Cationic Atom Research Articles

Intramolecular 1,2-Aroyl Migration in Spiro Donor-Acceptor Cyclopropanes: Formation of 1,4-Naphthoquinones and 1-Naphthols as Ring-Expansion Products.

Most of the known rearrangement reactions of donor-acceptor cyclopropanes (DACs) involve the migration of cationic carbon atom to anionic carbon or heteroatoms in 1,3- or 1,4-positions. In the present work, we observed that spiro DACs based on 1,3-indanedione or 1-indanone moiety undergo intramolecular 1,2-aroyl migration when treated with titanium(IV) chloride to afford 1,4-naphthoquinones and α-naphthols readily. The reactions take place through the formation of putative 1,3-dipolar intermediates, followed by cleavage and migration of the aroyl group to the adjacent carbon to afford the ring-expansion products.

N–N Bond Formation by a Small-Ring Phosphine Catalyst via the PIII/PV Cycle: Mechanistic Study and Guidelines to Obtain a Good Catalyst

The mechanism of the N–N cross-coupling of nitroarene and aniline catalyzed by 1,2,2,3,4,4-hexamethylphosphetane oxide (1PO) as well as the prediction of a better catalyst was theoretically investigated using DFT and DLPNO-CCSD(T) calculations. An active species 1P is generated through deoxygenation of 1PO by diphenylsilane. Then, 1P extracts one oxygen atom from nitroarene to produce nitrosoarene. In this deoxygenation step, the [3 + 1] cheletropic addition is a rate-determining step with the ΔG0≠ and ΔG0 values of 28.8 and −7.3 kcal/mol, respectively. Next, nitrosoarene exclusively undergoes a dehydrative condensation reaction with aniline to form an azo-cation intermediate, which is the origin of the high selectivity in this cross-coupling reaction. In this step, 2,4,6-trimethylbenzoic acid plays an essential role to significantly reduce the ΔG0≠ value from 41.1 to 14.8 kcal/mol. Subsequently, 1P reacts with the azo cation to form a stable hydrazinylphosphonium species through the nucleophilic attack of the phosphorus atom to the cationic nitrogen atom. The phosphonium center preferably accepts a hydroxyl group from water to ensure the formation of hydrazine in the subsequent step. In the [3 + 1] cheletropic addition step, the highest occupied molecular orbital (HOMO) of 1P plays an important role. The small-ring scaffold of 1P raises the HOMO energy compared to acyclic phosphorus compounds to achieve high activity of 1P. Substitution of a dimethylamino group for the methyl group in 1P was theoretically predicted to improve the activity by further increasing the HOMO energy.

Simulation of uranyl-biomolecule interaction using a cationic dummy atom model

We report a multisite cationic dummy atom model of the uranyl cation, suitable for atomistic simulation of the interaction of this ion with water and biomolecules. This reproduces geometry of model complexes with typical ligands, interactions and diffusion coefficient in water, and the structure of an adduct with a uranyl binding protein. A protocol for prediction of binding mode and strength of complexes formed with small peptides is proposed.

Comparison of Empirical Zn2+ Models in Protein–DNA Complexes

Zinc ions are the second most abundant ions found in humans. Their role in proteins can be merely structural but also catalytic, owing to their transition metal character. Modelling their geometric–coordination versatility by empirical force fields is, thus, a challenging task. In this work, we evaluated three popular models, specifically designed to represent zinc ions with regard to their capability of preserving structural integrity. To this end, we performed molecular dynamics simulations of two zinc-containing protein–DNA complexes, which differed in their zinc coordination, i.e., four cysteines or two cysteines and two histidines. The most flexible non-bonded 12-6-4 Lennard–Jones-type model shows a preference for six-fold coordination of the Zn2+-ions in contradiction to the crystal structure. The cationic dummy atom model favours tetrahedral geometry, whereas the bonded extended zinc AMBER force field model, by construction, best preserves the initial geometry of a regular or slightly distorted tetrahedron. Our data renders the extended zinc AMBER force field the best model for structural zinc ions in a given geometry. In more complicated cases, though, more flexible models may be advantageous.

