Kinetic isotope-effect probes of transition-state structure. Vibrational analysis of model transition states for carbonyl addition

Abstract

Model calculations of the 1 H/2H, l2C/l?C. and ,60/'l80 kinetic and equilibrium isotope effects at the starred positions for the carbonyl addition reaction of HjCC*H*0* with HO*have been made for two closely related sets of force fields, and for both curved and perpendicular trajectories of nucleophilic approach to carbonyl, for a series of possible transition-state structures at temperatures from 273 to 323 K. In all calculations, the geometrical features and force constants were assumed to change from reactant values toward product values in proportion to the Pauling bond order B of the nucleophile -carbonyl bond. The «-deuterium and /3-deuterium effects are nearly linear functions of B and should be good and consistent probes of transition-state structure. The carbonyl-18# effect is normal and increases steadily with B, as expected. The nucleophile-18# effect is normal for B < 0.5 and inverse for later transition states. The carbonyl-13C is about 1.03 for early transition states and falls to an inverse equilibrium effect. No strikingly anomalous temperature dependences were calculated.Carbonyl-addition reactions, exemplified by the process of eq 1, are of interest in chemistry and biochemistry3•4 and the understanding of their dynamics in terms of transition-state structure is the topic of much current research.5 A very appealing and effective approach to learning the structure of such transition states lies in the use of kinetic isotope effects.5 7 We have employed vibrational analysis of model structures8•9 for the transition state of eq 1 to explore relationships of such CHjCHO + HO CH.j CH.CH(1) OH structures to the following isotopic probes: (1) the «-deuterium secondary isotope effect10 (for the hydrogen attached to the electrophilic carbon); this effect is expected to be inverse (ko > k h), arising from restrictions to motion of the « hydrogen

Mechanistic investigations of the hydrolysis of amides, oxoesters and thioesters via kinetic isotope effects and positional isotope exchange

“…The formyl-H KIE is a secondary KIE because the H\C bond is not broken during the reaction; it is sensitive to changes in hybridization at the carbonyl-C on going to the transition state. It is known that going from an sp 2 ground state to an sp 3 -like transition state will give an inverse KIE, whereas the opposite transformation (sp 3 → sp 2 ) will show a normal KIE [21]. In the present case interpretation of the formyl-H KIE is more complex because the ratio k 3 /k 2 is only 1.05, indicating that the transition states for formation and breakdown of T − would be of comparable energy.…”

Carbon Isotope Effects on the Fructose-1,6-bisphosphate Aldolase Reaction, Origin for Non-statistical 13C Distributions in Carbohydrates

“…In agreement, the observation of large secondary tritium isotope effects for the conversion of the substrate with 3 H in positions C-3 and C-4 We cannot explain at present the observed 13 C equilibrium isotope effects on the aldolase reaction. The predictions of Cleland (39) for a substitution of a C-H bond for a C-C bond at C-3 and the substitution of a C-O bond for the cleaved C-C bond at C-4, as well as the suggestions of Hogg et al (41) for the hydration of aldehydes predict an inverse isotope effect for C-4, hence a 13 C enrichment in the released glyceraldehyde 3-P. On the other hand there are no examples available to which our observation could be compared.…”

Understanding the transition states of phosphodiester bond cleavage: Insights from heavy atom isotope effects

“…37 Such an effect is significantly larger than other precedents for intrinsic KIEs on bond formation. Maximal 18 O nucleophile effects are predicted by computational analysis to be around 3% for carbonyl addition, 43 and observed effects on ester and amide hydrolysis are in this range as described above. Thus, the observed effect must necessarily include a contribution from equilibrium deprotonation to yield hydroxide ( Figure 6).…”

“…Additionally, inverse nucleophile isotope effects are only predicted by computational studies in very late transition states in which the TDF contribution from bonding is dominant. 43 In contrast, equilibrium isotope effects are only the result of contributions from the TDF and can often be inverse (the heavier isotope is favored), when there is an increase in bonding between the two relevant species. For example, the equilibrium effect upon going from an O-H to an O-C bond is ca.…”

“…Computational studies of ester hydrolysis indicate that inverse effects can arise, but only in very late transition states with differences in ground state and transition state bonding to the nucleophile sufficiently advanced to overcome the effect from reaction coordinate motion. 43 In light of these arguments and additional primary and secondary KIEs, hydroxide ion appears to act as general base in catalysis of ester and amide hydrolysis.…”