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Three alternatives are discussed in comparison with the classical esterification of phosphinic chlorides by reaction with alcohols. All novel methods, such as microwave (MW)-assisted direct esterification, MW-assisted phase transfer catalyzed alkylating esterification and the propylphosphonic anhydride-promoted esterification, start from phosphinic acids and offer different advantages and disadvantages. The methods are analyzed from green chemical point of view.

In the area of esterification of heteroatomic acids, after the microwave-assisted ionic liquid-catalyzed esterification of phosphinic acids, the esterification of arylsulfonic acids was also developed applying a 14-fold excess of alcohols at 200 °C in the presence of 10% butyl-methylimidazolium hexafluorophosphate as an additive. The esterifications were optimized, and the effect of the substituents in the aromatic ring was evaluated. At the same time, a similar procedure described by Mandal et al. using only one equivalent of alcohol at 120 °C for 5 min in toluene was refuted. The mechanism and energetics of the reaction of benzenesulfonic acid and butyl alcohol were determined at the B3LYPD3/def2TZVP[PCM(BuOH)] level of theory using the explicit-implicit solvent model, and, as a comparison, the implicit solvent model. Three possible reaction pathways were explored: the direct esterification of benzenesulfonic acid through an S N 2 protocol including the nucleophilic addition of butyl alcohol to the SO function of the sulfonic acid via an intermediate with a hexavalent-pentacoordinated S atom ( Route I ), via protonation of the alcohol by the arenesulfonic acid followed by the recombination of the sulfonate anion and the alkyl cation formed by dehydration ( Route II ), and an S N 1 route involving the initial formation of a sulfonium cation by dehydration of the protonated sulfonic acid followed by the nucleophilic attack of the alcohol ( Route III ). Judging from the energetics of the three potential pathways, the alkylating esterification ( Route II ) seems to be the predominant route. Microwave irradiation may overcome the enthalpy of activation of 132 kJ mol -1 required for this protocol. The addition-elimination (S N 2) sequence ( Route I ) may also be operative as a minor reaction component.

The advancements in targeted drug release and experimental neuroscience have amplified the scientific interest in photolabile protecting groups (PPGs) and photouncaging. The growing need for the detection of uncaging events has led to the development of reporters with fluorescence turn-on upon uncaging. In contrast, fluorescent tags with turn-off properties have been drastically underexplored, although there are applications where they would be sought after. In this work, a rhodamine-based fluorescent tag is developed with signal turn-off following photouncaging. One-photon photolysis experiments reveal a ready loss of red fluorescence signal upon UV (365 nm) irradiation, while no significant change is observed in control experiments in the absence of PPG or with irradiation around the absorption maximum of the fluorophore (595 nm). The two-photon photolysis of the turn-off fluorescent tag is explored in hydrogel photolithography experiments. The hydrogel-bound tag enables the power-, dwell time-, and wavelength-dependent construction of intricate patterns and gradients. Finally, a prominent caged neurotransmitter (MNI-Glu) is modified with the fluorescent tag, resulting in the glutamate precursor named as GlutaTrace with fluorescence traceability and turn-off upon photouncaging. GlutaTrace is successfully applied for the visualization of glutamate precursor distribution following capillary microinjection and for the selective excitation of neurons in a mouse brain model.

Carbodiimides are important crosslinkers in organic synthesis and are used in the isocyanate industry as modifier additives. Therefore, the understanding of their formation is of high importance. In this work, we present a theoretical B3LYP/6-31G(d) and SMD solvent model and experimental investigation of the formation of diphenylcarbodiimide (CDI) from phenyl isocyanate using a phosphorus-based catalyst (MPPO) in ortho-dichlorobenzene (ODCB) solvent. Kinetic experiments were based on the volumetric quantitation of CO 2 evolved, at different temperatures between 40 and 80 °C. Based on DFT calculations, we managed to construct a more detailed reaction mechanism compared to previous studies which is supported by experimental results. DFT calculations revealed that the mechanism is composed of two main parts, and the rate determining step of the first part, controlling the CO 2 formation, is the first transition state with a 52.9 kJ mol -1 enthalpy barrier. The experimental activation energy was obtained from the Arrhenius plot (ln k vs. 1/ T ) using the observed second-order kinetics, and the obtained 55.8 ± 2.1 kJ mol -1 was in excellent agreement with the computational one, validating the complete mechanism, giving a better understanding of carbodiimide production from isocyanates.

Background: The organism-wide effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection are well studied, but little is known about the dynamics of how the infection spreads in time among or within cells due to the scarcity of suitable high-resolution experimental systems. It has been reported that SARS-CoV-2 infection pathways converge at calcium influx and subcellular calcium distribution changes. Imaging combined with a proper staining technique is an effective tool for studying subcellular calcium-related infection and replication mechanisms at such resolutions., Methods: Using two-photon (2P) fluorescence imaging with our novel Ca-selective dye, automated image analysis and clustering analysis were applied to reveal titer and variant effects on SARS-CoV-2-infected Vero E6 cells., Results: The application of a new calcium sensor molecule is shown, combined with a high-end 2P technique for imaging and identifying the patterns associated with cellular infection damage within cells. Vero E6 cells infected with SARS-CoV-2 variants, D614G or B.1.1.7, exhibit elevated cytosolic calcium levels, allowing infection monitoring by tracking the cellular changes in calcium level by the internalized calcium sensor. The imaging provides valuable information on how the level and intracellular distribution of calcium are perturbed during the infection. Moreover, two-photon calcium sensing allowed the distinction of infections by two studied viral variants via cluster analysis of the image parameters. This approach will facilitate the study of cellular correlates of infection and their quantification depending on viral variants and viral load., Conclusions: We propose a new two-photon microscopy-based method combined with a cell-internalized sensor to quantify the level of SARS-CoV-2 infection. We optimized the applied dye concentrations to not interfere with viral fusion and viral replication events. The presented method ensured the proper monitoring of viral infection, replication, and cell fate. It also enabled distinguishing intracellular details of cell damage, such as vacuole and apoptotic body formation. Using clustering analysis, 2P microscopy calcium fluorescence images were suitable to distinguish two different viral variants in cell cultures. Cellular harm levels read out by calcium imaging were quantitatively related to the initial viral multiplicity of infection numbers. Thus, 2P quantitative calcium imaging might be used as a correlate of infection or a correlate of activity in cellular antiviral studies., (© 2024. The Author(s).)

