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This work reports on new software for automatic conformer energy benchmarking calculations for flexible molecules. The software workflow consists of four parts: conformational search, preoptimization, optimization, and frequency calculations at a higher level and last calculations using several theoretical levels. The software was written to be user-friendly and versatile to be used by nonexperts in computational chemistry. Any theoretical levels available in either Gaussian 16 or ORCA 5 may be applied in the benchmarking study. The workflow will automatically run conformational search calculations and deal with conformers that converge to the same minimum and those that show a negative frequency. At the end of the workflow, the user will have the mean absolute deviations and the most accurate method/DFT functional and basis set in comparison to the benchmark to be applied for the molecular system of interest. Case examples are given at the end of the paper that may help users to get insight into the software's main features.
Assuntos
Benchmarking , Software , Conformação Molecular , Automação , Elétrons , Modelos MolecularesRESUMO
Theoretical decomposition of "through space" spin-spin coupling constants (SSCCs) in organofluorine compounds signal that intramolecular hydrogen bonds (H-bonds) are not the primary mechanism of transmission for SSCCs. Increasing solvent polarity may disrupt H-bonds, but not necessarily the JFH SSCC. Substituent effects may drastically alter the SSCC transmission pathway. Accurate SSCC analysis requires benchmarking theoretical calculations to support experimental data interpretation.
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Indolizines and their saturated derivatives are important structural motifs present in several biologically active compounds of both natural and synthetic origin. We describe herein a one-pot approach for the synthesis of tricyclic indolizines catalyzed by a bicyclic imidazole-alcohol. The protocol is based on an aqueous Morita-Baylis-Hillman reaction between pyridine-2-carboxaldehydes and six- or seven-membered cyclic enones, followed by sequential intramolecular cyclization and dehydration. So, in a single operational step two new bonds (C-C and C-N) are formed in an organocatalyzed process that takes place in simple conditions (stirring in water at 60 °C for 12 h) and with great atom economy (water as the sole byproduct), affording the purified compounds in yields ranging from 19 to 70%. The facility of the cyclization strongly depends on the size of the cycloalkenone ring: while MBH adducts derived from six-, seven- or eight-membered cycloenones are readily transformed into the corresponding indolizines, cyclopentenone-derived MBH adducts do not cyclize. A competition experiment revealed that cycloheptenone-derived MBH adducts cyclize faster than cyclohexenone-derived adducts. Model DFT calculations have been performed to rationalize these reactivity trends.
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The importance of electrostatic nonconventional hydrogen bonds (NCHBs) to the pseudo-anomeric effect of 4-substituted methoxycyclohexanes is evaluated using theory [natural bond orbital (NBO)] to deconvolute electrostatic from other contributing effects. There is an interesting interplay between σCH â σCX* hyperconjugation and the electropositive charge on 3,5-axial hydrogens (Hax). In essence, better σCX* (or πCO*) acceptors increase the charge on 3,5-CHax, which in turn strengthens Cδ+Hax···Î´-OMe NCHB interactions.
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The anti-tyrosinase activity of the leaf extract of Schinus terebinthifolius, also known as Brazilian peppertree, was evaluated using multiple inâ silico approaches, such as molecular homology, molecular docking, MM-GBSA, molecular dynamics, MM-PBSA, QSAR, and skin permeability predictions. With these computational tools, the compounds that downregulate tyrosinase enzyme activity could be evaluated, and more potent molecules could be identified. The results indicated that various compounds, especially luteolin, are accountable for the anti-tyrosinase activity of S.â terebinthifolius. For cosmetic application, further studies with luteolin are especially recommended, for having presented a good performance both in theoretical inhibition (30.92â kJ mol-1 ) and skin permeability (LogKp=-6.62â cm-1 ).
Assuntos
Anacardiaceae , Humanos , Luteolina , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase , Extratos Vegetais/farmacologiaRESUMO
Voltage-gated calcium (Cav) channels malfunction may lead to Alzheimer's and cardiovascular disorders, thus a critical protein target for drug development and treatment against several diseases. Indeed, dihydropyridines (DHPs) as nifedipine and amlodipine are top-selling pharmaceuticals and, respectively, the 121st and 5th most prescribed drugs in the United States that have been used as successful selective blockers for L-type Ca2+ channels (LCC) and may be helpful model structures to compare with new DHP analogs. In this context, we have performed a structure-based drug design (SBDD) study of several fluorinated DHPs by using homology modeling, molecular docking, quantitative structure activity relationship (QSAR) and molecular dynamics calculations. Such approaches combined with molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) interaction energy results and screening of ADMET (absorption, distribution, metabolism, excretion and toxicity) properties indicate that all ligands in this study are potential new candidates to be tested experimentally for inhibition of LCC and may have higher affinities than the commonly used drugs, being convenient synthetic routes proposed for 11-16, which are among the ligands that showed the best theoretical results concerning LCC inhibition. Furthermore, the ligand interactions with the binding site were carefully examined using the topological noncovalent interactions (NCI) method, which highlighted specifically responsible amino acid residues that increase the spontaneity of the new proposed DHP ligands.Communicated by Ramaswamy H. Sarma.
