Stable Zwitterion Research Articles

Systematic Synthesis of Thermally Stable Zwitterionic Energetic Materials Based on 4-Hydroxy-3,5-dinitropyrazole.

4-Hydroxy-3,5-dinitropyrazole (HODNP) was investigated as a precursor for synthesizing two thermally stable, insensitive zwitterionic energetic materials. The ability of the hydroxy functionality to carry negative charge was leveraged and further covalently bonded with two positively charged moieties (3,4-diamino-1,2,4-triazole and acetimidamide) via N-functionalization to form zwitterions 2 and 3. Structural characterization and a study of the energetic performance were carried out. The zwitterionic nature of compound 3 was confirmed by single-crystal analysis.

Understanding speciation and solvation of glyphosate from first principles simulations

The widespread adoption of the glyphosate (N-phosphonomethylglycine) herbicide has contributed to its increased environmental footprint. Consequently, the sequestration and degradation of excess contaminants are of significant interest, particularly in local aquatic environments. However, this inherently relies on a detailed understanding of glyphosate’s complex speciation and conformational flexibility in the condensed phase. In this work, we investigate the structure and speciation of glyphosate in the vapor and aqueous phases using first-principles simulations. Using the PBE-D3, B3LYP, and ωB97X-D functionals, we found multiple nonzwitterion and five stable zwitterion conformers in the gas phase. Ab initio molecular dynamics (AIMD) simulations in the canonical (NVT) and isothermal-isobaric (NpT) ensembles were employed using the PBE-D3 density functional. Analysis of the equilibrated trajectory allowed an understanding of condensed phase structure through the radial distribution function (RDF), hydrogen bond dynamics, and vibrational spectra. We found evidence that the phosphonate, carboxylic, and amine groups interact strongly with the solvent via hydrogen bonding leading to atypically long O-H bond length (∼ 1.1 Å) on glyphosate’s phosphonate and carboxylic functional groups. Metadynamics simulations using the PBE-D3 and optB88-vdW functionals were performed to estimate the free energy associated with the intramolecular H+ transfer separating the zwitterion and nonzwitterion conformers of glyphosate. Although both functionals confirm the stability of the zwitterion form in the aqueous phase, they differ significantly in the predicted free energy of the reaction.

α-Amino Phosphonic Acid as the Oxidized Ore Collector: Flexible Intra-Molecular Proton Transfer Providing an Improved Flotation Efficiency

The efficient separation of ilmenite is a difficult problem in minerals flotation. For this issue, α-aminooctyl phosphinic acid (APA) was developed as a selective collector to separate ilmenite. The flotation test result showed that APA was more efficient for improving ilmenite recovery compared with octylphosphonic acid (OPA). Adsorption, ZETA and FTIR measurements proved that the chemical interaction between collector APA and the surface of ilmenite was stronger than OPA, while the result is completely opposite in the case of titanaugite. Moreover, XPS test and DFT calculations indicated that the collector APA was coordinated with the surface of ilmenite through P-O-Fe and P-O-Ti bonding. The amine group in the α-site of the phosphonyl group facilitated APA to be a stable zwitterion in the solution, which greatly enhanced the nucleophilicity of the phosphonic acid group. On the other hand, more appropriate coordination energy was another reason for the superior collecting selectivity of APA than OPA.

Mechanistic Studies on the Base-Promoted Ring Opening of Glycal-Derived gem-Dibromocyclopropanes.

In the presence of a nucleophilic base, ring-fused gem-dibromocyclopropanes derived from d-glycals undergo ring opening to give 2-deoxy-2-(E-bromomethylene)glycosides. Such cleavage of an exocyclic cyclopropane bond contrasts with the more usual silver-promoted ring-expansion reactions in which endocyclic bond cleavage occurs. Experimental and theoretical studies are reported which provide insights into the reaction mechanism and the origin of its kinetic selectivity for E-configured bromoalkene products. Density functional theory computations (M06-2X) predict that the reaction commences with alkoxide-induced HBr elimination from the dibromocyclopropane to form a bromocyclopropene. Ring opening then gives a configurationally stable zwitterionic (oxocarbenium cation/vinyl carbanion) intermediate, which undergoes nucleophilic addition and protonation to give the bromoalkene. There are two competing sources of the proton in the final step: One is the alcohol (co)solvent, and the other is the molecule of alcohol produced during the initial deprotonation step. The roles of the formed alcohol molecule and the bulk (co)solvent are demonstrated by isotope-labeling studies performed with deuterated solvents. The acid-promoted isomerization of the E-bromoalkene product into the corresponding Z-bromoalkene is also described. The mechanistic knowledge gained in this investigation sheds light on the unusual chemistry of this system and facilitates its future application in new settings.

