Synthesis of amphiphilic sulfonamide halogenated porphyrins: MALDI-TOFMS characterization and evaluation of 1-octanol/water partition coefficients

Porphyrins are key precursors for development of photosensitizers for photodynamic therapy. A new series of ortho-halogenated tetraarylporphyrins with sulfonamide substituents have been synthesized via chlorosulfonation reaction and characterized by MALDI-TOFMS. To predict their partition properties, log K_OW of a selected range of the synthesized halogenated amphiphilic porphyrins is described. A significant effect of the number and type of halogen group as well as on the number of sulfonamide side chain was observed. The determined 1-octanol/water partition coefficients showed that it is possible to obtain compounds with a wide range of lipophilicities, from log K_OW=−2.71 till log K_OW>4, which are suitable to optimize the biological efficacy of this class of sensitizers.     

An exclusive fluoride receptor: fluoride-induced proton transfer to a quinoline-based thiourea

A new quinoline-based tripodal thiourea has been synthesized, which exclusively binds fluoride anion in DMSO, showing no affinity for other anions including chloride, bromide, iodide, perchlorate, nitrate, and hydrogen sulfate. As investigated by ¹H NMR, the receptor forms both 1:1 and 1:2 complexes yielding binding constants of 2.32(3) (in log β₁) and 4.39(4) (in log β₂), respectively. The quinoline groups are protonated by fluoride-induced proton transfer from the solution to the host molecule. The 1:2 binding is due to the interactions of one fluoride with NH binding sites of urea sites and another fluoride with secondary ⁺NH binding sites within the tripodal pocket. The formation of both 1:1 and 1:2 complexes has been confirmed by theoretical calculations based on density functional theory (DFT).     

Substituent effects in the ring-chain tautomerism of 1,3-diaryl-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazines

Condensation of Betti base analogue amino naphthols with substituted benzaldehydes led to 1,3-diaryl-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazines (3-9) which proved to be three-component (r¹-o-r²) tautomeric mixtures in CDCl₃ at 300 K. The electronic effects of the 3-aryl groups on the ratios of the ring-chain tautomeric forms at equilibrium could be described by the equation log K_X=ρσ⁺+log K_X=H. The value of the intercept was found to be strongly influenced by the steric arrangement of the 1,3-diaryl substituents.     

Amino acid binding in water by a new guanidiniocarbonyl pyrrole dication: the effect of the experimental conditions on complex stability and stoichiometry

The synthesis and binding properties of a new guanidiniocarbonyl pyrrole dication 2 are reported, which efficiently binds alanine carboxylate with log K_ass = 3.9 in buffered water. Due to the increased charge density in this dication, the binding constant is five times larger than for the parent guanidiniocarbonyl pyrrole monocation 1 (log K = 3.2). However, the experimental conditions for determining the binding constant significantly influence both complex stability and stoichiometry. With increasing amount of substrate added during the titration, the overall complex stability decreases due to the increasing ionic strength of the solution. Furthermore, the formation of 1:2 complexes between 2 and 7 becomes increasingly important. Therefore, for the comparison of binding data it has to be assured that exactly the same experimental conditions are used for their determination.     

Water-soluble aminocalix[4]arene receptors with hydrophobic and hydrophilic mouths

We report the new water-soluble aminocalix[4]arene hosts 1 and 2 with deep hydrophobic cavity facilitating hydrophobic mouth and hydrophilic mouth, respectively. The ¹H NMR titrations revealed that host 1 shows high selectivity for neutral guests 9 and 10, with log K of 4.2 and 4.6, respectively. The host 2 shows log K of 4.9 for binding with guest 15. Moreover, the binding ability of the host 2 for guest 14 is stronger by a factor of 1000 than that of the host 1.     

