Placing CF2 in the Center: Major Physicochemical Changes Upon a Minor Structural Alteration in Gem-Difunctional Compounds.

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 0.6-1.4 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.

Degradation of Sulfur Mustard on KF/Al2O3: The Role of Organic Solvents and Active Species.

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.

Oxidative Detoxification of Sulfur-Containing Chemical Warfare Agents by Electrophilic Iodine.

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 ∼ 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 ∼ 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.

Solvent Effects on the Reactions of the Nerve Agent VX with KF/Al2O3: Heterogeneous or Homogeneous Decontamination?

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.

Component mobility by a minute quantity of the appropriate solvent as a principal motif in the acceleration of solid-supported reactions.

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.

Polysaccharide-thickened aqueous fluoride solutions for rapid destruction of the nerve agent VX. Introducing the opportunity for extensive decontamination scenarios.

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.

Decontamination of adsorbed chemical warfare agents on activated carbon using hydrogen peroxide solutions.

Mild treatment with hydrogen peroxide solutions (3-30%) efficiently decomposes adsorbed chemical warfare agents (CWAs) on microporous activated carbons used in protective garments and air filters. Better than 95% decomposition of adsorbed sulfur mustard (HD), sarin, and VX was achieved at ambient temperatures within 1-24 h, depending on the H2O2 concentration. HD was oxidized to the nontoxic HD-sulfoxide. The nerve agents were perhydrolyzed to the respective nontoxic methylphosphonic acids. The relative rapidity of the oxidation and perhydrolysis under these conditions is attributed to the microenvironment of the micropores. Apparently, the reactions are favored due to basic sites on the carbon surface. Our findings suggest a potential environmentally friendly route for decontamination of adsorbed CWAs, using H2O2 without the need of cosolvents or activators.

Species-specific lipophilicities of fluorinated diketones in complex equilibria systems and their potential as multifaceted reversible covalent warheads.

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.

Role of the P-F bond in fluoride-promoted aqueous VX hydrolysis: an experimental and theoretical study.

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.

VX fate on common matrices: evaporation versus degradation.

A study of the volatilization rate of the nerve agent VX (O-ethyl S-2-(N,N-diisopropylamino)ethyl methylphosphonothiolate) from various urban matrices in a specially designed climatic chamber (model system) is described. The performance of the model system combined with the analytical procedure produced profiles of vapor concentration obtained from samples of VX dispersed as small droplets on the surfaces of the matrices. The results indicated that the bitumen-containing surfaces such as asphalt blocks and bitumen sheets conserve VX and slow-release part of it over a long period of time. No complete mass balance could be obtained for these surfaces. Influence of environmental and experimental parameters as well as the efficacy of decontamination procedure were also measured. From smooth surface tiles a fast release of VX was measured and almost a complete mass balance was obtained, which characterizes the behavior of inert surfaces. Experiments carried out on concrete blocks showed fast decay of the concentration profile along with a very poor reconstruction of the initial quantity of VX, implying that this matrix degraded VX actively due to its multiple basic catalytic sites. To complement this study, solid-state NMR measurements were compared to add data concerning agent-fate within the matrices.

Studying Lipophilicity Trends of Phosphorus Compounds by 31P-NMR Spectroscopy: A Powerful Tool for the Design of P-Containing Drugs.

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.

Catalytic degradation of the nerve agent VX by water-swelled polystyrene-supported ammonium fluorides.

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) ∼ 10-30 min) to form the "G-analogue" (O-ethyl methylphosphonofluoridate), which hydrolyzes (t(1/2) ∼ 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.

The reactivity of quaternary ammonium- versus potassium-fluorides supported on metal oxides: paving the way to an instantaneous detoxification of chemical warfare agents.

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.

Long-term evaluation of the fate of sulfur mustard on dry and humid soils, asphalt, and concrete.

The long-term fate of the blister agent sulfur mustard (HD, bis(2-chloroethyl)sulfide) was determined in a variety of commercial and natural matrices. HD was found to be extremely stable in dry matrices for over a year. The addition of 5% water to the matrices induced slow degradation of HD, which lasted several months. The major degradation product in sands and asphalt was found to be a sulfonium salt, S[CH(2)CH(2)S(+)(CH(2)CH(2)OH)(2)](2) (H-2TG). Red loam soil, which has not been examined before, exhibited strong interaction with HD, both in dry form and in the presence of water. Humid red loam soil gave rise to unique oxidative degradation products. On humid concrete HD degraded to a complex mixture of products, including vinyls. This may be attributed to the basic sites incorporated in concrete.

Active and Strippable PVA/Borax/NaBO3 Hydrogel for Effective Containment and Decontamination of Chemical Warfare Agents.

