Preferred Protonation Site Research Articles

Synthesis, Characterization, and Protonation Reactions of Ar‐BIAN and Ar‐BICAT Diimine Platinum Diphenyl Complexes

AbstractPtII diphenyl complexes (N–N)PtPh2 [N–N = diimines Ar–N=C(An)C=N–Ar with Ar = substituted aryl groups] have been prepared and characterized by 1H, 13C, and 195Pt NMR spectroscopy. The 195Pt NMR spectroscopic data establish the electronic influence exerted by substituents at the backbone of the diimine ligand system to the metal center. When compared to diimines Ar–N=CMe–CMe=N–Ar, the electron‐withdrawing ability of the Ar‐BIAN ligand and the electron‐donating ability of the O,O‐heterocyclic Ar‐BICAT systems are demonstrated. Trends in 195Pt NMR chemical shifts suggest that electronic tuning of the metal center is better achieved through variations of the diimine backbone substituents rather than variation of the substituents at the N‐Aryl groups. Protonation of (N–N)PtPh2 in dichloromethane/acetonitrile at –78 °C furnishes the corresponding PtIV hydrides (N–N)PtPh2H(NCMe)+. The PtIV hydrides liberate benzene with the formation of (N–N)PtPh(NCMe)+ when the temperature is raised. A second protonation and rapid benzene elimination produces the dicationic PtII species (N–N)Pt(NCMe)22+ at approximately 50 °C. Protonation of (N–N)PtPh2 in the absence of acetonitrile results in the clean formation of (N–N)PtPh(η2‐C6H6)+ at temperatures that depend on the steric hindrance provided by the alkyl substituents at the diimine N‐aryl groups. These findings support the notion that the metal is the kinetically preferred site of protonation. The results qualitatively agree with a recent mechanistic study of protonation‐induced reactions of (diimine)PtPh2 complexes that bear simple methyl substituents at the diimine backbone. Several compounds have been crystallographically characterized. All complexes have the expected square planar environment at the metal. Modest variations in the metric parameters suggest that the Ar‐BICAT system has a weaker trans influence than the Ar‐BIAN and Ar‐DAB systems.

The Protonated Guanine–Cytosine Base Pair

Protonated base pairs were recently implicated in the context of DNA proton transfer and charge migration. The effects of protonating different sites of the guanine-cytosine (GC) base pair are studied here by using the DZP++ B3LYP density functional method. Optimized structures for the protonated GC base pair are compared with those of parent GC and the neutral hydrogenated GC radical (GCH). Proton and hydrogen-atom additions significantly disturb the structure of the GC base pair. However, the structural perturbations arising from protonation are often less than those arising from hydrogenation of GC. Protonation of the GC base pair causes significant strengthening of the interstrand hydrogen bonds and a concomitant increase in the base dissociation energies. The adiabatic ionization potentials (AIPs), vertical ionization potentials (VIPs), and proton affinities (PAs) for the different protonation sites of the GC base pair are predicted. The N7 site of guanine is the preferred site for protonation of the GC base pair.

Electronic structure and reactivity of guanylthiourea: A quantum chemical study

Electronic structure analysis of guanylthiourea (GTU) and its isomers has been carried out using quantum chemical methods. Two major tautomeric classes (thione and thiol) have been identified on the potential energy (PE) surface. In both the cases conjugation of pi-electrons and intramolecular H-bonds have been found to play a stabilizing role. Various isomers of GTU on its PE surface have been analyzed in two different groups (thione and thiol). The interconversion from the most stable thione conformer (GTU-1) to the most stable thiol conformer (GTU-t1) was found to take place via bimolecular process which involves protonation at sulfur atom of GTU-1 followed by subsequent C-N bond rotation and deprotonation. The detailed analysis of the protonation has been carried out in gas phase and aqueous phase (using CPMC model). Sulfur atom (S1) was found to be the preferred protonation site (over N4) in GTU-1 in gas phase whereas N4 was found to be the preferred site of protonation in aqueous medium. The mechanism of S-alkylation reaction in GTU has also been studied. The formation of alkylated analogs of thiol isomers (alkylated guanylthiourea) is believed to take place via bimolecular process which involves alkyl cation attack at S atom followed by C-N bond rotation and deprotonation. The reactive intermediate RS(NH(2))C-N-C(NH(2))(2)(+) belongs to the newly identified [symbol: see text]N(<--L)(2) class of species and provides the necessary dynamism for easy conversion of thione to thiol.

