Ortho Position Research Articles

Intramolecular singlet fission: Quantum dynamical simulations including the effect of the laser field.

In the previous work [Reddy et al., J. Chem. Phys. 151, 044307 (2019)], we have analyzed the dynamics of the intramolecular singlet fission process in a series of prototypical pentacene-based dimers, where the pentacene monomers are covalently bonded to a phenylene linker in ortho, meta, and para positions. The results obtained were qualitatively consistent with the experimental data available, showing an ultrafast population of the multiexcitonic state that mainly takes place via a mediated (superexchange-like) mechanism involving charge transfer and doubly excited states. Our results also highlighted the instrumental role of molecular vibrations in the process as a sizable population of the multiexcitonic state could only be obtained through vibronic coupling. Here, we extend these studies and investigate the effect of the laser field on the dynamics of intramolecular singlet fission by explicitly including the coupling to the laser field in our model. In this manner, and by selectively tuning the laser field to the different low-lying absorption bands of the systems investigated, we analyze the wavelength dependence of the intramolecular singlet fission process. In addition, we have also analyzed how the nature of the initially photoexcited electronic state (either localized or delocalized) affects its dynamics. Altogether, our results provide new insights into the design of intramolecular singlet fission-active molecules.

Synthesis and evaluation of pyridine-3-carboxamide analogs as effective agents against bacterial wilt in tomatoes

This study focused on developing novel pyridine-3-carboxamide analogs to treat bacterial wilt in tomatoes caused by Ralstonia solanacearum. The analogs were synthesized through a multistep process and their structures confirmed using spectroscopy. Molecular docking studies identified the most potent analog from the series. A specific analog, compound 4a, was found to significantly enhance disease resistance in tomato plants infected with R. solanacearum. The structure–activity relationship analysis showed the positions and types of substituents on the aromatic rings of compounds 4a–i strongly influenced their biological activity. Compound 4a, with a chloro group at the para position on ring C and hydroxyl group at the ortho position on ring A, was exceptionally effective against R. solanacearum. When used to treat seeds, the analogs displayed remarkable efficacy, especially compound 4a which had specific activity against bacterial wilt pathogens. Compound 4a also promoted vegetative and reproductive growth of tomato plants, increasing seed germination and seedling vigor. In plants mechanically infected with bacteria, compound 4a substantially reduced the percentage of infection, pathogen quantity in young tissue, and disease progression. The analogs were highly potent due to their amide linkage. Molecular docking identified the best compounds with strong binding affinities. Overall, the strategic design and synthesis of these pyridine-3-carboxamide analogs offers an effective approach to targeting and controlling R. solanacearum and bacterial wilt in tomatoes.

Study of mesomorphism behavior and protonation-induced emission of symmetrical benzalazines

Rod-shaped and polycatenar symmetric benzalazines with protonation-induced emission were synthesized, characterized, and studied for their thermal and optical behavior. Benzalazines lacking hydroxy groups at the ortho position did not show luminescence in the solid state or solution. In the presence of HCl (either in solution or vapor form) these compounds became good emitters. The protonation of azine nitrogen that may hinder the NN bond rotation by intermolecular interactions toward aggregates provided an explanation for the emission characteristics observed. The protonation-induced emission was thermally reversible. A benzalazine derived from 4-alkoxysalicylaldehyde with AIE property was prepared. For this compound with ortho-OH groups, the optical properties were not affected by the presence of acidic media. It exhibited a stable SmC phase characterized by POM, DSC, and XRD. The luminescence capability of the molecular arrangement within the smectic phase was investigated. The intense yellow-green emission in the crystals decreased significantly at the phase transition due to the non-radiative decay that occurs with increasing temperature, and loss of intermolecular H-bonding which prevents molecular rotations in the crystal.

A hit expansion of 3-benzamidopyrazine-2-carboxamide: Towardinhibitors of prolyl-tRNA synthetase with antimycobacterial activity.

