Regioselective Transition Metal-Free Catalytic Ring Opening of 2H-Azirines by Phenols and Naphthols; One-Pot Access to Benzo- and Naphthofurans.

Benzofuran and naphthofuran derivatives are synthesized from readily available phenols and naphthols. Regioselective ring openings of 2H-azirine followed by in situ aromatization using a catalytic amount of Brønsted acid have established the novelty of the methodology. The involvement of a series of 2H-azirines with a variety of phenols, 1-naphthols, and 2-naphthols showed the generality of the protocol. In-depth density functional theory calculations revealed the reaction mechanism with the energies of the intermediates and transition states of a model reaction. An alternate pathway of the mechanism has also been proposed with computer modeling.

Regioselection Switch in Nucleophilic Addition to Isoquinolinequinones: Mechanism and Origin of the Regioselectivity in the Total Synthesis of Ellipticine.

Ellipticine was synthesized in six steps and 20% global yield starting from the readily available 2,5-dimethoxy isoquinoline. Unprecedented regioselective control of the nucleophilic attack on the isoquinoline-5,8-dione is first described. Investigation of the possible pathways of this transformation through density functional theory calculations reveals unexpected N-oxide assistance in cascade tautomerizations, which was crucial for directing the nucleophilic attack and hastening the overall process. Using this strategy, we prepared the aniline-isoquinolinedione adduct and submitted it to an intramolecular double C-H cross-coupling activation to furnish ellipticinequinone, which gave ellipticine after a MeLi addition/BH3 reduction sequence.

Theoretical investigation of the cooperative effect of solvent: a case study.

The effect of solvent was investigated at the DFT level, M06-2X/6-31++G(d,p), for the implicit, namely the universal solvent model based on solute electron density (SMD) and hybrid solvation models, and a new pathway for the Markovnikov for the addition of HCl to 1-butene was suggested, incorporating the solvent in the reaction. The results showed that the use of implicit solvent brings greater stabilization for a large part of the reaction coordinates and for the charges of the transition states (TS). Studying the hybrid solvent model, it was shown by quantum mechanics and molecular simulations that although the first solvation shell is composed of approximately 30 solvent molecules, most of the effect comes from just eight solvent molecules explicitly added, with a variation in energy that tends to about -19.3 kJ mol-1. The reaction rates for the hydration of 1-butene were only able to achieve a reasonable accuracy with the addition of three explicit solvent molecules of 5.97 × 10-8 M-1 s-1 and 2.33 × 10-9 M-1 s-1 for the calculated and the experimental values, respectively. This indicates that not only hybrid solvation may be required, but also the number of explicit molecules added may heavily influence the calculated reaction rates. It was found that for the intermediary product of hydration the hydrogen bonds are stronger than average, suggesting a partial covalent characteristic.

Structure-Based Molecular Networking for the Target Discovery of Oxahomoaporphine and 8-Oxohomoaporphine Alkaloids from Duguetia surinamensis.

In addition to seven known alkaloids (2, 6-11) and 1,2,4-trimethoxybenzene (1), three isoquinoline-derived alkaloids (3-5), namely, duguetinine (3), a compound based on an unprecedented oxahomoaporphine scaffold, and two new 8-oxohomoaporphine alkaloids, duguesuramine (4) and 11-methoxyduguesuramine (5), and a new asarone-derived phenylpropanoid (10) were isolated from the bark of Duguetia surinamensis. The isolation workflow was guided by HPLC-HRESIMS/MS and molecular networking-based analyses. Twenty-four known alkaloids were dereplicated from the D. surinamensis alkaloid-rich fraction network and were assigned by manual MS/MS interpretation. Their cytotoxic potential was evaluated.

Generation of a Chiral Giant Micelle.

