Segmental Deuterium Labeling of Alkyl Chains by Nickel–Mediated Desulfurization

Abstract A general means to access segmentally deuterium‐labeled alkyl chains for applications in mass spectrometry, neutron scattering, and related biochemical studies is reported, using a key nickel boride mediated reductive desulfurization of substituted thiophenes. This approach enabled the preparation of (3,3,4,4,5,5,6,6‐ 2 H 8 )undecanoic acid and 1‐amino(1,1,2,2,3,3,4,4‐ 2 H 8 )nonane, using only recrystallization or distillation for purification. Both compounds featured segments of four deuterated carbon atoms with > 98.5% overall deuterium incorporation. To assess site‐specific deuterium retention during desulfurization, we demonstrated the utility of molecular rotational resonance (MRR) spectroscopy, which revealed the degree, position, and magnitude of isotope scrambling in a key thiophene reductive desulfurization step and established the methods set forth herein as being suitable for the construction of mass spectrometric standards and applicable to the synthesis of any CH 3 (CH 2 ) a (CD 2 ) b (CH 2 ) c COOH (3 ≤ a ≤ 13, 3 ≤ b ≤ 6, c ≥ 1) using only commercially‐available materials. Our studies revealed extensive exchange of the hydrogen atoms on the thiophene carbons during saturation of the ring, ruling out an idealized schema of the reaction that is present in the literature. We further observed reagent‐dependent levels of isotopic scrambling at the benzylic position during desulfurization, challenging the assumption of benzylic stereospecificity in nickel‐mediated reductive desulfurization while affirming the reaction's applicability for segmental deuterium labeling.