Concerted proton-transfer reactions

In a very recent calculation by Markwick et al. targeted molecular dynamics methods were implemented in the framework of Car-Parinello molecular dynamics to study the nature of the double proton transfer [48]. They predict a concerted proton transfer reaction. In the very early stages of this reaction the system enters a vibrationally excited pretransitional state. Whereas in the global minima large amplitude fluctuations have been found in the pretransitional region, the frequency of these fluctuations is found to increase dramatically while the amplitude of the oscillation decreases when approaching the transition state. 

Certain molecules that can permit concerted proton transfers are efficient catalysts for reactions at carbonyl centers. An example is the catalytic effect that 2-pyridone has on the aminolysis of esters. Although neither a strong base (pA aH+ = 0.75) nor a strong acid (pJsfa = 11.6), 2-pyridone is an effective catalyst of the reaction of -butylamine with 4-nitrophenyl acetate. The overall rate is more than 500 times greater when 2-pyridone acts... 

Further studies have shown that there is evidence for the double proton transfer reaction arising from a two-proton concerted process <93JAioi58>. In addition to this excited-state double proton transfer, an excited state complex ((l)-alcohol exciplex) exists in alcohol solvents <83JPC3202>. This exciplex formation is responsible for the unusually long wavelength shift and the bandwidth of the fluorescence spectra of compound (1) in alcoholic and aqueous solvents. In aqueous solution at neutral pH, only one fluorescence is observed which corresponds to the fluorescence maximum displayed by the tautomeric species <92JA8343,93JPC11823). 

The central theme that the apoprotein facilitates the scission of the O—O bond is based on the established mechanisms of peroxide heterolysis 165). By invoking concerted proton transfer (s) in the transition state, such schemes illustrate that oxygen-oxygen heterolysis need not be attended by an electrostatically unfavorable charge separation. In addition, they offer some rationale for the observed high entropy of activation in the primary H202-catalase reaction (—25 cal mole" deg ) 166). This should be the case in a rigid lattice of interactions implied in Eq. (20) and formulas (VII) and (VIII). 

The mechanism of the alkylation of imines with electrophilic alkenes has been discussed by D Angelo and coworkers S who conclude that reaction occurs via an aza-ene reaction-like transition state 206 involving concerted proton transfer from the nitrogen and carbon-carbon bond formation (Scheme 206). ITiey further propose that the remarkable regiocontrol observed in these reactions originates from this crucial internal proton transfer which would not be possible in a conformation such as 207 of the less substituted enamine tautomer, since the N—H bond would be anti to the enamine double bond. However, although this seems probable, it is by no means proven. Inconsistencies in the argument and the evidence presented cast some doubt on the validity of these conclusions. For example ... 

The Grigg group also studied the tautomerization of oximes to N-H nitrones followed by a dipolar cycloaddition reaction. The well-known H-bonding dimeric association of oximes, in both solution and the solid state, allows for a concerted proton transfer to occur and provides nitrone 56 (Scheme 11) (91TL4007). Another possible pathway involves tautomerization of the oxime to an ene-hydroxylamine (i.e. 57) followed by a 1,4-hydride shift to give nitrone 58. To probe the ene-hydro-xylamine mechanism, deuterated oxime 59 was prepared and heated at 140 °C in xylene. The physical characteristics of the isolated product, however, were consistent with compound 60, suggesting that the 1,2-prototropic reactions does not proceed... 

One observes three groups of Arrhenius curves, i.e. the HHHH curve, the group of the HHHD and the HDHD curves, and the group of the HHDD, HDDD and DDDD curves. Within each group the differences are small. They are further attenuated by isotope fractionation (Fig. 6.19c). The overall kinetic isotope effect, given by feHHHH DDDD js typical for a concerted double proton transfer reaction. It is interesting to note that replacement of the first H by D already leads to a... 

Let us now examine how substituent effects in reactants influence the rates of nucleophilic additions to carbonyl groups. The most common mechanism for substitution reactions at carbon centers is by an addition-elimination mechanism. The adduct formed by the nucleophilic addition step is tetrahedral and has sp hybridization. This adduct may be the product (as in hydride reduction) or an intermediate (as in nucleophilic substitution). For carboxylic acid derivatives, all of the steps can be reversible, but often one direction will be strongly favored by product stability. The addition step can be acid-catalyzed or base-catalyzed or can occur without specific catalysis. In protic solvents, proton transfer reactions can be an integral part of the mechanism. Solvent molecules, the nucleophile, and the carbonyl compound can interact in a concerted addition reaction that includes proton transfer. The overall rate of reaction depends on the reactivity of the nucleophile and the position of the equilibria involving intermediates. We therefore have to consider how the substituent might affect the energy of the tetrahedral intermediate. 

Certain molecules that can permit concerted proton transfers are efficient catalysts for reaction at carbonyl centers. An example is the catalytic effect that 2-pyridone... 

Other compounds such as benzoic acid and pyrazole, which can effect similar concerted proton transfer and avoid charged species, also catalyze this and related reactions Another type of bifunctional catalysis has been noted with a, co-diamines in which one of the amino groups is primary and the other tertiary. These substituted diamines are from several times to as much as 1000 times more reactive toward imine formation than monofunctional amines. This is attributed to a catalytic intramolecular proton transfer. 

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