This study presents an exploration of the chemical space around derivatives of 3-benzamidopyrazine-2-carboxamides, previously identified as potent antimycobacterial compounds with predicted binding to mycobacterial prolyl-transfer RNA synthetase. New urea derivatives (Series-1) were generally inactive, probably due to their preference for cis-trans conformation (confirmed by density functional theory calculations and experimentally by nuclear overhauser effect spectroscopy NMR). Series-2 (3-benzamidopyrazine-2-carboxamides with disubstituted benzene ring) demonstrated that substituents larger than fluorine are not tolerated in the ortho position of the benzene ring. This series brought two new compounds (21: R = 2-F, 4-Cl and 22: R = 2-F, 4-Br) with in vitro activity against Mycobacterium tuberculosis H37Rv as well as multidrug-resistant clinical isolates, with minimum inhibitory concentration ranging from 6.25 to 25 μg/mL. The lactone-type derivatives 4H-pyrazino[2,3-d][1,3]oxazin-4-ones (Series-3) were inactive, but solvent stability studies of compound 29 indicated that they might be developed to usable lactone prodrugs of inhibitors of mycobacterial aspartate decarboxylase (PanD).

Synthesis, characterization, and comprehensive computational analysis of aromatic hydrazone compounds: Unveiling quantum parameters, evaluating antioxidant activity, and investigating molecular docking interactions

This study presents a synergistic approach encompassing experimental synthesis, computational analysis, and antioxidant activity evaluation of two aromatic hydrazone compounds, namely 4-[(2E)-2-(2-nitrobenzylidene) hydrazinyl] benzoic acid (NBHZ) and 4-[(2E)-2-(2-hydroxybenzylidene) hydrazinyl] benzoic acid (HBHZ). Efficient synthesis yielded impressive quantities (70 % and 58 %, respectively), and structural characterization employed IR, UV–Vis, and NMR spectroscopy. Antioxidant potential was assessed using the DPPH free radical scavenging assay, revealing distinct capabilities of NBHZ and HBHZ, each featuring a nitro (NO2) and a hydroxy (OH) group, respectively, at the ortho position. HBHZ exhibited superior efficacy (IC50 = 1.15 μg/mL) compared to NBHZ (IC50 = 2.1 μg/mL) and the standard antioxidant BHT (IC50 = 1.83 μg/mL). Computational analyses using Gaussian 09 at the B3LYP/6–311 G(d,p) level elucidated electronic characteristics, molecular electrostatic potential (MEP), HOMO-LUMO energies, and global reactivity descriptors. VEDA 4 further investigated vibrational behavior and potential energy distribution (PED), topological analyses electron localization function (ELF), localized orbital locator (LOL), average localized ionization energy (ALIE), and reduced density gradient (RDG) were identified to evaluate their interactions. Thermochemical parameters explored antioxidant mechanisms (hydrogen atom transfer (HAT), single electron transfer–proton transfer (SET–PT), and sequential proton loss electron transfer (SPLET)). Molecular docking via iGEMDOCK revealed binding interactions with the target NADPH oxidase. These findings not only provide insights into the compounds' antioxidant potential but also underscore the impact of specific molecular features on their properties. This integrated approach contributes to advancing the understanding of hydrazone compounds, guiding the design of materials with tailored functionalities for applications in oxidative stress mitigation.

Ir-Catalyzed ortho-C-H Borylation of Aromatic C(sp2)-H Bonds of Carbocyclic Compounds Assisted by N-Bearing Directing Groups

C-H borylation is a powerful strategy for the construction of C-B bonds due to the synthetic versatility of C-B bonds. Various transition metals affect the powerful functionalization of C-H bonds, of which Ir is the most common. Substrate-directed methods have enabled directed Ir-catalyzed C-H borylation at the ortho position. Amongst the powerful directing groups in Ir-catalyzed C-H borylation are N-containing carbocyclic systems. This review covers substrate-directed Ir-catalyzed ortho-C-H borylation of aromatic C(sp2)-H bonds in N-containing carbocyclic compounds, such as anilines, amides, benzyl amines, hydrazones, and triazines.

Chronic Behavioral and Neurochemical Effects of Four Novel N-Benzyl-2-phenylethylamine Derivatives Recently Identified as "Psychoactive" in Adult Zebrafish Screens.