Utilization of a Tris(carbene)borate Ligand for Umpolung Reactivity of a Nucleophilic Tin(II) Cation Salt.

We show that a tris(carbene)borate (TCB) ligand, namely [PhB(tBuIm)3]- ([PhB(tBuIm)3]- = phenyltris(3-tert-butylimidazol-2-ylidene)borato), is capable of stabilizing an unprecedented nucleophilic Sn(II) cation salt. Unlike known Sn(II) cations, the strong electron-donating ability of [PhB(tBuIm)3]- makes the cationic tin atom electron-rich, σ-donating yet slightly π-accepting, which allows for the ensuing facile oxidation with o-chloranil and S8 as well as coordination with coinage metals. The former oxidations give the Sn(IV) cation salts, while the latter reactions produce the metal complexes. The electronic structures of these species are thoroughly probed by quantum chemical computations. These results uncover an added role for TCB ligands in isolating unprecedented p-block species.

Conjugative Stabilization versus Anchimeric Assistance in Carbocations.

In this study, an old concept of anchimeric assistance is viewed from a different angle. Primary cations with two different heteroatomic substituents in the α-position to the cationic carbon atom CHXY−CH2+ (X, Y = Me2N, MeO, Me3Si, Me2P, MeS, MeS, Br) can be stabilized by the migration of either the X or Y group to the cation center. In each case, the migration can be either complete, resulting in the transfer of the migrating group to the adjacent carbon atom and the formation of a secondary carbocation stabilized by the remaining heteroatom, or incomplete, leading to an anchimerically assisted iranium ion. For all combinations of the above groups, these transformations have been studied by theoretical analysis at the MP2/aug-cc-pVTZ level and were shown to occur depending on the ability of anchimeric assistance by X and Y, as well as the conformation of the starting primary carbocation. In the conformers of α-amino cations with the p-orbital, C−N bond and the nitrogen lone pair in one plane, the Me2N group migrates to the cationic center to give aziranium ions. Otherwise, the second heteroatom is shifted to give iminium ions, without or with very slight anchimeric assistance. In the α-methoxy cations, the MeO group can be shifted to the cationic center to give the O-anchimerically assisted ions as local minima, the global minima being the ions anchimerically assisted by another heteroatom. The electropositive silicon tends to migrate towards the cationic center, but with the formation of a π-complex of the Me3Si cation with the C=C bond rather than a Si-anchimerically assisted cation. The phosphorus atom can either fully migrate to the cationic center (X = P, Y = S, Se) or form anchimerically stabilized phosphiranium ions (X = P, Y = O, Si, Br). The order of the anchimeric assistance for the heaviest atoms decreases in the order Se >> S > Br.

Abstract 2926: Structure-based design of quadruplex-binding small molecule compounds: The essential role of water molecules

Abstract The compounds CM03 and SOP1812 are tri- and tetra-substituted naphthalene diimide derivatives with high affinity for several human DNA quadruplexes. They have been designed by computer modelling based on co-crystal structures of 1st-generation substituted naphthalene diimides with human intramolecular telomeric quadruplexes. CM03 and SOP1812 have single-digit 1-20 nM anti-proliferative activity in a panel of human pancreatic ductal adenocarcinoma (PDAC) cell lines (Marchetti et al., J. Med. Chem, 2018, 61, 2500-2517: Ahmed et al., ACS Med Chem Lett, 2020, 11, 1634-1644) and significant anti-tumor activity in the MIA-PACA2 xenograft model for PDAC as well as in the more demanding KPC model. SOP1812 is bio-available at therapeutic doses and is well tolerated at these levels in animal models. It is currently being evaluated as a candidate for clinical development by Qualigen Therapeutics Inc. The role of water in protein-drug binding is well documented and known to be important for accurate estimates of drug binding energies and for docking/virtual screening studies. To date this factor has not been seriously considered in studies of ligand-quadruplex interactions even though virtual screening has emerged as an important tool for finding new chemotypes and optimizing compound libraries in silico. A high-resolution crystal structure of a naphthalene diimide quadruplex complex (PDB id 3UYH: Micco et al., J. Med. Chem., 2013, 56, 2959-2974) has now been analyzed in detail. Patterns of water molecules have been found in each of the four quadruplex grooves, associated with the cationic side chains. Only a nitrogen atom on each N-methyl-piperazine cationic end groups is in direct hydrogen bonded contact with a phosphate group. The morpholino groups each have a small and well-defined cluster of water molecules mediating between cationic nitrogen atom and phosphate group. The rest of each groove is filled by a second cluster of waters, suggesting that larger substituents can be accommodated. Data from a library of naphthalene diimide derivatives is being examined to validate the role of these waters, especially with respect to their relative mobilities and ease of displacement. Citation Format: Stephen Neidle. Structure-based design of quadruplex-binding small molecule compounds: The essential role of water molecules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2926.