Intrinsic barrier for protonation of radical anions

Ab initio calculations on radical anions show that, counterintuitively, protonation on the radicaloid carbon is favored. In the case of radical anions derived from acrylonitrile and acrylaldehyde, protonation on the heteroatom is less favored than protonation on the radicaloid carbon. However, in nitroethylene, the preferred protonation site is on the nitro oxygen in accordance with experimental observation.

New molecular species of potential interest to interstellar chemistry: A theoretical study of MgSiN, MgNSi and related species

An ab initio study has been performed to characterize the probable magnesium containing interstellar species MgSiN, MgNSi and their ionized, hydrogenated and protonated forms. We are able to locate four protonated and four hydrogenated magnesium species with planar geometry at MP2(Full)/cc-pVTZ level of theory. MgNSi is found to be more stable than MgSiN and their connecting transition state is also located. The ionization potential for both MgSiN and MgNSi are small, 7.91 eV and 7.01 eV, respectively. All possible protonation sites are considered for these two species but the preferred protonation sites are found to be silicon for MgNSi and nitrogen for MgSiN. Enthalpies of formation at 0 K (Δ f H°) and bond dissociation energies ( D o(X–Y)) are computed for all the species at G3 and G3MP2 level of theory. Finally, the reaction enthalpies for ion–molecule processes are calculated and most of the processes are found to be exothermic and hence thermodynamically favorable in interstellar region.

Theoretical studies on the activation mechanism of the histamine H2-receptor: The guanidine substitution and its role in the partial agonism of N(alpha)-guanylhistamine

Histamine [2-(4-imidazolyl)ethylamine, HA] is a neurotransmitter that was shown to act on two different receptors, the H1- and H2-receptors. Structure-activity considerations made it possible to identify molecular determinants for the action of drugs on the H2-receptors. A key probe of the resulting hypothesis relating molecular structure to activity on these receptors is its ability to explain the action of partial agonists which are pharmacologic intermediates between agonists and antagonists. We therefore studied the molecular structure and properties of N (alpha)-guanylhistamine [2-(4-imidazolyl)ethylguanidine, NAGHA], which differs from histamine by a substitution of the side chain amine by a guanidine group. To understand how the substitution with the guanidine determines this change in properties, we also studied separately the molecular structure of guanidine and guanidinium in various tautomeric forms, with geometry optimization and several different basis sets. The results suggest the preferred site of protonation and interaction of NAGHA with the negative site of the H2-receptor. For N(3)-H and N(1)-H tautomers of the neutral and cationic species of NAGHA, we did complete geometry optimization at the all electron Hartree-Fock level with the STO-3G basis set. The results support the working hypothesis that, like HA, NAGHA monocation approaches the H2-receptor as the N(3)-H tautomer. Neutralization at the anionic site also shifts the preference in tautomeric equilibrium toward the N(1)-H form, thereby triggering the charge relay sequence that was proposed as an activation mechanism of the H2-receptor. The dependence of these mechanisms of interaction with the receptor on the conformation of the side chain as well as on the position at which the negative receptor site interacts with the guanyl group suggests explanations both for the lower affinity and for the partial agonist properties of NAGHA at the H2-receptor.

