Calculated Proton Affinities Research Articles

Role of the hydrophobicity on the thermodynamic and kinetic acidity of Fischer thiocarbene complexes

Rate constants for the reversible deprotonation of (CO)(5)W=C(SR)CH(3) (W-SR) by OH(-), water and a number of primary aliphatic and secondary alicyclic amines, have been determined in 50% MeCN:50% water at 25 degrees C. In addition, solvation energy and proton affinities values for M-SR (M = Cr and W) in the gas phase and in acetonitrile have been computed at DFT level. Although there is not a linear correlation between the calculated proton affinities and the measured pK(a)s, the calculations reveal that when solvent effects are taken into account the substituted compounds studied show differences in their proton affinities. There is a good correlation between the change in cavitation energy (DeltaG(cav)) for the Fischer carbene complexes and log P of the thioalkyl substituents. In proton transfer reactions with amines, steric effects are more important for W complexes with respect to their Cr analogues as a consequence of differences in transition state progress. On the other hand, in reactions with OH(-), hydrophobicity of the R substituent is responsible for the observed changes in intrinsic kinetic acidities, which is supported by the good correlation obtained between log k(0) and log P. W complexes are more sensitive to hydrophobic effects due to the tighter solvation sphere with respect to their Cr counterparts. However, in the limit of log P = 0, the energy involved in the solvent reorganization process is the same regardless of the metal.

Photophysics and Photochemical Studies of the Vitamin B6 Group and Related Derivatives

The photophysics and photochemical properties of vitamin B6 constituents and analogs were studied as function of pH and solvent. The pK of the phenolic oxygen and the pyridine ring nitrogen depends on the electron donor-acceptor ability of the 4-substituent, and agrees with the calculated proton affinity. For all studied compounds, the fluorescence properties showed that the phenolic oxygen is 8 units more acidic in the lowest singlet excited state than in the ground state. The pyridine N-atom is slightly more basic in the excited state. At pH of biological significance, pH 6-8, pyridoxamine and 4-pyridoxic acid are the more efficient chromophores with higher fluorescence yield and longer lifetime. Spectroscopic studies showed that the tautomeric equilibrium depends on the nature of the 4-substituent. The quenching of the singlet excited state of pyridoxamine and 4-pyridoxic acid by amino acids, free or in a peptide, and DNA bases at pH 7 was studied by time-resolved fluorescence techniques. The quenching rate constants are well correlated with the redox properties of the pyridoxinic compound and amino acids, and are related to the free energy change in the electron transfer process. Guanosine and pyrimidine bases also are efficient quenchers, involving an electron transfer reaction.

Ring-opening polymerization of L-lactide using N-heterocyclic molecules: mechanistic, kinetics and DFT studies

We report here our investigations of the mechanism and kinetics of N-heterocyclic molecules as initiators for PLA synthesis. This is a step towards employing life saving drugs based on N-heterocyclic functional groups, to generate carrier-drug complexes in situ, via ring opening polymerization (ROP) of L-lactide. During administration, the drug may be released with well-defined release rate kinetics. With this motivation, five and six membered N-heterocyclic molecules such as 4-pyrrolidino-pyridine (PDP), 2-methyl-pyridine, pyridine, pyrrole and imidazole, are examined as initiators of bulk ROP of L-lactide, to yield metal-free poly(L-lactide) (PLA). NMR, IR and MALDI-TOF MS analyses, establish the reacting species in the polymerization. Side reactions such as formation of macrocycles, occur when permitted by lack of steric hindrance, as when polymerization is initiated by PDP + benzyl alcohol or by imidazole. Accordingly, we propose a PDP-based anionic polymerization mechanism, and then examine the effect of reaction parameters. The kinetics studies indicate an overall first order reaction with lactide, and low activation energy. Density functional theory (DFT) calculations of the initiators' proton affinities, provide a fundamental understanding, to enable selection of more efficient various N-heterocyclic drug molecules, which can be utilized as initiators, to generate PLA chains as carriers for drug administration. We find that PDP has the highest proton affinity, and that the order of the calculated proton affinities correlates broadly with the resulting PLA molecular weights. We also find that PDP appears to the most effective initiator, yielding Mw ∼28,000 Da in 90 min, which is in line with the correlation between initiator effectiveness and proton affinities, of the investigated five and six member N-heterocyclic molecules.

