Structure-Reactivity Insights on the Alkaline Hydrolysis of Organophosphates: Non-Leaving and Leaving Group Effects in a Bilinear Brønsted-Like Relationship.

The high toxicity of organophosphates, along with its wide use as agrochemicals and chemical warfare, urges efficient degradation methods. Alkaline hydrolysis stands out, which is strongly structure-dependent. The alkaline hydrolysis of various organophosphates is described using a bilinear variation of the Brønsted equation, which evaluates concomitantly the effect of the leaving and non-leaving groups. Over 50 reactions were successfully correlated linearly and the contribution of the usually underestimated non-leaving group seems to be as important as the leaving group. The hetero atom effect (P=O and P=S) seems to vary the contribution of these groups. This concise understanding of the structure-reactivity relationship allows to predict optimal neutralization processes and is key for chemical security, saving time, resources and avoiding unnecessary manipulation of toxic chemicals.

Soft detoxification of chemical warfare agent simulants and pesticides under pressure.

The neutralisation of structurally varied chemical warfare agent simulants (blister and nerve agents) and pesticides (Paraoxon) with the assistance of high pressure is reported. Chloroethyl amines and sulfides (nitrogen and sulfur mustards), phosphonothioates (V-series nerve agents) and phosphates (pesticide) readily react with simple nucleophilic scavengers (alcohols, amines) at P > 14 000 bar.

Nucleophilic Neutralization of Organophosphates: Lack of Selectivity or Plenty of Versatility?

Neutralization of organophosphates is an issue of public health and safety, involving agrochemicals and chemical warfare. A promising approach is the nucleophilic neutralization, scope of this review, which focuses on the molecular nucleophiles: hydroxide, imidazole derivatives, alpha nucleophiles, amines and other nucleophiles. A reactivity mapping is given correlating the pathways and reaction efficiency with structural dependence of the nucleophile (basicity) and the organophosphate (electrophilic centers, P=O/P=S shift, leaving and non-leaving group). Reactions extremely unfavorable (>20 years) can be reduced to seconds with various nucleophiles, some which are catalytic. Although there is no universal nucleophile, a lack of selectivity in some cases accounts for plenty of versatility in other reactions. The ideal neutralization requires a solid mechanistic understanding, together with balancing factors such as milder conditions, fast process, selectivity and less toxic products.

Competitive Reactivity of Tautomers in the Degradation of Organophosphates by Imidazole Derivatives.

The harmful impact caused by pesticides on human health and the environment necessitates the development of efficient degradation processes and control of prohibited stocks of such substances. Organophosphates (OPs) are among the most used agrochemicals in the world and their degradation can proceed through several possible pathways. Investigating the reactivity of OPs with nucleophilic species allows one to propose new and efficient catalyst scaffolds for use in detoxification. In light of the remarkable catalytic activity of imidazole (IMZ) at promoting dephosphorylation processes of OPs, the reactivity of 4(5)-hydroxymethylimidazole (HMZ) with diethyl-2,4-dinitrophenylphosphate (DEDNPP) and Paraoxon are evaluated by combining experimental and theoretical approaches. It is observed that HMZ is an efficient and regiospecific catalyst with reactivity modulated by competing tautomers. To propose an optimal IMZ-based catalyst, quantum chemical calculations were performed for monosubstituted 4(5)IMZ derivatives that might cleave DEDNPP. Both inductive effects and hydrogen bonding by the substituents are shown to influence barriers and mechanisms.

Puzzling Reaction of Imidazole with Methyl Parathion: P=S versus P=O Mechanistic Shift Dilemma in Organophosphates.

Organophosphates (OPs) constitute many toxic agrochemicals and warfare and can undergo a wide spectrum of mechanisms, some which are fairly unexplored. In this sense, concise mechanistic elucidation stands out as a strategic tool for achieving efficient detoxification and for monitoring processes. Particularly intriguing is the effect of substituting the oxygen atom of the phosphoryl moiety (P=O) in OPs with a sulfur atom to give the thio-derived OPs (i.e., OTPs, P=S). In general, imidazole (IMZ) reacts very efficiently with OPs by targeting the phosphorus atom, although herein we evidence a thio-driven shift with OTPs: IMZ undergoes unusual nucleophilic attack at the aliphatic carbon atom of methyl parathion. Alkylation of IMZ under mild conditions (aqueous weakly basic medium) is also novel and should be applicable to other novel IMZ-based architectures, and thereby, it can be a great ally for organic synthesis. Overall, a broader understanding of the mechanistic trend involved in such highly toxic agents is provided.

The Importance of Methyl Positioning and Tautomeric Equilibria for Imidazole Nucleophilicity.