Halogenation of ketones with N-halosuccinimides under solvent-free reaction conditions

Several aryl substituted ketones, cyclic ketones, 1,3-diketones and a β-ketoamide were halogenated with N-halosuccinimides under solvent-free reaction conditions (SFRC) at various temperatures (20-80 °C), whereas less enolized ketones required the presence of an acid catalyst (p-toluenesulfonic acid, PTSA). Bromination of substituted acetophenones obeys first order kinetics v=k_Br[ketone] and the following correlation with the keto-enol equilibrium constant: log k_Br=0.3pK_E+C₁, less enolized substrates being more reactive; the moderate positive charge developed in the rate determining step was confirmed by the Hammett correlation (ρ=−0.5). On the other hand, in cyclic ketones an opposite relation was observed: log k_Br=−0.6pK_E+C₂, indicating higher reactivity of substrates with higher enolization constant (K_E). The important role of the nature of the solvent (MeCN, MeOH) in preorganization of the ketone-NBS-PTSA mixture prior to SFRC bromination was found.     

Versatility of an intramolecularly hydrogen-bonded 4-(N,N-dimethylamino)benzoate group as a signaling subunit for anion recognition

The versatility of the 4-(N,N-dimethylamino)benzoate (DMAB) group embedded in host 1 as a signaling subunit for anion recognition was elucidated in terms of ¹H NMR, CD, and fluorescence studies. Host 1 showed 1:1 complexation with monovalent anions and stepwise 1:1 and 2:1 (host 1: anion) complexation with divalent phosphate anions. The binding constants between host 1 and anions were determined by means of ¹H NMR titrations in CD₃CN (HPO₄²⁻: log K_1:1=6.2, log K_2:1=4.9; H₂P₂O₇²⁻: log K_1:1=4.4, log K_2:1=1.8; AMP²⁻: log K_1:1>7, log K_2:1>5) and the affinity of host 1 toward divalent anions, HPO₄²⁻, H₂P₂O₇²⁻, and AMP²⁻, is stronger than that toward monovalent anions, NO₃⁻, BF₄⁻, ClO₄⁻, HSO₄⁻, and PF₆⁻. The CD exciton chirality studies of host 1 with divalent anions, HPO₄²⁻ and AMP²⁻, revealed that the two DMAB groups in the 2:1 complexes were arranged with negative chirality (counterclockwise). The dual fluorescence behavior of the DMAB group demonstrated not only the complexation stoichiometry but also the role(s) of the lipophilic countercation such as tetrabutylammonium and/or the hydrophilic residue in AMP during anion recognition.     

Ruthenium(III) catalysed oxidation of l-leucine by a new oxidant,diperiodatoargentate(III) in aqueous alkaline medium

The kinetics of Ru(III) catalysed oxidation of l-leucine by diperiodatoargentate(III) (DPA) in alkaline medium at 298 K and a constant ionic strength of 0.60 mol dm⁻³ was studied spectrophotometrically. The oxidation products are pentanoic acid and Ag(I). The stoichiometry is [l-leucine]:[DPA] = 1:2. The reaction is of first order in Ru(III) and [DPA] and has less than unit order in both [l-leu] and [alkali]. The oxidation reaction in alkaline medium has been shown to proceed via a Ru(III)–l-leucine complex, which further reacts with one molecule of monoperiodatoargentate(III) (MPA) in a rate determining step followed by other fast steps to give the products. The main products were identified by spot test and spectral studies. The reaction constants involved in the different steps of the mechanism are calculated. The catalytic constant (K_c) was also calculated for the Ru(III) catalysed reaction at different temperatures. From the plots of log K_c versus 1/T, values of activation parameters with respect to the catalyst have been evaluated. The activation parameters with respect to the slow step of the mechanism are computed and discussed, and thermodynamic quantities are also determined. The active species of catalyst and oxidant have been identified.     