Over the past few years, chiral supramolecular assemblies have been successfully used for recognition, sensing and enantioselective transformations. Several approaches are available to control chirality of discrete assemblies (e.g., cages and capsules), but few are efficient in assuring chirality for micellar aggregates. Optically active amino acid-derived surfactants are commonly used to generate chiral spherical micelles. To circumvent this limitation, we benefited from the uniaxial growth of spherical micelles into long cylindrical micelles usually called wormlike or giant micelles, upon the addition of cosolutes. This paper describes the unprecedented formation of chiral giant micelles in aqueous solutions of cetyltrimethylammonium bromide (CTAB) upon increasing addition of enantiopure sodium salt of 1,1'-bi-2-naphthol (Na-binaphtholate) as a cosolute. Depending on the concentrations of CTAB and Na-binaphtholate, chiral gel-like systems are obtained. The transition from spherical to giant micellar structures was probed using rheology, cryo-transmission electron microscopy, polarimetry, and electronic circular dichroism (CD). CD can be effectively used to monitor the incorporation of Na-binaphtholate into the micelle palisade as well as to determine its transition to giant micellar structures. Our approach expands the scope for chirality induction in micellar aggregates bringing the possibility to generate "smart" chiral systems and an alternative asymmetric chiral environment to perform enantioselective transformations.

Molecular variations in aromatic cosolutes: critical role in the rheology of cationic wormlike micelles.

Wormlike micelles formed by the addition to cetyltrimethylammonium bromide (CTAB) of a range of aromatic cosolutes with small molecular variations in their structure were systematically studied. Phenol and derivatives of benzoate and cinnamate were used, and the resulting mixtures were studied by oscillatory, steady-shear rheology, and the microstructure was probed by small-angle neutron scattering. The lengthening of the micelles and their entanglement result in remarkable viscoelastic properties, making rheology a useful tool to assess the effect of structural variations of the cosolutes on wormlike micelle formation. For a fixed concentration of CTAB and cosolute (200 mmol L(-1)), the relaxation time decreases in the following order: phenol > cinnamate> o-hydroxycinnamate > salicylate > o-methoxycinnamate > benzoate > o-methoxybenzoate. The variations in viscoelastic response are rationalized by using Mulliken population analysis to map out the electronic density of the cosolutes and quantify the barrier to rotation of specific groups on the aromatics. We find that the ability of the group attached to the aromatic ring to rotate is crucial in determining the packing of the cosolute at the micellar interface and thus critically impacts the micellar growth and, in turn, the rheological response. These results enable us for the first time to propose design rules for the self-assembly of the surfactants and cosolutes resulting in the formation of wormlike micelles with the cationic surfactant CTAB.

The influence of basis sets and ansatze building to quantum computing in chemistry.

CONTEXT: Quantum computing is an exciting area, which has grown at an astonishing rate in the last decade. It is especially promising for the computational and theoretical chemistry area. One algorithm has received a lot of attention lately, the variational quantum eigensolver (VQE). It is used to solve electronic structure problems and it is suitable to the noisy intermediate-scale quantum (NISQ) hardware. VQE calculations require ansatze and one of the most known is the unitary coupled cluster (UCC). It uses the chosen basis set to generate a quantum computing circuit which will be iteratively minimized. The present work investigates the circuit depth and the number of gates as a function of basis sets and molecular size. It has been shown that for the current quantum devices, only the smallest molecules and basis sets are tractable. The H 2 molecule with the cc-pVTZ and aug-cc-pVTZ basis sets have circuit depths in the order of 10 6 to 10 7 gates and the C 2 H 6 molecule with 3-21G basis set has a circuit depth of 2.2 × 10 8 gates. At the same time the analysis demonstrates that the H 2 molecule with STO-3G basis set, requires at least 500 shots to reduce the error and that, although error mitigation schemes can diminish the error, they were not able to completely negate it. METHODS: The quantum computing and electronic structure calculations were performed using the Qiskit package from IBM and the PySCF package, respectively. The ansatze were generated using the UCCSD method as implemented in Qiskit, using the basis sets STO-3G, 3-21G, 6-311G(d,p), def2-TZVP, cc-pVDZ, aug-cc-pVDZ, cc-pVTZ, and aug-cc-pVTZ. The operators and the Hamiltonian were mapped using the Jordan-Wigner scheme. The classical optimizer chosen was the simultaneous perturbation stochastic approximation (SPSA). The quantum computers used were the Nairobi and Osaka, with 7 and 127 qubits respectively.

Copper(II) complexes of a furan-containing aroylhydrazonic ligand: syntheses, structural studies, solution chemistry and interaction with HSA.

