss of activity, with the catalyst maintaining stability over 540 min of time-on-stream. Density functional theory calculations revealed a facile and preferential α–C–H activation of butyric acid via cooperative C- and O-metal interactions on Pt, effectively lowering activation barriers at other C-sites and thereby promoting perdeuteration compared to Pd. Process intensification under flow conditions resulted in a 4-fold increase in the production rate, underscoring the potential of this approach for the scalable, selective, and operationally efficient synthesis of deuterated short-chain fatty acids. This work presents a viable blueprint for platform-specific isotopic labeling using flow chemistry.