Protonation of aminopyrone: A four centers problem,CNDO/2 versus MNDO study

The mechanism of protonation of aminopyrones and the nature of the protonated forms are of some interest because of the biological importance of these compounds. The use of CNDO/2 molecular electrostatic potentials contour maps shows that the most reactive centre is the extracyclic oxygen. MNDO protonation energies confirm the protonation of this atom and elucidate the basicity of the nitrogen atom. The effect of a N substitution on the basicity of the N₁₃ atom has been studied. The calculations are in agreement with preliminary experimental results.     

The protonation of three-membered ring molecules Theab initio SCF versus the electrostatic picture of the proton approach

The protonation processes for eight three-membered ring molecules have been investigated using the SCF LCAO MO method with Gaussian basis sets and the results are compared with those obtained at the first order approximation, i.e. the electrostatic approximation. The electrostatic results are linearly connected with the SCF ones and are sufficient to get an ordering of the protonation energies in different chemical sites and to obtain reliable representations of the proton approaching paths.     

A simple electrostatic model of solvation for large molecules within the SCF MO theory

A very simple electrostatic model of solvation in which the solvent molecules are represented by point dipoles has been applied to simulate the hydration effect on molecular systems within the CNDO/2 method. The limitations of the model compared to the previous approaches as well as its feasible application to the study of tautomeric equilibria of cytosine and adenine in aqueous solution are discussed.     

Isomerism and Protonation of α-Diazocarbonyl Compounds. A Molecular Orbital Study

CNDO/2, MINDO/3 and ab initio molecular orbital calculations are used in a study of conformational isomerism, protonation site and mechanism of protonation of the title compounds.     

Valence shell calculations on polyatomic molecules

Dipole moments and charge distributions for twenty molecules of widely different types have been calculated using (a) the CNDO/2 method and (b) a CNDO/2D method in which the orbitals from the CNDO/2 method are deorthogonalized by a Löwdin transformation and are then used to calculate the dipole moments in a rigorous manner. A statistical analysis of the results for the dipole moments calculated by the CNDO/2D method shows that they are in very slightly better agreement with experiment than those from the CNDO/2 method. The net charge distributions from the CNDO/2D method follow more closely the trends of ab initio calculations than do the CNDO/2 net charges.

---

Zusammenfassung Dipolmomente und Ladungsdichten von Molekülen unterschiedlichen Typs wurden mittels des CNDO/2- und CNDO/2D-Verfahrens (d. i. mit delokalisierten Löwdin-Orbitalen als AO's) berechnet. Eine statistische Analyse zeigt, daß die Resultate der zweiten Methode etwas besser als die der ersten den experimentellen Ergebnissen folgen. Das Analoge gilt für die Nettoladungsverteilungen in bezug auf die Trends bei ab initio-Rechnungen.

---

Résumé Les moments dipolaires et les distributions de charge pour vingt molécules de types divers ont été calculés par: a) la méthode CNDO/2; b) une méthode CNDO/2D où les orbitales de CNDO/2 sont déorthogonalisées par une transformation de Löwdin. Une analyse statistique montre que les moments dipolaires calculés par CNDO/2D sont légèrement en meilleur accord avec l'expérience que ceux calculés par CNDO/2. Les distributions de charge de CNDO/2D sont plus ressemblantes à celles de calculs ab-initio que ne le sont les distributions de CNDO/2.

---

---

This work represents part of the Ph.D. Dissertation submitted to the University of Virginia by D. D. S. and was supported by Grants No. 1-F01-GM41986-01 from the National Institutes of Health, Bethesda, Maryland, U.S.A., and No. AF-AFOSR-1184-67 from the Air Force Directorate of Scientific Research.

---

NASA Research Trainee.     