An effective, GFP-inspired fluorescent Zn 2+ sensor is developed for two-photon microscopy and related biological application that features an 8-methoxyquinoline moiety. Excellent photophysical characteristics including a 37-fold fluorescence enhancement with excitation and emission maxima at 440 nm and 505 nm, respectively, as well as a high two-photon cross-section of 73 GM at 880 nm are reported. Based on the experimental data, the relationship between the structure and properties was elucidated and explained backed up by DFT calculations, particularly the observed PeT phenomenon for the turn-on process. Biological validation and detailed experimental and theoretical characterization of the free and the zinc-bound compounds are presented., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

1,5-hydride transfer-triggered cyclization reactions offering a robust method for C(sp 3 )-C(sp 3 ) coupling and the synthesis of e.g. tetrahydroquinolines have been thoroughly investigated in the literature. Catalysts allowing milder reaction conditions or the development of enantioselective processes were important recent contributions to the field, as well as the studies on subtrates with oxygen or sulfur heteroatoms (besides the originally described nitrogen heterocycles). In a series of studies, we focused on expanded, higher order H-transfers/cyclizations by positioning the interacting substituents on distanced rings. Cyclizations of appropriately functionalized biaryl and fused bicyclic systems led to 7-9 membered rings. In the frame of this research, we set out to study the feasibility of the cyclization and the factors affecting it by in silico methods. The conclusions drawn from computational studies were complemented by cyclization screens on 2-(2-vinyl)phenoxy- tert -anilines and their CH 2 -expanded analogues, the results of which are presented here. Besides isolating the expected oxazonine products in several cases, we also observed a unique dimer formation, leading to an interesting 5-6-5 ring system., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

The few commercially available chemosensors and published probes for in vitro Zn 2+ detection in two-photon microscopy are compromised by their flawed spectroscopic properties, causing issues in selectivity or challenging multistep syntheses. Herein, we present the development of an effective small molecular GFP chromophore-based fluorescent chemosensor with a 2,2'-bipyridine chelator moiety (GFZnP BIPY) for Zn 2+ detection that has straightforward synthesis and uncompromised properties. Detailed experimental characterizations of the free and the zinc-bound compounds within the physiologically relevant pH range are presented. Excellent photophysical characteristics are reported, including a 53-fold fluorescence enhancement with excitation and emission maxima at 422 nm and 492 nm, respectively. A high two-photon cross section of 3.0 GM at 840 nm as well as excellent metal ion selectivity are reported. In vitro experiments on HEK 293 cell culture were carried out using two-photon microscopy to demonstrate the applicability of the novel sensor for zinc bioimaging.

A new model, based on the presence of the excited state iminium ion (Ar = NH 2 + ), is proposed to interpret the solvatochromic behavior of symmetric 1,5- and 1,8-diaminonaphtahelenes (DANs) in aprotic to protic media. The importance of using explicit solvent models during DFT calculations in protic solvents to find the proper excited structure for symmetric molecules is also highlighted.

An asymmetric cyanine-type fluorescent dye was designed and synthesized via a versatile, multi-step process, aiming to conjugate with an Her2+ receptor specific antibody by an azide-alkyne click reaction. The aromaticity and the excitation and relaxation energetics of the fluorophore were characterized by computational methods. The synthesized dye exhibited excellent fluorescence properties for confocal microscopy, offering efficient applicability in in vitro imaging due to its merits such as a high molar absorption coefficient (36 816 M -1 cm -1 ), excellent brightness, optimal wavelength (627 nm), larger Stokes shift (26 nm) and appropriate photostability compared to cyanines. The conjugated cyanine-trastuzumab was constructed via an effective, metal-free, strain-promoted azide-alkyne click reaction leading to a regulated number of dyes being conjugated. This novel cyanine-labelled antibody was successfully applied for in vitro confocal imaging and flow cytometry of Her2+ tumor cells.

A less-studied halogen-free variation of the Hirao reaction involving the coupling of arylboronic acids with >P(O)H reagents, such as diarylphosphine oxides, diethyl phosphite, and ethyl phenyl- H -phosphinate, was investigated in detail using Pd(OAc) 2 as the catalyst precursor and applying some excess of the P-reagent to supply the ligand via its trivalent tautomeric (>P-OH) form. The optimum conditions (1.2 equiv of the P-reagent, 135-150 °C, and air) were explored for the synthesis of diaryl-phenylphosphine oxides, aryl-diphenylphosphine oxides, diethyl arylphosphonates, ethyl diphenylphosphinate, and two bisphosphinoyl derivatives. In the reaction of 4-chlorophenyl- or 3-chlorophenylboronic acid with Ph 2 P(O)H, triphenylphosphine oxide was also formed as a byproduct. Theoretical calculations suggested that the catalytic cycle of the P-C coupling of PhB(OH) 2 with Ph 2 P(O)H is different from that of the usual cross-coupling reactions. It comprises the addition of a phenyl anion and then the tautomeric form >P-OH of the >P(O)H reagent to the Pd 2+ catalyst complex. This is then followed by reductive elimination affording Ph 3 PO that is accompanied with the conversion of Pd 2+ to Pd 0 . There is a need for a subsequent stoichiometric oxidation of Pd(0) by molecular oxygen. The spontaneous formation of the self-assembling ligands around the Pd 2+ center from the >P(O)H reactant plays a crucial role in the mechanism and promotes the efficiency of the catalyst.