Synthesis and Optical Resolution of Configurationally Stable Zwitterionic Pentacoordinate Silicon Derivatives

AbstractStereogenic silicon centres in functionalised tetracoordinated organosilanes generally exhibit very high configurational stability under neutral conditions. This stability drops completely when higher coordination states of the silicon centre are reached due to rapid substituent exchange. Herein we describe the synthesis of chiral and neutral pentacoordinate silicon derivatives with high configurational stability. The zwitterionic nature of these air‐ and water‐tolerant species allows for the first time their direct and efficient optical resolution using chiral HPLC techniques. By means of this method, pentacoordinate silicon compounds exhibiting high Si‐inversion have been obtained as single enantiomers. A rationalisation of the enantiomerisation pathways has been also carried out using DFT calculations.

Synthesis and Optical Resolution of Configurationally Stable Zwitterionic Pentacoordinate Silicon Derivatives.

Stereogenic silicon centres in functionalised tetracoordinated organosilanes generally exhibit very high configurational stability under neutral conditions. This stability drops completely when higher coordination states of the silicon centre are reached due to rapid substituent exchange. Herein we describe the synthesis of chiral and neutral pentacoordinate silicon derivatives with high configurational stability. The zwitterionic nature of these air- and water-tolerant species allows for the first time their direct and efficient optical resolution using chiral HPLC techniques. By means of this method, pentacoordinate silicon compounds exhibiting high Si-inversion have been obtained as single enantiomers. A rationalisation of the enantiomerisation pathways has been also carried out using DFT calculations.

An investigation on the structure and group vibrations of balenine molecule by matrix isolation IR spectroscopy, DFT and MP2 based calculations

Stable conformers of neutral balenine were scanned through molecular dynamics simulations and energy minimizations using Allinger’s MM2 force field. For each of the found minimum-energy conformers, geometry optimization and thermochemistry calculations were performed by using B3LYP, MP2, G3MP2B3 methods, 6-31G(d), 6–311++G(d,p) and aug-cc-pvTZ basis sets. The calculation results have indicated that balenine has about twenty stable conformers whose relative energies are in the range of 0–9.5 kcal/mol. Three of these are thought to provide the major contribution to matrix isolation IR spectra of the molecule. Our solvent calculations using the polarized continuum model revealed the stable zwitterion structures which are predicted to dominate IR spectra of balenine in water and heavy water (D2O) solvents. Pulay’s SQM-FF method was used in scaling of the harmonic force constants and vibrational spectral data calculated for the neutral and zwitterion structures. These refined calculation data together with those obtained from anharmonic frequency calculations enabled us to correctly interpret the matrix isolation IR spectrum of balenine and the tautomerism-based changes observed in its KBr IR and solution (D2O) IR spectra. The results revealed the crucial role of conformation and zwitterionic tautomerism on the structure and vibrational spectral data of the molecule.

Unveiling Zwitterionization of Glycine in the Microhydration Limit.

Charge separation under solvation stress conditions is a fundamental process that comes in many forms in doped water clusters. Yet, the mechanism of intramolecular charge separation, where constraints due to the molecular structure might be intricately tied to restricted solvation structures, remains largely unexplored. Microhydrated amino acids are such paradigmatic molecules. Ab initio simulations are carried out at 300 K in the frameworks of metadynamics sampling and thermodynamic integration to map the thermal mechanisms of zwitterionization using Gly(H2O)n with n = 4 and 10. In both cases, a similar water-mediated proton transfer chain mechanism is observed; yet, detailed analyses of thermodynamics and kinetics demonstrate that the charge-separated zwitterion is the preferred species only for n = 10 mainly due to kinetic stabilization. Structural analyses disclose that bifurcated H-bonded water bridges, connecting the cationic and anionic sites in the fluctuating microhydration network at room temperature, are enhanced in the transition-state ensemble exclusively for n = 10 and become overwhelmingly abundant in the stable zwitterion. The findings offer potential insights into charge separation under solvation stress conditions beyond the present example.

