Determination of the Dissociation Constants of Urocanic Acid Isomers in Aqueous Solutions

(E)- and (Z)-Urocanic acids are endogenous chemicals in the normal mammalian skin. The first and the second thermodynamic dissociation constants (pK _a1 and pK _a2) of urocanic acid isomers were determined using UV spectrophotometry in aqueous solutions. The values with standard deviation (pK _a1 = 3.43 ± 0.12 and pK _a2 = 5.80 ± 0.04) and (pK _a1 = 2.7 ± 0.3 and pK _a2 = 6.65 ± 0.04) were obtained to (E)- and (Z)-urocanic acids, respectively. The second dissociations were studied also by potentiometric titration in aqueous sodium chloride solutions up to the isotonic salt concentration (0.154 mol dm⁻³), and the second thermodynamic dissociation constants as well as activity parameters for both isomers were determined at temperature 25°C and for (E)-urocanic acid also at 37°C. The obtained pK _a2 values were close to those found by UV spectrophotometry. The equations for the calculation of the second stoichiometric dissociation constants of urocanic acid isomers on molality and molarity scale in aqueous sodium chloride solutions were derived. The obtained pK _a1 and pK _a2 values for (Z)-urocanic acid appear to be essentially lower than some previously reported values in literature.     

Quantum-chemical gas-phase calculations on the protonation forms oftrans- andcis-urocanic acid

The neutral, cationic, and anionic structures of both prototropic tautomers oftrans- andcis-urocanic acid [(E)- and (Z)-3-(1H-imidazol-4(5)-yl)propenoic acid, respectively] were studied by using semiempirical andab initio gas-phase calculations. Potential energy surfaces of the structures were calculated by using the semiempirical AM1 method, and the geometries corresponding to global minima on these surfaces were optimized up to the MP2/6-31G^* level of theory. The calculated protonation forms of each urocanic acid isomer have a planar molecular structure due to a delocalized -electron system, and all of them prefer thes-trans conformation with respect to the bond between the imidazole and the propenoic acid moieties. Thecis-urocanic acid structures are stabilized by an intramolecular hydrogen bond. The chargedcis-urocanic acid isomers have a lower molecular energy than the correspondingtrans-isomers, whereas the neutral molecules have, after inclusion of thermodynamic corrections, approximately the same energy. The cationic urocanic acid structures have about 2500 kJ mol^–1 lower energy than the anionic ones and about 1000 kJ mol^–1 lower energy than the neutral ones. The nonzwitterionic forms of the neutral urocanic acid isomers have about 200 kJ mol^–1 lower energy than the zwitterionic ones. These energy differences are explained by the proton affinities of the imidazole and the propenoic acid moieties of the urocanic acid structures.     

Thermodynamical characteristics of acid-base equilibria in glycyl-glycyl-glycine aqueous solutions at 298 K

The constants and enthalpies of acid dissociation of glycyl-glycyl-glycine peptide in aqueous solutions at 298.15 K and ionic strength values of 0.1, 0.5, and 1.0 M containing NaCl as a background electrolyte, were determined by potentiometry and calorimetry. The standard values of pK ₁^° and pK ₂^° constants, the change of Gibbs energy, enthalpy, and entropy for the dissociation processes were calculated. It was found that the acidic properties of the carboxylic group in aqueous solution subside upon the transition from α-amino acids to peptides due to the lower entropy effect of dissociation. It was concluded that the increase of dissociation constant of a protonated peptide amino group upon an increase in the length of its molecule is determined by entropy factor associated with the attenuation of amino group solvation.     

Spectrophotometric Studies on Ferron and Thorium (IV)-Ferron Chelate

The ionization constants of ferron (7-iodo-8-hydroxyquinoline-5-sulphonic acid) and the interaction between Th(IV) and ferron have been studied spectrophotometrically at 25° and ionic strength of 0.1. The ionization constants were found to be pK₁=2.41±0.01, pK₂=7.10±0.01. The Th(IV)-ferron chelate in aqueous solution of pH 5.0 exhibited a characteristic absorption maximum at 365 mμ. The composition of Th(IV)-ferron chelate was 1:4 mole ratio of Th(IV) ion and ferron, and the stability constant (log K_g) was 26.22±0.16.     