Potently affecting human and animal brain and behavior, hallucinogenic drugs have recently emerged as potentially promising agents in psychopharmacotherapy. Complementing laboratory rodents, the zebrafish (Danio rerio) is a powerful model organism for screening neuroactive drugs, including hallucinogens. Here, we tested four novel N-benzyl-2-phenylethylamine (NBPEA) derivatives with 2,4- and 3,4-dimethoxy substitutions in the phenethylamine moiety and the -F, -Cl, and -OCF3 substitutions in the ortho position of the phenyl ring of the N-benzyl moiety (34H-NBF, 34H-NBCl, 24H-NBOMe(F), and 34H-NBOMe(F)), assessing their behavioral and neurochemical effects following chronic 14 day treatment in adult zebrafish. While the novel tank test behavioral data indicate anxiolytic-like effects of 24H-NBOMe(F) and 34H-NBOMe(F), neurochemical analyses reveal reduced brain norepinephrine by all four drugs, and (except 34H-NBCl) - reduced dopamine and serotonin levels. We also found reduced turnover rates for all three brain monoamines but unaltered levels of their respective metabolites. Collectively, these findings further our understanding of complex central behavioral and neurochemical effects of chronically administered novel NBPEAs and highlight the potential of zebrafish as a model for preclinical screening of small psychoactive molecules.

χ(2) and χ(3) enhancement by arylamine substituents in aromatic conjugated polyenyne polymers

In this work, we have determined the χ(1), χ(2), and χ(3) NLO properties of NH2substituted aromatic polyenynes in ortho, meta, and para positions. It is worth noting that Mednis-Genkin’s approximation takes into account the intraband contribution with a derivate of the dipole valence-conduction band moment transition, unlike, for example, Ward’s summation-over-sates (SOS) methodology, which considers the difference of these states. Indeed, we have selected these polymers because of the high asymmetry in their molecular wavefunction. In this way, the calculated χ(3) values of the para-NH2 substituted aromatic polyenyne with a higher degree of polymerization are near 1 X 10−7 esu. For its part, the ortho polymer has higher values, of the order of 1 X 10−6 esu, due to its high transition dipole moment. We have also found that the energy band distribution in the para position of these polymers produces van Hove points, which have a negligible proportion of the NLO properties, compared with singularity regions 1 and 2, which have a contribution of 100 %. These regions are due to the wavefunction coefficients’ first and second-order derivatives. Besides, without considering border effects nor correlation effects, and only the variation of excitation energy, we have calculated that the quaternary monomeric oligomers of these polymers have almost similar values of χ(2) and χ(3). Then, it implies building a methodology to synthesize the polymers to avoid canceling the NLO-χ(2) and -χ(3) values.

Anti‐Coronavirus Activity of Certain Herbacetin Derivatives, A Theoretical Study

AbstractFlavonoids are natural products commonly found in the human diet with anti‐viral activity. The electrochemical activity of flavonoids is effective in their inhibitory properties. Herbacetin is an anti‐coronavirus drug from the flavonoid family. To understand structure‐electrochemical activity relations, ab initio calculations on some selected herbacetin derivatives were carried out using Gaussian 09 in B3LYP/6‐311G*. The effect of the position and type of the various substituents in the ring A of the flavone backbone are considered. The oxygen charge density of the hydroxyl group on C8 (O8) in the considered herbacetins was compared using nuclear quadrupole coupling constants (NQCC) calculations. Results showed that the presence of the amino group in the ortho position of O8 has the most significant effect on increasing the charge density of the O8 atom (O8‐NQCC=9.23 MHz). Based on the proposed mechanism of these drugs, ortho‐amino herbacetin is expected to show a significant anti‐coronavirus effect. Comparison of calculated O8‐NQCCs of tangeretin and nobiletin with herbacetin shows that with the replacement of OH with OCH3, the charge density of oxygen atoms decreases (about 2 MHz). Therefore tangeretin and nobiletin have a lower drug effect than herbacetin. Natural bond orbital (NBO) results are in agreement with calculated NQCCs.

Proximity effects: Structural implications and quantum-chemical description. Review

Proximity effects occur between vicinal functional groups or between a group and a specific molecular fragment in close proximity, for example an endocyclic N atom in the ortho position relative to the group. They are a combination of through-bond inductive and resonance effects, and through-space interactions, which can be either attractive or repulsive. In this review, we discuss quantum-chemical tools and examples from the literature that explore the structural and physicochemical implications of proximity effects. We focus on derivatives of small molecules: benzene, small polycyclic aromatic hydrocarbons, simple heterocycles, and lastly, purine derivatives.