Imidazole (IMZ) rings catalyze many biological dephosphorylation processes. The methyl positioning effect on IMZs reactivity has long intrigued scientists and its full understanding comprises a promising tool for designing highly efficient IMZ-based catalysts. We evaluated all monosubstituted methylimidazoles (xMEI) in the reaction with diethyl 2,4-dinitrophenyl phosphate by kinetics studies, NMR analysis and DFT calculations. All xMEI showed remarkable rate enhancements, up to 1.9×105 fold, compared with spontaneous hydrolysis. Unexpectedly, the electron-donating methyl group acts to decrease the reactivity of the xMEI compared to IMZ, except for 4(5)methylimidazole, (4(5)MEI). This behavior was attributed to both electronic and steric effects. Moreover, reaction intermediates were monitored by NMR and surprisingly, the reactivity of the two different 4(5)MEI tautomers was distinguished.

An ionically tagged water-soluble artificial enzyme promotes the dephosphorylation reaction with nitroimidazole: enhanced ionic liquid effect and mechanism.

In this paper, we describe a novel synthesized ionically tagged water-soluble artificial enzyme (PI) that can efficiently cleave phosphate esters, with enhanced an ionic liquid effect through cooperative effects for the substrate activation and further nucleophilic reaction. The dephosphorylation reaction with PI was evaluated in the presence and absence of 2-methyl-4(5)-nitroimidazole, showing impressive rate enhancements of up to 2 × 10(6)-fold, ascribed to the imidazolide species known as excellent nucleophiles, and formed favorably at lower pH values in the presence of PI.

Reactivity of Imidazole Derivatives toward Phosphate Triester in DMSO/Water Mixtures: A Comprehensive Study on the Solvent Effect.

Many imidazole (IMZ) derivatives of pharmaceutical interest, which are potentially catalytic in dephosphorylation reactions, are soluble solely in mixtures of water and organic solvent. In order to understand these poorly explored reactions and properly compare them, a thorough study related to solvent effects for the analogous spontaneous reaction and with common IMZ derivatives is necessary, which is lacking in the literature. Herein, we report a quantitative solvent effect analysis in DMSO/water mixtures for (i) the hydrolysis reaction of diethyl 2,4-dinitrophenylphosphate (DEDNPP) and (ii) the nucleophilic reaction of IMZ and 1-methylimidazole (MEI) with DEDNPP. The solvent effect was fitted satisfactorily with multiple regression analysis, correlating the obtained second-order rate constants with solvent parameters such as acidity, basicity, and polarity/polarizability from Catalán's scale. The contribution of these parameters can be taken into account to elucidate the reactivity in these media. Interestingly, IMZ is more reactive than MEI in DMSO, compared to water alone, which is attributed to the availability of hydrogen-bond formation. Nuclear magnetic resonance spectroscopy ((1)H, (13)C, and (31)P), mass spectrometry, thermodynamic analysis, and density functional theory calculations were carried out to corroborate the proposed nucleophilic mechanism.

Thio-Induced Organophosphate Breakdown Promoted by Methimazole: an Experimental and Theoretical Study.

Investigating the reactivity of small nucleophilic scaffolds is a strategic approach for the design of new catalysts aiming at effective detoxification processes of organophosphorus compounds. The drug methimazole (MMZ) is an interesting candidate featuring two non-equivalent nucleophilic centers. Herein, phosphoryl transfer reactions mediated by MMZ were assessed by means of spectrophotometric kinetic studies, mass spectrometry (MS) analyses, and density functional theory (DFT) calculations using the multi-electrophilic compound O,O-diethyl 2,4-dinitrophenyl phosphate (DEDNPP). MMZ anion acts primarily as an S-nucleophile, exhibiting a nucleophilic activity comparable to that of certain oximes featuring alpha-effect. Selective nucleophilic aromatic substitution was observed, consistent with the DFT prediction of a low energy barrier. Overall, the results bring important advances regarding the mechanistic understanding of nucleophilic dephosphorylation reactions, which comprises a strategic tool for neutralizing toxic organophosphates, hence promoting chemical security.

Amidoxime-derived rice husk as biocatalyst and scavenger for organophosphate neutralization and removal.