Oxidation of formic acid by bromine in aqueous,strongly acid media

Spectrophotometric methods were used to investigate the rate of the reaction of Br₂ with HCOOH in aqueous, acidic media. The reaction products are Br^? and CO₂. The kinetics of this reaction are complicated by both the formation of Br₃^? as Br^? is formed and the dissociation of HCOOH into HCOO^? and H⁺. Previous work on this reaction was carried out at acidities lower than the highest used here and led to the conclusion that only HCOO^? reacts with Br₂. It is agreed that this is by far the principal reaction. However, at the highest acidity experiments, an added small component of reaction was found, and it is suggested that it results from the direct reaction of Br₂ with HCOOH itself. On this assumption, values of the rate constants for both reactions are derived here. The rate constant for the reaction of HCOO^? with Br₂ agrees with values previously reported, within a factor of 2 on the low side. The reaction involving HCOOH is more than 2000 times slower than the reaction involving HCOO^?, but it does contribute to the overall rate as [H⁺] approaches 1M. These derived rate constants are able to simulate quantitatively the authors' absorbance-versus-time data, demonstrating the validity of their data treatment methods, if not mechanistic assignments. Finally, activation parameters were determined for both rate constants. The values obtained are: ΔE^?(HCOOH + Br₂) = 13.3 ± 1.1 kcal/mol, ΔS^? (HCOOH + Br₂) = ?28 ± 3 cal/deg mol, ΔE^? (HCOO^? + Br₂) = 13.1 ± 0.9 kcal/mol, and ΔS^?(HCOO^? + Br₂) = ?12 ± 1 cal/deg mol. That the activation energies of the two reactions turn out to be essentially identical does not support the authors' suggestion that both HCOOH and HCOO^? react with Br₂.     

Chemistry of trifluorostyrenes and their dimmers: 3. Solvent effect on the kinetic parameters of the thermal cyclodimerization of α, β, β-trifluorostyrene1

Rate constants for the thermal cyclodimerization of α, β, β-trifluorostyrene (TFS) were determined in six solvents at 393°K. The products of this reaction were mixtures of roughly equal amounts of cis-trans isomers. The rate constants in 3 solvents, were calculated according to Arrhenius equation. In n-hexane, log A = 6.02±0.18, E_a= 19.5±0.3 kcal.mol^?1; in glyme, logA = 5.31 ± 0.19, E_a= 18.0±0.3 kcal.mol^?1; in methanol, IogA=4.93±0.13, E_a=17.1±0.3 kcal mol^?1. All data are consistent with a stepwise radical mechanism, and our reaction in this solvent series obeys an isokinetic relationship, with β = 478°K.     

Solute–solvent interaction effects on second‐order rate constants of reaction between 1‐chloro‐2,4‐dinitrobenzene and aniline in alcohol–water mixtures

The second‐order rate coefficients for aromatic nucleophilic substitution reaction between 1‐chloro‐2,4‐dinitrobenzene and aniline have been measured in aqueous solutions of ethanol and methanol at 25°C. The plots of rate constants versus mole fraction of water show a maximum in all‐aqueous solutions. The effect of four empirical solvent parameters including hydrogen bond donor acidity (α) dipolarity/polarizability (π^*) normalized polarity (E^N_T) and solvophobicity (Sp) has been investigated. This investigation has been carried out by means of simple and multiple regression models. A dual‐parameter equation of log k₂ versus Sp and α was obtained in all‐aqueous solutions (n = 41, r = 0.962, s = 0.053, p = 0.0000). This equation shows that solvophobicity and hydrogen bond donor acidity are important factors in the occurrence of the reaction and they have opposite effects on reaction rate. © 2004 Wiley Periodicals, Inc. Int J Chem Kinet 37: 90–97, 2005     

Acid properties of some phosphonocarboxylic acids

Thermodynamic acid dissociation constants were determined for phosphonoacetic acid (PAA) in aqueous solution at 25°C by coulometric titrations at different ionic strengths and extrapolation of the results to I=0. The respective values are pK₁2.0, pK₂=5.11±0.04, and pK₃=8.69±0.05. The enthalpy and entropy of dissociation for the second and the third dissociation steps, determined from the temperature dependence of pK's, are H ₂ ^o =0.2±0.3 kcal-mole^–1, S ₂ ^o =22.6±0.9 e.u., H ₃ ^o =1.3±0.4 kcal-mole^–1, and S ₃ ^o =11.7±0.4 e.u. Phosphorus-31 and carbon-13 NMR studies of PAA solutions as a function of pH gave the deprotonation sequence of the triacid. Acidity constants were also determined for phosphonoformic acid, 2-phosphonopropionic acid, and 3-phosphonopropionic acid at an ionic strenght of 0.05.To whom correspondence should be addressed.     

