RESUMEN
Fluorine atoms play an important role in all branches of chemistry and accordingly, it is very important to study their unique and varied effects systematically, in particular, the structure-physicochemical properties relationship. The present study describes exceptional physicochemical effects resulting from a H/F exchange at the methylene bridge of gem-difunctional compounds. The Δlog P(CF2-CH2) values, that is, the change in lipophilicity, observed for the CH2 /CF2 replacement in various α,α-phenoxy- and thiophenoxy-esters/amides, diketones, benzodioxoles and more, fall in the range of 0.6-1.4â units, which for most cases, is far above the values expected for such a replacement. Moreover, for compounds holding more than one such gem-difunctional moiety, the effect is nearly additive, so one can switch from a hydrophilic compound to a lipophilic one in a limited number of H/F exchanges. DFT studies of some of these systems revealed that polarity, conformational preference as well as charge distributions are strongly affected by such hydrogen to fluorine atom substitution. The pronounced effects described, are a result of the interplay between changes in polarity, H-bond basicity and molecular volume, which were obtained with a very low 'cost' in terms of molecular weight or steric effects and may have a great potential for implementation in various fields of chemical sciences.
RESUMEN
Supramolecular systems in water are of paramount importance and those based on hydrogen bonds are both intriguing and scarce. Here, after studying the peculiar host-guest complexes formed between per-dimethylamino-pillar[5]arene (1) and the bis-sulfonates 2 a-c, we describe the formation of the first hydrogen-bond-based supramolecular pentagonal boxes (SPBs), which are stable in water. These pH-responsive SPBs are constructed from 1 as a body, benzene polycarboxylic acids 3 a,b as lid compounds, and 2 a-c as guests. We demonstrate that encapsulation of 2 a-c in pillar[5]arene 1 and in the highly stable water-soluble SPBs, that is, 1(3 a)2 and 1(3 b)2 , is both temperature and pH dependent and, quite interestingly, depends, on the nature of the lid compounds used for capping the boxes even at high pH. We also highlight the difference in the 1 Hâ NMR characteristics of 2 b and 2 c in the cavity of 1 and the SPBs.
RESUMEN
We describe the preparation of the first water-soluble pH-responsive supramolecular hexagonal boxes (SHBs) based on multiple charge-assisted hydrogen bonds between peramino-pillar[6]arenes 2 with the molecular "lid" mellitic acid (1 a). The interaction between 2 and 1 a, as well as the other "lids" pyromellitic and trimesic acids (1 b and 1 c, respecively) were studied by a combination of experimental and computational methods. Interestingly, the addition of 1 a to the complexes of the protonated form of pillar[6]arene 2, that is, 3, with bis-sulfonate 4 a or 4 b, immediately led to guest escape along with the formation of closed 1 a2 2 supramolecular boxes. Moreover, the process of the openning and closing of the supramolecular boxes along with threading and escaping of the guests, respectively, was found to be reversible and pH-responsive. This study paves the way for the easy and modular preparation of different SHBs that may have myriad applications.
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Rationally designed two-component supramolecular organogels based on multiple chemical interactions between percarboxylato- and peramino-pillararenes are described. Mixing low concentration solutions (<1 % w/v) of decacarboxylato-pillar[5]areneâ (1) with decaamino-pillar[5]arenesâ (2 b-d) affords, rapidly and without heating, organogels displaying an exceptional combination of properties. These supramolecular organogels, the characteristics of which are tunable, were found to be thixotropic and thermally stable, with Tgel values in some cases exceeding the boiling point of the embedded solvent. It is demonstrated that both structural complementarity and multivalency are important determinants in the gelation process of these attractive soft materials.