A simple method for the synthesis of diarylamines containing a nitroso group in the ortho position based on the SNH arylamination of 5-nitroisoquinoline

A simple method for the synthesis of diarylamines containing a nitroso group in the ortho position based on the SNH arylamination of 5-nitroisoquinoline

Microwave assisted self-repairable vitrimeric coating for anti-corrosive applications

Vitrimeric coatings are revolutionary and most widely emerging materials for metal corrosion inhibition. As harsh environmental conditions damages polymer-derived protective films and results into micro cracks and corroded metal surfaces. In this work, an active microwave responsive vitrimeric epoxy coating embedded with weathering resistant properties is introduced along with systematic comparative study for the effect of ortho and para position of amine in hardening agent. The developed microwave radiation responsive coating system felicitates self-healing due to disulfide exchange mechanism and corrosion inhibition properties in marine environments. Compared to conventional coatings, prepared graphene oxide (GO) incorporated vitrimeric network showed more promising protection against corrosion in offshore applications with 95.4 % protection efficiency and hydrophobicity with 96-degree contact angle. This study covers the self-healing properties, thermal mechanical study, hydrophobicity measurement, and thorough corrosion examination of synthesized material coated on 304 grade SS substrate. The coating reports excellent self-healing efficiency, reliable mechanical strength (storage modulus-129GPa and loss modulus-83GPa), fast stress relaxation and low activation energy (63KJ/mol) for dynamic disulfide exchange reaction, furthermore low corrosion rate of 1.20 × 10−3mm/y was observed for the coating. Thus, demonstrates its importance for self-healable anti-corrosive application for the marine environment.

Design and synthesis of novel dihydropyridine- and benzylideneimine-based tyrosinase inhibitors.

Tyrosinase (TYR) inhibitors are very significant as they inhibit enzyme tyrosinase activity, and its inhibition is vital for skin care, anticancer medication, and antibrowning of fruits and vegetables. This work presents a novel and economical route for the preparation of new synthetic tyrosinase inhibitors using amlodipine (4). The novel conjugates 6 (a-o) were designed, synthesized, and characterized by spectroscopic analyses, including Fourier transform infrared and low- and high-resolution mass spectroscopy. The purified compound 4 was refluxed with various aldehydes and ketones 5 (a-o) for 5-8h in methanol at 60°C-90°C. This research modified the drug in a step-by-step manner to develop therapeutic properties as a tyrosinase inhibitor. The structures of synthesized ligands 6 (a-o) were established based on spectral and analytical data. The synthesized compounds 6 (a-o) were screened against tyrosinase enzyme. Kojic acid was taken as standard. All the prepared compounds 6 (a-o) have good inhibition potential against the enzyme tyrosinase. Compounds 6o, 6b, 6f, and 6k depicted excellent antityrosinase activity. Compound 6k, with an IC50 value of 5.34 ± 0.58µM, is as potent as the standard kojic acid (IC50 6.04 ± 0.11µM), standing out among all synthesized compounds 6 (a-o). The in silico studies of the conjugates 6 (a-o) were evaluated via PatchDock. Compound 6k showed a binding affinity score of 8,999 and an atomic contact energy (ACE) value of -219.66kcal/mol. The structure-activity relationship illustrated that the presence of dihydropyridine nuclei and some activating groups at the ortho and para positions of the benzylideneimine moiety is the main factor for good tyrosinase activity. The compound 6k could be used as a lead compound for drug modification as a tyrosinase inhibitor for skin care, anticancer medication, and antibrowning for fruits and vegetables.

Influence of Hydroxyl Groups on the Oxidative Reaction Characteristics of Active Groups in Lignite at Room Temperature.

In this paper, through the Fourier infrared spectrum analysis of the Inner Mongolia Hulunbeier Yannan coal mine lignite sample, phenyl and active groups, methoxy (-OCH3) and methylene (-CH2-), were taken as the research objects, and a simple small molecule model of hydroxyl (-OH) at the ortho, meta, and para positions of active groups was constructed. The structural optimization and simulation calculation of simple small molecules were carried out by Gaussview 6.0.16 and Gaussian 16 software at room temperature and pressure. The DFT-B3LYP method and 6-311G(d,p) basis set were used to study the effect of the -OH position on the oxidation reaction characteristics from various aspects of electrostatic potential, frontier orbital, activation energy, enthalpy change, and Gibbs free energy change. The results show that the coexistence of the active groups -OCH3 and -CH2- with -OH makes the small molecule model add an active site, that is, the oxygen atom in -OH, which makes the active groups generate hydrogen radicals (H•). Comparing different positions of -OH, the analysis shows that -OH at the ortho position has a vital impact on the oxidation reaction, and the oxidation reaction releases the largest amount of heat and has the fastest occurrence rate, making it easier to overcome energy barriers and making the reaction easier to proceed. The purpose of this study is to reveal the interaction and complex reaction path of lignite through an in-depth study of its properties, structural composition, and reaction behavior and to accurately grasp its chemical composition, thermal properties, and microstructure, so as to lay a foundation for further efficient conversion and comprehensive utilization.

