Theoretische Untersuchungen zur Basizität substituierter Pyridine

The applicability of the MINDO/3 method for the interpretation of the basicity of a series of substituted pyridines is critically discussed. Special attention is paid to the difference in thepK _a -values of the two isomeric 4,6-diamino-2-methoxy-(2) and 2,4-diamino-6-methoxy-3-pyridine-carbonitrile (3) (2=2.01,3=4.17). Based on the concept of charge- and orbital-controlled reactions this difference can be explained readily.

     

On the chemistry of pyrrole pigments,XC: Pyridinologous linear tri- and tetrapyrroles

Summary One pyridinologous linear tripyrrole and two pyridinologous linear tetrapyrroles were prepared, and their structural aspects derived from spectroscopic measurements and force field calculations. The properties of these novel pyrrole pigments are compared with those of analogous linear tri- and tetrapyrroles.

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Zur Chemie von Pyrrolpigmenten, 90. Mitt.: Pyridinologe lineare Tri- und Tetrapyrrole

Zusammenfassung Ein pyridinologes lineares Tripyrrol und zwei pyridinologe lineare Tetrapyrrole wurden dargestellt und ihre strukturellen Aspekte aus spektroskopischen Messungen und Kraftfeldrechnungen abgeleitet. Die Eigenschaften dieser neuen Pyrrolpigmente werden mit jenen analoger linearer Tri- und Tetrapyrrole verglichen.

     

On the synthesis of hypericin by oxidative trimethylemodin anthrone and emodin anthrone dimerization: Isohypericin

Summary The base catalyzed oxidative dimerization of emodin anthrone exclusively yields hypericin. However, on oxidative dimerization of trimethylemodinanthrone a mixture of hexamethylhypericin and hexamethylisohypericin was obtained. Chromatographic separation of the hexabenzoyl derivatives was achieved, and by saponification about equal amounts of hypericin and isohypericrin were produced. Isohypericin could be characterized for the first time by its spectroscopic data and its protonation and deprotonationpK _a andpK _a ^* values.

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Zur Synthese von Hypericin durch oxidative Dimerisierung von Trimethylemodinanthron und Emodinanthron: Isohypericin

Zusammenfassung Die basenkatalysierte oxidative Dimerisierung von Emodinanthron liefert ausschließlich Hypericin. Oxidative Dimerisierung von Trimethylemodinanthron ergibt jedoch ein Gemisch von Hexamethylhypericin und Hexamethylisohypericin. Die Hexabenzoylderivate wurden chromatographisch getrennt, und Hypericin und Isohypericin konnten aus diesen Derivaten durch Verseifung freigesetzt werden. Isohypercin konnte erstmals durch seine spektroskopischen Daten und seine Protonierungs- und Deprotonierungs-pK _aundpK _a ^* -Werte charakterisiert werden.

     

Effect of anionic and nonionic water-in-oil microemulsions on acid-base equilibria of hydrophilic indicators

ApparentpK _a values (hereafter writtenpK) for the hydrophilic, negatively-charged indicators 2-hydroxy-5-bromo sodium benzenesulphonate (HBBS), 2-hydroxy-5-nitro sodium benzenesulphonate (HNBS), and 2-(5,7-dinitro-8-hydroxy) sodium naphthalenesulphonate (napthol yellow, NY) in the presence of water-in-heptane microemulsions of bis(2-ethylhexyl) sodium sulphosuccinate (AOT, anionic) and polyoxyethylene (4) dodecyl ether (Brij-30, nonionic) were determined spectrophotometrically. The variables studied were the type of buffer (borate, imidazole, nicotinamide, phosphate, and piperidine) and the ratios [water]/[surfactant] and [buffer]/[surfactant]. Partition experiments between water and heptane and UV-VIS spectra of the indicators in aqueous buffer in the presence of anionic and nonionic aqueous and reversed micelles showed that these indicators are confined within the second hydration shell of the microemulsion, i.e., are not adsorbed at the water-in-oil (W/O) interface. Buffer-independentpK values were obtained after the initial pHs of the solubilized buffer solutions were corrected for the ion exchange with counter-ion of the surfactant (AOT) and for the lower polarity of the micelle-solubilized water (Brij-30 and AOT). The micelle-inducedpK shifts were in the range 1.66–2.08 units for HBBS/AOT, 1.17–2.14 units for HNBS/AOT, 0.73–1.31 units for NY/AOT, 1.06–1.40 units for HNBS/Brij-30, and 0.12–0.33 units for NY/Brij-30. The observed pK shifts are explained as due to the effect of two factors, i.e., the lower polarity of the micelle-solubilized water (relative to bulk water, AOT, and Brij-30) and electrostatic perturbation of the equilibria by the negatively charged surfactant. The smaller micellar effect on thepK of NY was attributed to the extensive electron delocalization in its conjugate base.     