A novel family of julolidine-containing fluorescent rhodols equipped with a wide variety of substituents was synthesized in a versatile two-step process. The prepared compounds were fully characterized and exhibited excellent fluorescence properties for microscopy imaging. The best candidate was conjugated to the therapeutic antibody trastuzumab through a copper-free strain-promoted azide-alkyne click reaction. The rhodol-labeled antibody was successfully applied for in vitro confocal and two-photon microscopy imaging of Her2+ cells., Competing Interests: The authors declare the following competing financial interest(s): Gergely Katona and Balzs J. Rzsa are founder of Femtonics and members of its scientific advisory board. The other authors declare that no conflict of interest exists. However, two of my co-author have, as they are founder of Femtonics, the company which employed researchers also., (© 2023 The Authors. Published by American Chemical Society.)

Diphyllin ( 1 ) and justicidin B ( 2 ) are arylnaphthalene lignans with antiviral and antiproliferative effects. Compound 1 is also known as an effective inhibitor of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). To evaluate the in vitro antiviral and cytotoxic potency of both lignans in SARS-CoV-2 -infected cells and various cancer cell lines, respectively, 1 and 2 were isolated from the underground organs of Linum austriacum and Linum perenne . Two previously undescribed arylnaphthalene lignans, denominated linadiacin A and B ( 3 and 4 ), were also isolated and identified. In acidic media, 3 was converted by a two-step reaction into 2 via the intermediate 4 . Optimum acid treatment conditions were determined to isolate lignans by one-step preparative high-performance liquid chromatography (HPLC). The results of the conversion, HPLC-tandem mass spectrometry, nuclear magnetic resonance spectroscopy, and molecular modeling studies allowed complete structure analysis. Compounds 1 and 2 were the most effective against SARS-CoV-2 with a 3-log reduction in the viral copy number at a 12.5 μM concentration. Ten human cancer cell lines showed sensitivity to at least one of the isolated lignans.

Aromatic isocyanides have gained a lot of attention lately as promising antifungal and anticancer drugs, as well as high-performance fluorescent analytical probes for the detection of toxic metals, such as mercury, even in vivo. Since this topic is relatively new and aromatic isocyanides possess unique photophysical properties, the understanding of structure-behavior relationships and the preparation of novel potentially biologically active derivatives are of paramount importance. Here, we report the photophysical characterization of 1,5-diisocyanonaphthalene (DIN) backed by quantum chemical calculations. It was discovered that DIN undergoes hydrolysis in certain solvents in the presence of oxonium ions. By the careful control of the reaction conditions for the first time, the nonsymmetric product 1-formamido-5-isocyanonaphthalene (ICNF) could be prepared. Contrary to expectations, the monoformamido derivative showed a significant solvatochromic behavior with a ~50 nm range from hexane to water. This behavior was explained by the enhanced H-bond-forming ability of the formamide group. The significance of the hydrolysis reaction is that the isocyano group is converted to formamide in living organisms. Therefore, ICNF could be a potential drug (for example, antifungal) and the reaction can be used as a model for the preparation of other nonsymmetric formamido-isocyanoarenes. In contrast to its relative 1-amino-5-iscyanonaphthalene (ICAN), ICNF is highly fluorescent in water, enabling the development of a fluorescent turnoff probe.

Neuronal plasticity has been shown to be causally linked to coincidence detection through dendritic spikes (dSpikes). We demonstrate the existence of SPW-R-associated, branch-specific, local dSpikes and their computational role in basal dendrites of hippocampal PV+ interneurons in awake animals. To measure the entire dendritic arbor of long thin dendrites during SPW-Rs, we used fast 3D acousto-optical imaging through an eccentric deep-brain adapter and ipsilateral local field potential recording. The regenerative calcium spike started at variable, NMDA-AMPA-dependent, hot spots and propagated in both direction with a high amplitude beyond a critical distance threshold (~150 µm) involving voltage-gated calcium channels. A supralinear dendritic summation emerged during SPW-R doublets when two successive SPW-R events coincide within a short temporal window (~150 ms), e.g., during more complex association tasks, and generated large dSpikes with an about 2.5-3-fold amplitude increase which propagated down to the soma. Our results suggest that these doublet-associated dSpikes can work as a dendritic-level temporal and spatial coincidence detector during SPW-R-related network computation in awake mice., (© 2022. The Author(s).)

In this paper, we present an additional, new cage-GABA compound, called 4-amino-1-(4'-dimethylaminoisopropoxy-5',7'-dinitro-2',3'-dihydro-indol-1-yl)-1-oxobutane-γ-aminobutyric acid (iDMPO-DNI-GABA), and currently, this compound is the only photoreagent, which can be applied for GABA uncaging without experimental compromises. By a systematic theoretical design and successful synthesis of several compounds, the best reagent exhibits a high two-photon efficiency within the 700-760 nm range with excellent pharmacological behavior, which proved to be suitable for a complex epileptic study. Quantum chemical design showed that the optimal length of the cationic side chain enhances the two-photon absorption by 1 order of magnitude due to the cooperating internal hydrogen bonding to the extra nitro group on the core. This feature increased solubility while suppressing membrane permeability. The efficiency was demonstrated in a systematic, wide range of in vitro single-cell neurophysiological experiments by electrophysiological as well as calcium imaging techniques. Scalable inhibitory ion currents were elicited by iDMPO-DNI-GABA with appropriate spatial-temporal precision, blocking both spontaneous and evoked cell activity with excellent efficiency. Additionally, to demonstrate its applicability in a real neurobiological study, we could smoothly and selectively modulate neuronal activities during artificial epileptic rhythms first time in a neural network of GCaMP6f transgenic mouse brain slices., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