Description of phosphate hydrolysis reactions with the Self-Consistent-Charge Density-Functional-Tight-Binding (SCC-DFTB) theory. 1. Parameterization.

Phosphate chemistry is involved in many key biological processes yet the underlying mechanism often remains unclear. For theoretical analysis to effectively complement experimental mechanistic analysis, it is essential to develop computational methods that can capture the complexity of the underlying potential energy surface and allow for sufficient sampling of the configurational space. To this end, we report the parameterization of an approximate density functional theory, Self-Consistent-Charge Density-Functional Tight-Binding (SCC-DFTB) method for systems containing phosphorus. Compared to high-level density functional theory and ab initio (MP2 and G3B3) results, the standard second-order parameterization is shown to give reliable structures for a diverse set of phosphate compounds but inaccurate energetics. With the on-site third-order terms included, referred to as SCC-DFTBPA, calculated proton affinities of phosphate compounds are substantially improved, although it remains difficult to obtain reliable proton affinity for both phosphates and compounds that do not contain phosphorus, indicating that further improvement in the formulation of SCC-DFTB is still a challenge to meet. To make SCC-DFTB applicable to phosphate reactions in the current (on-site-third-order-only) formulation, a "reaction-specific" parameterization, referred to as SCC-DFTBPR, is developed based on hydrolysis reactions of model phosphate species. Benchmark calculations in both the gas-phase and solution-phase indicate that SCC-DFTBPR gives reliable structural properties and semi-quantitative energetics for phosphate hydrolysis reactions. Since the number of reaction-specific parameters is small, it is likely that SCC-DFTBPR is applicable to a broad set of phosphate species. Indeed, for 56 reaction exothermicities and 47 energy barriers related to RNA catalysis model reactions collected from the QCRNA database, which involve molecules rather different from those used to parameterize SCC-DFTBPR, the corresponding root-mean-square difference between SCC-DFTBPR and high-level DFT results is only 5.3 kcal/mol. We hope that the parameterized SCC-DFTB models will complement NDDO based reaction-specific models (e.g., AM1-d/PhoT) and high-level ab initio QM/MM methods in better understanding the mechanism of phosphate chemistry in condensed phase, particularly biological systems.

Thermochemical Parameters of CHFO and CF2O

Thermochemical properties of CHFO and CF 2O and their derivatives were calculated by using coupled-cluster theory (U)CCSD(T) calculations with the aug-cc-pV nZ ( n = D, T, Q, 5) basis sets extrapolated to the complete basis set limit with additional corrections. The predicted properties include the following. Enthalpies of formation (298 K, kcal/mol): Delta H f (CF 2O) = -144.7, Delta H f(CHFO) = -91.1, Delta H f (CFO (*)) = -41.6. Bond dissociation energy (0 K, kcal/mol): BDE(CFO-F) = 120.7, BDE(CHO-F) = 119.1, BDE(CFO-H) = 100.2. Ionization potential (eV): IP 1(CF 2O) = 13.04, IP 2(CF 2O) = 14.09, IP 1(CHFO) = 12.41, IP 2(CHFO) = 13.99, IP 1(CFO (*)) = 9.34. Proton affinity (298 K, kcal/mol), PA O(CF 2O) = 148.8, PA O(CHFO) = 156.7, PA F(CHFO) = 154.5 kcal/mol. Electron affinity: EA(CFO (*)) = 2.38 eV. Triplet-singlet separation gap (eV): Delta E T1-S0(CF 2O) = 4.47, Delta E T1-S0(CHFO) = 4.36. Triplet-triplet transition energy (eV): Delta E T2-T1(CF 2O) = 0.44. The new calculated values contribute to solving some persistent discrepancies in the literature. The effects of F-atoms on thermochemical parameters are not linearly additive, and the changes are largely dominated by the first F-substitution. On the basis of the calculated proton affinities of CF 2O and CF 3OH, the nucleophilicities of the oxygen atoms are, within computational errors, the same in both compounds.