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Solvent effects on the ability of KF/Al2O3 supports to degrade the warfare agent sulfur mustard (HD) were explored. RP-KF/Al2O3 possessing hydroxide ions and ECUF/KF/Al2O3 holding fluoride ions were examined. Reactions on RP-KF/Al2O3 containing 10 wt % of organic solvents were faster than those on ECUF/KF/Al2O3. Additionally, RP-KF/Al2O3 led to elimination products, while ECUF/KF/Al2O3 mainly led to substitution derivatives. Enlarging the solvent amounts to 90 wt % resulted in decreased reaction rates. The significance of solvent identity/amount and active species is discussed.
RESUMEN
Mild oxidation of sulfur-containing chemical warfare agents was performed in organic medium by electrophilic iodine reagents. Kinetic experiments on sulfur mustard (HD) showed rapid ( t1/2 < 3 min) and selective oxidation to the nonvesicant sulfoxide product (HD-SO) in acetonitrile or propylene carbonate solutions (9% water added) containing excess N-iodosuccinimide (NIS). Molecular iodine solutions in these solvents led to similar results as with NIS but at much slower rates ( t1/2 â¼ 90 min). Higher donor number solvents, such as THF, DMF, or DMSO, showed slower rates with both iodine and NIS. The oxidation of the nerve agent O-ethyl- S-2-( N,N-diisopropylaminoethyl)methylphosphonothioate (VX) selectively to the nontoxic ethyl methylphosphonic acid product exhibited fast rates ( t1/2 = 6 min) using NIS in DMSO solution. In all other solvents tested with VX, rates were slower ( t1/2 â¼ 30-70 min). Oxidation experiments under the same conditions with chloroethyl ethyl sulfide (HD simulant) and O,S-diethyl methylphosphonothioate (VX simulant) led to much faster reaction rates. These transformations are believed to proceed through electrophilic iodine attack on the sulfur moiety and display solvent dependency based on the agents' structural and chemical properties.
RESUMEN
Solvent effects on the reactions of the extremely toxic nerve agent VX with KF/Al2O3 powder were explored. Small quantities of water or methanol (5-10 wt %), which effectively mobilized all components while maintaining the heterogeneous nature of the reaction, promoted much faster rates than those obtained with larger quantities. Any amount of acetonitrile resulted in extremely slow transformations. Surprisingly, 5-50 wt % of heptane led to fast reactions due to the combination of its ability to mediate fast diffusion of VX and a MAS centrifugation effect.
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A practical, convenient, and general method for the difluoromethylation of tertiary amines, using diethyl bromodifluoromethylphosphonate and fluoride, is described. This commercially available phosphonate smoothly reacts with a fluoride ion to liberate a difluorocarbene intermediate that in the presence of a proton source and a tertiary amine generates the corresponding α-difluoromethylammonium compound in good to excellent yields. Despite the involvement of a difluorocarbene intermediate, this difluoromethylation occurs almost exclusively on the nitrogen atom with diverse molecular structures, including drugs, surfactants, chiral phase transfer catalysts, polymers, ionic liquids, and other fine chemicals. A preliminary assessment of the effects that an α-difluoromethyl groupT has on hydrogen bonding and logP of quaternary ammonium salts is also described.
RESUMEN
The effects solvents have on fluoride-promoted heterogeneous hydrolysis and alcoholysis of various organo-phosphorus (OP) compounds on the surface of KF/Al2O3 are described. Solid-state magic angle spinning NMR analyses and SEM microscopy have shown that not only is the identity of the solvent important in these reactions but also its quantity. That is, minimal solvent amounts are favored and much more effective in such solid-supported reactions (and maybe generally) than those featuring solvent-free or excess solvent (>50 wt %) conditions. The addition of a minute quantity of the correct solvent (3-10 wt %, molar equivalent scale) avoids reagents leaching from the matrix, permits mobility (mass transport) of the reaction components and ensures their very high local concentration in close proximity to the solid-support large porous surface area. Accordingly, significant acceleration of reactions rates by orders of magnitude is obtained. Fascinatingly, even challenging phosphoesters with poor leaving groups, which were found to be very stable in the presence of solvent-free KF/Al2O3 or wetted with excess water, were efficiently hydrolyzed with a minute amount of this solvent.