Copper(II) complexes have become a potential alternative to the use of platinum drugs in cancer therapy due to their multi-target mode of action. In this context, we report the syntheses of new mononuclear and dinuclear coordination compounds of this element, 1 and 2, derived from the ligand 5-methylsalicylaldehyde 2-furoyl hydrazone (H2L). All three compounds were structurally and spectroscopically characterized, both in the solid state and in solution. In 1, Cu is coordinated by three donor-atoms from the hydrazonic ligand and one chloride ion. H2L is deprotonated at the phenol oxygen. The dinuclear complex 2 is, on the other hand, a dimeric form of 1 in which the chloride ions of a pair of mononuclear units are lost and phenoxo bridges take their places, double-connecting the metal centres and resulting in a single species with the ligand fully deprotonated. The compounds were fairly stable in aqueous medium at room temperature. An experimental-theoretical combined approach demonstrated that all of them are able to bind human serum albumin (HSA), although at different sites and with diverse stoichiometries and affinities (as concluded by the calculated binding energies). In view of this, and due to the well-known antiproliferative activity of hydrazone-containing copper complexes, we consider the compounds presented in here promising, and believe that they deserve more profound studies regarding the assessment of their potential against tumour cell lines.

Ammonia quantum tunneling in cold rare-gas He and Ar clusters and factorial design approach for methodology evaluation.

Quantum tunneling of the ammonia inversion motion and energy level splittings in He and Ar clusters were investigated. It was found that the double well potential (DWP) in He clusters is symmetrical and that the first layer of He atoms is able to model the system. The calculated tunneling splitting was in good agreement with the experimental, 36.4 and 24.6 cm[Formula: see text] respectively. For NH[Formula: see text] in Ar clusters, the DWP becomes slightly asymmetric, which is enough to decrease the resonance and make the symmetric DWP unable to model the system. An asymmetric potential was used and the result was in excellent agreement with the experimental splitting, of 9.0 and 10.6 cm[Formula: see text] respectively. Non-covalent interactions revealed that the asymmetry is caused by dissimilar interactions in each minimum of the double well potential. The effects of different methodologies were analyzed via a design of experiments approach. For the gas-phase NH[Formula: see text] molecule, only diffuse functions were statistically significant while for the NH[Formula: see text] embedded in He cluster both the MP2 method and polarization functions were significant. This tendency suggests higher order polarization functions may be essential to generate accurate barrier heights.

819 molecular knot: a theoretical analysis of the electronic structure using an ONIOM approach.

The present work analyzes the electronic and molecular properties of the 819 ([Fe(II)4]Cℓ) and metal-free knot ligand complexes obtained from X-ray crystal structure of molecular 819 knot complex [Fe(II)4(PF6)7]Cℓ. The studies were theoretically investigated by means of DFT, TD-DFT, and ONIOM approaches. Basis sets functions from all-electron calculations for bromine, iodine, and iron atoms were adapted to be used along with relativistic effective core potential, while H, C, N, O, and Cℓ atoms were described by Pople basis sets. The diffusion effect of halogen into the 819 cavity, UV-Vis, and Electronic Circular Dichroism spectra were also analyzed. All calculations were performed using solvent effect through the SCRF/SMD model and dispersion effects by Grimme methodology. The value of mean separation distance between Cℓ and iron atom (7.218 Å) is in good agreement with X-ray experimental result (7.258 Å). Circular dichroism spectrum of metal-free 819 knot ligand was calculated and the maximum absorption in 262 nm, Δ𝜖 obtained was 67 L mol- 1 cm- 1. These results are qualitatively similar to those obtained experimentally, 295 nm and 80 L mol- 1 cm- 1, respectively. In this study, we report the electronic and molecular properties of the 819 ([Fe(II)4]Cl and metal-free knot ligand complexes and compare with the results obtained from X-ray crystallographic data of 819 knot complex [Fe(II)4(PF6)7]Cl. The 819 knot were investigated by means of DFT, TD-DFT, and ONIOM approaches. Basis sets functions from all-electron for Br, I, and Fe atoms were adapted to be used along with relativistic effective core potential, while H, C, N, O, and Cl atoms were described by Pople basis sets. The objective was to understand the stability of the 819 knot as a function of the substitution of the central halogen atom (Cl), and the signal in the circular dichroism spectra. From the equilibrium geometries, we have obtained good results for values of the bond distance, bond angle, and dihedral angle along the molecular structure when these variables are compared with the results obtained from X-ray data. The diffusion effect of halogen into the 819 cavity, UV-Vis, and Electronic Circular Dichroism spectra was also analyzed. Circular dichroism spectrum of metal-free 819 knot ligand was calculated, and the maximum absorption is in good agreement with the experimental value. The ONIOM methodology combined with the relativistic effective core potential and the atomic basis sets provide good results for systems with a complex topology, such as knots.