G3 calculations of the proton affinity and ionization energy of dimethyl methylphosphonate

Dimethyl methylphosphonate (DMMP), an important flame retardant in lithium-ion batteries, has been studied theoretically. The energy, enthalpy, and Gibbs free energy of DMMP and its protonated form (DMMP-H +) have been calculated using the high-level ab initio methods G3(MP2), G3(MP2)//B3LYP, G3, G3//B3-LYP, and CBS-QB3. All calculated proton affinities showed good agreement with experiment (within 1.5%), with the best values being obtained with G3MP2. At this level of theory, the calculated proton affinity of DMMP is 895 kJ · mol −1. The ionization potential (9.94 eV) was calculated using the related procedure G3(MP2)-RAD, and also showed excellent with experiment (0.6%). Hydrogen bonding in DMMP-H + has also been studied.

Theoretical studies on the carcinogenic activity of diol epoxide derivatives of PAH: proton affinity and aromaticity as decisive descriptors

A comparative study between bay-region and nonbay-region diol epoxide (DE) derivatives of seventeen carcinogenic polycyclic aromatic hydrocarbons (PAHs) was carried out using the B3LYP/6-31G(d,p) level of density functional theory to understand the factors responsible for the increased carcinogenic activity of bay-region derivatives. Molecular electrostatic potential analysis as well as proton affinity calculations showed that the epoxide sites of bay-region derivatives are much more reactive than the corresponding nonbay-region analogs. The charge delocalization mode in the carbocation intermediates resulting from the protonation reactions was followed through LUMO analysis. The relative aromaticity in the different rings in the arenium ions was gauged by NICS(1)(zz) computations. Both these calculations revealed that the protonated DEs (DEH(+)) are stabilized by higher aromaticity in the bay-region derivatives than the nonbay-region derivatives. Hence, a bay-region DEH(+) can be retained in the reacting medium for a longer time than compared with the DEH(+) formed from a nonbay-region DEs. Thus the high carcinogenic activity of bay-region DEs is attributed to the high reactivity of the epoxide system for protonation and the high thermodynamic stability of the resulting cation. Multiple regression analysis also confirms the above results wherein proton affinity and aromaticity significantly explain the variations in the carcinogenic activity of the molecules under study.

Acidity and defect sites in titanium silicalite catalyst

With density functional calculations and in situ 29Si and 31P MAS NMR experiments, a novel defect site (defect site II, dsII) was identified in titanium silicalite molecular sieve (TS-1 zeolite), supported by the previous experimental results. The conversion from Q3 species [(SiO)3Si(OH)] into Q4-like species [Si(OSi)4] due to TMP adsorption indicated the presence of Brönsted acidity in TS-1 zeolite. The thermodynamic analysis and Ti/Si substitution energies further confirmed that the proton transferring process of defect site II is much facilitated in TS-1 zeolite whereas on the contrary in silicalite-1. With the proton-affinity calculations, the Brönsted acidities of several cation-doped zeolites were found to decrease in the order of Al-ZSM-5 > Fe-ZSM-5 > B-ZSM-5 > TS-1. The Brönsted acidity of TS-1 zeolite is even weaker than that of B-ZSM-5 zeolite, suggesting the potential role as a new acid catalyst. As to silicalite-1, its acidity is even weaker than that of defect site I (dsI) in TS-1 zeolite.

Ab initio and density functional theory calculations of proton affinities for volatile organic compounds

The Hatree-Fock method with 6-311G** split-valence molecular orbitals basis sets and the density function theory-B3LYP have been applied to geometrical optimizations and calculations of total electronic, zero point vibrational energies and proton affinities at 298 K for volatile organic compounds. Calculated values of proton affinities are compared with experimental data.