Asunto(s)
Fluoruros/química , Compuestos Organofosforados/química , Solventes/química , Agua/química , Espectroscopía de Resonancia Magnética , Técnicas de Síntesis en Fase SólidaRESUMEN
Among the chemical warfare agents, the extremely toxic nerve agent VX (O-ethyl S-2-(diisopropylamino)ethyl methylphosphonothioate) is a target of high importance in the development of decontamination methods, due to its indefinite persistence on common environmental surfaces. Liquid decontaminants are mostly characterized by high corrosivity, usually offer poor coverage, and tend to flow and accumulate in low areas. Therefore, the development of a noncorrosive decontaminant, sufficiently viscous to resist dripping from the contaminated surface, is necessary. In the present paper we studied different polysaccharides-thickened fluoride aqueous solutions as noncorrosive decontaminants for rapid and efficient VX degradation to the nontoxic product EMPA (ethyl methylphosphonic acid). Polysaccharides are environmentally benign, natural, and inexpensive. Other known decontaminants cannot be thickened by polysaccharides, due to the sensitivity of the latter toward basic or oxidizing agents. We found that the efficiency of VX degradation in these viscous solutions in terms of kinetics and product identity is similar to that of KF aqueous solutions. Guar gum (1.5 wt %) with 4 wt % KF was chosen for further evaluation. The benign nature, rheological properties, adhering capabilities to different surfaces, and decontamination from a porous matrix were examined. This formulation showed promising properties for implementation as a spray decontaminant for common and sensitive environmental surfaces.
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Sustancias para la Guerra Química/metabolismo , Descontaminación/métodos , Fluoruros/química , Organofosfonatos/metabolismo , Compuestos Organotiofosforados/metabolismo , Polisacáridos/químicaRESUMEN
A systematic study of trends in the lipophilicity of prominent representatives of the opioid family, including natural, semisynthetic, synthetic, and endogenous neuropeptide opioids, is described. This was enabled by a straightforward 1H NMR-based logP/D determination method developed for compounds holding at least one aromatic hydrogen atom. Moreover, the new method enables a direct simultaneous logD determination of opioid mixtures, overcoming the high sensitivity of this family to the measurement conditions, which is critical when a determination of the exact ΔlogD values of matched pairs is required. Interpretation of the experimental ΔlogD7.4 values of selected matched pairs, focusing inter alia on the 3-OMe and 14-OMe motifs in morphinan opioids, is suggested with the aid of DFT calculations and may be useful for the discovery of new opioid therapeutics.
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Analgésicos Opioides , Analgésicos Opioides/química , Espectroscopía de Protones por Resonancia Magnética , Interacciones Hidrofóbicas e Hidrofílicas , Teoría Funcional de la Densidad , Espectroscopía de Resonancia Magnética , Estructura MolecularRESUMEN
Combined molecular, physicochemical and chemical properties of electrophilic warheads can be applied to create covalent drugs with diverse facets. Here we study these properties in fluorinated diketones (FDKs) and their multicomponent equilibrium systems in the presence of protic nucleophiles, revealing the potential of the CF2(CO)2 group to act as a multifaceted warhead for reversible covalent drugs. The equilibria compositions of various FDKs in water/octanol contain up to nine species. A simultaneous direct species-specific 19F-NMR-based log P determination of these complex equilibria systems was achieved and revealed in some cases lipophilic to hydrophilic shifts, indicating possible adaptation to different environments. This was also demonstrated in 19F-MAS-NMR-based water-membrane partitioning measurements. An interpretation of the results is suggested by the aid of a DFT study and 19F-DOSY-NMR spectroscopy. In dilute solutions, a model FDK reacted with protected cysteine to form two hemi-thioketal regioisomers, indicating possible flexible regio-reactivity of CF2(CO)2 warheads toward cysteine residues.