Single-Atom High-Temperature Catalysis on a Rh1O5 Cluster for Production of Syngas from Methane.

Single-atom catalysts are a relatively new type of catalyst active for numerous reactions but mainly for chemical transformations performed at low or intermediate temperatures. Here we report that singly dispersed Rh1O5 clusters on TiO2 can catalyze the partial oxidation of methane (POM) at high temperatures with a selectivity of 97% for producing syngas (CO + H2) and high activity with a long catalytic durability at 650 °C. The long durability results from the substitution of a Ti atom of the TiO2 surface lattice by Rh1, which forms a singly dispersed Rh1 atom coordinating with five oxygen atoms (Rh1O5) and an undercoordinated environment but with nearly saturated bonding with oxygen atoms. Computational studies show the back-donation of electrons from the dz2 orbital of the singly dispersed Rh1 atom to the unoccupied orbital of adsorbed CHn (n > 1) results in the charge depletion of the Rh1 atom and a strong binding of CHn to Rh1. This strong binding decreases the barrier for activating C-H, thus leading to high activity of Rh1/TiO2. A cationic Rh1 single atom anchored on TiO2 exhibits a weak binding to atomic carbon, in contrast to the strong binding of the metallic Rh surface to atomic carbon. The weak binding of atomic carbon to Rh1 atoms and the spatial isolation of Rh1 on TiO2 prevent atomic carbon from coupling on Rh1/TiO2 to form carbon layers, making Rh1/TiO2 resistant to carbon deposition than supported metal catalysts for POM. The highly active, selective, and durable high-temperature single-atom catalysis performed at 650 °C demonstrates an avenue of application of single-atom catalysis to chemical transformations at high temperatures.

Pd0‐Mediated Cross‐Coupling of [11C]Methyl Iodide with Carboxysilane for Synthesis of [11C]Acetic Acid and its Active Esters: 11C‐Acetylation of Small, Medium, and Large Molecules

AbstractA rapid Pd0‐mediated cross‐coupling of [11C]CH3I with carboxytriphenylsilane (1) to synthesize [2‐11C]acetic acid ([11C]2) and its corresponding imidyl esters as radiolabeling reagents for 11C‐acetylation is reported. The reaction of [11C]CH3I with 1 using a Pd2(dibenzylideneacetone)3/P(o‐tolyl)3 (1 : 4) catalyst in tetrahydrofuran/H2O (9 : 1) at 90 °C for 4 min afforded [11C]2 having satisfactory radioactivity and a good yield. The coupling of the cationic carbon atom of methyl iodide and the carboxyl group in 1 is an ionicity‐driven reversed‐polarity reaction. An injectable radiopharmaceutical formulation of [11C]2 prepared using 33 GBq of [11C]CH3I had a radioactivity of 7.4–7.8 GBq, and the decay‐corrected radiochemical yield of [11C]CH3I into [11C]2 was 63–73 %. [11C]2 was converted to [2‐11C]acetic acid phthalimidyl ester ([11C]3) or its succinimidyl ester ([11C]10), which were used for the 11C‐acetylation of 4‐aminophenol, oxytocin, and albumin. Injectable solutions of these products (0.25–2.0 GBq) are suitable for in vivo positron emission tomography studies.