Gas‐Phase versus Liquid‐Phase Structures by Electrospray Ionization Mass Spectrometry

Preferred protonation: Does electrospray ionization mass spectrometry produce gas-phase or liquid-phase structures? The preferred protonation site in p-aminobenzoic acid depends upon the medium, and the structure of its conjugate acid varies with the solvent used during spraying.

Theoretical studies on redox properties, protonation sites, and electronic spectrum of a new type of polyoxometalate [Ti12Nb6O44]10− by DFT

AbstractThe electronic structure of a new type of polyoxometalate [Ti12Nb6O44]10− has been investigated using density functional theory (DFT). The calculations represent that the LUMO in fully oxidized [Ti12Nb6O44]10− delocalizes among the titanium (Ti) and niobium (Nb). Therefore, both Ti and Nb have the probability to accept extra electron when [Ti12Nb6O44]10− as catalyst is reduced, which has been reinforced by the spin density for the monoreduced specie [Ti12Nb6O44]11−. Three kinds of possible protonated isomers [HTi12Nb6O44]9− are discussed. The results reveal that the preferred protonation sites correspond to bridging oxygens NbOTi. In addition, the calculation of electronic spectrum shows that there is an obvious intramolecular charge transfer from oxygen to metal. The solvent effects were also considered in the calculations by using a conductor‐like screening model (COSMO) of solvation with the solvent‐excluding surface. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2009

The effects of oxidation and protonation on the N-glycosidic bond stability of 8-oxo-2′-deoxyguanosine: DFT study

This work is an attempt to evaluate the ability of protonation of 8-oxo-2′-deoxyguanosine (8-oxodG) and the effects of oxidation and protonation on its N-glycosidic bond stability by using the density functional theory B3LYP/6-31++G(d, p) method. In all modified forms, the length of the N9–C1′ bond increases as compared to the neutral system 8-oxodG. Especially, the changes are much more obvious for the di-cationic systems. The analysis for the ability of protonation indicates that for the mono-protonated systems, the O8 atom becomes the preferred protonation site in the gas phase. From the dissociation energies of the N-glycosidic bond, it has been found that the homolytic cleavage becomes more difficult upon introducing positive charge in the base ring. In contrast, these systems favor significantly the heterolytic cleavage, especially for the di-cationic systems in which the dissociation energy values are negative. The influence is most prominent with the mono-cation obtained by O8 protonation.

Infrared spectroscopy and structure of photochemically protonated biomolecules in the gas phase: a noradrenaline analogue, lysine and alanyl alanine

A novel photochemical technique combined with mass spectrometry and resonant infrared multiphoton dissociation spectroscopy (R-IRMPD) has been used to record infrared vibrational spectra of the free protonated noradrenaline analogue, 2-amino-1-phenylethanol (APE-H(+)), the amino acid, lysine (Lys-H(+)), and the dipeptide, alanyl alanine (Ala-Ala-H(+)) in the gas phase. Coupling their spectra, obtained in the OH, NH and CH stretch regions, with ab initio calculations has allowed assignment of their preferred protonation sites and conformations. This simple technique will have wide applicability in future investigations of protonated biomolecular structure and conformation.

Reactions of Artemisinin and Arteether with Acid: Implications for Stability and Mode of Antimalarial Action

The currently accepted mechanism of trioxane antimalarial action involves generation of free radicals within or near susceptible sites probably arising from the production of distonic radical anions. An alternative mechanistic proposal involving the ionic scission of the peroxide group and consequent generation of a carbocation at C-4 has been suggested to account for antimalarial activity. We have investigated this latter mechanism using DFT (B3LYP/6-31+G* level) and established the preferred Lewis acid protonation sites (artemisinin O5a>>O4a approximately O3a>O2a>O1a; arteether O4a>or=O3a>O5b>>O2a>O1a; Figure 3) and the consequent decomposition pathways and hydrolysis sites. In neither molecule is protonation likely to occur on the peroxide bond O1-O2 and therefore lead to scission. Therefore, the alternative radical pathway remains the likeliest explanation for antimalarial action.