Highly selective complexation of metal ions by the self-tuning tetraazacalixpyridine macrocycles

By means of UV-vis and ¹H NMR titrations and X-ray crystallography, complexation of tetramethylazacalix[4]pyridine L1 and tetramethylazacalix[2]arene[2]pyridine L2 with metal ions was studied. While no interaction was observed with alkali and alkaline earth metal ions, both ligands have been found to act as powerful and selective macrocyclic hosts to complex a number of transition and heavy metal ions. Due to the intrinsic nature of the bridging nitrogen atoms that can adopt different electronic configurations and form varied degrees of conjugations with their adjacent pyridine rings, tetramethylazacalix[4]pyridine L1 regulated its conformation and cavity structure to best fit the guest metal ion species, yielding a 1:1 square planar L1-Mⁿ⁺ complex with binding constants log K_1:1 ranging from 2.7(1) to 8.2(8).     

Polymerized Nile Blue derivatives for plasticizer-free fluorescent ion optode microsphere sensors

Lipophilic H⁺-selective fluorophores such as Nile Blue derivatives are widely used in ISE-based pH sensors and bulk optodes, and are commonly dissolved in a plasticized matrix such as PVC. Unfortunately, leaching of the active sensing ingredients and plasticizer from the matrix dictates the lifetime of the sensors and hampers their applications in vivo, especially with miniaturized particle based sensors. We find that classical copolymerization of Nile Blue derivatives containing an acrylic side group gives rise to multiple reaction products with different spectral and H⁺-binding properties, making this approach unsuitable for the development of reliable sensor materials. This limitation was overcome by grafting Nile Blue to a self-plasticized poly(n-butyl acrylate) matrix via an urea or amide linkage between the Nile Blue base structure and the polymer. Optode leaching experiments into methanol confirmed the successful covalent attachment of the two chromoionophores to the polymer matrix. Both polymerized Nile Blue derivatives have satisfactory pH response and appropriate optical properties that are suitable for use in ion-selective electrodes and optodes. Plasticizer-free Na⁺-selective microsphere sensors using the polymerized chromoionophores were fabricated under mild conditions with an in-house sonic microparticle generator for the measurement of sodium activities at physiological pH. The measuring range for sodium was found as 10⁻¹-10⁻⁴ M and 1-10⁻³ M, for Nile Blue derivatives linked via urea and amide functionalities, respectively, at physiological pH. The observed ion-exchange constants of the plasticizer-free microsphere were log K_exch = −5.6 and log K_exch = −6.5 for the same two systems, respectively. Compared with earlier Na⁺-selective bulk optodes, the fabricated optical sensing microbeads reported here have agreeable selectivity patterns, reasonably fast response times, and more appropriate measuring ranges for determination of Na⁺ activity at physiological pH in undiluted blood samples.     

Chromogenic betaine lariates for highly selective calcium ion sensing in aqueous environment

This paper describes the design, synthesis, and the characterization of the two new chromogenic crown ethers 2,2′-[1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diylbis(methylene)]bis[4-[(1-methyl-4-(1H)-pyridinylidene)ethylidene]-2,5-cyclohexadien-1-one (KBC-001) and the lipophilic derivative 2,2′-[1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diylbis(methylene)]bis[4-[(1-dodecyl-4-(1H)-pyridinylidene)ethylidene]-2,5-cyclohexadien-1-one (KBC-002). A merocyanine dye that forms a betainic structure upon intramolecular charge transfer and shows solvent polarity dependent spectral sensitivity was selected as the chromophore system to develop the new chromoionophores. This approach allows the design of overall electrically neutral ligands bearing charged groups without the need of external counter ions. A proton ionizable group in the dye moiety acts as a charged ion-binding site and is an integral part of a lariat crown ether ionophore. A chromoionophore for calcium ion sensing has been developed, which combines the size-selective binding character of a crown ether with strong electrostatic attraction between the positively charged calcium ion and two negatively charged lariat side arms in the overall neutral compound. This water-soluble dye selectively responds to the presence of calcium ions in water at pH 8.5 with a dynamic response range between 10 μM and 10 mM. The binding event can be monitored both by absorption spectrometry and by fluorescence spectrometry. No cross-sensitivity was found for the physiologically important cations Mg²⁺, Li⁺, Na⁺, and K⁺ up to concentrations of 0.1 M under the same experimental conditions. In contrast to the water-soluble reagent KBC-001, the lipophilized derivative KBC-002 having two long alkyl chains was successfully applied to ion-exchange type optode membranes made from plasticized poly(vinyl chloride) (PVC). The dynamic response range of the optode at pH 9.0 was between 10 μM and 10 mM while retaining the high calcium selectivity.     