RESUMEN
Following our ongoing studies on the reactivity of the fluoride ion toward organophosphorus compounds, we established that the extremely toxic and environmentally persistent chemical warfare agent VX (O-ethyl S-2-(diisopropylamino)ethyl methylphosphonothioate) is exclusively and rapidly degraded to the nontoxic product EMPA (ethyl methylphosphonic acid) even in dilute aqueous solutions of fluoride. The unique role of the P-F bond formation in the reaction mechanism was explored using both experimental and computational mechanistic studies. In most cases, the "G-analogue" (O-ethyl methylphosphonofluoridate, Et-G) was observed as an intermediate. Noteworthy and of practical importance is the fact that the toxic side product desethyl-VX, which is formed in substantial quantities during the slow degradation of VX in unbuffered water, is completely avoided in the presence of fluoride. A computational study on a VX-model, O,S-diethyl methylphosphonothioate (1), clarifies the distinctive tendency of aqueous fluoride ions to react with such organophosphorus compounds. The facility of the degradation process even in dilute fluoride solutions is due to the increased reactivity of fluoride, which is caused by the significant low activation barrier for the P-F bond formation. In addition, the unique nucleophilicity of fluoride versus hydroxide toward VX, in contrast to their relative basicity, is discussed. Although the reaction outcomes were similar, much slower reaction rates were observed experimentally for the VX-model (1) in comparison to VX.
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Compuestos Organotiofosforados/química , Agua/química , Fluoruros/química , Hidrólisis , Cinética , Modelos TeóricosRESUMEN
V-type nerve agents are among the most toxic organophosphorus chemical warfare agents, and they are under strict regulation and supervision by the OPCW (Organization for the Prohibition of Chemical Weapons). The V-type class of materials refers to a potentially large number of analogues and isomers. In order to expose instances of unfulfillment of the OPCW treaty, it is essential to have the ability to detect and identify "unknown" analogues of this family, even in the absence of an analytical standard. This work demonstrates a new automated tool for the detection and identification of V-type analogues, using high-resolution-accurate-mass LC-MS analysis, followed by "Compound Discoverer" software data processing. This software, originally developed for metabolism and metabolomics screening, is used here to automatically detect various V-type analogues by picking peaks and comparing them to "in-silico" calculated modifications made on a predefined basic V-backbone structure (according to the OPCW definitions for V-type agents). Subsequently, a complete structural elucidation for the proposed molecular formula is obtained by MS/MS data analysis of the suspected component, for both the V-type analogue (using ESI(+) analysis) as well as its hydrolysis product (using ESI(-) analysis) for a better elucidation of the phosphonate "head" structure. This method was found to be useful for the detection and identification of several "unknown" analogues, at low ng/mL levels in soil extracts.
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Sustancias para la Guerra Química , Agentes Nerviosos , Sustancias para la Guerra Química/análisis , Sustancias para la Guerra Química/química , Cromatografía Liquida/métodos , Agentes Nerviosos/análisis , Programas Informáticos , Espectrometría de Masas en Tándem/métodosRESUMEN
Systematically studying the lipophilicity of phosphorus compounds is of great importance for many chemical and biological fields and particularly for medicinal chemistry. Here, we report on the study of trends in the lipophilicity of a wide set of phosphorus compounds relevant to drug design including phosphates, thiophosphates, phosphonates, thiophosphonates, bis-phosphonates, and phosphine chalcogenides. This was enabled by the development of a straightforward log P determination method for phosphorus compounds based on 31P-NMR spectroscopy. The log P values measured ranged between -3.2 and 3.6, and the trends observed were interpreted using a DFT study of the dipole moments and by H-bond basicity (pKHB) measurements of selected compounds. Clear signal separation in 31P-NMR spectroscopy grants the method high tolerability to impurities. Moreover, the wide range of chemical shifts for the phosphorus nucleus (250 to -250 ppm) enables a direct simultaneous log P determination of phosphorus compound mixtures in a single shake-flask experiment and 31P-NMR analysis.
