Chlorine kinetic isotope effects exceeding semiclassical limits were observed in enzyme-catalyzed reactions, but their source has not been yet identified. Herein we show that unusually large chlorine kinetic isotope effects are associated with reactions in which chlorine is the central atom that is being passed between two heavy atoms. The origin of these large values is the ratio of imaginary frequencies for light-to-heavy species (the so-called temperature-independent factor).