Aqueous L-alanine molecular interaction from Gibb’s free energy: CPCM and SMD in DFT and ultrasonic studies

L-Alanine (ALA) in water spontaneously forms stable zwitterions. It is observed in a present work that the stimulation to revert can be done by ultrasonic waves. It’s molecular interaction in aqueous system can be found from the Gibb’s free energy. It has been examined experimentally by estimating the Gibb’s free energy using the ultrasonic method for the verification of theoretical result. The theoretical work performed within the computational DFT framework for the different solvation models. This paper deals with two different solvation models, the CPCM and the SMD, which are implemented in a Density Functional Theory preferred with non-hybrid functional and analyzed interaction perspective. The weak interactions by NCI also analyzed for difference. Further, BP86 reported difference in both model. The SMD model is also tested by using B3LYP and PBEh-3 to compare ΔG.

Oxidation with a "Stopover" - Stable Zwitterions as Intermediates in the Oxidation of α-Tocopherol (Vitamin E) Model Compounds to their Corresponding ortho-Quinone Methides.

As a prominent member of the vitamin E group, α‐tocopherol is an important lipophilic antioxidant. It has a special oxidation chemistry that involves phenoxyl radicals, quinones and quinone methides. During the oxidation to the ortho‐quinone methide, an intermediary zwitterion is formed. This aromatic intermediate turns into the quinone methide by simply rotating the initially oxidized, exocyclic methyl group into the molecule's plane. This initial zwitterionic intermediate and the quinone methide are not resonance structures but individual species, whose distinct electronic structures are separated by a mere 90° bond rotation. In this work, we hindered this crucial rotation, by substituting the affected methyl group with alkyl or phenyl groups. The alkyl groups slowed down the conversion to the quinone methide by 18‐times, while the phenyl substituents, which additionally stabilize the zwitterion electronically, completely halted the conversion to the quinone methide at −78 °C, allowing for the first time the direct observation of a tocopherol‐derived zwitterion. Employing a 13C‐labeled model, the individual steps of the oxidation sequence could be observed directly by NMR, and the activation energy for the rotation could be estimated to be approximately 2.8 kcal/mol. Reaction rates were solvent dependent, with polar solvents exerting a stabilizing effect on the zwitterion.The observed effects confirmed the central relevance of the rotation step in the change from the aromatic to the quinoid state and allowed a more detailed examination of the oxidation behavior of tocopherol. The concept that a simple bond rotation can be used to switch between an aromatic and an anti‐aromatic structure could find its use in molecular switches or molecular engines, driven by the specific absorption of external energy.

Zwitterion membranes for selective cation separation via electrodialysis

Lithium extraction from saline water by electrodialysis is an energy-efficient process. Herein, we examined a synergetic impact of amino isophthalic acid (AIPA) and the fixed quaternized groups to produce stable, cost-effective, and efficient zwitterion membranes (ZIMs) via a sol-gel process. We developed different membranes such as QAIPA-10, QAIPA-15, and QAIPA-20 by varying the amount of AIPA from 10 to 20 wt% in the base membrane. It was found that when the amount of AIPA increases, the Li+ flux also improved from 1.66 × 10−10 mol cm−2 s−1 to 33.46 × 10−10 mol cm−2 s−1, respectively. By comparing the membranes based on the various amounts of AIPA, the membrane with 20 wt% (QAIPA-20) had a higher Li+ flux and reasonable permselectivity due to the high WU, CEC as compared with the QAIPA-10, QAIPA-15 and base membranes. To further explore the performance of the QAIPA-20, we also studied various cation systems such as Na+/Mg2+, K+/Mg2+, and H+/Fe2+, respectively. The obtained results proved that AIPA strongly dictates the cation transport channels, hydrophilicity, and repulsive centers of the ZIMs. We may conclude that QAIPA-20 is effective for lithium extraction, water desalination, and acid recovery.

Multicomponent Reaction of Phosphines, Benzynes, and CO2: Facile Synthesis of Stable Zwitterionic Phosphonium Inner Salts.