Pyridine and s-triazine as building blocks of nonionic organic superbases—a density functional theory B3LYP study

It is shown by reliable DFT B3LYP/6-311+G(2df,p)//B3LYP/6-31G* method that pyridine and s-triazine can serve as useful building blocks in tailoring neutral superbases. The former compound is used in constructing the four-fragment macrocycles substituted by a number of NMe2 substituents placed at strategic positions on the suprastructure’s backbone. The calculated proton affinities are within the range of 270–290 kcal mol−1, thus belonging to the upper part of the superbasicity ladder. It is shown that proton affinities of polysubstituted derivatives follow a simple additivity rule, which facilitates prediction and interpretation of the results in multiply substituted systems. The s-triazine motif is employed in forming manxane-like systems by using guanidine fragments or 1,1-dimethylaminoethylenes, which exhibit proton affinities spread over the lower part of the superbasicity scale (256–272 kcal mol−1). The amplified basicity in both families of compounds is a consequence of the strong cationic resonance in conjugate acids supported by stabilization provided by intramolecular hydrogen bonds (IMHB). The nature of the IMHBs is examined. It is found that IMHBs in large macrocycles constructed by pyridine moieties is of a bicentric type. They are not cationic resonance supported IMHBs in the first approximation. In contrast, protonation in one of the manxane-like systems yields the IMH bonds that are stabilized by substantial cationic resonance through the hydrogen Hδ+ bridge. Consequently, the cationic resonance supported hydrogen bonds (CRSHBs) do exist in some protonated species. The basicity of pyridine macrocycles is examined in acetonitrile. It is found that their pKa values span a range between 26–30 units meaning that they are also strong superbases in MeCN solutions compared to the threshold given by pKa(MeCN) of DMAN (18.2 units).

Elucidating the mechanism for the reduction of nitrite by copper nitrite reductase—A contribution from quantum chemical studies

Density functional methods have been applied to investigate the properties of the active site of copper-containing nitrite reductases and possible reaction mechanisms for the enzyme catalysis. The results for a model of the active site indicate that a hydroxyl intermediate is not formed during the catalytic cycle, but rather a state with a protonated nitrite bound to the reduced copper. Electron affinity calculations indicate that reduction of the T2 copper site does not occur immediately after nitrite binding. Proton affinity calculations are indicative of substantial pK(a) differences between different states of the T2 site. The calculations further suggest that the reaction does not proceed until uptake of a second proton from the bulk solution. They also indicate that Asp-92 may play both a key role as a proton donor to the substrate, and a structural role in promoting catalysis. In the D92N mutant another base, presumably a nearby histidine (His-249) may take the role as the proton donor. On the basis of these model calculations and available experimental evidence, an ordered reaction mechanism for the reduction of nitrite is suggested. An investigation of the binding modes of the nitric oxide product and the nitrite substrate to the model site has also been made, indicating that nitric oxide prefers to bind in an end-on fashion to the reduced T2 site.

Substituent Effects on the Basicity of 3,7-Diazabicyclo[3.3.1]nonanes

Basicity constants for a series of 3,7-diazabicyclo[3.3.1]nonane derivatives in acetonitrile with a variation over 13 orders of magnitude have been determined using a spectrophotometric titration technique. An excellent correlation between basicity and calculated proton affinities obtained at PCM-B3LYP/6-31+G(d)//B3LYP/6-31G(d) level was found. The results are discussed in terms of substituent effects and compared to (15)N NMR chemical shifts.

High basicity of tris-(tetramethylguanidinyl)-phosphine imide in the gas phase and acetonitrile—a DFT study

It is shown by reliable density functional theory (DFT) calculations that compounds 4 and 6 are very powerful neutral organic superbases as evidenced by the calculated proton affinities in the gas phase 305.4 kcal mol −1 (44.8) and 287.8 kcal mol −1 (37.8), respectively, and the corresponding calculated p K a values in acetonitrile given within parentheses.