1,3-bis(2,4,6-trinitrophenylaminooxy)propane and its 4-cyano-2,6-dinitrophenyl congener: Synthesis and properties

Starting from N-hydroxyphthalimide (5) and 1,3-dibromopropane (6) we obtained 1,3-bis(phthalimidooxy)propane (7) which led to 1,3-bis(aminooxy)propane dihydrochloride (8). From its reaction with picryl chloride or 4-cyano-2,6-dinitrochlorobenzene, the two title compounds (4b, 4a) were obtained. ¹H-NMR and ¹³C-NMR spectra are presented. For comparison with the analogous N-methoxy-2,6-dinitro-4-R-anilines 1a, 1b (R=CN or R=NO₂), wer report the hydrophobic characteristics (by RPTLC), electronic spectra for the neutral compounds and their anions, pK _a values, and the behavior towards oxidizers (DPPH, PbO₂, Pb(CH₃COO)₄, KMnO₄ and Ag₂O); DPPH converts compounds 1a, 1b and 4a, 4b into betainic structures 2a, 2b respectively.     

Calculation of acidic dissociation constants in water: solvation free energy terms. Their accuracy and impact

Three polarizable continuum models, DPCM, CPCM, and IEFPCM, have been applied to calculate free energy differences for nine neutral compounds and their anions. On the basis of solvation free energies, the pK_a values were obtained for the compounds in question by using three thermodynamic cycles: one, involving the combined experimental and calculated data, as well as two other cycles solely with calculated data. This paper deals with the influence of factors such as the SCRF model applied, choice of a particular thermodynamic cycle, atomic radii used to build a cavity in the solvent (water), optimization of geometry in water, inclusion of electron correlation, and the dimension of the basis set on the solvation free energies and on the calculated pK_a values. Electronic supplementary material The online version of this article (doi: ) contains supplementary material, which is available to authorized users.     

Epik: a software program for pK<Subscript><Emphasis Type="Italic">a</Emphasis></Subscript> prediction and protonation state generation for drug-like molecules

Epik is a computer program for predicting pK_a values for drug-like molecules. Epik can use this capability in combination with technology for tautomerization to adjust the protonation state of small drug-like molecules to automatically generate one or more of the most probable forms for use in further molecular modeling studies. Many medicinal chemicals can exchange protons with their environment, resulting in various ionization and tautomeric states, collectively known as protonation states. The protonation state of a drug can affect its solubility and membrane permeability. In modeling, the protonation state of a ligand will also affect which conformations are predicted for the molecule, as well as predictions for binding modes and ligand affinities based upon protein–ligand interactions. Despite the importance of the protonation state, many databases of candidate molecules used in drug development do not store reliable information on the most probable protonation states. Epik is sufficiently rapid and accurate to process large databases of drug-like molecules to provide this information. Several new technologies are employed. Extensions to the well-established Hammett and Taft approaches are used for pK_a prediction, namely, mesomer standardization, charge cancellation, and charge spreading to make the predicted results reflect the nature of the molecule itself rather just for the particular Lewis structure used on input. In addition, a new iterative technology for generating, ranking and culling the generated protonation states is employed. Electronic Supplementary Material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

On the bromination of hypericin: The gymnochrome chromophores

Summary Stepwise electrophilic bromination of hypericin in pyridine as the solvent yields regioselectively 2,5-dibromohypericin, 2,5,9-tribromohypericin, and 2,5,9,12-tetrabromohypericin. The compounds were characterized by means of NMR-, UV-Vis-, and fluorescence-spectra, andpK _a andpK* _a measurements. These properties were compared with those of hypericin on the one hand and of the recently isolated gymnochromes on the other hand.

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Zur Bromierung des Hypericins: Die Gymnochrom-Chromophore

Zusammenfassung Schrittweise elektrophile Bromierung von Hypericin in Pyridin als Lösungsmittel liefert regioselektiv 2,5-Dibromhypericin, 2,5,9-Tribromhypericin und 2,5,9,12-Tetrabromhypericin. Diese Verbindungen wurden durch NMR-, UV-Vis- und Fluoreszenz-Spektrometrie sowie durchpK _a - undpk* _a -Messungen charakterisiert. Diese Eigenschaften wurden mit jenen des Hypericins und der kürzlich isolierten Gymnochrome verglichen.