A comparative phytochemical study on the phenylethanoid glycoside (PhEG) composition of the underground organs of three Plantago species ( P. lanceolata , P. major, and P. media ) and that of the fruit wall and seed parts of Forsythia suspensa and F. europaea fruits was performed. The leaves of these Forsythia species and six cultivars of the hybrid F. × intermedia were also analyzed, demonstrating the tissue-specific accumulation and decomposition of PhEGs. Our analyses confirmed the significance of selected tissues as new and abundant sources of these valuable natural compounds. The optimized heat treatment of tissues containing high amounts of the PhEG plantamajoside (PM) or forsythoside A (FA), which was performed in distilled water, resulted in their characteristic isomerizations. In addition to PM and FA, high amounts of the isomerization products could also be isolated after heat treatment. The isomerization mechanisms were elucidated by molecular modeling, and the structures of PhEGs were identified by nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry (HR-MS) techniques, also confirming the possibility of discriminating regioisomeric PhEGs by tandem MS. The PhEGs showed no cytostatic activity in non-human primate Vero E6 cells, supporting their safe use as natural medicines and allowing their antiviral potency to be tested.

It was found by us that the P-C coupling reaction of >P(O)H reagents with PhX (X = I and Br) in the presence of NiCl 2 /Zn as the precursors for the assumed Ni(0) complexant together with 2,2'-bipyridine as the ligand took place only with PhI at 50/70 °C. M06-2 X /6-31G(d,p)//PCM(MeCN) calculations for the reaction of Ph 2 P(O)H and PhX revealed a favorable energetics only for the loss of iodide following the oxidative addition of PhI on the Ni(0) atom. However, the assumed transition states with Ni(II) formed after P-ligand uptake and deprotonation could not undergo reductive elimination meaning a "dead-end route". Hence, it was assumed that the initial complexation of the remaining Ni 2+ ions with 2,2'-bipyridine may move the P-C coupling forward via a Ni(II) → Ni(IV) transition. This route was also confirmed by calculations, and this mechanism was justified by preparative experiments carried out using NiCl 2 /bipyridine in the absence of Zn. Hence, the generally accepted Ni(0) → Ni(II) route was refuted by us, confirming the generality of the Ni(II) → N(IV) protocol, either in the presence of bipyridine, or using the excess of the >P(O)H reagent as the P -ligand. The results of the calculations on the complex forming ability of Ni(0) and Ni(II) with 2,2'-bipyridine or the P -reagents were in accord with our mechanistic proposition.

A general, scalable two-step regio- and diastereoselective method has been described for the synthesis of versatile alkaloid-type azetidines from simple building blocks with excellent overall yields. In the kinetically controlled reaction, only the formation of the strained four-membered ring can be achieved instead of the thermodynamically favorable five-membered rings under appropriate conditions. Remarkable functional group tolerance has also been demonstrated. In this paper, we give a new scope of Baldwin's rules by density functional theory (DFT) calculations with an explicit solvent model, confirming the proposed reaction mechanisms and the role of kinetic controls in the stereochemical outcome of the reported transition-metal-free carbon-carbon bond formation reactions.

The Hirao reaction involving the phosphinoylation or phosphonation of aryl halides by >P(O)H reagents is a P-C bond forming transformation belonging to the recently very hot topic of cross-couplings. The Pd- or Ni-catalyzed variations take place via the usual cycle including oxidative addition, ligand exchange, and reductive elimination. However, according to the literature, the nature of the transition metal catalysts is not unambiguous. In this feature article, the catalysts described for the Pd(OAc) 2 -promoted cases are summarized, and it is concluded that the "(HOY 2 P) 2 Pd(0)" species (Y = aryl, alkoxy) is the real catalyst. In our model, the excess of the >P(O)H reagent served as the P-ligand. During the less studied Ni(II)-catalyzed instances the "(HOY 2 P)(-OY 2 P)Ni(II)Cl - " form was found to enter the catalytic cycle. The newest conclusions involving the exact structure of the catalysts, and the mechanism for their formation explored by us were supported by our earlier experimental data and theoretical calculations.

A series of 1-substituted-3-methyl-2-phospholene oxides was prepared from the corresponding 3-phospholene oxides by double bond rearrangement. The 2-phospholene oxides could be obtained by heating the 3-phospholene oxides in methanesulfonic acid, or via the formation of cyclic chlorophosphonium salts. Whereas mixtures of the 2- and 3-phospholene oxides formed, when the isomerization of 3-phospholene oxides was attempted under thermal conditions, or in the presence of a base. The mechanisms of the various double bond migration pathways were elucidated by quantum chemical calculations., (Copyright © 2020, Bagi et al.; licensee Beilstein-Institut.)

Herein we comparatively comment on the molecular metric 'amidicity', a descriptor of amide reactivity, and differing methods to determining it; with focus on lactam-rings. Specifically, our established amidicity percentage (AM%) approach is quantitatively contrasted with the transamidation (TA) method. This comment is organised into two sections, firstly addressing the differing methods in context of the computational bases of amidicity. This is followed by the quantitative demonstration that although both the AM% and H RS methods provide estimates of resonance enthalpy (ΔH RE ), the former is more reliable across a wider set of systems. The robustness of the AM% approach is affirmed by quantitative matching of experimental NMR and kinetics measurements tracking changes in amide reactivities, including in Penicillin arising from modulation of its amide group and environmental effects.

