## 4 Discussion  
The data on HAT thermodynamics and kinetics for fluoxetine and its two metabolites show a selectivity for hydroxyl and alkoxyl radicals, in analogy to what has been reported for melatonin [46]. The most reactive sites are the hydroxyl group and the amine groups. Rather large negative \(\Delta\mathrm{G^{\circ}}_{\mathrm{HAT}}\) values are also computed from the C atoms of the hydrocarbon chain, which is in agreement with the reactivity described for melatonin and zolpidem [38]. In order to verify whether there are more efficient scavenging channels for fluoxetine, we have also investigated the RAF mechanism involving the aromatic C sites. \(\Delta\mathrm{G^{\circ}}_{\mathrm{RAF}}\) values for HO\({}^{\bullet}\) were computed for **1** as well as for **2**, and are reported in Tables S5 and S6. Focusing on HO\({}^{\bullet}\), it is worth noticing that the scavenging reactions of **1** that are less exergonic via HAT are significantly more exergonic via RAF, as it emerges for when comparing sites 1, 5, and 13, for which the \(\Delta\mathrm{G^{\circ}}_{\mathrm{HAT}}\) values are \(-\)6.14, \(-\)3.40, and \(-\)5.68 kcal mol\({}^{-1}\), and the \(\Delta\mathrm{G^{\circ}}_{\mathrm{RAF}}\) values are \(-\)7.98, \(-\)9.20, and \(-\)8.29 kcal mol\({}^{-1}\), respectively. Small negative Gibbs free reaction energies imply a larger stabilization of the reactants than the products. When comparing HAT and RAF, since the reactants are the same, it is useful to inspect the radical product. In Figure 6, the example of the spin densities computed for the radical products obtained from HAT and RAF involving site 1 and HO\({}^{\bullet}\) is shown. RAF leads to the formation of a radical product in which the spin density is significantly more delocalized on the benzene ring and the adjacent oxygen atom.  
\begin{table}
\begin{tabular}{c c c c c c c} \hline \hline
**Site** & **Gas Phase** & **Benzene** & **Water** & **Gas Phase** & **Benzene** & **Water** \\ \hline  & & HO\({}^{\bullet}\) & & & CH\({}_{3}\)O\({}^{\bullet}\) & \\ \hline
9 & 5.61 & 6.87 & 0.08 & 11.97 & 14.14 & 11.12 \\
10 & 6.86 & 8.02 & 7.40 & 14.43 & 15.73 & 14.08 \\
11 & 6.35 & 6.91 & 6.46 & 12.12 & 12.92 & 11.44 \\
12 & 5.40 & 6.06 & 5.14 & 13.13 & 14.10 & 13.10 \\
5a & 5.02 & 6.14 & 11.23 & 7.29 & 8.50 & 5.36 \\ \hline \hline \end{tabular}
\end{table}
Table 3: \(\Delta\mathrm{G^{\ddagger}}_{\mathrm{HAT}}\) (kcal mol\({}^{-1}\)) in the gas phase, benzene, and water, for the scavenging of HO\({}^{\bullet}\) and CH\({}_{3}\)O\({}^{\bullet}\) through HAT in **2**. Level of theory: (SMD)-M06-2X/6-311+G(d,p)//M06-2X/6-31G(d).  
There is no clear trend for RAF exergonicity when going from the gas phase to benzene and water. In general, the reactants should be more stabilized with increasing solvent polarity, and so the reaction Gibbs free energies should become more negative from benzene to water. However, this is not observed for sites 5, 6, and 8, which are located in a sterically crowded region of fluoxetine between the two orthogonal phenyl rings. In **2**, both hydroxyl and methoxyl radicals were tested, and we found that in gas-phase serotonin is selective via RAF for HO\({}^{\bullet}\) except from site 3. The process is weakly exergonic from site 8, too; these sites correspond to the junction carbon atoms. When CH\({}_{3}\)O\({}^{\bullet}\) is considered, the HAT from these sites becomes strongly endergonic. Conversely, exergonic RAF occurs only on sites 1 and 4. The trend in solvent shows that the exergonicity increases with increasing solvent polarity, with the exceptions of sites 2-4 (HO\({}^{\bullet}\)) and 4 (CH\({}_{3}\)O\({}^{\bullet}\)).