Spectroscopic Fingerprints of Cavity Formation and Solute Insertion as a Measure of Hydration Entropic Loss and Enthalpic Gain

Hydration free energies are dictated by a subtle balance of hydrophobic and hydrophilic interactions. We present here a spectroscopic approach, which gives direct access to the two main contributions: Using THz‐spectroscopy to probe the frequency range of the intermolecular stretch (150–200 cm(−1)) and the hindered rotations (450–600 cm(−1)), the local contributions due to cavity formation and hydrophilic interactions can be traced back. We show that via THz calorimetry these fingerprints can be correlated 1 : 1 with the group specific solvation entropy and enthalpy. This allows to deduce separately the hydrophobic (i.e. cavity formation) and hydrophilic contributions to thermodynamics, as shown for hydrated alcohols as a case study. Accompanying molecular dynamics simulations quantitatively support our experimental results. In the future our approach will allow to dissect hydration contributions in inhomogeneous mixtures and under non‐equilibrium conditions.