A secondary kinetic isotope effect is observed when no bond to the isotopically labeled atom in the reactant is broken or formed. Secondary kinetic isotope effects tend to be much smaller than primary kinetic isotope effects; however, secondary deuterium isotope effects can be as large as 1.4 per deuterium atom, and techniques have been developed to measure heavy-element isotope effects to very high precision, so secondary kinetic isotope effects are still very useful for elucidating reaction mechanisms.
For the aforementioned nucleophilic substitution reactions, secondary hydrogen kinetic isotope effects at the α-carbon provide a direct means to distinguish between S1 and S2 reactions. It has been found that S1 reactions typically lead to large secondary kinetic isotope effects, approaching to their theoretical maximum at about 1.22, while S2 reactions typically yield secondary kinetic isotope effects that are very close to or less than unity. Kinetic isotope effects that are greater than 1 are referred to as normal kinetic isotope effects, while kinetic isotope effects that are less than one are referred to as inverse kinetic isotope effects. In general, smaller force constants in the transition state are expected to yield a normal kinetic isotope effect, and larger force constants in the transition state are expected to yield an inverse kinetic isotope effect when stretching vibrational contributions dominate the kinetic isotope effect.
The magnitudes of such secondary isotope effects at the α-carbon atom are largely determined by the C-H(D) vibrations. For an S1 reaction, since the carbon atom is converted into an sp hybridized carbenium ion during the transition state for the rate-determining step with an increase in C-H(D) bond order, an inverse kinetic isotope effect would be expected if only the stretching vibrations were important. The observed large normal kinetic isotope effects are found to be caused by significant out-of-plane bending vibrational contributions when going from the reactants to the transition state of carbenium ion formation. For S2 reactions, bending vibrations still play an important role for the kinetic isotope effect, but stretching vibrational contributions are of more comparable magnitude, and the resulting kinetic isotope effect may be normal or inverse depending on the specific contributions of the respective vibrations.