Photocatalyst-free photochemical deuteration via H/D exchange with D2O

Abstract

Deuterium labeling is increasingly important across scientific fields, from drug development to materials engineering, but current methods often require expensive catalysts. Here we demonstrate a simple, photocatalyst-free approach for incorporating deuterium into organic molecules using visible light. By employing common thiol compounds under mild blue-light irradiation (380-420 nm), we successfully modify two key chemical groups (formyl and α-amino) with high efficiency (up to 96% deuterium incorporation). This method eliminates the need for specialized PCs, significantly reducing costs and complexity. Surprisingly, we find that the system generates reactive intermediates (thiyl radicals and hydrogen atoms) through previously unrecognized light-activated pathways. These discoveries challenge conventional assumptions about photochemical deuteration and offer practical advantages for both laboratory research and industrial-scale production. Our results provide a more sustainable and scalable route to deuterated compounds while opening possibilities for light-driven chemistry without expensive catalysts. This work advances isotope labeling technology and suggests broader applications for simple, light-powered reactions in chemical synthesis.

Fig. 1. Deuterated compounds and deuteration methods.

a Deuterated materials and drugs. b Deuteration of formyl group. c Deuteration ofα-amines. d Photocatalyst and thiols. e Photocatalyst-free photocatalytic preparation of deuterated aldehydes and α-amines via HDE (this work). HDE hydrogen-deuterium exchange, TBADT tetra-n-butylammonium decatungstate.

Fig. 2. Substrate scope of aldehydes.

^a24h, ^b30 mol% thiol I ^c48h, ^d36h, ^e2h, ^f10h, ^g420 nm, ^h400 nm, ⁱ1 h. Detailed procedure is seen in S8 in the Supplementary Information.

Fig. 3. Substrate scope of amines.

The detailed procedure is seen in S9 in the supplementary information.

Fig. 4. Mechanism study of deuterating formyl groups and α-amines.

a Radicals trapped by TEMPO in the deuteration of the formyl group. b Radicals trapped by TEMPO in the deuteration of α-amines. c Radicals trapped by TEMPO in irradiation of thiol I. d H₂ gas analysis in deuteration of aldehydes. e H₂ gas analysis in deuteration of α-amines. f H₂ gas analysis in irradiation of thiol I in EtOAc. g Deuteration of aldehydes with disulfide as addictive. h Deuteration of α-amines with disulfide as addictive. i EPR analysis in irradiation of thiol I in EtOAc. j EPR analysis in deuteration of aldehydes. k EPR analysis in deuteration of α-amines. l Byproduct N-Methylcarbazole detection. m ON/OFF experiment for deuteration of aldehydes. n ON/OFF experiment for deuteration of α-amines.

Fig. 5. DFT calculation for transition states for the key step.

a Gibbs energy of transition states in the reaction between thiyl radical and p-Methylaldehyde. b Gibbs energy of transition states in the reaction between thiyl radical and N-methyldiphenylamine. Values presented in brackets are single-point energy calculation results, which were conducted using the B3LYP/6-31G(d) optimized geometries with DFT B3LYP/6-31 + + G(d, p) basis set.

Fig. 6. Proposed mechanism for deuteration.

a Proposed mechanism for the deuteration of the formyl group. b Proposed mechanism (Path a) for deuteration of α-amines. c Proposed mechanism (Path b) for deuteration of α-amines.