The first synthesis of benzyne-derived stable zwitterions is reported. Benzynes generated in situ from 2-(trimethylsilyl)aryl triflates undergo a multicomponent reaction with phosphines and CO2 to produce the stable 1,5-zwitterionic species in moderate to excellent isolated yields, which provides a novel method for the preparation of phosphonium inner salts under mild and transition-metal-free conditions.

A novel S-nitrosocaptopril monohydrate for pulmonary arterial hypertension: H2O and –SNO intermolecular stabilization chemistry

S-nitrosocaptopril (CapNO) possesses dual capacities of both Captopril and an NO donor with enhanced efficacy and reduced side effects. CapNO crystals are difficult to make due to its unstable S-NO bond. Here, we report a novel stable S-nitrosocaptopril monohydrate (CapNO·H2O) that is stabilized by intermolecular five-membered structure, where one H of H2O forms a hydrogen bond with O- of the stable resonance zwitterion Cap–S+=N–O-, and the O in H2O forms the dipole-dipole interaction with S+ through two unpaired electrons. With the chelation and common ion effect, we synthesized and characterized CapNO·H2O that is stable at 4 °C for 180 days and thereafter without significant degradation. Compared to Captopril, CapNO showed direct vasorelaxation and beneficial effect on PAH rats, and could be self-assembled in rat stomach when Captopril and NaNO2 were given separately. This novel CapNO·H2O with low entropy paves an avenue for its clinical trials and commercialization.

Synthesis and structure of rare zwitterionic complexes involving the presence of N(py)MCl3− moieties (M = Pt(II), Pd(II))

The monocation 2,3-dicyano-5-[(N-methyl)-2-pyridyl}-6-(2-pyridyl)pyrazine, [(CN)2(2-Mepy)PyPyz]+ (1) reacts, as the iodide salt (2), under mild experimental conditions, with dichloro-di(benzonitrile)platinum(II), [(C6H5CN)2PtCl2], forming trans-diiodo-di(benzonitrile)platinum(II), [(C6H5CN)2PtI2] (3), and the complex [(CN)2Py(2-Mepy)PyzPtCl3]∙CH3CN (4), both structurally elucidated by single-crystal X-ray work. Using a parallel procedure, reaction of 2 with dichloro-di(benzonitrile)palladium(II), [(C6H5CN)2PdCl2], results in the formation of complex 5, [(CN)2Py(2-Mepy)PyzPdCl3]∙CH3CN, isostructural with 4. Complex 5 is also formed by reaction of the same reactant 2 with PdCl2. Complexes 4 and 5, further characterized by IR and UV–vis spectral data, are neutral stable zwitterions presenting both a +1 pyridinium component neutralized by rare N(py)PtCl3− and N(py)PdCl3− anionic moieties, respectively (py = 2-pyridyl group). DFT calculations fit reasonably well with the observed UV–vis absorptions and provide information on the localization of the HOMO and LUMO within the species 4 and 5.

An air-stable N-heterocyclic carbene iminoxyl borate radical zwitterion.

A remarkably stable radical zwitterion derived from N-heterocyclic carbene nitric oxide and B(C6F5)3 is reported. The presented radical was generated by steric and electronic protection of the nitric oxide moiety using B(C6F5)3, which secured its stability toward air and moisture. An analogous yet less stable radical derived from C(C6H5)3+ is also synthesized and characterized.

Preparation, characterization, and the selective antimicrobial activity of N-alkylammonium 8-diethyleneglycol cobalt bis-dicarbollide derivatives

A consistent series of N-alkylammonium derivatives of 8-diethyleneglycol-CoIII-bisdicarbollide has been prepared via straightforward method, and characterized using NMR, HPLC, MS and X-ray. The structure of the most stable dimethylammonium zwitterion 5 was verified by the XRD. The antibacterial, and antifungal activity of the seven studied derivatives was found based on the determination of minimum inhibitory concentrations (MIC80). The growth of the Staphylococcus aureus, the most common isolated from nosocomial infections, was inhibited with high selectivity by compound 3 in concentration 3.8 mg L−1. A significant observation was the absolute selective activity of 4 in inhibiting the growth of the filamentous fungus Trichosporon cutaneum. The high selectivity and the lowest MIC80 concentrations of the designed inhibitors allow generally to decrease the number of possible side effects usually occurred during medical treatment of the specific pathogen. Our results provide a new knowledge about the possible use of metallacarboranes as antimicrobial agents; this subject is highly topical due to the emerging antibiotic resistance of a number of pathogenic microorganisms of high concern.