Syntheses and configurations of some heterocyclic amidoximes. X-Ray crystal structure of 3-phenyl-5,6-dihydro-2(1H)-pyrazinone-O-methyloxime

O-Methyl-α-ketophenylacetohydroximoyl chloride ( 1 ) was prepared by the reaction of O-methyl-α-methoxyphenylacetohydroximoyl chloride ( 5 ) with N-bromosuccinimide and concentrated hydrobromic acid. Reaction of 1 with ethylenediamine gave 3-phenyl-5,6-dihydro-2(1H)-pyrazinone-O-methyloxime ( 6 ). 3-Phenyl-5,6-cyclohexano-5,6-dihydro-2(1H)-pyrazininone-O-methyloxime ( 7 ) was prepared by reaction of 1 with trans-1,2-diaminocyclohexane. The X-ray structure of 6 has been determined. The crystals are orthorhombic, space group Pbca with a = 10.264(3), b = 18.262(4), c = 23.530(4)Å, V = 4411(2)ų, and Z = 16. The structure, which was refined to R = 0.038 using 1652 observed reflections, shows the amidoxime moiety to be the Z configuration. Reaction of benzohydroximoyl chloride with aziridine gave (Z)-aziridinylbenzaldoxime ( 16a ). Ultraviolet irradiation of a benzene solution of 16a gave a mixture of the Z and E isomers 16a and 16b . The E isomer 16b underwent thermal isomerization to 16a at 100°. Reaction of 16a with dimethyl sulfate in sodium hydroxide solution gave (Z)-O-methylaziridinylbenzaldoxime ( 17a ). Photoisomerization of a hexane solution of 17a gave a mixture of the Z and E isomers 17a and 17b which were separated by preparative glc. The isomers 17a and 17b are resistant to thermal Z = E isomerization. The mechanisms of thermal isomerization of benzamidoximes are discussed.     

Polarographic studies of uranyl complexes with trans-and cis-butenedioic acids

The complexation of uranyl ion with fumaric and maleic acids was investigated by polarography and conductometry. The uranyl complexes of the two isomers differ: with fumaric acid, UO₂(HFum)₂ and UO₂Fum₂^2- were observed whereas with maleic acid, only one chelate, UO₂Mal₂^2-, was obtained. The dissociation constants obtained from the half-wave potential vs. pH plots were pK₁=3.05 and pK₂=4.55 for fumaric acid and pK₁=1.90 and pK₂=5.60 for maleic acid.     

Protonation of Chloro-, Bromo- and Iodo-pentacyanocobaltate(III) Complexes

The reactions between Fe(Phen)₃²⁺[phen = tris-(1,10) phenanthroline] and Co(CN)₅X³⁻ (X = Cl, Br or I) have been studied in aqueous acidic solutions at 25 °C and ionic strength in the range I = 0.001–0.02 mol dm⁻³ (NaCl/HCl). Plots of k₂ versus √I, applying Debye–Huckel Theory, gave the values −1.79 ± 0.18, −1.65 ± 0.18 and 1.81 ± 0.10 as the product of charges (Z_AZ_B) for the reactions of Fe(Phen)₃²⁺ with the chloro-, bromo- and iodo- complexes respectively. Z_AZ_B of ≈ −2 suggests that the charge on these Co^III complexes cannot be −3 but is −1. This suggests the possibility of protonation of these Co^III complexes. Protonation was investigated over the range [H⁺] = 0.0001 −0.06 mol dm⁻³ and the protonation constants K_a obtained are 1.22 × 10³, 7.31 × 10³ and 9.90 × 10² dm⁶ mol⁻³ for X = Cl, Br and I, respectively.     