Calculation of proton affinity using the CR‐CCSD[T]/ECP method

AbstractHigh‐level calculations of proton and electron affinities (PA and EA) of CH2X− and CH2CHCHX− (with X = F, Cl, Br, and I) systems were obtained. The methodology employed in the PA and EA calculations is based on CR‐CCSD[T]/B1//MP2/B0 and CCSD(T)/B1//MP2/B0 levels, respectively. B0 is a (small) valence basis set developed by Stevens and colleagues (SBKJC), and B1 is a larger basis set, with extra diffuse and polarization functions (B0 + s, p, d, and f functions). This scheme has been tested on systems containing H, C, and X atoms, and is shown to give good results. The differences between calculated results of PA and EA and the experimental values are in the range of 0.2–4.5 kJ · mol−1 and 0.01 to 0.10 eV, respectively. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2006

Computational study of iminium ion formation: effects of amine structure

Density functional calculations are used to explore the formation of iminium ions from secondary amines and acrolein and the subsequent reactivity of the resulting iminium ions. After establishing a feasible profile for this reaction in simulated experimental conditions, we focus on the effect of variation in amine structure on calculated barriers. This analysis shows that incorporation of a heteroatom (N or O) in the alpha-position to the reactive amine results in significantly reduced energy barriers, as does an electron-withdrawing group (carbonyl or thiocarbonyl) in the beta-position. Electron density analysis is used to monitor reactions at a detailed level, and to identify important intermolecular interactions at both minima and transition states. Barriers to reaction are linked to calculated proton affinities of secondary amines, suggesting that the relative ease of protonation-deprotonation of the amine is a key property of effective catalysts. Moreover, barriers for subsequent Diels-Alder reaction of iminium ions with cyclopentadiene are lower than for their formation, suggesting that formation may be the rate determining step in the catalytic cycle.

Multilevel and Density Functional Electronic Structure Calculations of Proton Affinities and Gas-Phase Basicities Involved in Biological Phosphoryl Transfer

Five multilevel model chemistries (CBS-QB3, G3B3, G3MP2B3, MCG3/3, and MC-QCISD/3) and seven hybrid density functional methods (PBE0, B1B95, B3LYP, MPW1KCIS, PBE1KCIS, and MPW1B95) have been applied to the calculation of gas-phase basicity and proton affinity values for a series of 17 molecules relevant to the study of biological phosphoryl transfer. In addition, W1 calculations were performed on a subset of molecules. The accuracy of the methods was assessed and the nature of systematic errors was explored, leading to the introduction of a set of effective bond enthalpy and entropy correction terms. The multicoefficient correlation methods (MCG3/3 and MC-QCISD), with inclusion of specific zero-point scale factors, slightly outperform the other multilevel methods tested (CBS-QB3, G3B3, and G3MP2B3), with significantly less computational cost, and in the case of MC-QCISD, slightly less severe scaling. Four density functional methods, PBE1KCIS, MPW1B95, PBE0, and B1B95 perform nearly as well as the multilevel methods. These results provide an important set of benchmarks relevant to biological phosphoryl transfer reactions.

A Critical Evaluation of Different QM/MM Frontier Treatments with SCC-DFTB as the QM Method