Tailoring the donor moieties in TPA‐based organic dyes for efficient photovoltaic, optical and nonlinear optical response properties

AbstractThe current study reports tailoring the electronic donor structures of organic dyes to modify their optical and nonlinear optical (NLO) response properties. Five (5) tri‐phenyl amine (TPA) based Donor‐π‐Acceptor (D‐π‐A) organic dyes with the codes ICAA1, ICAA2, ICAA3, ICAA4, and ICAA5 were designed and investigated for their optical and NLO properties using quantum chemical methods. Optical and NLO properties of these dyes were studied by CAM‐B3LYP method and 6‐311G* basis set. The focus has been on the impact of adding secondary donors and shifting their substitutions at ortho (o), meta (m) and para (p) positions. Among all designed compounds, ICAA4 showed the highest amplitude of average third‐order NLO polarizability <γ>, which is calculated to be 1316 × 10−36 esu. Time‐dependent Density Functional Theory (TD‐DFT) method was used to determine how a change in the position of the donor affected the excitation energy (Eg) and NLO response properties. The findings showed that changing the position of the secondary donor results in a red shift among absorption spectra as well as the increase in their NLO responses. Complete process of intramolecular charge transfer (ICT) has been investigated in terms of different optical parameters such as frontier molecular orbitals (FMOs), molecular electrostatic potentials (MEPs), transition density matrix (TDMs), density of states (DOS), electron density difference (EDD), and natural bond orbital (NBO) analysis. Our calculations for study of ICT process indicate that p‐position of methoxy group performs better among all other positions and even it has better NLO response properties than the compound with three collective methoxy groups. The calculated Voc values of all designed molecules range from 1.09 to 1.30, all of them are positive while their ΔGinject is found to be in the range of −0.87 to −1.79 eV indicating their decent potential for photovoltaic applications. The studied optical, NLO and photovoltaic parameters illustrated that ICAA1 to ICAA5 are appropriate molecules not only for NLO applications but also for efficient photovoltaic purposes.

Novel secondary pyridinyl amides: Synthesis, in vitro antiproliferative screenings, and molecular docking studies

A novel series of secondary pyridinyl amides, reinforced with the methylsulfonyl pharmacophore unit, was designed and synthesized. Further, we determined the antiproliferative activities of these compounds through experimental assays and analyzed their interactions with Breakpoint Cluster Region/Abelson (bcr/abl), Epidermal Growth Factor Receptor (EGFR), and Human Epidermal Growth Factor Receptor 2 (HER2) tyrosine kinases using molecular autodocking techniques. We grouped these amides into three categories, classified by the type of spacer that binds the pyridine ring to the amide nitrogen atom. Additionally, within each group, we strategically positioned the amide moiety at the ortho, meta, or para position on the pyridyl ring. Among the studied amides, compound 3 exhibited the best overall antiproliferative activity against human immortalized myelogenous leukemia (K562) (IC50 = 26 µM), human leukemia monocytic cell line (THP-1) (IC50 = 81 µM), and human hepatocellular carcinoma (HepG2) (IC50 = 210 µM). Molecular docking studies revealed that compound 3 binds effectively to bcr/abl, EGFR, and HER2 tyrosine kinases, demonstrating strong interactions with crucial active site amino acids, indicative of its targeted antiproliferative mechanism. All investigated compounds showed either very minor or no cytotoxicity against human dermal fibroblast adult cells.

On-Surface Synthesis of Silole and Disila-Cyclooctene Derivatives.

