Exploring the mechanism of the reductive amination of acetophenones via the Borch approach: the role of the acid catalyst.

The energetic viability of several mechanistic variations of the reductive amination of acetophenones via the Borch approach was re-examined through density functional theory calculations. The crucial involvement of the acid catalyst is evident not only in the elimination of water, but also in the initial nucleophilic step. This role increases with the electron-donating capability of the substituent positioned at the para-position of acetophenone.

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.

Substituent effects on intramolecular Schmidt reactions: a theoretical study on the formation of bridged lactams.

The competitive formation of isomeric bridged lactams via acid-catalyzed intramolecular Schmidt reactions from 3-azidoethylcyclopentanones is explored using density functional theory (DFT) calculations, primarily performed at the M06-2X/6-311++G(d,p) level of theory. The results indicate that specific substituents installed at α-carbons can efficiently control the regioselectivity of the reaction by lone pair-cation interactions or steric hindrance reversing the main product preference, whereas cation-π interactions are not so effective.

Silver-catalyzed direct selanylation of indoles: synthesis and mechanistic insights.

Herein we describe the Ag(i)-catalyzed direct selanylation of indoles with diorganoyl diselenides. The reaction gave 3-selanylindoles with high regioselectivity and also allowed direct access to 2-selanylindoles when the C3 position of the indole ring was blocked via a process similar to Plancher rearrangement. Experimental analyses and density functional theory calculations were carried out in order to picture the reaction mechanism. Among the pathways considered (via concerted metalation-deprotonation, Ag(iii), radical, and electrophilic aromatic substitution), our findings support a classic electrophilic aromatic substitution via Lewis adducts between Ag(i) and diorganoyl diselenides. The results also afforded new insights into the interactions between Ag(i) and diorganoyl diselenides.

Mechanistic insights into the amidolysis of a phosphate triester: the antagonistic role of water.

The breakdown of O,O-diethyl-2,4-dinitrophenyl phosphate in formamide (FMD) solutions is assessed using kinetic studies and 31P nuclear magnetic resonance (NMR) analysis. Regiospecific nucleophilic amidolysis via P-O bond cleavage is observed, leading to non-toxic diester and FMD regeneration. In the systems evaluated, water plays an antagonistic role: while it is key for the breakdown of the reaction intermediate, it inhibits the nucleophilic activity of FMD by hydrogen bonding effects.

Synthesis, Mechanism Elucidation and Biological Insights of Tellurium(IV)-Containing Heterocycles.

Inspired by the synthetic and biological potential of organotellurium substances, a series of five- and six-membered ring organotelluranes containing a Te-O bond were synthesized and characterized. Theoretical calculations elucidated the mechanism for the oxidation-cyclization processes involved in the formation of the heterocycles, consistent with chlorine transfer to hydroxy telluride, followed by a cyclization step with simultaneous formation of the new Te-O bond and deprotonation of the OH group. Moreover, theoretical calculations also indicated anti-diastereoisomers to be major products for two chirality center-containing compounds. Antileishmanial assays against Leishmania amazonensis promastigotes disclosed 1,2λ4 -oxatellurane LQ50 (IC50 =4.1±1.0; SI=12), 1,2λ4 -oxatellurolane LQ04 (IC50 =7.0±1.3; SI=7) and 1,2λ4 -benzoxatellurole LQ56 (IC50 =5.7±0.3; SI=6) as more powerful and more selective compounds than the reference, being up to four times more active. A stability study supported by 125 Te NMR analyses showed that these heterocycles do not suffer structural modifications in aqueous-organic media or at temperatures up to 65 °C.

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.

Degradation of Organophosphates Promoted by 1,2,4-Triazole Anion: Exploring Scaffolds for Efficient Catalytic Systems.

Organophosphate (OP) pesticides are responsible for numerous human deaths every year. Nucleophilic substitution is an important method to mitigate the toxicity of obsolete stocks of OPs. Herein, the degradation of O,O-diethyl-2,4-dinitrophenyl phosphate (DEDNPP) and pesticide diethyl-4-nitrophenyl phosphate (Paraoxon) promoted by 1,2,4-triazole (TAZ) was investigated by means of kinetic studies, nuclear magnetic resonance (NMR) analyses, and theoretical calculations. Results showed fast degradation of OPs is promoted by the anionic form of the nucleophile (TAZ(-)) in pH > 8.5 (optimal at pH = 11). Rate enhancements of 106 and 105-fold in relation to neutral hydrolysis of DEDNPP and Paraoxon were observed, respectively, consistent with alpha-nucleophiles reactivity. TAZ(-) regioselectively promotes the degradation of DEDNPP via P-O bond break, forming a quickly hydrolyzable phosphorylated intermediate, regenerating the nucleophile. Calculations using M06-2X/6-311++G(d,p) level of theory revealed that the equivalent nitrogen atoms of TAZ(-) are the main nucleophilic center of the molecule. This study expands the knowledge on the reactivity of iminic compounds as detoxificant agents of OPs, indicating the efficiency and selectivity of TAZ(-) in aqueous medium, encouraging the design of novel TAZ-based catalysts.

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.

Coupled Electrocyclization/Prototropic Shift in the Biosynthesis of Crotinsulidane Diterpenoids.

The energetic viability of proposed mechanisms for the formation of the five-membered ring in crotinsulidane diterpenes is assessed using density functional theory calculations. A protonation-assisted coupled four-electron electrocyclization/prototropic shift mechanism is predicted to have a low (biologically relevant) barrier.

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.

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.