A minimalist model for exploring conformational effects on the electrospray charge state distribution of proteins

The electrospray ionization (ESI) charge state distribution of proteins is highly sensitive to the protein structure in solution. Unfolded conformations generally form higher charge states than tightly folded structures. The current study employs a minimalist molecular dynamics model for simulating the final stages of the ESI process in order to gain insights into the physical reasons underlying this empirical relationship. The protein is described as a string of 27 beads ("residues"), 9 of which are negatively charged and represent possible protonation sites. The unfolded state of this bead string is a random coil, whereas the native conformation adopts a compact fold. The ESI process is simulated by placing the protein inside a solvent droplet with a 2.5 nm radius consisting of 1600 Lennard-Jones particles. In addition, the droplet contains 14 protons which are modeled as highly mobile point charges. Disintegration of the droplet rapidly releases the protein into the gas phase, resulting in average charge states of 4.8+ and 7.4+ for the folded and unfolded conformation, respectively. The protonation probabilities of individual residues in the folded state reveal a characteristic pattern, with values ranging from 0.2 to 0.8. In contrast, the protonation probabilities of the unfolded protein are more uniform and cover the range from 0.8 to 1.0. The origin of these differences can be traced back to a combination of steric and electrostatic effects. Residues exhibiting a small accessible surface area are less likely to capture a proton, an effect that is exacerbated by partial electrostatic shielding from nearby positive residues. Conversely, sites that are sterically exposed are associated with electrostatic funnels that greatly increase the likelihood of protonation. Unfolding enhances the steric and electrostatic exposure of protonation sites, thereby causing the protein to capture a greater number of protons during the droplet disintegration process.     

Accurate pKa determination for a heterogeneous group of organic molecules.

Single-molecule studies that allow to compute pKa values, proton affinities (gas-phase acidity/basicity) and the electrostatic energy of solvation have been performed for a heterogeneous set of 26 organic compounds. Quantum mechanical density functional theory (DFT) using the Becke-half&half and B3LYP functionals on optimized molecular geometries have been carried out to investigate the energetics of gas-phase protonation. The electrostatic contribution to the solvation energies of protonated and deprotonated compounds were calculated by solving the Poisson equation using atomic charges generated by fitting the electrostatic potential derived from the molecular wave functions in vacuum. The combination of gas-phase and electrostatic solvation energies by means of the thermodynamic cycle enabled us to compute pKa values for the 26 compounds, which cover six distinct chemical groups (carboxylic acids, benzoic acids, phenols, imides, pyridines and imidazoles). The computational procedure for determining pKa values is accurate and transferable with a root-mean-square deviation of 0.53 and 0.57 pKa units and a maximum error of 1.0 pKa and 1.3 pKa units for Becke-half&half and B3LYP DFT functionals, respectively.     

Torsional isomerization of biologically active bicyclic molecules

Rotational isomerization of bipyridines C₅H₄N? C₅H₄N was studied by CNDO /2, PPP /CI , and CNDO /CI methods. It is shown that CNDO /2 overestimates the angle of rotation ? between the pyridine rings ca. two times. The angle ? was determined for 2,2′-bipyridine by means of correlation of the theoretical (CNDO /2) and experimental dipole moment. It was also found from the correlation between the theoretical and experimental UV spectra. It is shown that there is an explicit dependence of the results upon the distance between heteroatoms (PPP /CI ). It has been found that the CNDO /CI method correctly predicts the value of the rotational angles and their sequence in bipyridines.     

Theoretical treatment of multiple site reactivity in large molecules

The method of electrostatic potentials is generalized via a double perturbation theory to describe the simultaneous attack of a large molecule by two or more charged species. The interaction term is found to reproduce accurately the full “super-molecule” calculation. The scheme is illustrated by treating the diprotonation of adenine and N7-methyladenine. For adenine, the most stable diprotonated species is found to be the N1, N7 combination, while the N3, N9 couple is predicted for the N7 substituted derivative if N3 is the first protonation site.     

