Studies on the Protonation and Complexations of Dioxotetraamine Macrocycles

ＳｔｕｄｉｅｓｏｎｔｈｅＰｒｏｔｏｎａｔｉｏｎａｎｄＣｏｍｐｌｅｘａｔｉｏｎｓｏｆＤｉｏｘｏｔｅｔｒａａｍｉｎｅＭａｃｒｏｃｙｃｌｅｓＳｔｕｄｉｅｓｏｎｔｈｅＰｒｏｔｏｎａｔｉｏｎａｎｄＣｏｍｐｌｅｘａｔｉｏｎｓｏｆＤｉｏｘｏｔｅｔｒａａｍｉｎｅＭａ...     

Protonation of γ-Butyrolactone and γ-Butyrolactam

Abstract : γ-Butyrolactone and γ-butyrolactam were reacted in the superacidic systems XF/MF₅ (X=H, D; M=As, Sb). Salts of the monoprotonated species of γ-butyrolactone were obtained in terms of [(CH₂)₃OCOH]⁺[AsF₆]⁻, [(CH₂)₃OCOH]⁺[SbF₆]⁻ and [(CH₂)₃OCOD]⁺[AsF₆]⁻ and the analogous lactam salts in terms of [(CH₂)₃NHCOH]⁺[AsF₆]⁻, [(CH₂)₃NHCOH]⁺[SbF₆]⁻ and [(CH₂)₃NDCOD]⁺[AsF₆]⁻. The salts were characterized by low temperature Raman and infrared spectroscopy and for both protonated hexafluoridoarsenates, [(CH₂)₃OCOH]⁺[AsF₆]⁻ and [(CH₂)₃NHCOH]⁺[AsF₆]⁻, single-crystal X-ray structure analyses were conducted. In addition to the experimental results, quantum chemical calculations were performed on the B3LYP/aug-cc-pVTZ level of theory. As in both crystal structures C⋅⋅⋅F contacts were observed, the nature of these contacts is discussed with Mapped Electrostatic Potential as a rate of strength.     

Effect of Ionic Strength and Temperature on the Protonation of Oxidized Glutathione

The protonation constants for oxidized glutathione, H _i−1L^(4−i+1)−, K _i ^H=[H _i L⁽⁴⁻ⁱ⁾⁻]/[H _i−1L^(4−i+1)−][H⁺] i=1,2,…,6 have been measured at 5, 25 and 45 °C as a function of the ionic strength (0.1 to 5.4 mol⋅[kg(H₂O)]⁻¹) in NaCl solutions. The effect of ionic strength on the measured protonation constants has been used to determine the thermodynamic values (K _i ^H0) and the enthalpy (ΔH _i ) for the dissociation reaction using the SIT model and Pitzer equations. The SIT (ε) and Pitzer parameters (β ⁽⁰⁾, β ⁽¹⁾ and C) for the dissociation products (L⁴⁻, HL³⁻, H₂L²⁻, H₃L⁻, H₄L, H₅L⁺, H₆L²⁺) have been determined as a function of temperature. These results can be used to examine the effect of ionic strength and temperature on glutathione in aqueous solutions with NaCl as the major component (body fluids, seawater and brines).     

On the Role of the Solvent and Substituent on the Protonation Equilibria of Di-Substituted Anilines in Dioxane–Water Mixed Solvents

Protonation constants of a number of di-substituted anilines were determined potentiometrically in 0, 20, 30, 40, 50, and 60% (v/v) dioxane–water mixtures at (25.00 ± 0.02) ^∘C with an ionic strength of 0.10 mol-dm⁻³ sodium perchlorate. The data are discussed in terms of the electronic character of the substituents. Two different methods were used to study the effects of the solvents on the protonation constants; one involved a single polarity parameter, the Dimroth–Reichardt parameter E_T(30); the other involved the Kamlet–Taft multi-parametric method. The protonation constants of di-substituted anilines correlate with the molecular parameters for the dipolarity/polarizability of the solvent, π^∗, and its hydrogen-bond acceptor ability, β.     

Study of Solvent Effects on the Protonation of Functional Group of Disubstituted Anilines: Factor Analysis Applied to the Correlation between Protonation Constants and Solvatochromic Parameters in Ethanol–Water Mixtures

Summary. The stoichiometric protonation constants (log β) of some disubstituted aniline derivatives in ethanol–water mixtures (0–90% ethanol by volume) at 25.0 ± 0.1°C were firstly submitted to factor analysis in order to obtain the number factors which affect the variation of the whole data sets and, afterwards, submitted to target factor analysis to identify these factors. The influence of solvatochromic parameters in the interactions between aniline derivatives and the solvent studied was identified and quantified. The general equation of Kamlet and Taft was reduced for these mixtures to two terms using combined factor analysis (FA) and target factor analysis (TFA): the independent term and the hydrogen-bond donating ability, α (HBD), solvatochromic parameters. Further, the quasi-lattice quasi-chemical (QLQC) theory of preferential solvation has been applied to quantify the preferential solvation by water of electrolytes in ethanol–water mixtures. The effects of the substituents on the protonation constants, the additivities of these effects, and the applicability of the Hammett equation to the behavior of substituents are also discussed. Further, Hammett’s reaction constant for the protonation of disubstituted anilines has been obtained for all the solvent mixtures and correlates well with α (HBD) of the solvent.     