The Suzuki-Miyaura reaction is one of the most used transformations in drug research. Thus making this reaction more sustainable is of considerable current interest. Here we show that propylene carbonate (PC) can be used as a solvent for the Suzuki-Miyaura reaction. PC is one of the greenest solvents since it is synthesized under green conditions by the use of carbon dioxide in the air. All reactions proceeded well and good or excellent yields were observed for the biaryl products. Nonetheless in the case of pyridazinones, 2-hydroxypropyl- chain containing side-products were observed. Importantly, this fact allowed the isolation of several novel compounds which were generated under prominently green conditions., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Baicalin is a flavone glycoside extracted from Scutellaria baicalensis, a traditional Chinese herbal medicine. Numerous pharmacological effects of baicalin were reported (e.g. antioxidant, anxiolytic); nevertheless, the most important physicochemical properties influencing the pharmacokinetic behaviour and the concomitant oral bioavailability have not yet been described in a comprehensive study. The aim of this project was to characterize the acid-base, lipophilicity, biorelevant solubility and permeability properties of the drug substance and providing scientific data to support the dosage form design. Another important objective was the comparative evaluation of six various baicalin-cyclodextrin (CD) inclusion complexes along with the creation of a suitable Drug Delivery System (DDS) for this BCS IV drug. Biorelevant profiling was carried out by NMR-pH titrations, saturation shake-flask and distribution coefficients (logP) measurements, while CD inclusion studies were fulfilled by experimental methods (phase solubility, 1 H/ 13 C NMR, 2D ROESY) and computational approaches. Due to low aqueous solubility (67.03 ± 1.60 μg/ml) and low permeability (P app  = 0.037 × 10 -6  cm/s), baicalin is classified as BCS IV. The γ-CD complexation significantly increased the solubility of baicalin (~ 5 times). The most promoted chemical shift change occurred in baicalin-γ-CD complex. Computational studies showed disparate binding pattern for baicalin in case of β- and γ-CD; furthermore, the calculated complexation energy was - 162.4 kJ mol -1 for β-CD, while it was significantly stronger for γ-CD (- 181.5 kJ mol -1 ). The physicochemical and structural information of baicalin and its CD complexes introduced herein can create molecular basis for a promising DDS with enhanced bioavailability containing a bioactive phytopharmacon.

In order to improve the fluorescence properties of the green fluorescent protein chromophore, p‑HOBDI ((5‑(4‑hydroxybenzylidene)‑2,3‑dimethyl‑3,5‑dihydro‑4H‑imidazol‑4‑one), sixteen dihydroimidazolone derivates were synthesized from thiohydantoin and arylaldehydes. The synthesis developed is an efficient, novel, one-pot procedure. The study provides a detailed description of the spectroscopic characteristics of the newly synthesized compounds, using p‑HOBDI as a reference. The new compounds all exhibited significantly stronger fluorescence than p‑HOBDI, up to 28 times higher quantum yields. An experimental and theoretical investigation of the relationship of the fluorescence properties with the molecular structure was also carried out. A good correlation was found between the emission wavenumber and the Hammett constant of the functional group, which suggests the intermolecular charge transfer (ICT) mechanism between the aromatic groups., (Copyright © 2019. Published by Elsevier B.V.)

The present study reports regio- and highly diastereoselective preparative methods for the synthesis of versatile alkaloid-type compounds from oxiranylmethyl tetrahydroisoquinolines. 2,5-Methanobenzo[ c]azepines or azetidine-fused heterocycles were synthesized in tandem reactions depending on the absence or presence of a BF 3 co-reagent. A high functional group tolerance has also been demonstrated. DFT calculations with an explicit solvent model confirmed the proposed reaction mechanisms and the role of kinetic controls on the stereochemical outcome of the reported new methods.

Not all amide bonds are created equally. The purpose of the present paper is the reinterpretation of the amide group by means of two concepts: amidicity and carbonylicity. These concepts are meant to provide a new viewpoint in defining the stability and reactivity of amides. With the help of simple quantum-chemical calculations, practicing chemists can easily predict the outcome of a desired process. The main benefit of the concepts is their simplicity. They provide intuitive, but quasi-thermodynamic data, making them a practical rule of thumb for routine use. In the current paper we demonstrate the performance of our methods to describe the chemical character of an amide bond strength and the way of its activation methods. Examples include transamidation, acyl transfer and amide reductions. Also, the method is highly capable for simple interpretation of mechanisms for biological processes, such as protein splicing and drug mechanisms. Finally, we demonstrate how these methods can provide information about photo-activation of amides, through the examples of two caged neurotransmitter derivatives.

Two-photon (TP) uncaging of neurotransmitter molecules is the method of choice to mimic and study the subtleties of neuronal communication either in the intact brain or in slice preparations. However, the currently available caged materials are just at the limit of their usability and have several drawbacks. The local and focal nature of their use may for example be jeopardized by a high spontaneous hydrolysis rate of the commercially available compounds with increased photochemical release rate. Here, using quantum chemical modelling we show the mechanisms of hydrolysis and two-photon activation, and synthesized more effective caged compounds. Furthermore, we have developed a new enzymatic elimination method removing neurotransmitters inadvertently escaping from their compound during experiment. This method, usable both in one and two-photon experiments, allows for the use of materials with an increased rate of photochemical release. The efficiency of the new compound and the enzymatic method and of the new compound are demonstrated in neurophysiological experiments.

