Theoretical Study for Evaluating and Discovering Organic Hydride Compounds as Potential Novel Methylation Reagents

[Image: see text] Methylation reaction is a fundamental chemical reaction that plays an important role in the modification of drug molecules, DNA, as well as proteins. This work focuses on seeking potential novel methylation reagents through a systematic investigation of the thermodynamics and reactivity of methyl-substituted organic hydride radical cations (XH(•+)s). In this work, 45 classical and important XH(•+)s were designed to investigate the relationship between their structure and reactivity, to find excellent or potential methylation reagents. The Gibbs free energy and activation free energy of XH(•+) to release the methyl radical in MeCN at 298.15 and 355 K are calculated with the density functional theory (DFT) method to quantitatively measure the reactivity of XH(•+) as a methylation reagent in this work. The relationships between structures and reactivities on XH(•+)s as methylation reagents are well examined. Since we have calculated the Gibbs free energy and activation free energy of trifluoromethyl-substituted organic hydride compound radical cations (X′H(•+)) releasing trifluoromethyl radicals in MeCN with the DFT method in our previous work, accordingly, the relationship of thermodynamics and reactivity between X′H(•+) releasing trifluoromethyl radical and XH(•+) releasing methyl radical is discussed in detail. Excitingly, 4 XH(•+)s (1H(•+), 3H(•+)∼4H(•+), and 44H(•+)) are found to be excellent methyl radical reagents, while 9 XH(•+)s (5H(•+), 6H(•+), 9H(•+), 10H(•+), 12H(•+), 13H(•+), 15H(•+), 43H(•+), and 45H(•+)) are found to be potential methyl radical reagents in chemical synthesis. The molecular library and reactivity database of novel methylation reagents could be established for synthetic chemists to query and use. Our work may offer a theoretical basis and reference experience for screening different substituted organic hydride compounds (YRHs) as alkylation reagents.