Temperature dependences of the reactions of O(3P) atoms with selected chlorofluoroethenes between 298 and 359 K

The rate constants for the gas‐phase reactions of ground‐state oxygen atoms with CF₂?CFCl (1), (E/Z)‐CFCl?CFCl (2), CFCl?CH₂ (3), and (E/Z)‐CFH?CHCl (4) have been measured directly using a discharge flow tube coupled to a chemiluminescence detection system. The experiments were carried out under pseudo‐first‐order conditions with [O³P)]₀ ? [ethene]₀. The temperature dependences of the reactions were studied for the first time in the range 298–359 K. The proposed Arrhenius expressions (in units of cm³ molecule^?1 s^?1) were k₁ = (1.07 ± 0.32) × 10^?11 exp{?(8000±1600)/RT}, k₂ = (0.56 ± 0.10) × 10^?11 exp{?(8700±500)/RT}, k₃ = (4.23 ± 1.25) × 10^?11 exp{?(12,700 ± 800)/RT}, and k₄ = (1.13 ± 0.62) × 10^?11 exp{?(10,500 ± 1500)/RT}. All the rate coefficients display a positive temperature dependence, which highlights the importance of the irreversibility of the addition mechanism for these reactions. Halogen substitution in the ethene is discussed in terms of reactivity with O(³P). © 2005 Wiley Periodicals, Inc. Int J Chem Kinet 37: 763–769, 2005     

Réaction d’isomérisation de l’acide urocanique et de ses dérivés: stabilité comparée des isomères Z et E

Thermal and photochemical isomérisation of urocanic acid and its derivatives (O- and/or N-alkylated) have been studied. The data show the wavelength and the molar extinction coefficient-dependent photochemistry of E urocanic acid and its derivatives. Thermal isomérisation of these compounds is difficult and undergoes a “one-way” Z → E reaction. Thus, E isomers are thermodynamically more stable than the Z ones. Under basic conditions, derivatives having an unsubstitued imidazole ring (NH function free) exist in their anionic forms, which lowers the energy barrier without changing the isomérisation pathway.     

A reliable and efficient first principles‐based method for predicting pKa values. 4. organic bases

The ionization (dissociation) constant (pK_a) is one of the most important properties of a drug molecule. It is reported that almost 68% of ionized drugs are weak bases. To be able to predict accurately the pK_a value(s) for a drug candidate is very important, especially in the early stages of drug discovery, as calculations are much cheaper than determining pK_a values experimentally. In this study, we derive two linear fitting equations (pK_a = a × ΔE + b; where a and b are constants and ΔE is the energy difference between the cationic and neutral forms, i.e., ΔE = E_neutral?E_cationic) for predicting pK_as for organic bases in aqueous solution based on a training/test set of almost 500 compounds using our previously developed protocol (OLYP/6‐311+G**//3‐21G(d) with the the conductor‐like screening model solvation model, water as solvent; see Zhang, Baker, Pulay, J. Phys. Chem. A 2010 , 114, 432). One equation is for saturated bases such as aliphatic and cyclic amines, anilines, guanidines, imines, and amidines; the other is for unsaturated bases such as heterocyclic aromatic bases and their derivatives. The mean absolute deviations for saturated and unsaturated bases were 0.45 and 0.52 pK_a units, respectively. Over 60% and 86% of the computed pK_a values lie within ±0.5 and ±1.0 pK_a units, respectively, of the corresponding experimental values. The results further demonstrate that our protocol is reliable and can accurately predict pK_a values for organic bases. © 2012 Wiley Periodicals, Inc.     