Taurine Chloramine and Hydrogen Peroxide as a Potential Source of Singlet Oxygen for Topical Application.

Singlet oxygen (1 O2 ) is the "active principle" in photodynamic therapy. Taurine chloramine (Tau-NHCl) and hydrogen peroxide (H2 O2 ) are well-tolerated and widely used antiseptics. Due to its mild oxidizing features and stability, Tau-NHCl can be directly used to treat skin diseases. We found that a diluted aqueous mixture of Tau-NHCl and H2 O2 acts as a slow and long-lasting potential source of 1 O2 . The reactions were studied by luminol-enhanced chemiluminescence. Evidence of the formation of 1 O2 was obtained using deuterium oxide, sodium azide and 9,10-Anthracenediyl-bis(methylene)dimalonic acid, a chemical trap of 1 O2 . The reaction was optimized, and a mechanism was proposed, including theoretical calculations at B3LYP/6-311++G(3df,2p) level of theory, adding D3Bj empirical dispersion and SMD (Water) solvent effects. Chloramines produced by the reactions between HOCl and L-alanine, 3-amino-1-propanesulfonic acid and gamma-aminobutyric acid were also prepared, and their reactivity and stability were compared with Tau-NHCl. We found that Tau-NHCl is more stable and adequate for the production of 1 O2 . In conclusion, we propose applying these drugs combination as a potential source of 1 O2 with applications for skin diseases treatment.

Potential activity of Linezolid against SARS-CoV-2 using electronic and molecular docking study.

The crescent evolution of a global pandemic COVID-19 and its respiratory syndrome (SARS-Cov-2) has been a constant concern (Ghosh 2021; Khan et al. 2021; Alazmi and Motwalli 2020; Vargas et al. 2020). The absence of a proven and effective medication has compelled all the scientific community to search for a new drug. The use of known drugs is a faster way to develop new therapies. Molecular docking is a powerful tool (Gao et al. J Mol Model 10: 44-54, 2004; Singh et al. J Mol Model 18: 39-51, 2012; Schulz-Gasch and Stahl J Mol Model 9:47-57, 2003) to study the interaction of potential drugs with SARS-CoV-2, Alsalme et al. (2020) and Sanders et al. (2020) spike protein as a consequence the main goal of this article is to present the result of the study of an interaction between (R and S)-Linezolid with receptor-binding domain (RBD) of SARS-Cov-2 spike protein complexed with human Angiostensin-converting enzyme 2 (ACE2) (6vW1 - from PDB). The Linezolid enantiomers were optimized at B3LYP/6-311++G(2d,p) level of theory. Molecular docking of the system (S)-Linezolid⋯RBD⋯ACE2 and (R)-Linezolid⋯RBD⋯ACE2 was performed, the analysis was made using LigPlot+ and NCIplot software packages, to understand the intermolecular interactions. The UV-Vis and ECD of the complexes - (R and S)-Linezolid⋯RBD⋯ACE2 were performed in two layers with DFT/6-311++G(3df,2p) and DFT/6-31G(d), respectively. The results showed that only the (S)-Linezolid had a stable interaction with - 8.05 kcal.mol- 1, whereas all the R-enantiomeric configurations had positive values of binding energy. The (S)-Linezolid had the same interactions as in the (S)-Linezolid ⋯ Haluarcula morismortui Ribosomal system, where it is well-known the fact that the latter has biological activity. A specific interaction on the fluorine ring justified an attenuation on the ECD signal, in comparison to isolated species. Therefore, some biological activity of (S)-Linezolid with SARS-CoV-2 RBD was expected, indicated by the modification of its ECD signal and justified by a similar interaction in the S-Linezolid⋯Haluarcula marismortui Ribosomal system.