Iron(III) complexes of the tris-(3-aminopropyl) derivative of a 14-membered tetraazamacrocycle: Potentiometric,spectroscopic and electrochemical studies

The properties of the iron(III) complexes of the ditopic macrocyclic ligand with three aminopropyl pendant arms, L¹ = 3,7,11-tris-(3-aminopropyl)-3,7,11,17-tetraazabicyclo[11.3.1]heptadeca-1(17),13,15-triene were investigated in aqueous solution. Potentiometric studies indicated the presence of mononuclear [FeH_hL¹]^h+3 (h = 0–3), and dinuclear [Fe₂L¹]⁶⁺, [Fe₂L¹(OH)]⁵⁺ and [Fe₂L¹(OH)₂]⁴⁺ complexes, and their stability constants were determined at 298.2 K and ionic strength 0.10 mol dm⁻³ in KNO₃. The log K values of mononuclear protonated species indicated the consecutive deprotonation of the aminopropyl arms, suggesting the nitrogen donor atoms from the macrocycle as the preferred coordination environment for the first metal centre, and the amines from the pendant arms for the second one. The dinuclear complex is formed at about 85% of the total amount of the metal ion for 2:1 Fe:L¹ ratio solutions at pH 4.0–4.5. The log K values of the deprotonation of dinuclear hydrolysed species are consistent with the presence of two water molecules directly bound to the metal centres. Spectroscopic UV–Vis and IR data for 2:1 Fe³⁺:L¹ ratio samples confirmed the existence of dinuclear and hydroxo dinuclear species. EPR spectra of these solutions were interpreted by an equilibrium of two high-spin d⁵ state of iron(III) species with different rhombic E/D distortions. Electrochemical studies also established the formation of mono- and dinuclear complexes, showing irreversible redox behaviour. The two metal centres on the dinuclear complexes have only weak interactions.     

Solvent effect on the complex formation of distally dialkylated calix[4]arenes with 1-chloro-4-(trifluoromethyl)benzene

The complexation behavior of the distally dialkylated calix[4]arenes and 4-tert-butylcalix[4]arenes (hosts) with 1-chloro-4-(trifluoromethyl)benzene (guest) was examined in four different alcohols (MeOH, EtOH, n-PrOH, n-BuOH) as solvents. The complex stability constants (K_s) and the complexation energy of the host-guest complexes were determined. Fair ‘by group’ linear correlations between each log K series determined in the same solvent and the complex stabilization energies were found. As a consequence, the solvents having high permittivities result in less stability of the host-guest complex in these particular cases examined.     

Improving the lower detection limit of potentiometric sensors by covalently binding the ionophore to a polymer backbone

The lower detection limit of polymeric membrane ion-selective electrodes (ISEs) is impaired by zero-current ion fluxes through the organic phase. This adverse effect is largely eliminated by covalently attaching the ionophore to a polymer backbone. To this purpose, the Pb²⁺-selective ligand, 4-tert-butylcalix[4] arene-tetrakis(N,N′-dimethylthioacetamide) is substituted on its upper rim by a diol derivative which is subsequently copolymerized with poly(tetrahydrofuran)diol and 2,2,4-trimethylhexamethylene diisocyanate to the corresponding polyurethane. By measurements on sandwich membranes, it is shown that through binding the ionophore to the polymer, the mobility of Pb²⁺ in the ISE membrane is strongly reduced. As a consequence, the response range of such an ISE is extended by several orders of magnitude. This is the case even when using an internal electrolyte that with an ISE based on a mobile ionophore leads to strong deviations from the linear response because of ion uptake from the sample into the membrane or ion release from the membrane into the sample. With a conventional inner filling solution of 10⁻¹ M Pb(NO₃)₂, a lower detection limit of 1.7×10⁻⁹ M Pb²⁺ has been achieved in the presence of 10⁻⁴ M Na⁺.     