Comprehensive Study of the Effects of Methylation on Tautomeric Equilibria of Nucleic Acid Bases

Minor tautomers of nucleic acid bases can result by intramolecular proton transfer. These rare tautomers could be stabilized through the addition of methyl groups to DNA bases. A comprehensive theoretical study of tautomers of methylated derivatives of guanine, adenine, cytosine, thymine, and uracil was performed. Molecular geometries of all tautomers were obtained at the density functional theory and MP2 levels with the 6-31G(d,p) basis set, and single-point calculations were performed at the CCSD(T)/6-311G(d,p) level. Tautomers obtained by protonation at the preferred protonation site for methylated isolated bases were compared to their nonmethylated counterparts. The effects of methylation on the relative stabilities of nucleic acid base tautomers are also studied and discussed in this work. The results suggest that some sites on the bases may not be mutagenic and may even stabilize the canonical Watson-Crick form. The results also indicate that a number of methylation sites can stabilize the tautomers, suggesting possible mechanisms for mutagenic changes.

Density functional study of protonation sites of α‐Keggin isopolyanions

AbstractDensity functional theory (DFT) calculations were carried out to characterize the optimal site of the protons and the precise protonation state in the polyoxometalate (POM) anions [V13O40]15− and [H12V13O40]3−. Six kinds of possible protonated stable isomers with the whole Keggin anion units are discussed. The calculations reveal that the preferred protonation site corresponds to bridging oxygens that belong to the same trimetallic group (isomers B and C). Both isomers B and C are comparatively stable in the gas phase, but only isomer B could exist stably in aqueous solution because of being stabilized by the electrostatic interaction. The solvent effects and protonation are also discussed. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2006

Polyglycine Conformational Analysis: Calculated vs Experimental Gas-Phase Basicities and Proton Affinities

Structures of neutral and protonated polyglycines (Gly(n) and Gly(n)H(+) with n = 1-6) in the vicinity of global energy minima were calculated using the density functional theory at the B3LYP/6-311++G** (A) and B3LYP/6-31+G** (B) levels. Ninety-three structures were chosen for conformation and protonation studies. Geometries of the peptides are found to vary from open chains to multiple rings. Intramolecular hydrogen bonding is deduced to be the driving force for conformational stability. The preferred protonation sites are shown to be the terminal nitrogen atom and its adjacent amide oxygen atom. Structural series are developed according to geometrical form, hydrogen bonding, and protonation site. Physical factors that influence the relative electronic and thermodynamic stabilities of different structural series are examined. To obtain ab initio values of highest quality for gas-phase basicity (GB) and proton affinity (PA), electronic energies for n = 1-6 and thermal corrections to Gibbs free energy and enthalpy for n = 1-3 were calculated at level A, supplemented by thermal corrections for n = 4-6 at level B. Calculated GB and PA values are compared with mass spectral results obtained by the kinetic method (KM) and reaction bracketing (RB). The KM results and the ab initio values derived from structurally compatible pairs of lowest free energies are generally in good agreement, but the RB results for GB are lower by 2-8 kcal/mol for n = 2-6. Several reaction pathways are proposed to elucidate the experimental results. On the basis of theoretical structures consistent with the measurements, it is concluded that KM mostly samples the neutral and protonated structures of highest populations at thermal equilibrium, whereas RB targets those with sterically most accessible sites for protonation and deprotonation.

