Kinetic isotope effects are next computed for the reactions with rates k1-4 as shown in Scheme1, where 𝑘 ! /𝑘 " is the protium/deuterium rate ratio for the endo-TS and 𝑘 # /𝑘 $ that for exo-TS. For the condition already established where kinv << k1-k4 ("forbidden inversion"), 9 the overall isotope effect combining the rates of both endo-and exotransition state reactions can be derived 9 as: