A DFT-based Raman spectral atlas and vibrational assignment of aqueous glucose structures and derivatives

Diabetes mellitus affects approximately 589 million adults worldwide, underscoring the need for accurate and noninvasive glucose monitoring to reduce complications. Although Raman spectroscopy shows promise for noninvasive blood glucose detection due to its molecular specificity and minimal interference, its application has been limited by the oversimplification of glucose as an open-chain structure in solution and unresolved assignments of characteristic bands-particularly the widely used 1125 cm⁻¹ peak. In this study, we combine density functional theory simulations with experimental Raman spectroscopy to elucidate the vibrational origins of glucose bands across all physiologically relevant tautomers and derivatives, including α-D-Glucopyranose and β-D-Glucopyranose, α-D-Glucofuranose and β-D-Glucofuranose, the open-chain form, D-Glucose-monohydrate, and 1,5-Anhydroglucitol. We present the first comprehensive, assignment-validated Raman spectral atlas and vibrational assignment of accurate aqueous glucose structures, achieving unprecedented agreement between theory and experiment. Highly specific spectral markers are identified to distinguish pyranose and furanose rings, anomeric configurations, hydration states, and the bicyclic features of 1,5-Anhydroglucitol. These findings resolve decades-long controversies in glucose vibrational spectroscopy and provide essential reference standards to advance Raman-based noninvasive monitoring of short-term glycemic control and early glycation risk in diabetic patients.