On the Relationship between the Preferred Site of Hydrogen Bonding and Protonation

Ab initio molecular orbital calculations have been employed to investigate the interactions between a set of basic substrates (B) with H+ and HF, and the interaction between acids of varying strength (AH+) with two bases, vinylamine and furan. The preferred site for protonation of the substrates appears to be determined primarily by the ability of the protonated species (BH+) to delocalize the acquired positive charge. On the other hand, localization of a pair of electrons at a proton-acceptor site of B tends to be more important in determining the preferred site for hydrogen bonding with HF. The behavior of acids stronger than HF lies between these extremes. Consistent with a previously proposed Hammond postulate for complexes, when a substrate (B) interacts with a range of acids (AH+), proton transfer is generally found to occur when the proton affinity of A is significantly less than that of B. When the proton affinity of A is greater than that of B, a hydrogen-bonded complex is generally formed without proton transfer. Strongest binding (relative to the lowest energy components) occurs when the proton affinities of A and B are comparable. Proton transfer from AH+ is found to take place in some cases when this would not be predicted on the basis of protonation energies alone, because of specific interactions in the resulting complexes.

Proton Affinity of β-Oxalylaminoalanine (BOAA): Incorporation of Direct Entropy Correction into the Single-Reference Kinetic Method

A new version of the single-reference-extended kinetic method is presented in which direct entropy correction is incorporated. Results of calibration experiments with the monodentate base pyridine and the bidentate base ethylenediamine are presented for which the method provides proton affinities in excellent agreement with published values and reasonable predictions for the protonation entropies. The method is then used to determine the proton affinity and protonation entropy of the non-protein amino acid beta-oxalylaminoalanine (BOAA). The PA of BOAA is found to be 933.1 +/- 7.8 kJ/mol and a prediction for the protonation entropy of -39 J mol(-1) K(-1) is also obtained, indicating a significant degree of intramolecular hydrogen bonding in the protonated form. These results are supported by hybrid density functional theory calculations at the B3LYP/6-311++G**//B3LYP/6-31+G* level. They indicate that the preferred site of protonation is the alpha-nitrogen atom (PA = 935.0 kJ/mol) and that protonated BOAA has a strong hydrogen bond between the hydrogen on the alpha-amino group and one of the carbonyl oxygen atoms on the side chain.

Electronic Properties and Stability of DititaniumIV Substituted α‐Keggin Polyoxotungstate with Heteroatom Phosphorus by DFT

AbstractFor Abstract see ChemInform Abstract in Full Text.

Ab initio study of the energetics of protonation and deprotonation of the methyl 3-amino-2,3-dideoxyhexopyranosides isomers

In order to determine the preferred protonation and deprotonation sites for four isomers of methyl 3-amino-2,3-dideoxyhexopyranoside with the α/β- d- arabino and β/α- d- ribo configurations, ab initio quantum chemical calculations were performed in the gaseous phase with two methods: Restricted Hartree Fock (RHF) and Møller-Plesset (MP2), as well as after consideration of the solvation effects within the Polarizable Continuum Model (PCM). The energy and Gibbs free energy of the protonation and deprotonation were calculated using a Gaussian 6-31+G* basis set. Hydrogen bond lengths in the studied compounds were calculated using theoretical methods applied (RHF<MP2 and PCM). The proposed mechanism for the protonation and deprotonation process includes the formation of intramolecular hydrogen bonds.

Competitive Trapping of Equilibrating Pt(IV) Hydridoalkyl and Pt(II) Alkane Complexes: A Valuable Tool for the Mechanistic Investigation of C—H Activation Reactions

AbstractFor Abstract see ChemInform Abstract in Full Text.

1H, 13C and 15N NMR assignments of phenazopyridine derivatives

Phenazopyridine hydrochloride (1), a drug in clinical use for many decades, and some derivatives were studied by one- and two-dimensional (1)H, (13)C and (15)N NMR methodology. The assignments, combined with DFT calculations, reveal that the preferred protonation site of the drug is the pyridine ring nitrogen atom. The chemoselective acetylation of phenazopyridine (2) and its influence on the polarization of the azo nitrogen atoms were evidenced by the (15)N NMR spectra. Molecular calculations of the phenazopyridines 2-4 show that the pyridine and phenyl groups are oriented in an antiperiplanar conformation with intramolecular hydrogen bonding between the N-b atom and the C-2 amino group preserving the E-azo stereochemistry.