It was proved by our experiments that on microwave irradiation, the mono- or bidentate phosphorus ligands generally applied in the palladium(II)-catalyzed P-C coupling reaction of aryl bromides and dialkyl phosphites or secondary phosphine oxides may be substituted by the excess of the >P(O)H reagent that exists under a tautomeric equilibrium. Taking into account that the reduction of the palladium(II) salt and the ligation of the palladium(0) so formed requires 3 equivalents of the P-species for the catalyst applied in a quantity of 5-10%, all together, 15-30% of the P-reagent is necessary beyond its stoichiometric quantity. In the coupling reaction of diphenylphosphine oxide, it was possible to apply diethyl phosphite as the reducing agent and as the P-ligand. The reactivities of the diethyl phosphite and diphenylphosphine oxide reagents were compared in a competitive reaction. The mechanism and the energetics of this new variation of the Hirao reaction of bromobenzene with Y 2 P(O)H reagents (Y=EtO and Ph) was explored by quantum chemical calculations. The first detailed study on simple reaction models justified our assumption that, under the conditions of the reaction, the trivalent form of the >P(O)H reagent may serve as the P-ligand in the palladium(0) catalyst, and shed light on the fine mechanism of the reaction sequence. The existence of the earlier described bis(palladium complex) {[H(OPh 2 P) 2 PdOAc] 2 } was refuted by high level theoretical calculations. This kind of complex may be formed only with chloride anions instead of the acetate anion. The interaction of palladium acetate and Y 2 P(O)H may result in only the formation of the [(HO)Y 2 P] 2 Pd complex that is the active catalyst in the Hirao reaction. The new variation of the Hirao reaction is of a more general value, and represents the greenest protocol, as there is no need for the usual P-ligands. Instead, the >P(O)H reagent should be used in an excess of up to 30%. Hence, the costs and environmental burdens may be decreased.

The industrially relevant reaction between nitriles and hydroxylamine yielding amidoximes was studied in different molecular solvents and in ionic liquids. In industry, this procedure is carried out on the ton scale in alcohol solutions and the above transformation produces a significant amount of unexpected amide by-product, depending on the nature of the nitrile, which can cause further analytical and purification issues. Although there were earlier attempts to propose mechanisms for this transformation, the real reaction pathway is still under discussion. A new detailed reaction mechanistic explanation, based on theoretical and experimental proof, is given to augment the former mechanisms, which allowed us to find a more efficient, side-product free procedure. Interpreting the theoretical results obtained, it was shown that the application of specific imidazolium, phosphonium and quaternary ammonium based ionic liquids could decrease simultaneously the reaction time while eliminating the amide side-product, leading to the targeted product selectively. This robust and economic procedure now affords a fast, selective amide free synthesis of amidoximes.

Penicillin, travels through bodily fluids, targeting and acylatively inactivating enzymes responsible for cell-wall synthesis in gram-positive bacteria. Somehow, it avoids metabolic degradation remaining inactive en route. To resolve this ability to switch from a non-active, to a highly reactive form, we investigated the dynamic structure-activity relationship of penicillin by inelastic neutron spectroscopy, reaction kinetics, NMR and multi-scale theoretical modelling (QM/MM and post-HF ab initio). Results show that by a self-activating physiological pH-dependent two-step proton-mediated process, penicillin changes geometry to activate its irreversibly reactive acylation, facilitated by systemic intramolecular energy management and cooperative vibrations. This dynamic mechanism is confirmed by the first ever reported characterisation of an antibiotic by neutrons, achieved on the TOSCA instrument (ISIS facility, RAL, UK).

The routine prediction of the reactivity of a complex, multifunctional molecule is a challenging and time-consuming procedure. In the last step of the synthesis of the well-known drug substance tenidap, a nonexpected difference was observed between the reactivities of two closely related carbamate moieties, the N-ethoxycarbonyl and the N-phenoxycarbonyl group. A detailed kinetic study, necessitating a significant computational effort, is described in the present paper for this reaction step. On the other hand, the systems chemistry concept, by analyzing the details of the electronic structure and the connections between functional groups in a fast and simple way, is also able to answer this question using various "-icity" parameters (aromaticity, carbonylicity, olefinicity). The complete systems chemistry approach involves all these conjugativicity parameters, while its further simplified version is based on only one key parameter, which is carbonylicity in the present case. The above methods were compared in terms of their predictive power. The results show that the systems chemistry concept, even its one-parameter version, is applicable for the characterization of this challenging reactivity issue.

It is well-known that phosphinic acids do not undergo direct esterifications with alcohols under thermal conditions. However, the esterifications take place under microwave (MW) irradiation due to the beneficial effect of MW. As a comparison, maximum 12-15% conversions were observed on traditional heating. It was proved experimentally that the MW-assisted esterifications are not reversible under the conditions applied that may be the consequence of the hydrophobic medium established by the long chain alcohol/phosphinic ester. Neither the thermodynamic, nor the kinetic data obtained by high level quantum chemical calculations justify the direct esterification of phosphinic acids under thermal conditions. The thermodynamic data show that there is no driving force for the reactions under discussion. As a consequence of the relatively high values of activation enthalpy (102-161 kJ mol(-1)), these esterifications are controlled kinetically. Comparing the energetics of the esterification of phosphinic acids and the preparative results obtained under MW conditions, one can see the potential of the MW technique in the synthesis of phosphinates. During our study, a series of new cyclic phosphinates with lipophilic alkyl groups was synthesized.

The palladium-catalyzed Suzuki-Miyaura cross-coupling reactions of halo derivatives of 4H-pyrido[1,2-a]pyrimidin-4-one with (het)arylboronic acids allow easy access to (het)aryl and vinyl derivatives of this bicycle in good to excellent yields, even from chloro derivatives. The sequence of reactivity of the halogen in the different positions of the ring system was also investigated. 6-Phenyl-4H-pyrido[1,2-a]pyrimidin-4-one could be prepared by thermal cyclization of isopropylidene (6-phenylpyrid-2-ylamino)methylenemalonate, together with a small amount of 7-phenyl-1,4-dihydro-1,8-naphthyridin-4-one.

