The oxidation of L-proline (Pro) by HO^● radical in water and the influence of transition metal ions on this process has been revisited by using the density functional theory (DFT) method at the M05-2X/6-311++G(3df,3pd)//M05-2X/6-311++G(d,p) level of theory at the temperature of 298.15 K. HO^●-initiated oxidation of Pro via hydrogen atom transfer (HAT) reactions is more favourable at the b- and g-carbon than at the a- and d-carbon. The total branching ratios are 44.6% and 39.5% for the β- and γ-carbon and 11.5% and 4.2% for the a- and d-carbon, respectively. The overall rate constant at 298.15 K is 6.04 × 10⁸ M^-1 s^-1. In addition, Pro tends to form the stable mono- and bi-dentate complexes with both Fe and Cu ions via the –COO functional group of dipole-salt form. The most stable Cu(II)-Pro complexes have high potential oxidant risks by enhancing the HO^● radical formation in the presence of reducing agents such as superoxide anion or ascorbate anion. Besides, the complexes of the metal at a high oxidation state, i.e., Fe(III)-Pro and Cu(II)-Pro, show their ability to be oxidized by HO^● radical via HAT reactions but with a lower rate constant than that of free Pro. Unsurprisingly, the oxidation enhancement is insignificant for SET reactions with almost negligible rate constants. In contrast, the rate constants of SET reactions of low oxidation state complexes (i.e., Fe(II)-Pro and Cu(I)-Pro) are faster than the oxidation rate of free ligands, and thus, these complexes promote the oxidation of Pro.

All geometry optimizations and vibrational frequency calculations for reactants, transition states, pre-reactive complexes, post-reactive complexes and products were performed by Gaussian 16 Rev. A.03 package in aqueous phase using M05-2X functional and 6-311++G(d,p) basis set. The accuracy of the energy values was then improved by single point calculations at M05-2X/6-311++G(3df,2pd) level of theory.

The standard enthalpies (Δ_rH⁰) and Gibbs free energies (Δ_rG⁰) of the reactions forming complexes were calculated as the differences between total reactant and total product molar enthalpies and Gibbs free energies, respectively. The kinetics calculations of the redox reactions as well as the oxidation reaction of Pro in free and complexation form by HO^● radical were determined using the pre-reactive complexes scheme proposed by Singleton and Cvetanovic for FHT reactions and the conventional transition state theory for SET ones.

- The ESI file (Proline-ESI.docx) contains the Cartesian coordinates, thermochemistry properties and the figures of two forms of L-proline (Pro); the 1:1 metal-to-ligand stoichiometric ratio mono-dentate and bi-dentate Pro complexes with iron and copper ions; and the transition states of FHT reaction of Pro in free form as well as complexation ones towards HO^● radical. All structures are optimized and calculated for thermochemical parameter values in water at the M05-2X/6-311++G(3df,3dp)//M05-2X/6-311++G(d,p) level of theory.

- the data file (thermo-kinetics-Proline.xlsx) contains the thermodynamic and kinetic data.