In physical organic chemistry, a kinetic isotope effect (KIE) is the change in the reaction rate of a chemical reaction when one of the atoms in the reactants is replaced by one of its isotopes. Formally, it is the ratio of rate constants for the reactions involving the light (kL) and the heavy (kH) isotopically substituted reactants (isotopologues): This change in reaction rate is a quantum mechanical effect that primarily results from heavier isotopologues having lower vibrational frequencies compared to their lighter counterparts. In most cases, this implies a greater energetic input needed for heavier isotopologues to reach the transition state (or, in rare cases, the dissociation limit), and consequently, a slower reaction rate. The study of kinetic isotope effects can help the elucidation of the reaction mechanism of certain chemical reactions and is occasionally exploited in drug development to improve unfavorable pharmacokinetics by protecting metabolically vulnerable C-H bonds. Background The kinetic isotope effect is considered to be one of the most essential and sensitive tools for the study of reaction mechanisms, the knowledge of which allows the improvement of the desirable qualities of the corresponding reactions. For example, kinetic isotope effects can be used to reveal whether a nucleophilic substitution reaction follows a unimolecular (SN1) or bimolecular (SN2) pathway. In the reaction of methyl bromide and cyanide (shown in the introduction), the observed methyl carbon kinetic isotope effect indicates an SN2 mechanism. Depending on the pathway, different strategies may be used to stabilize the transition state of the rate-determining step of the reaction and improve the reaction rate and selectivity, which are important for industrial applications. Isotopic rate changes are most pronounced when the relative mass change is greatest, since the effect is related to vibrational frequencies of the affected bonds. For instance, changing a hydrogen atom (H) to its isotope deuterium (D) represents a 100% increase in mass, whereas in replacing carbon-12 with carbon-13, the mass increases by only 8 percent. The rate of a reaction involving a C–H bond is typically 6–10 times faster than the corresponding C–D bond, whereas a 12C reaction is only 4 percent faster than the corresponding 13C reaction (even though, in both cases, the isotope is one atomic mass unit heavier). Isotopic substitution can modify the rate of reaction in a variety of ways. In many cases, the rate difference can be rationalized by noting that the mass of an atom affects