Imaging fiber microarray fluorescent ion sensors based on bulk optode microspheres

Optical imaging fibers with micrometer-sized wells were used as a sensing platform for the development of microarray optical ion sensors based on selective bulk extraction principles established earlier for optodes. Uniform 10 μm sized microspheres based on plasticized poly(vinyl chloride) containing various combinations of ionophores, fluoroionophores and lipophilic ion-exchangers were prepared for the detection of sodium, potassium, calcium and chloride, and deposited onto the wells of etched fiber bundles. Specifically, sodium sensing particles were based on tert-butylcalix[4]arene tetraacetic acid tetraethylester, potassium particles on 2-dodecyl-2-methyl-1,3-propanediyl bis[N-[5′-nitro(benzo-15-crown-5)-4′-yl]carbamate] (BME-44), calcium particles on an acrylic derivative of ETH 129 (AU-1) covalently attached to a methacrylic polymer, and chloride particles based on the anticrown ionophore [9]mercuracarborand-3 (MC-3). The fluorescence emission characteristics of individual microspheres were observed from the backside of the fibers and were found to selectively and rapidly change as a function of the sample composition. The optical characteristics of the particles were found to be comparable to that of corresponding thin optode films and particles deposited onto microscope glass slides. The measuring ranges (logarithmic molar concentrations) at pH 7.0 were found as −3 to 0 for sodium, −3.5 to −0.5 for potassium, −7 to −2 for calcium, and −5 to 0.5 for chloride. Selectivities were determined over other common electrolytes and found to be sufficient for physiological applications. The simultaneous deposition of sodium and chloride sensing particles was successfully performed, demonstrating that such microarray sensors are capable of simultaneously sensing multiple analytes. This technology is compatible with other microsphere-based fluorescent sensing principles, forming a promising total analysis platform for a variety of applications.     

Quantitative parameters for the sequestering capacity of polyacrylates towards alkaline earth metal ions

The complex formation constants of polyacrylic (PAA) ligands (1.4≤log N≤2.4, N=number of monomer units) with calcium and magnesium ions were determined in different ionic media at different ionic strengths, 0≤I≤1 mol l⁻¹, at t=25 °C. Experimental pH-metric data in the presence of Ca²⁺ or Mg²⁺ were firstly analysed in terms of apparent protonation constants, log K^H*, using the “three parameter model” proposed by Högfeldt; differences in log K^H*, determined in different ionic media, were interpreted in terms of complex species formation. The only species present in the system M-PAA (M=Ca²⁺ or Mg²⁺) is ML₂: attempts to find species of different stoichiometry were unsuccessful. The stability dependence of this species on ionic strength, on the degree of neutralisation (α) and on PAA molecular weight is discussed using empirical equations. The formation constant, log β₂, is significantly higher for Ca²⁺ than for Mg²⁺: at I=0.1 mol l⁻¹ (NaCl), log N=1.8 and α=0.5, log β₂^Ca=4.43 and log β₂^Mg=4.24. The formation of polyacrylate-alkaline earth metal complexes is discussed in the light of sequestering effects in natural waters.     