Photochemische Reaktionen. 118. Mitteilung [1] Zur vinylogen β-Spaltung von Enonen. UV.-Bestrahlung von 4-(3',7',7'-Trimethyl-2'-oxabicyclo [3.2.0]hept-3'-en-1'-yl)but-3-en-2-on

Vinylogous β-Cleavage of Enones: UV.-irradiation of 4-(3′,7′,7′-trimethyl-2′-oxabicyclo[3.2.0]hept-3′-ene-1′-yl)but-3-ene-2-on On ¹π,π*-excitation (λ = 254 nm) in acetonitrile (E/Z)- 2 is converted into the isomers 4–9 and undergoes fragmentation yielding 10 ; in methanol (E/Z)- 2 gives 7–10 and is transformed into 11 by incorporation of the solvent. On ¹π,π*-excitation (λ λ?347 nm; benzene-d₆) (E)- 2 is isomerized into (Z)- 2 , which is converted into the isomers 3 and 4 by further irradiation. ¹π,π*-Excitation (λ = 254 nm; acetonitrile) of 4 gives 6 and (E)- 9 , whereas UV.-irradiation (λ = 254 nm; acetonitrile-d₃) of 5 yields (E)- 7 and 8 . On ¹π,π*-excitation (λ = 254 nm; acetonitrile) of (E/Z)- 12 the compounds (E)- 14 and (E)- 15 are obtained.     

Equilibrium models of Cr3+ and Cu2+ with glutamate

Speciation diagrams and stability constants for glutamate (Glu) with (Cr³⁺) and (Cu²⁺) in aqueous solutions are presented. The current study covers a larger pH-range affording accurate results, and reveal a different set of species for Cu²⁺ and species not previously reported for Cr³⁺. For the Cu²⁺ Glu system, the most successful model that refined the potentiometric data contains the simple one-to-one complex, the bis-complex and the mono-hydroxo complex. The overall stability constants for Cu²⁺–Glu complexes have respective values of log β₁₁₀ = 7.6 ± 0.2, log β_11-1 = 1.3 ± 0.7, log β₁₂₀ = 13.6 ± 0.2. Attempts to refine the stability constant for the mono-protonated metal complex (log β₁₁₁) that was reported in the literature indicated that this mono-protonated species did not form to an appreciable amount to be important for the model presented here. For the Cr³⁺ Glu system, the overall stability constants for the complexes formed have the values of log β₁₁₀ = 8.34 ± 0.03, log β_11-1 = 1.9 ± 0.1 and log β_11-2 = ?4.6 ± 0.1. These results for Cr³⁺ system covers wider pH-range and have more accuracy than those reported previously. The NMR experiments for Glu revealed downfield shifts of all protons as pH values decrease from 11.21 to 2.85.     

The thermodynamic dissociation constants of methotrexate by the nonlinear regression and factor analysis of multiwavelength spectrophotometric pH-titration data

The mixed dissociation constants of methotrexate — chemically (2S)-2-[(4-{[(2,4-diamino-7,8-dihydropteridin-6-yl)methyl] (methyl)amino}phenyl)formamido]pentanedioic acid (the cas number 59-05-2) at various ionic strengths I of range 0.01–0.4, and at temperatures of 25°C and 37°C, were determined with the use of two different multiwavelength and multivariate treatments of spectral data, SPECFIT32 and SQUAD(84) nonlinear regression analyses and INDICES factor analysis according to a general rule of first, determining the number of components, and then calculating the spectral responses and concentrations of the components. Concurrently, the experimental determination of the thermodynamic dissociation constants was in agreement with its computational prediction of the PALLAS programme based on knowledge of the chemical structures of the drug. The factor analysis in the INDICES programme predicts the correct number of light-absorbing components when the data quality is high and the instrumental error is known. Three thermodynamic dissociation constants were estimated by nonlinear regression of {pK _a , I} data: for methotrexate pK_a1^T= 2.895(13), pK_a2^T= 4.410(14), pK_a3^T= 5.726(15) at 25°C and pK_a1^T= 3.089(15), pK_a2^T= 4.392(12), pK_a3^T= 5.585(11) at 37°C, where the figure in brackets is the standard deviation in last significant digits. The reliability of the dissociation constants of the drug were proven by conducting goodness-of-fit tests of the multiwavelength spectrophotometric pH-titration data.      

Anthill Earth as a Gold Occurrence Indicator,and Gold Determination by Solid Sampling Flame Atomic Absorption Spectrometry

With the aim of avoiding cumbersome sample treatment, we present a device for the introduction of solid soil samples into AAS-flames for gold determination, as well as the proposition of earth from anthills as a gold occurrence indicator. A previous ground sample of anthill earth (0.50 mg) was weighed directly into a small recipient of polyethylene which was then connected to a sampling boronsilicate glass chamber. The sample was carried by an airflow (5 L min⁻¹) to a quartz cell positioned between the burner top and the optical beam. The generated atomic vapor produced a transient signal which was totally integrated in three seconds. The performance was compared with conventional flame atomic absorption spectrometry after proper sample digestion. No significant differences were observed between both procedures (mean deviation ±1.90%), and a LOQ of 0.03 μg Au was achieved using the proposed method. The anthill earth was found to be very suitable for indication of gold occurrence in soils and related materials.     