Thermal ring transformation ability of unsaturated N-bridgehead fused pyrimidin-4(3H)-ones A is governed by both the steric and the electrostatic interactions between the oxygen of the carbonyl group and the substituent in the peri position.

First principle quantum molecular computations have been carried out at the B3LYP/6-31G(d,p) and G3MP2B3 levels of theory on ethyl mercaptan and diethyl disulfide to study their full conformational space. The consequences of molecular axis chirality for the potential energy hypersurface of diethyl disulfide was fully explored. Thermodynamic functions (U, H, S, and G) have been computed for every conformer of the products as well as the reactants of the redox systems studied. Relative values of the thermodynamic functions were calculated with respect to the reference structures with anti orientation. The energetics of the following Red-Ox reactions Et-SH+HO-OH+HS-Et --> 2H2O+Et-S-S-Et Et-SH+HO-OCOO(-)+HS-Et --> H2O+Et-S-S-Et+HCO3- have been chosen to mimic the biologically important Red-Ox reactions of glutathione G-SH+H2O2+HS-G --> 2H2O+G-S-S-G G-SH+HCO4-+HS-G --> H2O+G-S-S-G+HCO3-. The Red-Ox reaction of Et-SH --> Et-S-S-Et was found to be exothermic by first principle molecular computations and the intramolecular interactions, such as the unusual C-H...H-C noncovalent bondings were studied by Bader's atoms in molecules analysis of the electron density topology. The present paper focuses attention on the thermodynamic aspect of the redox reaction of glutathione. It has been noted previously that on going from a cancerous to a healthy cell, the entropy change is negative, corresponding to information accumulation. Likewise, the dissociation of peptide parallel beta-sheets, that dominate the plaques in Alzheimer's Disease, governs negative entropy change. It may be interesting to note, according to the results obtained in the present paper, a negative entropy change, corresponding to information accumulation.

A novel concept and, therefore, a novel discipline is defined, wherein molecules are described as frameworks of strategically located functional components within molecular structures, acting in unison to effect efficient energy management. The term "systems chemistry" effectively serves to define the phenomenon of an assembly of atoms and functional groups within a molecule having systemic properties "valued" at more than their component sum. The reduction of NAD+ and FAD is complimented by an enthalpy transfer between organic functional components (aromatic ring, amide and olefinic functionalities), yet the sum of the overall energy values (the total system) remains nearly constant, irrespective of which direction the redox reaction proceeds. From this aspect, both NAD+ and FAD operate as real chemical systems of atoms and functional groups, working together within the individual molecules to store the reaction enthalpy as resonance enthalpy, rather than manifesting it as emitted or absorbed heat. In this way, the thermoneutral reaction of the wet combustion occurring in all living cells is made possible by an internal "cooling process".

The olefinic functional group is among the most important chemical building blocks, also playing an important role in organic and bioorganic reactions. The exact description and precise quantification of the degree of the olefinic conjugation in substituted alkenes is not trivial. The present work suggests a novel, yet simple, method toward quantifying the conjugation in a general olefin group (e.g., alkenes) on a linear scale, defined as the "olefinicity scale", achieved using the computed enthalpy of hydrogenation (DeltaH(H2)) of the compound examined. In the present conceptual work, the DeltaH(H2) value for allyl anion is used to define perfect conjugated character (olefinicity = +100%), while ethene represents complete absence of conjugation (olefinicity = 0%). The component DeltaH(H2) values were computed at different levels of theory, providing a near-"method-independent" measure of olefinicity. A total of 67 well-known olefinic compounds were examined to demonstrate the practicality of this protocol. For the compounds examined, a correlation has been made between the computed olefinicity percentage values and their associated proton affinities, as well as their reactivity values in a nucleophilic addition reaction; selected chemical reactions were also studied.

Highly diastereoselective Lewis acid induced intramolecular 1,3-dipolar cycloadditions of alkenyl phenylhydrazones (containing various substituents on the aromatic ring) obtained from a d-secopregnene aldehyde were carried out under fairly mild conditions to furnish androst-5-ene-fused arylpyrazolines in good to excellent yields. The ability of phenylhydrazones to undergo cyclization was found to be affected significantly by the electronic features of the substituents on the aromatic moiety. The rates of the ring-closure reactions were observed to be increased by electron-donating and decreased by electron-withdrawing groups. The experimental findings on the BF(3)-catalyzed transformations were supported by calculations of the proposed mechanism at the BLYP/6-31G(d) level of theory, indicating a noteworthy dependence, mainly of the initial complexation step, and hence of the whole process, on the character of the substituent. The cycloaddition was estimated to occur via a zwitterionic intermediate rather than involving a pure concerted mechanism. The antiproliferative activities of the structurally related pyrazoline derivatives were tested in vitro on three malignant human cell lines (HeLa, MCF7, and A431): the microculture tetrazolium assay revealed that several compounds exerted marked cell growth-inhibitory effects. The highest cytotoxic activities, displayed by the p-methoxyphenylpyrazoline derivative 7d (IC(50) values: 2.01, 2.16, and 1.41 microM on HeLa, MCF7, and A341 cells, respectively), were better than those of cisplatin (IC(50) values: 12.43, 9.63, and 2.84 microM, respectively).