Active gels present unique potential for the decontamination of chemical warfare agents (CWAs) as they strongly adhere to surfaces, thus allowing prolonged decontamination time. Herein, we present a decontamination hydrogel based on polyvinyl alcohol/borax, which contains sodium perborate (NaBO3), as an in situ source of the active ingredient hydrogen peroxide. Developed as a binary formulation, this gel instantly forms and effectively sticks when sprayed on various matrices, including porous and vertically positioned matrices. The gel efficiently detoxified the CWAs sarin (GB), O-ethyl S-2-(diisopropylamino)ethyl methylphosphonothioate (VX), and sulfur mustard (HD) in test tubes (2 µL CWA/0.5 mL gel) to provide nontoxic products with reaction half-lives of <3, 45 and 113 min, respectively. The gel was also shown to efficiently decontaminate surfaces contaminated with VX (5-7 mg, 8-12 mL of gel, i.e., >99%) and to prevent GB evaporation, as proven by laboratory wind tunnel experiments. The universal decontamination abilities of this mild hydrogel, as well as its facile application and removal processes suggest that it holds high potential for future development as a new CWA decontamination tool.

Degradation of sulfur mustard on KF/Al2O3 supports: insights into the products and the reactions mechanisms.

The degradation of the warfare agent sulfur mustard (HD) adsorbed onto KF/Al(2)O(3) sorbents is described. These processes were explored by MAS NMR, using (13)C-labeled sulfur mustard (HD*) and LC-MS techniques. Our study on the detoxification of this blister agent showed the formation of nontoxic substitution and less-toxic elimination products (t(1/2) = 3.5-355 h). Interestingly, the reaction rates were found to be affected by MAS conditions, i.e., by a centrifugation effect. The products and the mechanisms of these processes are discussed.

Effective neutralization of chemical warfare agents (HD, VX) by Me-DABCOF: a small molecule with dual action.

The ability of mono N-methyl-1,4-diazabicyclo[2.2.2]octane fluoride (Me-DABCOF, 1) to act as a bifunctional reagent that effectively and universally neutralizes both the persistent and extremely toxic blister agent HD and the nerve agent VX in nearly neutral aqueous solution, alumina powder or a hydrogel formulation, is described.

Functionalization of the methylene bridges of the calix[6]arene scaffold.

The bromine atoms of the hexabromo calixarene derivative 3 were replaced by other groups under S(N)1 conditions, allowing the facile synthesis of calix[6]arene derivatives incorporating identical functionalities at all bridges. Heating at reflux a mixture of 3 and the appropriate alcohol incorporated primary and secondary alkoxy substituents. Hydride abstraction was observed when the reaction with EtOH and i-PrOH was conducted in hexafluoroisopropanol (HFIP). Solvolysis of 3 in TFE in the presence of strong nucleophiles (such as N3(-) and aniline) afforded the corresponding hexaazido and hexaanilino derivatives. Hydroxyl groups were incorporated into the calix[6]arene scaffold via acetolysis of 3, followed by LiAlH4 reduction of the hexaacetate derivative obtained. Friedel-Crafts alkylations in the absence of Lewis acids were conducted by heating at reflux a mixture of 3, HFIP, and a substituted benzene derivative (e.g, m-xylene, p-methyl anisole, mesitylene). The calix[6]arene bridges were alkylated by heating at reflux a mixture of 3 and 2,4-pentanedione in TFE or HFIP. In all cases the reaction proceeded with high diastereoselectivity, and the major isomer isolated was assigned to the rc5 (i.e., all-cis) form. NMR spectroscopy indicates that the conformation adopted by the macrocycle possesses 3-fold symmetry (a "pinched cone") that is rigid in the laboratory time scale in the mesityl-substituted derivative.

The nucleophilic substitution route. A facile method for the fourfold functionalization of the methylene bridges of calix[4]arene.

The radical bromination of p-tert-butylcalixarene tetramethyl ether was reinvestigated and the product (2b) characterized by X-ray crystallography. The tetrabromo calixarene derivatives 2a or 2b react with alcohols (TFE, EtOH), azide, and 2-methylfuran under solvolytic conditions affording calixarene derivatives functionalized at the four bridges. The reaction with alcohols and the aromatic compound proceeds in stereoselective fashion and affords the rccc isomer of the tetrasubstituted product.

Synthesis, Characterization, and Reactivity of Thermally Stable Anhydrous Quaternary Ammonium Fluorides.

The synthesis and properties of a new class of anhydrous quaternary ammonium fluorides, based on the rigid skeleton azabicyclo[2.2.2]octane, is described. Compounds 2a-d were easily prepared by passing the corresponding ammonium iodides over fluoride-based resin followed by drying their hydrated form at 100 or 140 °C under reduced pressure. The stability (experimental and theoretical study), solubility, reactivity, and characterization by solution and solid-state MAS NMR are discussed.