Z/E‐Isomerism of 3‐[4‐(dimethylamino)phenyl]‐2‐(2,4,6‐tribromophenyl)acrylonitrile: crystal structures and secondary intermolecular interactions

The Z and E isomers of 3‐[4‐(dimethylamino)phenyl]‐2‐(2,4,6‐tribromophenyl)acrylonitrile, C₁₇H₁₃Br₃N₂, ( 1 ), were obtained simultaneously by a Knoevenagel condensation between 4‐(dimethylamino)benzaldehyde and 2‐(2,4,6‐tribromophenyl)acetonitrile, and were investigated by X‐ray diffraction and density functional theory (DFT) quantum‐chemical calculations. The (Z)‐( 1 ) isomer is monoclinic (space group P2₁/n, Z′ = 1), whereas the (E)‐( 1 ) isomer is triclinic (space group P, Z′ = 2). The two crystallographically‐independent molecules of (E)‐( 1 ) adopt similar geometries. The corresponding bond lengths and angles in the two isomers of ( 1 ) are very similar. The difference in the calculated total energies of isolated molecules of (Z)‐( 1 ) and (E)‐( 1 ) with DFT‐optimized geometries is ∼4.47 kJ mol⁻¹, with the minimum value corresponding to the Z isomer. The crystal structure of (Z)‐( 1 ) reveals strong intermolecular nonvalent Br…N [3.100 (2) and 3.216 (3) Å] interactions which link the molecules into layers parallel to (10). In contrast, molecules of (E)‐( 1 ) in the crystal are bound to each other by strong nonvalent Br…Br [3.5556 (10) Å] and weak Br…N [3.433 (4) Å] interactions, forming chains propagating along [110]. The crystal packing of (Z)‐( 1 ) is denser than that of (E)‐( 1 ), implying that the crystal structure realized for (Z)‐( 1 ) is more stable than that for (E)‐( 1 ).     

Synthesis and antiproliferative activity of (Z + E)‐1‐[4‐(2‐(cyclopentadienyltricarbonylmanganese)‐2‐oxo‐ethoxy)phenyl]‐1,2‐di(p‐hydroxyphenyl)‐but‐1‐ene against breast cancer cells

This paper describes the synthesis of (Z + E)‐1‐[4‐(2‐(cyclopentadienyltricarbonylmanganese)‐2‐oxo‐ethoxy)phenyl]‐1,2‐di(p‐hydroxyphenyl)‐but‐1‐ene. Two synthetic pathways were explored. The best pathway consisted of the alkylation of 1,2‐bis‐[4‐(tert‐butyl‐dimethylsilyloxy)phenyl]‐1‐(4‐hydroxyphenyl)but‐1‐ene with BrCH₂COOEt. The ester obtained was transformed into the Weinreb amide by reaction with HN(OMe)Me–HCl. The reaction of lithium manganese tricarbonylcyclopentadienide with the Weinreb amide produced 1‐[4‐(2‐(cyclopentadienyltricarbonylmanganese)‐2‐oxo‐ethoxy)phenyl]‐1,2‐di(p‐tert‐butyldimethylsiloxyphenyl)‐but‐1‐ene. The deprotection of phenolic functions of the latter compound led to the formation of the final compound. The Z and E isomers could be separated but the isomerization of these isomers from one to another is an easy process. The Z + E compound 2 was tested against the hormone‐dependent MCF‐7 and hormone‐independent MDA‐MB‐231 breast cancer cell lines. The IC₅₀ values of compound 2 were 4.80 ± 2.00 µm and 4.79 ± 0.70 µm for MCF‐7 cells and MDA‐MB‐231 cells, respectively, which was three times better than the ferrocenyl analogue. Copyright © 2012 John Wiley & Sons, Ltd.