Heat Effect of the Protonation of Glycine and the Enthalpies of Resolvation of Participating Chemical Species in Water–Dimethylsulfoxide Solvent Mixtures

Enthalpies of the protonation of glycine in water?dimethylsulfoxide (DMSO) mixed solvents are determined calorimetrically in the range of DMSO mole fractions of 0.0 to 0.9, at T = 298.15 K and an ionic strength μ = 0.3 (NaClO₄). It is established that the protonation of glycine becomes more exothermic with an increasing mole fraction of DMSO, and the enthalpies of resolvation of glycine and glycinium ions in water?DMSO solvent mixtures are calculated. It is shown that the small changes in the enthalpy of protonation observed at low mole fractions of DMSO are caused by the contributions from the solvation of proton and protonated glycine cancelling each other out. The enthalpy term of the Gibbs energy of the reaction leading to the formation of glycinium ion is estimated along with the enthalpy of resolvation of the reacting species in the water?DMSO mixed solvent.     

Enantioselective Protonation of Itaconimides with Thiols and the Rotational Kinetics of the Axially Chiral C?N Bond

Bicyclic guanidines are able to catalyze the protonation reactions of 2‐phthalimidoacrylates with thiols in excellent yields and enantioselectivities. The protonation reaction of itaconimides with secondary phosphine oxides is also known. Herein, the tandem conjugate addition–enantioselective protonation of N‐substituted itaconimides with thiols catalyzed by chiral bicyclic guanidine is investigated. The rotational barrier of the C? N axis of N‐2‐tert‐butyl phenylitaconimide is also studied, both experimentally and computationally.     

Protonation and coordination ability of small peptides – theoretical and experimental approaches for elucidation

This review deals with modern theoretical and experimental approaches as well as structural elucidation of small peptides (SP), their protonated forms and metal complexes. Free peptide bond rotation in amino acids (AA) and peptides yielded various conformers, which may possess differing biological activities. Inter- and/or intramolecular stacking observed in aromatic SP is another phenomenon typical for both peptide salts and complexes. These phenomenological effects can be successfully studied, both theoretically and experimentally, using a combination of the theoretical approximations and physical methods, such as electronic absorption spectroscopy, vibrational spectroscopy (including IR and Raman), nuclear magnetic resonance, mass spectrometry, as well as single-crystal X-ray diffraction. The physical and chemical properties of these systems can be precisely calculated by ab initio and DFT methods, varying basis sets and the results obtained allow elucidation of their conformations as a function of the reaction conditions (pH, type of the solvent, temperature, metal to ligand molar ratio). Although the 3-D structures of many peptides have been determined over the past decades, peptide crystallization is still a major obstacle to crystallographic work and the presence of chiral center/s adds further difficulties. For this reason, a specific part of the review is focused on the study of the absolute structure of the peptides, their salts and metal complexes, discussing the conformational preferences of the peptides during these processes. The available crystallographic data for metal complexes are successfully used for the correlation between the structures and the spectroscopic properties.     

The Determination of the Protonation Constants of A New Macrocyclic Dinucleating Ligand, BDBPH

One of our current interests focuses on the design and synthesis of polyaza macrocyclic ligands, the determination of their protonation constants, and the stabilities of corresponding metal complexes. Two polyazadiphenol macrocycles, R(babp)2(dfc)21 and [24]RBPyBC2, one octaazamacrocycle, BPBD3,4, and several hexaaza macrocyclic ligands, BFBD5, BMXD6, and OBISDIEN7, have been reported recently. We have also reported the synthesis of a new dinucleating 24-membered hexaazadiphenol macr…     

Effect of Water–Ethanol Solvents on the Protonation Constants of Cryptand[2.2.2]

The protonation constants of cryptand[2.2.2] are determined potentiometrically at 298 K in water–ethanol solvents of variable composition. An increase in the concentration of a solution’s nonaqueous component reduces the equilibrium constants of the reactions of mono- and biprotonated cryptand[2.2.2] formation. The contribution from the resolvation of reagents to the change in the Gibbs energy of the studied reactions is estimated. The reduction in the protonation constants of cryptand[2.2.2] in water–ethanol solvents is mainly due to enhancement of the solvation of protons in water–ethanol mixtures.     