Photoisomerization induced scission of rod-like micelles unravelled with multiscale modeling.

HYPOTHESIS: In photorheological fluids, subtle molecular changes caused by light lead to abrupt macroscopic alterations. Upon UV irradiation of an aqueous cetyltrimethylammonium bromide (CTAB) and trans-ortho-methoxycinnamic acid (trans-OMCA) solution, for instance, the viscosity drops over orders of magnitude. Multiscale modeling allows to elucidate the mechanisms behind these photorheological effects. EXPERIMENTS: We use time-dependent DFT calculations to study the photoisomerization, and a combination of atomistic molecular dynamics (MD) and DFT to probe the influence of both OMCA isomers on the micellar solutions. FINDINGS: The time-dependent DFT calculations show that the isomerization pathway occurs in the first triplet excited state with a minimum energy conformation closest to the after photoisomerization predominant cis configuration. In the MD simulations, with sub-microsecond timescales much shorter than the experimental morphological transition, already a clear difference is observed in the packing of the two OMCA isomers: contrary to trans-OMCA, cis-OMCA exposes notable part of its hydrophobic aromatic rings at the micelle surface. This can explain why trans-OMCA adopts rod-like micellar packing (high viscosity) while cis-OMCA spherical micellar packing (low viscosity). Moreover, lowering of the OMCA co-solute concentration allowed us to perform full simulation of the breakup process of the rod-like micelles which are stable prior to isomerization.

Guaianolide sesquiterpene lactones and aporphine alkaloids from the stem bark of Guatteria friesiana.

Three guaianolide sesquiterpenes, denoted guatterfriesols A-C, and four aporphine alkaloid derivatives were isolated from the stem bark of the Amazonian plant Guatteria friesiana. Thus far, sesquiterpene lactones have not been described in Annonaceae. Structures of the previously undescribed compounds were established by using 1D and 2D NMR spectroscopy in combination with MS. The absolute stereochemistry was assigned via NOE NMR experiments, ECD spectroscopy, and theoretical calculations using the TDDFT approach. Among the isolated compounds, the alkaloid guatterfriesidine showed anti-glycation activity by inhibiting the formation of advanced glycation end-products (AGEs) through the prevention of oxidation in both BSA/methylglyoxal and BSA/fructose systems.

Separation of glycosidic catiomers by TWIM-MS using CO2 as a drift gas.

Traveling wave ion mobility mass spectrometry (TWIM-MS) is shown to be able to separate and characterize several isomeric forms of diterpene glycosides stevioside (Stv) and rebaudioside A (RebA) that are cationized by Na(+) and K(+) at different sites. Determination and characterization of these coexisting isomeric species, herein termed catiomers, arising from cationization at different and highly competitive coordinating sites, is particularly challenging for glycosides. To achieve this goal, the advantage of using CO2 as a more massive and polarizable drift gas, over N2, was demonstrated. Post-TWIM-MS/MS experiments were used to confirm the separation. Optimization of the possible geometries and cross-sectional calculations for mobility peak assignments were also performed.

Computational characterization of the role of the base in the Suzuki-Miyaura cross-coupling reaction.

The role of the base in the transmetalation step of the Suzuki-Miyaura cross-coupling reaction is analyzed computationally by means of DFT calculations with the Becke3LYP functional. The model system studied consists of Pd(CH=CH2)(PH3)2Br as the starting catalyst complex, CH2=CHB(OH)2 as the organoboronic acid, and OH- as the base. The two main mechanistic proposals, consisting of the base attacking first either the palladium complex or the organoboronic acid, are evaluated through geometry optimization of the corresponding intermediates and transition states. Supplementary calculations are carried out on the uncatalyzed reaction and on a process where the starting complex is Pd(CH=CH2)(PH3)2(OH). These calculations, considered together with available experimental data, strongly suggest that the main mechanism of transmetalation in the catalytic cycle starts with the reaction of the base and the organoboronic acid.