The impact of a single atom O-glycosides are hydrolyzed under acidic conditions more readily than their S-counterparts. This is primarily caused by the lower basicity of S compared to O in acidic aqueous media favoring protonation of O, and the lower nucleofugacity of RSH versus ROH. The degradation kinetics of Fdx in MeOH in presence of HCl have been studied previously. To test our hypothesis, that a single atom exchange would render Fdx derivatives more acid stable (Fig. ), we performed analogous acidic degradation studies in MeOH. In presence of 68 equiv. HCl in MeOH at 25 °C Fdx undergoes acid-mediated degradation with a half-life of 62.7 min (Fig. ), providing primarily one new peak in the UHPLC-MS chromatogram, with the mass corresponding to the MeOH adduct (m/z: [M+NH4 + ]: 858, [M+Na + ]: 863). NMR analysis of HCl-mediated degradation of Fdx in MeOD-d4 revealed the formation of at least three new species, likely corresponding to regioisomers of the MeOH adduct (Suppl. Fig. ). In contrast, S-Fdx was found to be stable over a time frame of 540 min (Fig. ). This finding was confirmed by NMR studies in MeOD-d4 (Suppl. Fig. ). For direct comparability, a competition experiment was performed by subjecting a mixture of Fdx and S-Fdx in MeOH to acidic conditions. A much faster degradation of Fdx than S-Fdx was observed (Fig. , Suppl. Fig. ). These results confirm the initial hypothesis that replacing the O-for a S-glycosidic linkage renders Fdx derivatives less amenable to acid-mediated reactions with nucleophiles.