Electronic structure of molecules of diphenyl bridge compounds

Using the CNDO/2 method, we have calculated the valence electron density distribution in molecules of diphenylamine and its 13 derivatives with the substituents COOH, NO₂, OCH₃ on the aromatic rings of ionized forms of some diaryl amines, and also 4-amino- and 4-amino-4-adnitro substituted compounds with bridge groups NH, O, S, CH₂, CH=CH and analogous diphenyl derivatives. We have shown that independently of the nature of the bridge group, the principle of uncoupling of the aromatic rings is basically retained. Strong long-range effects of the substitutents along the chain of chemical bonds are not apparent. We have calculated the electrostatic molecular potential of the indicated compounds. We have established correlations between the electrostatic molecular potential and the protonization constants, the oxidation-reduction potentials of diarylamines; and also between the electrostatic molecular potential and the reaction rate constant for acylation of primary bridged amines at the amino group.Translated from Teoreticheskaya i Éksperimental'naya Khimiya, Vol. 21, No. 1, pp. 84–88, January–February, 1985.     

Theoretical study on the protonation of AZA-aromatics

The protonation of azanaphthalenes and azabenzenes has been studied theoretically using CNDO/2 wavefunctions and perturbation theory in order to examine the correlation between pK_a values and quantum-mechanical quantities.[/p]     

PPP and CNDO calculations for protonated molecules

CNDO calculations have been used to obtain the one-centre core integrals for protonated azines required in calculating the ^* absorption spectra of such molecules using the PPP method. Calculated spectra for both the parent and the protonated molecules are obtained in satisfactory agreement with experiment. The changes in the -framework of the molecules on protonation are also discussed in terms of the CNDO results.

---

Zusammenfassung CNDO-Rechnungen wurden benutzt, um die Einzentren-Rumpf-Integrale für protonierte Azine zu erhalten, die bei der Berechnung der ^* -Absorptionsspektren mit Hilfe der PPP-Methode benötigt werden.Die berechneten Spektren für die Ausgangsmoleküle und die protonierten Moleküle sind in zufriedenstellender Übereinstimmung mit dem Experiment. Die Veränderungen im -Rumpf der Moleküle bei der Protonierung werden ebenfalls mit Hilfe der CNDO-Resultate diskutiert.

---

Résumé Des CNDO ont tét utilisés pour obtenir les intégrales de coeur monocentriques des azines protonées nécessaires au calcul de leur spectre d'absorption ^* par la méthode PPP. Les spectres calculés pour les molécules protonées ou non sont en accord satisfaisant avec l'expérience. Les modifications subies lors de la protonation par le squelette sont discutées en fonction des résultats des calculs CNDO.

     

Properties of atoms in molecules

Atomic charges calculated by the population analysis method for three types of semi-empirical wave functions have been compared with charges obtained by integrating the corresponding electronic density functions over individual atomic regions. It was found that the two sets of charges compare quite well for CNDO wave functions and for extended-Hückel functions which are in terms of orthogonalized basis orbitals. However only the CNDO charges are reasonably close to those obtained by integrating near-Hartree-Fock electronic density functions.     

Molecular Orbital Studies of the Protonation of Diazomethane

CNDO/Z, MINDO/3 and ab initio molecular orbital calculations indicate that C-protonated diazomethane is more stable than N(end)-protonated diazomethane. Extrapolation of these results to solution chemistry as well as the kinetic references of protonation of diazomethane are discussed.     

Structure electronique de derives sulfures—III: Dithiole-1,2 thione-3 et mercapto-3 dithiolylium-1,2

CNDO/2 calculations with modified parametrization for d orbitals have been performed on 1,2-dithiol-3-thione and the 3-mercapto 1,2-dithiolium cation. The electronic structures are discussed and compared with some experimental data. The modification of electronic spectra of 1,2-dithiol-3-thione by protonation is interpreted theoretically.     