Nonaqueous Solution Studies on the Protonation Equilibria of some Phenolic Acids

The protonation equilibria for some phenolic acids in nonaqueous solutions have been studied by pH-potentiometry. The dissociation constants, pK _a, of these phenolic acids and the thermodynamic functions, ΔG ^o,ΔH ^o and ΔS ^o, for the successive and overall protonation processes of these phenolic acids have been derived at different temperatures in three different mixtures of water and dioxane (mole fractions of dioxane were 0.083, 0.174 and 0.33). Titrations were also carried out in (water + dioxane) with ionic strengths of 0.15, 0.20 and 0.25 mol⋅dm⁻³ NaNO₃, and the resulting dissociation constants are reported. A detailed thermodynamic analysis of the effects of organic solvent, dioxane, temperature and ionic strength on the protonation processes of phenolic acids is presented and discussed to determine the factors which control these processes. Ahmed E. Fazary; previous address: Egyptian Organization for Biological Products and Vaccines, 51 Wezaret El-Zeraa Street, Agouza, Giza, Egypt. Tel. +2010-3017357.     

Studies of the dissociation and the protonation of TB-chlorosulphophenol

The dissociation constant of each step for TB-chlorosulphophenol has been determined by potentiometric method, and the thermodynamic constants, △G°, △H° and △S°, of the dissociation process have been calculated. The protonation constants were measured by the spectrophotometric method. The pH values of various forms of anions of the chromogenic reagent at their concentrations were also calculated.     

Protonation sites in methyl nitrate and the formation of transient CH4NO3 radicals. A neutralization—reionization mass spectrometric and computational study

Protonation sites in methyl nitrate (1) were evaluated computationally at the Gaussian 2(MP2) level of ab initio theory. The methoxy oxygen was the most basic site that had a calculated proton affinity of PA = 728–738 kJ mol⁻¹ depending on the optimization method used to calculate the equilibrium geometry of the CH₃O(H)-NO₂⁺ ion (2⁺). Protonation at the terminal oxygen atoms in methyl nitrate was less exothermic; the calculated proton affinities were 725, 722, and 712 kJ mol⁻¹ for the formation of the syn-syn, anti-syn, and syn-anti ion rotamers 3a⁺, 3b⁺, and 3c⁺, respectively. Ion 2⁺ was prepared by an ion-molecule reaction of NO₂⁺ with methanol and used to generate the transient CH₃O(H)-NO₂^. radical (2) by femtosecond collisional electron transfer. Exothermic protonation of 1 produced a mixture of 3a⁺–3c⁺ with 2⁺ that was used to generate transient radicals 3a–3c. Radical 2 was found to be unbound and dissociated without barrier to methanol and NO₂. Radicals 3a–3c were calculated to be weakly bound. When formed by vertical neutralization, 3a–3c dissociated completely on the 4.2 μs time scale of the experiment. The main dissociations of 3a–3c were formations of CH₃O^. + HONO and CH₃ONO + OH^.. The gas-phase chemistry of radicals 3a–3c and their dissociation products, as studied by neutralization—reionization mass spectrometry, was dominated by Franck—Condon effects on collisional neutralization and reionization. The adiabatic ionization energies of 3a–3c were calculated as 7.54, 7.57, and 7.66 eV, respectively.     

Protonation states of the catalytic dyad of β-secretase (BACE1) in the presence of chemically diverse inhibitors: a molecular docking study

In this molecular docking study, the protonation states of the catalytic Asp dyad of the beta-secretase (BACE1) enzyme in the presence of eight chemically diverse inhibitors have been predicted. BACE1 catalyzes the rate-determining step in the generation of Alzheimer amyloid beta peptides and is widely considered as a promising therapeutic target. All the inhibitors were redocked into their corresponding X-ray structures using a combination of eight different protonation states of the Asp dyad for each inhibitor. Five inhibitors were primarily found to favor two different monoprotonated states, and the remaining three favor a dideprotonated state. In addition, five of them exhibited secondary preference for a diprotonated state. These results show that the knowledge of a single protonation state of the Asp dyad is not sufficient to search for the novel inhibitors of BACE1 and the most plausible state for each inhibitor must be determined prior to conducting in-silico screening.     