This paper reports the structural and thermodynamic consequences of substitution of the OH group by the isoelectronic F-atom in the case of the adrenaline family of molecules. The conformational landscapes were explored for the two enantiomeric forms of N-protonated-beta-fluoro-beta-phenyl-ethylamine, also called (2-fluoro-2-phenyl-1-ethyl)-ammonium ion (Model 1) and that of N-protonated-beta-hydroxy-beta-phenyl-ethylamine, also referred to as (2-hydroxy-2-phenyl-1-ethyl)-ammonium (Model 2) models of noradrenaline and adrenaline molecules. These full conformational studies were carried out by first principles of quantum mechanical computations at the B3LYP/6-31G(d,p) and G3MP2B3 levels of theory, using the Gaussian03 program. Also, frequency calculations of the stable structures were performed at the B3LYP/6-31G(d,p), and G3MP2B3 levels of theory. The thermodynamic functions (U, H, S, and G) of the various stable conformations of the title compounds were calculated at these levels of theory for the R and S stereoisomers. Relative values of the thermodynamic functions have been calculated with respect of the chosen reference conformers in which all relevant dihedral angles assumed anti orientation for the Model 1 and Model 2. Through the combination of both point and axis chirality, the enantiomeric and diastereomeric relationships of the six structures for each molecule investigated were established. Intramolecular hydrogen bonding interactions have been studied by the atoms in molecules (AIM) analysis of the electron density. The aromaticity of phenyl group has been determined by a selective hydrogenation protocol. The pattern of the extent of aromacity, due intramolecular interactions, varies very little between the two models studied.

Despite the carbonyl group being one of the most pervasive chemical building blocks in natural, synthetic, and industrial processes, its exact description in terms of precise quantification of the degree of carbonyl conjugation has yet to be determined. The present work suggests a novel yet simple method for quantifying the conjugation in general carbonyl groups (such as ketones, aldehydes, carboxylic acids and their respective halogenides, amides, etc.) on a linear scale, defined as the "carbonylicity scale". This was achieved by use of the computed enthalpy of hydrogenation (DeltaH(H2)) of the > C=O group in the compounds examined. In the present conceptual work, the DeltaH(H2) value for formate ion is used to define complete conjugated character (carbonylicity = +100%), while formaldehyde represents complete absence of conjugation (carbonylicity = 0%). The component DeltaH(H2) values were computed at differing levels of theory, providing a nearly "method-independent" measure of carbonylicity computationally. A total of 49 common carbonyl compounds were used as accuracy scoring criteria of the methodology. For the compounds examined, correlations have been made between the computed carbonylicity percentage and the > C=O proton affinities, IR frequencies, and their reactivity values in a nucleophilic addition reaction. Selected chemical reactions were also studied to illustrate the utility of carbonylicity scale. Examples herein include demonstrating that change in the carbonylicity value represents a thermodynamic driving force in acylation reactions. The definition was extended to substituted thiocarbonyl and imino compounds.

Although essential in medicinal and industrial chemistry, transamidation reactions are still poorly understood mechanistically and in particular in terms of the extreme nature for their proceeding either very smoothly or not occurring at all. As yet, there exists no qualitative rule to predict the outcome of an amide interacting with an amine, with quantitative evaluations far from being established. In this paper we aim to clarify the thermodynamic selection rule and driving force of transamidation reactions based on amidicity value, measuring numerically the amide bond strength, toward providing a relatively simple protocol for practicing organic chemists to predict the outcome of an experiment. The change of amidicity over the course of a reaction made it possible to see that the process is favorable or unfavorable. This recently evaluated driving force of amidicity behaves analogously to the driving force of aromaticity in other organic reactions. This paper presents a successful comparison between empirical synthetic results and relevant computational characterizations, for a variety of transamidation reactions, all toward a synergy between experiments and theory. In this paper, we are re-examining experimentally and theoretically earlier experimental findings in relation to transamidation reactions and interpreting them from the aspect of amidicity change and stabilization enthalpies.

The amide bond may be considered as one of the most important chemical building blocks, playing an important role not only in living organisms but in organic chemistry as well. The exact description and precise quantification of the amide bond strength is difficult, requiring a particular type of theoretical investigation. The present paper suggests a novel, yet simple, method toward quantifying amide bond strength on a linear scale, defined as the "amidity scale". This is achieved using the computed enthalpy of hydrogenation (DeltaHH2) of the compound examined. In the present conceptual work, the DeltaHH2 value for dimethylacetamide is used to define perfect amidic character (amidity=+100%), while azaadamantane-2-on represents complete absence of amidic character (amidity=0%). The component DeltaHH2 values were computed at differing levels of theory, providing a computational and quasi-"method-independent" measure of amidity. A total of 29 well-known amides were examined to demonstrate the "scoring" accuracy of this methodology. For the compounds examined, a correlation has been made between the computed amidity percentage and their common COSNAR resonance energy values, proton affinities, and reactivity in a nucleophilic addition reaction. Selected chemical reactions were also studied. It has been shown that the change of the amidity value, during acyl transfer reactions, represents a thermodynamic driving force for the reaction.

16Beta-aminomethyl-17beta-hydroxyestrone 3-methyl ether 6 and its N-propyl (17), N-benzyl (18) and N-arylmethyl derivatives (19-22) were subjected to ring closure reactions with phenylphosphonic dichloride in order to synthetize P-epimeric oxazaphosphorinanes 23a, 24-29 in which the hetero ring is condensed to ring D of the sterane skeleton. The stereostructures of the products were evaluated by 1H, 13C and 31P NMR spectroscopy. The geometry was optimized by utilizing the B3LYP DFT method. The NMR spectral data and the results of the ab initio calculations demonstrated that the stereostructure of the hetero ring was strongly affected by the rigid sterane framework condensed to it, and the phosphoramidate ring proved to adopt predominantly a distorted-boat conformation, regardless of the P-configuration.