Characterization and development of new anti‐toxins targeting Clostridium difficile

Clostridium difficile is a bacterial pathogen that causes serious and potentially fatal inflammatory disease of the colon. One strategy for targeting C. difficile infection is to development treatments that target bacterial virulence. Anti-virulence strategies to treat C. difficile infection are attractive options to antibiotic therapy because the human microbiota is spared and damage to host tissue is minimized. The Tcd toxins, TcdA and TcdB, are the major virulence factors produced by C. difficile and mediate host cytotoxicity by glucosylating and inactivating Rho family GTPases using UDP-glucose as a glucosyl donor. Glucosylation of Rho GTPases leads to cell rounding and eventually cell death. We used kinetic isotope effects (KIEs) and transition state theory to solve the transition state structure of the glycosyltransferase domain of TcdB (TcdB-GTD). This permits the design of transition state analogues which are potent enzyme inhibitors. KIEs compare the chemical steps of enzymatic reaction rates with isotopically labeled substrates and unlabeled substrates and provide critical information on the catalytic mechanism, bond lengths and geometry at the transition state. KIE analysis on the glycohydrolase reaction of TcdB-GTD supported the formation of a late, dissociative glucocation-like transition state where positive charge develops on the anomeric carbon. Glucocationic transition states are best mimicked by cationic nitrogen groups at or near the anomeric carbon. Iminosugars contain a nitrogen atom in the sugar ring in place of oxygen and mimic glucocationic transition states. We tested iminosugars for inhibition of TcdB-GTD and TcdA-GTD. Isofagomine (Ki TcdB-GTD = 1.4 µM and Ki TcdA-GTD = 0.24 µM) and noeuromycin (Ki TcdB-GTD = 10.6 µM and Ki TcdA-GTD = 4.7 µM) were the most potent iminosugars identified. Isofagomine and noeuromycin were shown to exhibit an uncompetitive mechanism of inhibition suggesting that both iminosugars act by binding to the enzyme-UDP complex. Isothermal titration calorimetry experiments with TcdB-GTD supported this finding where isofagomine and noeuromycin could only bind to TcdB-GTD in the presence of UDP with Kd = 0.133 µM and Kd = 0.4 µM respectively. In addition, the X-ray crystal structure of TcdB-GTD in complex with either Isofagomine or noeuromycin with UDP revealed the formation of an ion-pair interaction between the cationic nitrogen atom of the iminosugar and the β-phosphate of UDP. Finally, we confirmed that isofagomine and noeuromycin could prevent Tcd toxin-induced cytotoxicity of IMR90 cells. Firstly, both iminosugars were able to prevent Tcd toxin-induced cell rounding as visualized by light microscopy. Secondly, Western blot analysis of Tcd toxin treated IMR90 cell lysates revealed that both isofagomine and noeuromycin could prevent glucosylation of Rac1 by Tcd toxin. Isofagomine and noeuromycin are effective in preventing Tcd toxin action. Transition state analogues against TcdA and TcdB have the potential to be used as treatments for C. difficile infections.

Nonbonded Zr4+ and Hf4+ Models for Simulations of Condensed Phase Metal–Organic Frameworks

Recently, the practical applications of tetravalent metal-based metal–organic frameworks (MOFs) have been drawing increasing attention due to their excellent stability and varied functionality. Understanding the behavior of MOFs at the atomic level is important for their rational design and postsynthetic optimization. In classical simulations, the cationic dummy atom model, where the charge of the metal ion is distributed to surrounding dummy particles, has shown robustness in providing the appropriate coordination geometry while retaining the flexibility in the metal ligand interaction. Here, we present a set of eight-coordinated tetravalent metal (Zr4+, Hf4+) dummy model force fields with 12-6-4 type Lennard–Jones potential for describing ion-induced dipole interactions. This model can reproduce both the experimental solvation free energy of the bare ion and good metal–ligand distances and has been validated as useful and transferable among MOFs with the same metal-core topology. The model is inherently modular since nodes and linkers are independently parametrized. It was tested with three different solvents which all led to stable structures. It also was been further validated with different metal node structures and different linkers, Zr/Hf mixed MOFs, and defects containing MOFs. Since the model is nonbonded, the process of metal–ligand substitutions could be studied. The flexibility of the model makes its applicability to chemical problems broad.

