Proton affinities computational methods

Considering the abundant evidence for carbene protonation, some quantitative estimate for the base strength of carbenes is clearly desirable. The conventional spectrometric or potentiometric methods of determining the pKa in solution are not applicable, with the exception of some onium ions 1 and their conjugate bases 2 (Section V.B). In favorable cases, equilibria of carbenes with the conjugate carbenium ions have been studied in the gas phase. Proton affinities of various carbenes can be obtained from their enthalpies of formation, and by ab initio computation (Section V.A). Kinetic data have been evaluated to obtain the pKa of carbenes in solution (Section V.B). 

W1/W2 theory and their variants would appear to represent a valuable addition to the computational chemist s toolbox, both for applications that require high-accuracy energetics for small molecules and as a potential source of parameterization data for more approximate methods. The extra cost of W2 theory (compared to W1 theory) does appear to translate into better results for heats of formation and electron affinities, but does not appear to be justified for ionization potentials and proton affinities, for which the W1 approach yields basically converged results. Explicit calculation of anharmonic zero-point energies (as opposed to scaling of harmonic ones) does lead to a further improvement in the quality of W2 heats of formation at the W1 level, the improvement is not sufficiently noticeable to justify the extra expense and difficulty. 

Computational methods have also been used frequently to estimate the thermodynamic stabilities of superelectrophiles. These calculations have often involved the estimation of barriers to gas phase dissociation or deprotonation, and the proton affinities of conventional electrophilic intermediates. Other useful studies have calculated the heats of reactions for isodesmic processes. An interesting example of these calculations comes from a study of the protoacetyl dication (Cf COH2"1- ).42 In calculations at the 6-31G //4-31G level of theoiy, the protoacetyl dication (83) is estimated to react with methane by hydride abstraction with a very favorable... 

A steric parameter based on the proton affinity Ah and methyl cation affinity Ach3, calculated by computational chemistry methods, for reaction at the nitrogen atom series of compounds in which the nitrogen atom was unhindered, e.g. pyridines in which the 2- and 6-positions are unsubstituted [Jenkins et al, 1994 Jenkins et al., 1995 Baxter et al, 1996]. Using these affinity values, a reference regression model was found which correlates the methyl cation affinity Achs to the proton affinity Ah for unhindered compounds ... 

Gargallo, R., Sotriffer, C.A., Liedl, K.R. and Rode, B. M. (1999) Application of multivariate data analysis methods to comparative molecular field analysis (CoMEA) data proton affinities and plG prediction for nucleic acids components. J. Comput. Aid. Mol Des., 13, 611-623. 

There have been several studies aimed at using computations to examine hydrocarbon acidity. The proton affinity values for a number of hydrocarbons were calculated by both ab initio and DFT methods. Some of the results are shown in Table 3.39. 

The specific properties studied here include charge distributions, energies, geometric structures and conformations, dipole moments, isomerization energies, bond dissociation energies, proton affinities, electron affinities, ionization potentials and spin populations, as well as the general trends in these and other properties, such as hypervalency character, and their underlying electronic structure causes. The comparison of calculated with experimental property values affords an opportunity to evaluate the computational methods. 

Organophosphorus Chemistry series regularly lists new mass spectra in the Physical Methods chapter . With this in mind, an approach which considers fundamental aspects of organophosphorus ions (i.e. structure and reactivity) in the gas phase has been adopted. The gas-phase structure and reactivity of ions can be probed via several different techniques, including thermochemical measurements, kinetic energy release of metastable ions, collisional activation mass spectrometry, neutralization reionization mass spectrometry and ion-molecule reactions. An example is the molecule HCP (Table 1) its ionization potentiaP, proton affinity and the IR and rotational spectroscopy of the HCP ion " have all been determined in the gas phase. Another important tool for understanding the structure and reactivity of gas phase ions is ab initio molecular orbital theory. With advances in computational hardware and software, it is now possible to carry out high-level ab initio calculations on smaller systems. Indeed, the interplay between experiment and theory has fuelled many studies ... 

Smith and Radom [92-94] showed that the G2(MP2) theoretical procedure is able to estimate proton affinity within a target accuracy of about 2 kcal/mol. The compounds studied by these authors are of small size (containing from 1 to 4 first row atoms) because of the relatively great computational efforts required by the method. Recently, the possibility to use the DF methods in the PA evaluation has been tested by different authors [12,14,17,19] with encouraging results. From these studies it emerges that DF prediction of PA has almost the same accuracy of G2(MP2) one, but in a fraction of computer time. 

The gas phase basicities and pKa values of tris(phosphazeno) substituted azacalix[3](2,6) pyridine in acetonitrile and some related compounds were examined by the density functional theory (DFT) computational method. It was shown that the hexakis(phospha-zeno) derivative of azacalx[3](2,6)pyridine is a hyperstrong neutral base, as evidenced by the absolute proton affinity of 314.6kcal/mol and pKa (MeCN) of 37.3 units. It is a consequence of the very strong bifurcated hydrogen bond (32kcal/mol) and substantial cationic resonance effect [14]. 

It is difficult to determine these thermochemical parameters from experiment, because it is hard to monitor the precursor hydrocarbon radical and the formed peroxy radical. The experiment is further complicated by the presence of reactions to new products by the energized peroxy radicals which can prevent the monitoring of equilibrium. Experiments on ion methods using proton affinity or basicity, often with mass spectrometric analysis, are also utilized to determine enthalpies of formation of radicals. Our methods rely heavily on experimentally determined thermochemical data and we would like to point out that this data is very valuable to validate the computational methods. 

Kollman and coworkers apphed a variety of computational methods to this mechanistic problem—including quantum mechanics on small model systems, molecular dynamics simulations with the AMBER force field on the whole ODCase-substrate system, and MM-PBSA free energy calculations on ODCase with bound OMP [38]. Based on their results, they proposed a decarboxylation mechanism for ODCase that involves C5 protonation. Their calculations at the MP2/6-31+G //HF/6-31+G level showed that C5 has a greater intrinsic proton affinity than C6, 02, and even 04. This, coupled with the fact that Lys72 (M. thermoautotrophicum numbering see Table 2) is near C5 and C6 in the inhibitor-bound crystal structures, prompted the authors to embrace a C5 protonation mechanism. However, the authors themselves acknowledged the uncertainties of their calculations because of approximations employed in representing the enzyme active site. 

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