Organophosphates are a worldwide threat because of their presence in agrochemicals and chemical warfare. Situations of misuse, apprehensions of prohibited chemicals (e.g. pesticides), undesired stockpiles and chemical attacks require effective measures for neutralization and removal. Herein, a green approach is shown by functionalizing the agricultural waste rice husk with amidoximes leading to heterogeneous catalysts that were applied in the degradation/scavenging of toxic organophosphates. In aqueous medium, the waste-derived catalyst was efficient in the catalytic neutralization of a phosphotriester (increments up to 1 × 104-fold), while allying important features: selective, recyclable and lead to less toxic products. Curiously, the amidoximated rice husk behaved as a scavenger in the aprotic polar solvents MeCN and acetone by covalently bonding to the phosphoryl moiety. Upon addition of water, this bond is broken and the phosphoryl liberated (hydrolyzed) to the aqueous medium. Thus, the scavenging process is reversible and can be used to remove toxic organophosphates. 31P nuclear magnetic resonance spectroscopy was crucial for confirming the overall mechanisms involved. In summary, a sustainable material was synthetized from a waste source and employed as catalyst and scavenger for eliminating threatening organophosphates. This is promising for assuring chemical security such as in chemical emergencies.

Dephosphorylation reactions of mono-, di-, and triesters of 2,4-dinitrophenyl phosphate with deferoxamine and benzohydroxamic acid.

This work presents a detailed kinetic and mechanistic study of biologically interesting dephosphorylation reactions involving the exceptionally reactive nucleophilic group, hydroxamate. We compare results for hydroxamate groups anchored on the simple molecular backbone of benzohydroxamate (BHA) and on the more complex structure of the widely used drug, deferoxamine (DFO). BHA shows extraordinary reactivity toward the triester diethyl 2,4-dinitrophenyl phosphate (DEDNPP) and the diester ethyl 2,4-dinitrophenyl phosphate (EDNPP) but reacts very slowly with the monoester 2,4-dinitrophenyl phosphate (DNPP). Nucleophilic attack on phosphorus is confirmed by the detection of the phosphorylated intermediates formed. These undergo Lossen-type rearrangements, resulting in the decomposition of the nucleophile. DFO, which is used therapeutically for the treatment of acute iron intoxication, carries three hydroxamate groups and shows correspondingly high nucleophilic activity toward both triester DEDNPP and diester EDNPP. This result suggests a potential use for DFO in cases of acute poisoning with phosphorus pesticides.

Waste-derived biocatalysts for pesticide degradation.

A green approach to produce a cellulose-derived biocatalyst containing hydroxamic acids targeted for the neutralization of toxic organophosphates is shown. The cellulose source, rice husk, is among the largest agricultural waste worldwide and can be strategically functionalized, broadening its sustainable application. Herein, rice husk was oxidized in different degrees, leading to carboxylic acid-based colloidal and solid samples. These were functionalized with hydroxamic acids via amide bonds and fully characterized. The hydroxamic acid derived biocatalysts were evaluated in the cleavage of toxic organophosphates, including the pesticide Paraoxon. Catalytic increments reached up to 107-fold compared to non-catalyzed reactions. Most impressively, the materials showed P atom-selectivity and recyclability features. This guarantees only one reaction pathway that leads to less toxic products, hereby, detoxifies. Overall, highly sustainable catalysts are presented, that benefits from waste source, its green functionalization and is successfully employed for the promotion of chemical security of threatening organophosphates. To the best of our knowledge, this is the first report of a hydroxamate-derived rice husk (selectively modified at the C6 of cellulose) and its application in organophosphates reaction.

Activating water: important effects of non-leaving groups on the hydrolysis of phosphate triesters.

The high rate of spontaneous hydrolysis of tris-2-pyridyl phosphate (TPP) is explained by the activating effects of the non-leaving ("spectator") groups on P-OAr cleavage, and not by intramolecular catalysis. Previous work on phosphate-transfer reactions has concentrated on the contributions to reactivity of the nucleophile and the leaving group, but our results make clear that the effects of the non-leaving groups on phosphorus can be equally significant. Rate measurements for three series of phosphate triesters showed that sensitivities to the non-leaving groups are substantial for spontaneous hydrolysis reactions, although significantly smaller for reactions with good nucleophiles. There are clear differences between triaryl and dialkyl aryl triesters in sensitivities to leaving and non-leaving groups with the more reactive triaryl systems showing lower values for both ß(LG) and ß(NLG). Intramolecular catalysis of the hydrolysis of TPP by the neighbouring pyridine nitrogens is insignificant, primarily because of their low basicity.

Polymers containing hydroxamate groups: nanoreactors for hydrolysis of phosphoryl esters.