Cationic Boron Formazanate Dyes**

AbstractIncorporation of cationic boron atoms into molecular frameworks is an established strategy for creating chemical species with unusual bonding and reactivity but is rarely thought of as a way of enhancing molecular optoelectronic properties. Using boron formazanate dyes as examples, we demonstrate that the wavelengths, intensities, and type of the first electronic transitions in BN heterocycles can be modulated by varying the charge, coordination number, and supporting ligands at the cationic boron atom. UV‐vis absorption spectroscopy measurements and density‐functional (DFT) calculations show that these modulations are caused by changes in the geometry and extent of π‐conjugation of the boron formazanate ring. These findings suggest a new strategy for designing optoelectronic materials based on π‐conjugated heterocycles containing boron and other main‐group elements.

Cationic Boron Formazanate Dyes*.

Incorporation of cationic boron atoms into molecular frameworks is an established strategy for creating chemical species with unusual bonding and reactivity but is rarely thought of as a way of enhancing molecular optoelectronic properties. Using boron formazanate dyes as examples, we demonstrate that the wavelengths, intensities, and type of the first electronic transitions in BN heterocycles can be modulated by varying the charge, coordination number, and supporting ligands at the cationic boron atom. UV-vis absorption spectroscopy measurements and density-functional (DFT) calculations show that these modulations are caused by changes in the geometry and extent of π-conjugation of the boron formazanate ring. These findings suggest a new strategy for designing optoelectronic materials based on π-conjugated heterocycles containing boron and other main-group elements.

Molecular dynamics simulation of the Pb(II) coordination in biological media via cationic dummy atom models

The coordination of Pb(II) in aqueous solutions containing thiols is a pivotal topic to the understanding of the pollutant potential of this cation. Based on its hard/soft borderline nature, Pb(II) forms stable hydrated ions as well as stable complexes with the thiol groups of proteins. In this paper, the modeling of Pb(II) coordination via classical molecular dynamics simulations was investigated to assess the possible use of non-bonded potentials for the description of the metal–ligand interaction. In particular, this study aimed at testing the capability of cationic dummy atom schemes—in which part of the mass and charge of the Pb(II) is fractioned in three or four sites anchored to the metal center—in reproducing the correct coordination geometry and, also, in describing the hard/soft borderline character of this cation. Preliminary DFT calculations were used to design two topological schemes, PB3 and PB4, that were subsequently implemented in the Amber force field and employed in molecular dynamics simulation of either pure water or thiol/thiolate-containing aqueous solutions. The PB3 scheme was then tested to model the binding of Pb(II) to the lead-sensing protein pbrR. The potential use of CDA topological schemes in the modeling of Pb(II) coordination was here critically discussed.

Lewis base-free thiophosphonium ion: a cationic sulfur atom transfer reagent.

Phosphorus(v) sulfide and Lawesson's reagent are commonly used thionating reagents which are considered to operate after dissociation into highly reactive dithiophosphorane fragments. We report the synthesis and properties of a monomeric thiophosphonium ion [R2P[double bond, length as m-dash]S]+. The highly electrophilic species reacts with carbonyls in oxo-for-sulfido exchange reactions at room temperature and undergoes phosphorus-chalcogen bond metathesis reactions with phosphine chalcogenides.

Asymmetric Hydrogenation of Cationic Intermediates for the Synthesis of Chiral N,O-Acetals.

For over half a century, transition-metal-catalyzed homogeneous hydrogenation has been mainly focused on neutral and readily prepared unsaturated substrates. Although the addition of molecular hydrogen to C=C, C=N, and C=O bonds represents a well-studied paradigm, the asymmetric hydrogenation of cationic species remains an underdeveloped area. In this study, we were seeking a breakthrough in asymmetric hydrogenation, with cationic intermediates as targets, and thereby anticipating applying this powerful tool to the construction of challenging chiral molecules. Under acidic conditions, both N- or O-acetylsalicylamides underwent cyclization to generate cationic intermediates, which were subsequently reduced by an iridium or rhodium hydride complex. The resulting N,O-acetals were synthesized with remarkably high enantioselectivity. This catalytic strategy exhibited high efficiency (turnover number of up to 4400) and high chemoselectivity. Mechanistic studies supported the hypothesis that a cationic intermediate was formed in situ and hydrogenated afterwards. A catalytic cycle has been proposed with hydride transfer from the iridium complex to the cationic sp2 carbon atom being the rate-determining step. A steric map of the catalyst has been created to illustrate the chiral environment, and a quantitative structure-selectivity relationship analysis showed how enantiomeric induction was achieved in this chemical transformation.