The performance of different link atom based frontier treatments in QM/MM simulations was evaluated critically with SCC-DFTB as the QM method. In addition to the analysis of gas-phase molecules as in previous studies, an important element of the present work is that chemical reactions in realistic enzyme systems were also examined. The schemes tested include all options available in the program CHARMM for SCC-DFTB/MM simulation, which treat electrostatic interactions due to the MM atoms close to the QM/MM boundary in different ways. In addition, a new approach, the divided frontier charge (DIV), has been implemented in which the partial charge associated with the frontier MM atom ("link host") is evenly distributed to the other MM atoms in the same group. The performance of these schemes was evaluated based on properties including proton affinities, deprotonation energies, dipole moments, and energetics of proton transfer reactions. Similar to previous work, it was found that calculated proton affinities and deprotonation energies of alcohols, carbonic acids, amino acids, and model DNA bases are very sensitive to the link atom scheme; the commonly used single link atom approach often gives error on the order of 15 to 20 kcal/mol. Other schemes give better and, on average, mutually comparable results. For proton transfer reactions, encouragingly, both activation barriers and reaction energies are fairly insensitive (within a typical range of 2-4 kcal/mol) to the link atom scheme due to error cancellation, and this was observed for both gas-phase and enzyme systems. Therefore, the effect of using different link atom schemes in QM/MM simulations is rather small for chemical reactions that conserve the total charge. Although the current study used an approximate DFT method as the QM level, the observed trends are expected to be applicable to QM/MM methods with use of other QM approaches. This observation does not mean to encourage QM/MM simulations without careful benchmark in the study of specific systems, rather it emphasizes that other technical details, such as the treatment of long-range electrostatics, tend to play a more important role and need to be handled carefully.

Proton Affinities of Borane−Amines: Consequences on Dihydrogen Bonding

The calculated proton affinities of four borane-amines using Gaussian-2 theory have been found to be comparable to conventional bases such as water, methanol, and ammonia. On the other hand the structure of protonated borane-ammonia, [HBH(3)-NH(3)](+), is found to be drastically different from that of protonated ammonia, [HNH(3)](+), and can appropriately be described as a eta(2)-H(2) complex with [BH(2)-NH(3)](+) molecular cation. Further, the proton affinities of borane-amines are related to the ease of H(2) elimination.

Acidities of azoles in the gas phase and in DMSO: an ab initio and DFT study§

Acidity of azoles, a very important family of biological molecules with useful pharmacological applications, is examined in the gas phase and in DMSO. The gas phase proton affinities of the corresponding conjugate bases are calculated by the G3 computational scheme and used as a measure of acidity. A good accordance with available experimental data is obtained. It is confirmed that acidity increases with the number of nitrogen atoms in the five-membered ring. The calculated deprotonation energies are interpreted by the triadic formula. It turns out that acidity of azoles is a result of the final state effect and the relaxation energy contribution. It is shown, by using NICS(1) values, that azoles are aromatic compounds and that their aromatic character increases with the number of N atoms. It is also found that aromaticity slightly increases upon deprotonation. Acidity of azoles in DMSO is considered using the isodensity polarized continuum model (IPCM) at the DFT-B3LYP level. A good agreement with accessible experimental results is obtained again. In other cases pKa values are theoretically predicted and it was found that pentaazole is the most acidic compound with pKa = 2. A very good linear relation between theoretical pKa values and calculated proton affinities of conjugate bases is obtained implying that the trend of changes in the gas phase and in the DMSO solutions is the same.

Benchmark calculations of proton affinities and gas-phase basicities of molecules important in the study of biological phosphoryl transfer

Benchmark calculations of proton affinities and gas-phase basicities of molecules most relevant to biological phosphoryl transfer reactions are presented and compared with available experimental results. The accuracy of proton affinity and gas-phase basicity results obtained from several multi-level model chemistries (CBS-QB3, G3B3, and G3MP2B3) and density-functional quantum models (PBE0, B1B95, and B3LYP) are assessed and compared. From these data, a set of empirical bond enthalpy, entropy, and free energy corrections are introduced that considerably improve the accuracy and predictive capability of the methods. These corrections are applied to the prediction of proton affinity and gas-phase basicity values of important biological phosphates and phosphoranes for which experimental data does not currently exist. Comparison is made with results from semiempirical quantum models that are commonly employed in hybrid quantum mechanical/molecular mechanical simulations. Data suggest that the design of improved semiempirical quantum models with increased accuracy for relative proton affinity values is necessary to obtain quantitative accuracy for phosphoryl transfer reactions in solution, enzymes, and ribozymes.