Interaction of different hydrophilic (His, Asp, Glu,) and hydrophobic (Ala, Phe, Tyr, Trp) amino acids in water with a scorpiand aza-macrocycle (L1) containing a pyridine group in the ring and its derivative (L2) bearing a naphthalene group in the tail has been analysed by potentiometric and calorimetric measurements. Theoretical calculations corroborate that major attractive forces that hold the adduct together are hydrogen bonds and salt-bridges, even though other interactions such as π-stacking or NH+•••π may contribute in the case of hydrophobic amino acids and L2. Calorimetric measurements conclude that interaction between L1 and the different amino acids is principally driven by entropy, often associated to solvation/desolvation processes.