Selective activation of methane C[sbnd]H bond in the presence of methanol

Direct methane to methanol (MTM) conversion over heterogeneous catalysts is a promising route for valorization of methane. The methane CH bond activation is considered as the key step of the MTM and is the focus of considerable research activity. However, the formed methanol typically suffers from overoxidation largely due to the cleavage of a methanol CH bond, whose bond dissociation energy is ca. 0.5 eV lower than that of the methane CH bond, which usually translates to a transition state energy of the methanol CH bond cleavage that is ca. 0.55 eV lower than that of methane whenever the reactions proceed through a radical mechanism. Here, we propose a general approach for decreasing the transition state energy difference between the CH4 and CH3OH CH bond dissociation. When a metal-oxide supported cationic transition metal atom and a neighboring oxygen on the oxide surface serve as the active site, the transition state energy difference through a surface-stabilized pathway can be noticeably narrowed as compared with that of a radical pathway. For Ir, Pt and Rh-doped anatase TiO2(1 0 1), the CH4 CH bond activation can be preferred over that of CH3OH at significant methanol mole fraction. Also, for PdAu alloys containing adsorbed oxygen and positively charged Pd, calculations suggest in agreement with recent experiments (Science367 (6474), 193–197) that the CH4 CH bond can be selectively activated in the presence of CH3OH.

Interfacial reactions in Al2O3/Cr2O3 layers: Electronic structure calculations and X-ray photoelectron spectra

The interfacial reactions were found in Al2O3/Cr2O3 layers prepared by ion assisted deposition of α-Al2O3 coatings by anodic evaporation in the arc discharge on Cr2O3/stainless steel substrate. The X-ray photoelectron spectra (XPS) measurements (core levels and valence bands) revealed the diffusion of Cr-ions from substrate, which is accompanied by partial substitution of Al-sites. This conclusion is confirmed by specially performed density functional theory calculation in the coherent potential approximation of Al1.95Cr0.05O3, which in full agreement with XPS valence band data shows the location of Cr-impurity states in the region of the energy gap of pure Al2O3 and Fermi level crosses the Cr 3d-band of the effective cationic atom.

Nitrogen-Based Lewis Acids: Synthesis and Reactivity of a Cyclic (Alkyl)(Amino)Nitrenium Cation.

A room-temperature-stable crystalline cyclic (alkyl)(amino)nitrenium cation 2 features cationic nitrogen atom with a smaller HOMO-LUMO gap compared to that of a 1,2,3-triazolium 5 (an N-heterocyclic nitrenium cation). The low-lying LUMO of 2 results in an enhanced electrophilicity, which allowed for the formation of Lewis adducts with neutral Lewis bases, such as Me3 P, nBu3 P, and IiPr. The N-based Lewis acid 2 also forms an FLP with tBu3 P but subsequently reacts with (PrS)2 to cleave the S-S bond. Both experimental and theoretical results suggest that the Lewis acidity of 2 is stronger than its N3 analogues.

Nitrogen‐Based Lewis Acids: Synthesis and Reactivity of a Cyclic (Alkyl)(Amino)Nitrenium Cation

AbstractA room‐temperature‐stable crystalline cyclic (alkyl)(amino)nitrenium cation 2 features cationic nitrogen atom with a smaller HOMO–LUMO gap compared to that of a 1,2,3‐triazolium 5 (an N‐heterocyclic nitrenium cation). The low‐lying LUMO of 2 results in an enhanced electrophilicity, which allowed for the formation of Lewis adducts with neutral Lewis bases, such as Me3P, nBu3P, and IiPr. The N‐based Lewis acid 2 also forms an FLP with tBu3P but subsequently reacts with (PrS)2 to cleave the S−S bond. Both experimental and theoretical results suggest that the Lewis acidity of 2 is stronger than its N3 analogues.