Understanding the Origins of Site Selectivity in Hydrogen Atom Transfer Reactions from Carbohydrates to the Quinuclidinium Radical Cation: A Computational Study

Abstract

The use of quinuclidine as a hydrogen atom transfer (HAT) mediator, along with a light-absorbing photoredox catalyst, has proved to be a powerful and general approach for achieving site-selective radical formation from carbohydrate substrates. Despite numerous literature reports documenting the scope and limitations of such processes, a general rationale for the origins of site selectivity in the key HAT step has not been advanced. In this study, density functional theory calculations (M06-2X/def2-TZVP/PCM(acetonitrile)) were used to model transition states for HAT to the quinuclidinium radical cation from pyranosides and furanosides having various configurations and substitution patterns. The data set (>120 transition state geometries and energies) has allowed for a detailed examination of the factors that influence the relative rates, augmented by additional analysis using the atoms in molecules (AIM) and distortion/interaction–activation strain frameworks. The trends that have emerged regarding the effects of configuration, conformation, substitution, and noncovalent interactions are consistent with experimental observations and reveal a key role for C–H···O hydrogen bonds in stabilizing transition states for HAT to the quinuclidinium radical cation.

Competition between C–C and C–H Bond Fluorination: A Continuum of Electron Transfer and Hydrogen Atom Transfer Mechanisms

“…To contextualize these findings, our previous TS study on HAT from galactose diacetonide (a substrate in which only HAT-type fluorination occurred) determined an activation energy barrier of 7.4 kcal/mol, which is in reasonable accord . These values are also lower than activation energy barriers reported for HAT reaction mechanisms involving quinuclidine-based N -centered radical cations by several kcal/mol …”

Site‐Selective Electrochemical Oxidation of Carbohydrates

“…The lower bond dissociation energy of the CÀ H bond compared to the OÀ H bond allows for homolytic cleavage primarily on the carbon atom. [23] TEMPO-mediated electrochemical oxidation of carbohydrates is a model example of a successful protectinggroup free approach with high yields and mild conditions. It would be of great interest to further investigate this field and study the steric tunability of the regioselectivity of TEMPOmediated electrosynthesis.…”

Transformations of carbohydrate derivatives enabled by photocatalysis and visible light photochemistry

“…A subsequent computational study using density functional theory (DFT) indicates that the transition state for HAT from the 3-position is stabilized by C–H⋯O hydrogen bonding interactions between the electron-deficient α-hydrogens of the quinuclidinium cation and the nonbonding electrons of the axially oriented anomeric oxygen. 116,117…”