A polyhydroxamicalkanoate (PHA) polymer containing the functional groups hydroxamic acid and carboxylic acid with the ability to accelerate dephosphorylation reactions is proposed. The methodology used to prepare this polymer favored the position of the two functional groups next to each other, which allows for the cooperativity between these groups. This cooperative effect has an important role when one wants to mimic enzymes. The catalytic effect promoted by the polymer was evaluated on the cleavage of the bis(2,4-dinitrophenyl) phosphate (BDNPP) and diethyl 2,4-dinitrophenyl phosphate (DEDNPP) esters. Indeed, PHA was very efficient and promiscuous because it increased the rate of both reactions by a factor of up to 10(6)-fold. Isothermal titration calorimetry (ITC) experiments showed that the presence of PHA aids the formation of cetyltrimethylammonium bromide (CTABr) micelles. Thus, the effect of the cationic surfactant CTABr on the dephosphorylation of BDNPP by PHA was also investigated, and it was observed that, when CTABr is added to PHA, the reaction is ca. 15-fold faster compared to the reaction when only PHA is present.

Dephosphorylation reactions with deferoxamine, a potential chemical nuclease.

We report a detailed kinetic and mechanistic study of the reaction of a widely used therapeutic agent, deferoxamine (DFO), which contains three nucleophilic hydroxamate groups, with the model phosphate diester bis-2,4-dinitrophenylphosphate BDNPP. We clarify the mechanism by detecting important phosphorylated intermediates in the model reaction and show that the mechanism can be extended to the reaction with DNA. The effectiveness of DFO in cleaving DNA was examined over a range of pH in the absence and presence of a biologically available metal (Zn(2+)). The results inform and complement ongoing studies involving DFO, which can act as a powerful nucleophile toward DNA and other targets susceptible to nucleophilic attack.

Phosphorylimidazole derivatives: potentially biosignaling molecules.

The phosphorylation of imidazole by two activated phosphate diesters and a triester gives phosphorylimidazole derivatives that are stable enough in aqueous solution to be observed and identified by ESI-MS/MS and NMR. Half-lives ranging from hours to days (in the case of the monoethyl ester) show that it is possible to design molecules with variable half-lives with potential to be used for biological intervention experiments as possible inhibitors of biosignaling processes or as haptens for the generation of antibodies.

Intramolecular catalysis of phosphodiester hydrolysis by two imidazoles.

Two imidazole groups act together to catalyze the hydrolysis of the phosphodiester bis(2-(1-methyl-1H-imidazolyl)phenyl) phosphate (BMIPP). A full investigation involving searching computational and electrospray ionization (ESI-MS-/MS) and ultra mass spectrometry (LTQ-FT) experiments made possible a choice between two kinetically equivalent mechanisms. The preferred pathway, involving intramolecular nucleophilic catalysis by imidazole, assisted by intramolecular general acid catalysis by the imidazolium group, offers the first simple model for the mechanism used by the extensive phospholipase D superfamily.

A black phosphorus-based cathode for aqueous Na-ion batteries operating under ambient conditions.

We present the unprecedented application of a black phosphorus-based nanocomposite as an electrode for aqueous Na-ion batteries under ambient conditions. An impressive specific capacity of up to 200 mA h g-1 was reached after 50 cycles in a NaCl aqueous solution used as a supporting electrolyte. Post-characterization indicated the integrity of the black phosphorus.

A simple enzymeless approach for Paraoxon determination using imidazole-functionalized carbon nanotubes.

This work describes the application of a glassy carbon electrode (GCE) modified with imidazole functionalized carbon nanotubes (CNT-H-IMZ) for Paraoxon (PX) determination in samples of commercial, fresh and 100% orange juice. Homemade multi-walled CNTs were treated according to the Hummers procedure to oxidize graphite and later chemically functionalized with imidazole groups. Modified electrodes with CNT-H-IMZ presented a high peak current of PX reduction and an electrocatalytic effect in comparison to the other electrodes. This behavior was associated with the synergistic contribution of IMZ and CNT that increases the electrochemical activity of PX. Repeatability and reproducibility studies showed that the relative peak current values did not show significant differences between them, less than 10%, and it was possible to define that the diffusional process is the mechanism that limits the electrode mass transport. After the optimization of parameters inherent to the methodology and the voltammetric technique, the proposed device presented a linear region of 1.0 to 16.0 µM-1 (R2 = 0.99), presenting LOD and LOQ as 120 and 400 nM-1, respectively. The method proposed was successfully applied to PX determination in spiked samples.

Characterization data and kinetic studies of novel lipophilic analogues from 2,4-dichlorophenoxyacetic acid and Propanil herbicides.

This work describes the data collection of new lipophilic esters and amides herbicides, analogues to 2,4-dichlorophenoxyacetic acid (2,4-D) and Propanil. The data include 1H and 13C NMR spectra and UV-VIS spectroscopic experiments, from the work "Novel lipophilic analogues from 2,4-D and Propanil herbicides: Biological activity and kinetic studies". The UV-VIS and 1H NMR spectra were employed to kinetic degradation design, and could be used to access new herbicides derivatives with better environmental properties.