     

Spectrophotometric determination of the acid dissociation constants for cacodylic acid and p-Nitrophenol at elevated temperatures

Using 2.5-dinitrophenol as an optical indicator, the pK_a of cacodylic acid were spectrophotometrically determined at elevated temperatures under saturation vapor pressures. The result is pK_a = -26.41 + 1296/T + 4.973 InT whereT is in Kelvin. In a similar way, the pK_a ofp-nitrophenol were obtained up to 200‡C giving pK_a = -24.82 + 2135/T + 4.353 InT From these results, several thermodynamic functions of cacodylic acid andp- nitrophenol were calculated.     

Local environments and dynamics of hydrogen atoms in protonated forms of ion-exchangeable layered perovskites estimated by solid-state H NMR

The local environments and dynamics of hydrogen atoms in five samples of protonated forms of ion-exchangeable layered perovskites, Dion-Jacobson-type H[LaNb₂O₇] and H[LaTa₂O₇], Ruddlesden-Popper-type H₂[SrTa₂O₇] and H₂[La₂Ti₃O₁₀], and H_1.8[(Sr_0.8Bi_0.2)Ta₂O₇] derived from an Aurivillius phase, Bi₂Sr₂Ta₂O₉, have been investigated by solid-state ¹H nuclear magnetic resonance spectroscopy (NMR). Solid-state ¹H NMR with a magic-angle spinning technique conducted at room temperature reveals that the mean electron densities around the ¹H nuclei in these protonated forms are relatively low, and that they decrease in the following order: H_1.8[(Sr_0.8Bi_0.2)Ta₂O₇]>H[LaNb₂O₇]>H₂[SrTa₂O₇]>H[LaTa₂O₇]>H₂[La₂Ti₃O₁₀]. The temperature-dependent solid-state ¹H broad-line NMR spectra measured at 140-400 K reveal a decrease in the signal width for all of these five samples upon heating due to motional narrowing. The NMR spectra of H[LaNb₂O₇] and H[LaTa₂O₇] are different from the other three protonated forms due to the weaker dipole-dipole interactions at low temperatures and lower mobility of the hydrogen atoms at high temperatures.     

The influence of micellization ofn-decylamine on its basicity and reactivity toward carboxylic acid esters

Micellization ofn-decylamine in aqueous solution leads to substantial decrease in its pK _a, and increase in its reactivity in the nucleophilic substitution ofp-nitrophenylic esters of carboxylic acids (up to 70 times compared to ethylamine which forms no micelles). The influence of cetylpyridinium bromide on the acid-base properties ofn-decylamine and its reactivity was investigated. It was found that the reaction withn-decylamine can be accelerated or retarded depending on the hydrophobicity of the esters. The quantitative characteristics of the mieellar catalytic processes were estimated.Translated fromIzvestiya Akademii Nauk Seriya Khimicheskaya, No. 2, pp. 366–370, February, 1996.     

Acid Dissociation Constants of the Benzimidazole Unit in the Polybenzimidazole Chain: Configuration Effects

The acid dissociation constant of three benzimidazoles, namely 2,2′-bibenzo[d]imidazole, 2,5′-bibenzo[d]imidazole, and 5,5′-bibenzo[d]imidazole, have been investigated by means of density functional theory calculations in gas phase and in aqueous solution. The theoretical approach was validated by the comparing of predicted and experimentally determined pK_a values in imidazole, benzimidazole, and 2-phenylbenzimidazole. From the studied compounds, 2,2′-bibenzo[d]imidazole was found to be the most acidic, which made it a valuable candidate as a material for polymer electrolyte membrane fuel cells.     

Pyridazines with heteroatom substituents in position 3 and 5, part 1: 5-Hydroxy-3(2H)-pyridazinone and its derivatives

Summary The synthesis of the title compound7 was achieved starting with mucochloric acidvia the pyridazinones1,2 and6. The electrolytic ionisation constants for7 were found to be 4.81 (±0.03) and –0.3 (±0.3). Crystal structure analyses were performed for7 and its fixed derivatives6 and9.Dedicated to Prof. Dr. Hans Junek on the occasion of his 60th birthday     

Uncertainty estimation in measurement of pKa values in nonaqueous media: A case study on basicity scale in acetonitrile medium