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Organofosfonatos , Compuestos de Fósforo , Espectroscopía de Resonancia Magnética/métodos , Fósforo/químicaRESUMEN
The catalytic degradation of the nerve agent VX (O-ethyl S-2-(diisopropylamino)ethyl methylphosphonothioate) by water-swelled polymer-supported ammonium fluorides is described. VX (0.06-0.53 mol/mol F(-)) is rapidly degraded (t(1/2) â¼ 10-30 min) to form the "G-analogue" (O-ethyl methylphosphonofluoridate), which hydrolyzes (t(1/2) â¼ 1-1.5 h) to the nontoxic EMPA (ethyl methylphosphonic acid). The toxic desethyl-VX is not formed. The catalytic effect of fluoride is maintained even when 6 equiv of VX are loaded. GB (O-isopropyl methylphosphonofluoridate) and desethyl-VX agents are also degraded under these conditions.
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Sustancias para la Guerra Química/química , Química Orgánica/métodos , Fluoruros/química , Compuestos Organotiofosforados/química , Compuestos de Amonio Cuaternario/química , Sarín/química , Adsorción , Compuestos de Amonio , Animales , Catálisis , Defensa Civil , Humanos , Concentración de Iones de Hidrógeno , Hidrólisis , Cinética , Organofosfonatos/análisis , Organofosfonatos/química , Poliestirenos/química , AguaRESUMEN
The reactions of the chemical warfare agents (CWAs) 2,2'-dichloroethyl sulfide (HD), O-ethyl S-2-(diisopropylamino)-ethyl methylphosphonothioate (VX) and isopropyl methylphosphonofluoridate (GB) with various metal oxide-supported quaternary ammonium fluorides (QAF) and/or potassium fluoride (KF) reagents are described. These active sorbents, which were prepared by a modified procedure, include alumina, silica and titania, enriched with "available" (not bound to the surface) fluoride ions. Alumina-based fluoride reagents were found to be more active than their silica or titania counterparts. QAF/Al(2)O(3) reagents, compared to KF/Al(2)O(3), exhibit an exceptional reactivity toward HD, as demonstrated both in reaction rates and product identity. For example, with TBAF, t(1/2) is 15 min for the formation of the elimination product divinyl sulfide (DVS), while with KF, t(1/2) is 10 h for the formation of the hydrolysis product thiodiglycol (TDG). On the other hand, both sorbents reacted similarly against the nerve agents GB or VX. In order to increase the "available" fluoride content on the solid surface, the mixed active sorbent TBAF/KF/Al(2)O(3) (20/20/60) was developed. On this powder, all three CWAs were degraded instantaneously at the low loading of 1 wt% (t(1/2) < 2 min) and rapidly at the higher loadings of 5-10 wt% (t(1/2) of minutes scale). We assume that the relatively large amount of inorganic fluoride (KF) acts synergistically as a reservoir for the more reactive organic fluorides (TBAF). Moreover, the alumina surface hydroxyl groups may also operate as a water reservoir for the hydrolysis of VX or GB. Therefore, TBAF/KF/Al(2)O(3) might be considered as a promising destructive sorbent for CWAs.
