Deuteration of organic compounds by hydrothermal process

Abstract

Deuterium-labeled compounds are in great demand in many applications, especially as reference standards for various analytical techniques. The objective of this study is to develop two complementary methods for deuterium labeling of organic compounds including the hydrogen-deuterium exchange (HDx) and halogen-deuterium exchange (XDx) reactions under hydrothermal conditions. For HDx, several aliphatic, alicyclic, aromatic, heterocyclic, and amino acid compounds were used as model substrates to determine the reactivity pattern and scope of the reaction. It was found that the HDx at the ortho- and para-Hs of phenolic compounds and a-position of amino acids as well as certain heteroaromatic compounds occurred efficiently in D2O under the developed hydrothermal reaction without the need for any catalyst or additive. However, the addition of acid or base could accelerate the HDx reaction or change the reactivity pattern. Epimerization at the a-position of amino acids also occurred along the deuteration. On the other hand, the HDx at the a-position of carboxylic acids or esters proceeded poorly in the absence of a catalyst. To avoid the limitation of HDx that occurs only at specific types of C-H, the complementary strategy of deuterium labeling – namely halogen-deuterium exchange (XDx) was also developed. In the XDx, halogenated aromatic compounds bearing various functional groups were dehalogenated efficiently by formate salts in the presence of Pd/C as a catalyst in D2O under hydrothermal conditions. Importantly, normal (i.e. non-deuterated) formates gave acceptable XDx:XHx ratios (>80:20) in several instances. In the case of phenol substrates, ortho-HDx was observed as a competing side reaction that could be minimized by performing the reaction at a lower temperature and with less basic reagents. In some cases where the XDx:XHx ratios were poor, the use of DCOONa generated in situ from DCOOD and Na2CO3 instead of HCOONa offered better results. The two developed methods provided a green, efficient, and practical method for the synthesis of deuterium-labeled compounds, although further improvements are still required to increase the efficiency and broaden the scope of the reactions.