The incorporation of Si atoms into organic compounds significantly increases a variety of functionality, facilitating further applications. Recently, on-surface synthesis was introduced into organosilicon chemistry as 1,4-disilabenzene bridged nanostructures were obtained via coupling between silicon atoms and brominated phenyl groups at the ortho position on Au(111). Here, we demonstrate a high generality of this strategy via syntheses of silole derivatives and nanoribbon structures with eight-membered sila-cyclic rings from dibrominated molecules at the bay and peri positions on Au(111), respectively. Their structures and electronic properties were investigated by a combination of scanning tunneling microscopy/spectroscopy and density functional theory calculations. This work demonstrates a great potential to deal with heavy group 14 elements in on-surface silicon chemistry.

On‐Surface Synthesis of Silole and Disila‐Cyclooctene Derivatives

AbstractThe incorporation of Si atoms into organic compounds significantly increases a variety of functionality, facilitating further applications. Recently, on‐surface synthesis was introduced into organosilicon chemistry as 1,4‐disilabenzene bridged nanostructures were obtained via coupling between silicon atoms and brominated phenyl groups at the ortho position on Au(111). Here, we demonstrate a high generality of this strategy via syntheses of silole derivatives and nanoribbon structures with eight‐membered sila‐cyclic rings from dibrominated molecules at the bay and peri positions on Au(111), respectively. Their structures and electronic properties were investigated by a combination of scanning tunneling microscopy/spectroscopy and density functional theory calculations. This work demonstrates a great potential to deal with heavy group 14 elements in on‐surface silicon chemistry.

Significantly enhanced gas separation properties of membranes by debromination and thermal rearrangement simultaneously

One important challenge in advanced gas separation membranes is breaking the trade-off effect between gas permeability and selectivity. Here, we developed a method by combining the debromination and thermal rearrangement (TR) techniques together to significantly enhance the gas separation properties of the resulting membrane for the first time. First, we designed a co-polyimide (DBOH) containing both hydroxyl and bromine (50/50) groups in the ortho position of the imide group. After thermal treatment at 450 °C, the TR and debromination happened simultaneously as proved by TG-MS, FT-IR and XPS results, the resulting DBPO showed a larger d-spacing (7.03–9.71 Å), a 18-fold enhanced BET surface area, and 2-fold improved in ultra-microporosity (<7 Å) than its DBOH precursor. Hence, DBPO demonstrated not only an over 100 times improved CO2 permeability (7933 vs 76 Barrer) but also keep a high CO2/CH4 selectivity of 31, and the overall performance surpassed the latest 2019 trade-off curve. Besides, wonderful anti-plasticization and mixed-gas separation properties were also observed for DBPO, which showed a CO2 permeability of 3324 Barrer and CO2/CH4 selectivity of 14.7 even under the upstream CO2/CH4 mixed-gas pressure of 435 psi (1 psi = 6894.8 Pa), outperforming the latest 2018 CO2/CH4 mixed-gas upper limit. It showed 100 times improved CO2 permeability while maintain selectivity of DBPO is attributed to the significantly enhanced ultra-microporosity that increases the diffusion and solubility coefficient, whereas maintain their diffusion and solubility selectivity. Conclusively, the debromination coupled with TR provides a novel direction for designing advanced TR membranes.

On-surface cyclization of vinyl groups on poly-para-phenylene involving an unusual pentagon to hexagon transformation

On-surface synthesis relies on carefully designed molecular precursors that are thermally activated to afford desired, covalently coupled architectures. Here, we study the intramolecular reactions of vinyl groups in a poly-para-phenylene-based model system and provide a comprehensive description of the reaction steps taking place on the Au(111) surface under ultrahigh vacuum conditions. We find that vinyl groups successfully cyclize with the phenylene rings in the ortho positions, forming a dimethyl-dihydroindenofluorene as the repeating unit, which can be further dehydrogenated to a dimethylene-dihydroindenofluorene structure. Interestingly, the obtained polymer can be transformed cleanly into thermodynamically stable polybenzo[k]tetraphene at higher temperature, involving a previously elusive pentagon-to-hexagon transformation via ring opening and rearrangement on a metal surface. Our insights into the reaction cascade unveil fundamental chemical processes involving vinyl groups on surfaces. Because the formation of specific products is highly temperature-dependent, this innovative approach offers a valuable tool for fabricating complex, low-dimensional nanostructures with high precision and yield.