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Óxido de Aluminio/química , Sustancias para la Guerra Química/química , Fluoruros/química , Compuestos de Potasio/química , Compuestos de Amonio Cuaternario/químicaRESUMEN
Bacterial biofilms are a major threat to human health, causing persistent infections that lead to millions of fatalities worldwide every year. Biofilms also cause billions of dollars of damage annually by interfering with industrial processes. Recently, cationic pillararenes were found to be potent inhibitors of biofilm formation in Gram-positive bacteria. To identify the structural features of pillararenes that result in antibiofilm activity, we evaluated the activity of 16 cationic pillar[5]arene derivatives including that of the first cationic water-soluble pillar[5]arene-based rotaxane. Twelve of the derivatives were potent inhibitors of biofilm formation by Gram-positive pathogens. Structure activity analyses of our pillararene derivatives indicated that positively charged head groups are critical for the observed antibiofilm activity. Although certain changes in the lipophilicity of the substituents on the positively charged head groups are tolerated, dramatic elevation in the hydrophobicity of the substituents or an increase in steric bulk on these positive charges abolishes the antibiofilm activity. An increase in the overall positive charge from 10 to 20 did not affect the activity significantly, but pillararenes with 5 positive charges and 5 long alkyl chains had reduced activity. Surprisingly, the cavity of the pillar[n]arene is not essential for the observed activity, although the macrocyclic structure of the pillar[n]arene core, which facilitates the clustering of the positive charges, appears important. Interestingly, the compounds found to be efficient inhibitors of biofilm formation were nonhemolytic at concentrations that are â¼100-fold of their MBIC50 (the minimal concentration of a compound at which at least 50% inhibition of biofilm formation was observed compared to untreated cells). The structure-activity relationship guidelines established here pave the way for a rational design of potent cationic pillar[n]arene-based antibiofilm agents.
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Antibacterianos , Biopelículas , Antibacterianos/farmacología , Cationes , Bacterias Grampositivas , Humanos , Relación Estructura-ActividadRESUMEN
Modulation of the H-bond basicity (pKHB) of various functional groups (FGs) by attaching fluorine functions and its impact on lipophilicity and bioisosterism considerations are described. In general, H/F replacement at the α-position to H-bond acceptors leads to a decrease of the pKHB value, resulting, in many cases, in a dramatic increase in the compounds' lipophilicity (logâ¯Po/w). In the case of α-CF2H, we found that these properties may also be affected by intramolecular H-bonds between CF2H and the FG. A computational study of ketone and sulfone series revealed that α-fluorination can significantly affect overall polarity, charge distribution, and conformational preference. The unique case of α-di- and trifluoromethyl ketones, which exist in octanol/water phases as ketone, hemiketal, and gem-diol forms, in equilibrium, prevents direct logâ¯Po/w determination by conventional methods, and therefore, the specific logâ¯Po/w values of these species were determined directly, for the first time, using Linclau's 19F NMR-based method.
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Flúor/química , Cetonas/química , Teoría Funcional de la Densidad , Halogenación , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Isomerismo , Cetonas/síntesis química , Cinética , Espectroscopía de Resonancia Magnética , Piridinas/síntesis química , Piridinas/química , Sulfonas/síntesis química , Sulfonas/químicaRESUMEN
Fluorescent semiconductor nanocrystals (q-dots) benefit from practical features such as high fluorescence intensity, broad excitation band and emission diameter dependency. These unique spectroscopic characterizations make q-dots excellent candidates for new fluorescent labels in multi-chromatic analysis, such as Flow-Cytometry (FCM). In this work we shall present new possibilities of multi-labeling and multiplex analysis of pathogenic bacteria, by Flow-Cytometry (FCM) analysis and new specific IgG-q-dots conjugates. We have prepared specific conjugates against B. anthracis spores (q-dots585-IgGalphaB. anthracis and q-dots655-IgGalphaB.anthracis). These conjugates enabled us to achieve double staining of B. anthracis spores which improve the FCM analysis specificity versus control Bacillus spores. Moreover, multiplexed analysis of B. anthracis spores and Y. pestis bacteria was achieved by using specific antibodies labeled with different q-dots to obtain: q-dots585-IgGalphaB. anthracis and q-dots655-IgGalphaY.pestis, each characterized by its own emission peak as a marker. Specific and sensitive multiplex analysis for both pathogens has been achieved, down to 10(3) bacteria per ml in the sample.