Distorted commo-Cobaltacarboranes Based on the 5,6-Dicarba-nido-decaborane(12): The First Bimetal Cobalt-Copper Zwitterion-Containing Cluster with Four (B-H)4···Cu Bonds Not Showing Fluxional Behavior in Solution.

Treatment of a recently reported complex [Ph4P][closo,nido-CoH(2,4-C2B8H10)(7,8-C2B8H11)] (1) either by H2O2 in acetone or NaH in THF leads to the loss of both the bridging and terminal hydrides yielding the diamagnetic salt of an anionic commo-cobaltacarborane [Ph4P][Co(2,4-isonido-C2B8H10)2] (2) with the {CoC2B8}-cluster units adopting a distorted skeletal geometry of the isonido-type. The anionic commo complex 2 reacts with in situ generated cationic [CuPPh3]+ species to give stable copper-cobalt zwitterion [Ph3PCu][Co(2,4-isonido-C2B8H10)2] (3) with four two-electron, three-center (B-H)4···Cu bonds, and exhibits no fluxional behavior in solution. Complex 3, at the same time, in CH2Cl2 in the presence of 2-fold excess of PPh3 readily converts to a new anionic species [(Ph3P)3Cu][Co(2,4-isonido-C2B8H10)2] (4) which retains initial isonido geometry. All newly obtained diamagnetic commo complexes were characterized by a combination of analytical and multinuclear NMR spectroscopic data and by single-crystal X-ray diffraction studies of complexes 2 and 3.

Metabolic Enzymes of Cocaine Metabolite Benzoylecgonine.

Cocaine is one of the most addictive drugs without a U.S. Food and Drug Administration (FDA)-approved medication. Enzyme therapy using an efficient cocaine-metabolizing enzyme is recognized as the most promising approach to cocaine overdose treatment. The actual enzyme, known as RBP-8000, under current clinical development for cocaine overdose treatment is our previously designed T172R/G173Q mutant of bacterial cocaine esterase (CocE). The T172R/G173Q mutant is effective in hydrolyzing cocaine but inactive against benzoylecgonine (a major, biologically active metabolite of cocaine). Unlike cocaine itself, benzoylecgonine has an unusually stable zwitterion structure resistant to further hydrolysis in the body and environment. In fact, benzoylecgonine can last in the body for a very long time (a few days) and, thus, is responsible for the long-term toxicity of cocaine and a commonly used marker for drug addiction diagnosis in pre-employment drug tests. Because CocE and its mutants are all active against cocaine and inactive against benzoylecgonine, one might simply assume that other enzymes that are active against cocaine are also inactive against benzoylecgonine. Here, through combined computational modeling and experimental studies, we demonstrate for the first time that human butyrylcholinesterase (BChE) is actually active against benzoylecgonine, and that a rationally designed BChE mutant can not only more efficiently accelerate cocaine hydrolysis but also significantly hydrolyze benzoylecgonine in vitro and in vivo. This sets the stage for advanced studies to design more efficient mutant enzymes valuable for the development of an ideal cocaine overdose enzyme therapy and for benzoylecgonine detoxification in the environment.

Synthesis and structures of stable phosphorus zwitterions derived from mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates.

Trialkyl phosphites were evaluated as phosphorus nucleophiles for addition to mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates (1), thereby producing tetravalent phosphorus zwitterions (2) in good yields. The structure of 2 was determined to be a tetravalent phosphonium enolate via single crystal X-ray analysis.

Thermodynamic and kinetic stability of zwitterionic histidine: Effects of gas phase hydration

We present calculations for histidine–(H2O)n (n=0–6) to examine the effects of micro-hydrating water molecules on the relative stability of the zwitterionic vs. canonical forms of histidine. We calculate the structures and Gibbs free energies of the conformers at wB97XD/6-311++G(d,p) level of theory. We find that six water molecules are required to produce the thermodynamically stable histidine zwitterion. By calculating the barriers of canonical↔zwitterionic transformation, we predict that both the most stable canonical and zwitterionic forms of histidine–(H2O)6 may be observed in low temperature gas phase environment.