CNDO calculation of the diamagnetic susceptibilities of cyclic conjugated molecules

We present the results obtained within the CNDO /2 method for the diamagnetic susceptibilities of a series of conjugated molecules including benzene, fulvene, pyridine, pyrrole, and furan. The calculations have been carried out, according to Bley's method, in the framework of coupled Hartree–Fock perturbation theory, using gauge invariant atomic orbitals and the London approximation. The two usual CNDO parametrizations, due respectively to Pople, Santry, and Segal and to Del Bene and Jaffe, did not enable one to obtain the principal susceptibilities of the molecules under consideration. We investigated the effect of the CNDO parametrizations on the different contributions to the susceptibility, and gave a first improvement to Bley's method, which permits the calculation of the mean susceptibility of conjugated molecules with less than 9% error.     

Superelectrophilic activation of 4-heterocyclohexanones. Implications for polymer synthesis. A theoretical study

The stability and the reactivity of mono- and diprotonated 4-heterocyclohexanones as well as cyclohexanone in triflic acid have been studied at the PBE0/aug-cc-pvtz//PBE0/6-31+G** level of theory. In all cases the first protonation is an exergonic process occurring at a carbonyl oxygen except for 4-piperidone where a nitrogen atom is protonated fist. Second protonation is only slightly endergonic for all studied molecules except for cyclohexanone where the second protonation is very unfavorable thermodynamically. According to calculations, diprotonated 4-heterocyclohexanones are much more active in the reactions of triflic acid mediated polyalkoxyalkylation with aromatic hydrocarbons compared to monoprotonated ones. The increase of the reactivity of diprotonated 4-heterocyclohexanones is due to inductive effect rather than through space electrostatic influence as follows from the electronic structure analysis of dications. Moreover, the second protonation reduces the possibility of an aldol condensation side reaction, reducing the enol electrophilicity rendering heterocyclohexanones as promising monomers for superacid mediated polyhydroxyalkylation.     

Calculation of excited-state properties of some small molecules: Comparative study of the CNDO/S and CNDO/2-vn−1 potential methods

The transition energy and geometry of the lowest excited (nπ*) singlet and triplet states of CO, CS, HNO, H₂CO, HFCO, and F₂CO molecules are calculated by CNDO /S and CNDO /2-V_N?1 potential methods, and the results are compared with those of experimental and ab initio theoretical studies, wherever available. In the calculation of the vertical transition energy, the performance of the CNDO /S method is seen to be generally more satisfactory than that of the CNDO /2-V_N?1 potential method, while the reverse is true for the excited-state geometry. The CNDO /S method as such fails to describe the geometry of the excited state, but a combined version (CNDO /S-2) of CNDO /S and CNDO /2, as well as the CNDO /2-V_N?1 potential method is fairly successful in this regard.     

Calculation of chlorine Kα1,2 X-ray emission shifts in molecules

Shifts of the chlorine Kα_1,2 X-ray emission line in gaseous molecules and in crystalline NaCl are correlated with effective atomic charges from CNDO/2 molecular orbital calculations made (i) for the neutral atomic ground states. and (ii) within the equivalent core approximation. For the latter case CNDO/2 parameters are derived for argon. The best agreement with experimental chemical shifts is obtained with the equivalent cores approximation. The results for NaCl depend strongly upon the CNDO/2 treatment of sodium.     

Systémes aromatiques á dix electrons π derives de l'aza-3a-pentalene—XXI: Etude Théorique et expérimentale de tetraazapentalénes

Four tetra-azapentalenes, pyrazolo[1,5-b], pyrazolo[3,2-c], imidazo[1,2-b] and imidazo[2,1-c]s-triazole, have been studied. The synthesis of the third compound and of a salt of the last are described for the first time. Physical properties calculated for the more stable tautomer by CNDO/2 and CNDO/S (reactivity, proton chemical shift, dipole moment and electronic absorption) are in good agreement with experimental values.The protonation sites of imidazo[1,2-b] and imidazo[2,1-c]s-triazole as shown by UV and NMR are compared with theoretical results.