Naphthalene-ring containing diamine and resulting thermally stable polyamides

A new naphthalene-ring containing diamine, bis-[4-(5-amino-naphthalene-1-yloxy)-phenyl]-methanone was prepared from reaction of 5-amino-1-naphthol with 4,4′-dichlorobenzophenone in the presence of K₂CO₃. A series of novel polyamides were prepared by direct polycondensation of the diamine with various commercially available diacid chlorides including terephthaloyl chloride, isophthaloyl chloride, adipoyl chloride, and sebacoyl chloride. All the synthesized polyamides showed good solubility in amide type solvents such as N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and N,N-dimethylformamide and they exhibited inherent viscosities in the range of 0.44-0.52 dL/g. According to the DMTA analysis, the glass transition temperatures of the polyamides were found to be 131-187 °C. Thermogravimetric analysis indicated that the polymers were stable up to 190 °C and the 10% weight loss temperatures were recorded in the range of 350-418 °C in air atmosphere.     

Formation of pseudo[3]rotaxanes containing calix-bis-crowns and secondary ammonium ions and their thermodynamic stabilities in a solution: preorganization by second macrocycle and nonallosteric behavior exhibited by large crown cavities

This Letter describes the formation of pseudo[3]rotaxanes containing calix[4]-bis-crowns, exhibiting a 1,3-alternate conformation and large crown cavities, and secondary ammonium ions. The first and second association constants of pseudo[3]rotaxane formation are moderate (K₁ = 175, K₂ = 100 M⁻¹) and are higher than that of the corresponding pseudo[2]rotaxane (K = 24 M⁻¹), consisting of a calix[4]-mono-crown and the same secondary ammonium ion.     

Cs+ -selective membrane electrodes based on ethylene glycol-functionalized polymeric microspheres

A new strategy for improving the robustness of membrane-based ion-selective electrodes (ISEs) is introduced based on the incorporation of microsphere-immobilized ionophores into plasticized polymer membranes. As a model system, a Cs⁺-selective electrode was developed by doping ethylene glycol-functionalized cross-linked polystyrene microspheres (P-EG) into a plasticized poly(vinyl chloride) (PVC) matrix containing sodium tetrakis-[3,5-bis(trifluoromethyl)phenyl] borate (TFPB) as the ion exchanger. Electrodes were evaluated with respect to Cs⁺ in terms of sensitivity, selectivity, and dynamic response. ISEs containing P-EG and TFPB that were plasticized with 2-nitrophenyl octyl ether (NPOE) yielded a linear range from 10⁻¹ to 10⁻⁵ M Cs⁺, a slope of 55.4 mV/decade, and a lower detection limit (log a_Cs) of −5.3. In addition, these membranes also demonstrated superior selectivity over Li⁺, Na⁺, and alkaline earth metal ion interferents when compared to analogous membranes plasticized with bis(2-ethylhexyl) sebacate (DOS) or membranes containing a lipophilic, mobile ethylene glycol derivative (ethylene glycol monooctadecyl ether (U-EG)) as ionophore.     

Fluorophilicity of alkyl and polyfluoroalkyl nicotinic acid ester prodrugs

The fluorophilicity of a series of hydrocarbon and fluorocarbon-functionalized nicotinic acid esters (nicotinates) is measured from their partitioning behavior (log K_p) in the biphasic solvent system of perfluoro(methylcyclohexane) (PFMC) and toluene. The chain length of the hydrocarbon or fluorocarbon alkyl group of the ester ranges from one to twelve carbon atoms. Knowledge of the fluorophilicity of these solutes is relevant to the design of these prodrugs for fluorocarbon-based drug delivery. The experimental log K_p values range from −1.72 to −3.40 for the hydrocarbon nicotinates and −1.64 to 0.13 for the fluorinated nicotinates, where only the prodrug with the longest fluorinated chain (2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctyl nicotinic acid ester) partitions preferentially into the fluorinated phase (log K_p = 0.13). Predictions of the partition coefficients using solubility parameters calculated from group contribution techniques or molecular dynamics simulation are in reasonable agreement for the perhydrocarbon nicotinates and short chained perfluorinated nicotinates (≈0.3-39% deviation). Significant deviations from experimental partition coefficients (greater than 100%) are observed for the longest chain perfluoroalkyl nicotinates.