The difficulties in estimating uncertainty of pK_a values determined in nonaqueous media are reviewed and two different uncertainty estimation approaches are presented and applied to the pK_a values of the compounds on a previously established self-consistent spectrophotometric basicity scale in acetonitrile. One approach is based on the ISO GUM methodology (the “ISO GUM” approach) and involves careful analysis of the uncertainty sources and quantifying the respective uncertainty components. The second approach is based on the standard-deviation-like statistical parameter that has been used for characterization of the consistency of the scale (the “statistical” approach). It is demonstrated that the ISO GUM approach somewhat overestimates the uncertainty. The statistical approach is based on long-term within-laboratory statistical data and it is demonstrated that it underestimates the uncertainty. In particular it neglects the laboratory bias effects that are taken into account at least to some extent by the ISO GUM approach. Thus, together these two approaches allow to “bracket” the uncertainties of the pK_a values on the scale. The uncertainties of the pK_a values are defined in two different ways. Definition (a) includes the uncertainty of the pK_a of the reference base (anchor base of the scale) pyridine. Definition (b) excludes it. It is demonstrated that both definitions have their virtues. Definition (a) leads to the uncertainty ranges of 0.12-0.22 and 0.12-0.14 pK_a units at standard uncertainty level for different bases using the ISO GUM and statistical approach, respectively. Definition (b) leads to the uncertainty ranges of 0.04-0.19 and 0.02-0.08 pK_a units, respectively. The uncertainty of the pK_a of a given base is dependent on the quality of the measurements involved and on the distance from the reference base on the scale. The importance of the correlation between the pK_a values of bases belonging to the same scale is stressed.     

Network properties of mixtures of protonated and deuterated polyethylene

Mixtures of protonated and deuterated polyethylene were irradiated in the melt. The degree of crystallinity, the degree of crosslinking, as well as the enthalpyH and the melting pointT _M were determined. No significant differences in the degree of crosslinking between protonated and deuterated chains were found. The mass specific entropyS of the uncrosslinked samples remained constant and independent of the deuterium concentration. For the crosslinked samples, a netpoint entropy was postulated. A weaker Van der Waals interaction could explain the decrease in melting temperature by deuteration (for weakly crosslinked samples).     

Validation of pH-Metric Technique for Measurement of pKa and log Pow of Ionizable Herbicides

Abstract

Knowing the values of pK_a and partition coefficients between 1-octanol and water (P_ow) of ionizable herbicides helps us to understand the movement of these compounds in plants and soil. However, shake-flask and high-pressure liquid chromatography (HPLC) techniques. though valuable for measurement of log P_ow of herbicide molecules that do not ionize in aqueous solution, are difficult to use for ionizable molecules; this is especially so for molecules that form ion pairs having appreciable log P_ow values, those with multiple ionizations and for bases with high pK_a values. Our aim in this study was to validate the use of the pH-metric technique (based on potentiometric titration) for measurements of pK_a and log P_ow of ionizable standard substances and herbicides. The values obtained show good correlation with results from other techniques, including shake-flask and HPLC. The OECD Guideline for Testing of Chemicals 117, adopted 30th March 1989, describes the use of HPLC for the measurement of log P_ow. It is hoped that these studies and further testing of this technique will permit it to be included in these OECD guidelines.     

Gradient reversed-phase high-performance chromatography of ionogenic analytes

This review highlights the basis of gradient reversed-phase high-performance liquid chromatography (RP-HPLC) of ionogenic analytes.We describe pH-gradient RP-HPLC in strict theoretical terms, with examples of experiments to provide improvements in analyte separations and peak shapes, and an original method of pK_a determination.Finally, we present the concept of the combined pH/organic-modifier gradient mode of RP-HPLC and illustrate it with applications. It allows optimization of separation of ionogenic analytes, along with a method for determining their biorelevant physico-chemical parameters [e.g., hydrophobicity (log k_w) and acidity (pK_a)]. The method is applicable to drugs and other xenobiotic mixtures, including individual analytes of interest assayed in biological fluids.     

Inhibition of microbial xylitol production by acetic acid and its relation with fermentative parameters

Precipitated sugarcane bagasse hemicellulosic hydrolysate containing acetic acid was fermented by Candida guilliermondii FTI 20037 under different operational conditions (pH 4.0 and 7.0, three aeration rates). At pH 7.0 and k _L a of 10 (0.75 vvm) and 22.5/h (3.0 vvm) the acetic acid had not been consumed until the end of the fermentations, whereas at the same pH and k _L a of 35/h (4.5 vvm) the acid was rapidly consumed and acetic acid inhibition was not important. On the other hand, fermentations at an initial pH of 4.0 and k _L a of 22.5 and 35/h required less time for the acid uptake than fermentations at k _L a of 10/h. The acetic acid assimilation by the yeast indicates the ability of this strain to ferment in partially detoxified medium, making possible the utilization of the sugarcane bagasse hydrolysate in this bioprocess. The effects on xylitol yield and production are reported.