Computational Optimization of Alkoxyamine-based Electrochemical Methylation.

Area of Science:

• Computational Chemistry
• Organic Electrochemistry
• Reaction Mechanism Studies

Background:

• In situ electrochemical methylation offers a versatile synthetic route but is limited by the functional group tolerance of existing reagents like TEMPO-Me.
• Nitroxide radicals, Blatter's radicals, and verdazyls are classes of compounds with tunable redox properties that could be explored for methylation.
• Understanding the relationship between oxidation potential and subsequent reactivity is crucial for designing improved methylation agents.

Purpose of the Study:

• To computationally investigate the oxidation of various methyl adducts of nitroxide radicals, Blatter's radicals, and verdazyls.
• To evaluate the S_N2 reaction barriers and energies of the oxidized species with pyridine.
• To identify novel methylating agents with low oxidation potentials and low S_N2 barriers for enhanced functional group tolerance in electrochemical methylation.

Main Methods:

• Utilized computational chemistry at the G3(MP2)-RAD//M06-2X/6-31+G(d,p)//SMD level of theory.
• Calculated oxidation potentials and S_N2 reaction barriers and energies for a test set of methyl adducts.
• Analyzed trends in oxidation potentials based on electrostatics, ring strain, and charge transfer, and correlated them with S_N2 reactivity using the Evans-Polanyi principle.

Main Results:

• Oxidation potentials varied across the studied compounds, with Blatter's radical adducts and verdazyl derivatives exhibiting particularly low potentials due to extended π-systems stabilizing positive charge.
• A strong inverse correlation (Evans-Polanyi, R² = 0.92) was observed between decreasing oxidation potential and increasing S_N2 reaction barriers.
• Identified 7-methoxy-7-azadispiro[5.1.5.⁸3⁶]hexadecane, N,N-di-tert-butyl-O-methylhydroxylamine, and 1-methoxy-2,2,5,5-tetramethylpyrrolidine as promising candidates.

Conclusions:

• Despite the inherent trade-off between low oxidation potential and increased S_N2 barriers, specific compounds show potential for broader application in electrochemical methylation.
• The identified candidates offer comparable kinetics to existing reagents while potentially improving functional group tolerance.
• These findings pave the way for developing more versatile in situ electrochemical methylation protocols.