Solute–Solvent Interaction Effects on Protonation and Aggregation Constants of TTMAPP in Different Aqueous Solutions of Methanol

The protonation constants of 5,10,15,20-tetrakis(4-trimethyl-ammonio-phenyl)-porphine tetratosylate (TTMAPP) were determined in water–methanol mixed solvents, using a combination of spectrophotometric and potentiometric methods at 25 °C in 0.1 mol·dm^?3 sodium perchlorate. Two protonation constants, K ₁ and K ₂, were characterized and analyzed in various media in terms of the normalized polarity parameter ( $ E_{\text{T}}^{\text{N}} $ E T N ). A linear correlation is observed when the experimental log₁₀ K ₁ and log₁₀ K ₂ values are plotted versus the calculated ones over the range of 40–90 % (v/v) methanol. The self aggregation of TTMAPP was observed from acidic media (pH ? 3) to alkaline pH, where it reached its highest intensity, when methanol is lower than 40 % in solution. The formation of aggregate species prevents a quantitative analysis of titration curves and thus, the determination of the protonation constants of TTMAPP. Therefore, to evaluate the protonation constants of TTMAPP in low or zero percent of methanol, the Yasuda–Shedlovsky extrapolation approach has been used.     

Isocyanide in Biochemistry? A Theoretical Investigation of the Electronic Effects and Energetics of Cyanide Ligand Protonation in [FeFe]‐Hydrogenases

The presence of Fe‐bound cyanide ligands in the active site of the proton‐reducing enzymes [FeFe]‐hydrogenases has led to the hypothesis that such Brønsted–Lowry bases could be protonated during the catalytic cycle, thus implying that hydrogen isocyanide (HNC) might have a relevant role in such crucial microbial metabolic paths. We present a hybrid quantum mechanical/molecular mechanical (QM/MM) study of the energetics of CN^? protonation in the enzyme, and of the effects that cyanide protonation can have on [FeFe]‐hydrogenase active sites. A detailed analysis of the electronic properties of the models and of the energy profile associated with H₂ evolution clearly shows that such protonation is dysfunctional for the catalytic process. However, the inclusion of the protein matrix surrounding the active site in our QM/MM models allowed us to demonstrate that the amino acid environment was finely selected through evolution, specifically to lower the Brønsted–Lowry basicity of the cyanide ligands. In fact, the conserved hydrogen‐bonding network formed by these ligands and the neighboring amino acid residues is able to impede CN^? protonation, as shown by the fact that the isocyanide forms of [FeFe]‐hydrogenases do not correspond to stationary points on the enzyme QM/MM potential‐energy surface.     

Protonation Constants of Uridine 5′-Monophosphate in Different Aqueous Solutions of Methanol

The protonation equilibria of uridine 5′-monophosphate disodium salt (UMP) was determined in binary solvent mixtures of water–methanol containing 0, 10, 15, 20, 25, 30, 35, 40, 45, and 50 % (v/v) methanol, using a combination of spectrophotometric and potentiometric methods at 25 °C and constant ionic strength (0.1 mol·dm^?3 NaClO₄). The protonation constants were analyzed using Kamlet, Abboud, and Taft parameters. A good linear correlation of the protonation constants (on the logarithmic scale) was obtained. Dual-parameter correlation of log₁₀ K versus π* (dipolarity/polarizability) and α (hydrogen-bond donor acidity), as well as π* and β (hydrogen-bond acceptor basicity), gave good results in various aqueous solutions of methanol. Finally, the results are compared with CMP, a homolog of UMP, and are discussed in terms of the effect of the solvent on the protonation constants.     

Density functional theory (DFT) and ab initio investigations of the electronic and molecular structures of the monomer and the dimer of trimethylaluminium

The electronic and molecular structures of the monomer and dimer of trimethylalu-minium have been studied using density functional theory and ab initio MP2 method. The optimized geometry of the monomer Al(CH3)3 is of C3h symmetry, whereas that of the dimer [A1(CH3)3]2 contains a carbon-bridged four-membered ring structure with C2h symmetry. The hydrogen-bridged six-membered ring structure is found to be unstable. The calculated dimerization energy for the four-membered ring structure is 78 kJ/mol, in close proximity to the experimental value of 85.27 kJ/mol.     

Analysis of the hyperfine structures and

From the theories of the nuclear hyperfine structure (HFS) and Λ doubling of diatomic molecules, several brief algebraic equations for interpretation of HFS and Λ doubling of transitions of diatomic molecule have been developed. A few important parameters of HFS and Λ doubling of¹⁵N¹⁶O have been efficiently and accurately obtained from the analysis of the high resolution spectra of¹⁵N¹⁶O (X²∏) observed in our experiments with these equations. This method can provide an effective approach to obtain important hyperfine parameters of novel radicals from their high resolution laser magnetic resonance spectra. Liu Yu-yan, Guo Yuan-qing, Assignments of FIR-LMR spectra of CF X²∏(υ= 1) and MIR-LMR spectra of NO X²∏ (υ =1←0), Spectroscopy and Spectral Analysis (in press).