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Di-Hidropiridinas , Di-Hidropiridinas/química , Canais de Cálcio Tipo L/química , Canais de Cálcio Tipo L/metabolismo , Simulação de Acoplamento Molecular , Nifedipino , Sítios de Ligação , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/metabolismo , Cálcio/metabolismoRESUMO
In this work the DBL3x domain of the erythrocyte membrane protein from Plasmodium Falciparum (PfEMP1), was revisited as a potential molecular target for the development of new drugs against malaria. This protein interacts with chondroitin sulfate A (CSA), a glycosaminoglycan present in the substance fundamental for connective tissues of vertebrates and is implicated in malaria complications in pregnant women. We performed molecular docking and molecular dynamic studies of DBL3x complexed with CSA and five analogues, where the sulfate group was replaced by phosphate, in order to evaluate if the better electrostatic interactions provided by phosphate groups could afford better binders capable of preventing the binding of CSA to DBL3x. Results suggest that all proposed compounds have high affinity towards DBL3x and could bind better to the DBL3x domain of PfEMP1 than CSA, qualifying as potential inhibitors of this protein and, therefore, new potential leads for the drug design against malaria.Communicated by Ramaswamy H. Sarma.
Assuntos
Malária Falciparum , Malária , Complicações Parasitárias na Gravidez , Animais , Antígenos de Protozoários/química , Sulfatos de Condroitina/química , Sulfatos de Condroitina/metabolismo , Sulfatos de Condroitina/farmacologia , Eritrócitos/metabolismo , Feminino , Glicosaminoglicanos/metabolismo , Humanos , Malária/complicações , Malária/metabolismo , Malária Falciparum/tratamento farmacológico , Proteínas de Membrana/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fosfatos , Placenta/metabolismo , Plasmodium falciparum/química , Gravidez , Complicações Parasitárias na Gravidez/metabolismo , Proteínas de Protozoários/química , Sulfatos/metabolismoRESUMO
The origin of the fluorine gauche effect has been debated for decades and recently different interpretations have been raised in the scientific community as new computational methods emerged and were applied to rationalize 1,2-difluoroethane (DFE) gauche preference. In this context, we revisited 1,2-difluoroethane (DFE) and its chlorine and bromine derivative conformational preferences through a comparative approach: the conformational behavior and hyperconjugative, steric and electrostatic contributions for the internal rotational barrier of DFE were compared with several analogue backbones, such as peroxides, disulfides and ammonia boranes. By using the Natural Bond Orbital (NBO) analysis it was found that hyperconjugation is the driving force of the conformational preference in DFE and its chlorine and bromine analogues. Electrostatics was found to be negligible and steric effects played a minor role in general, but are important in ClCH2CH2Cl and BrCH2CH2Br to counterbalance gauche stabilization by hyperconjugation and for the preference of the anti conformer.
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In this theory study we demonstrate the dominance of non-classical 1,3-diaxial CHaxOC hydrogen bonds (NCHBs) dictating a 'pseudo' anomeric effect in selectively fluorinated methoxycyclohexanes and also influencing the axial preference in the classical anomeric exhibitor 2-methoxytetrahydropyran, a phenomenon which is most often described as a consequence of hyperconjugation. Analogues of methoxycyclohexane where ring CH2's are replaced by CF2 can switch to an axial preference and theory methods (NBO, QTAIM, NCI) indicate the dominance of 1,3-CHaxOMe interactions over hyperconjugation. For 2-methoxytetrahydropyran, it is revealed that the global contribution to the anomeric effect is from electrostatic interactions including NCHBs, not hyperconjugation, although hyperconjugation (nOâσ*CO or nOâσ*CC) remains the main contributor to the exo-anomeric phenomenon. When two and three ether oxygens are introduced into the ring, then both the NCHB interactions and hyperconjugative contributions become weaker, not stronger as might have been anticipated, and the equatorial anomers progressively dominate.
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Given its importance and the possibility of organic F to participate in hydrogen bonds (H-bonds), the understanding of its behavior as a H-bond acceptor with different donors is crucial. The interest in organofluorine compounds and the works related to the study of the participation of this atom in non-covalent interactions is constantly growing. Following recent studies in this subject, we evaluated the existence of two bifurcated intramolecular interactions, a bifurcated CFHS H-bond in the cis conformer of 2-trifluoromethylthiophenol and an unusual, bifurcated CFSH interaction in the trans conformer. The JFH spin-spin coupling constant (SSCC) was evaluated for 2-trifluoromethylthiophenol both experimentally by 1H and 19F NMR and theoretically using the natural bond orbitals (NBO), the quantum theory of atoms in molecules (QTAIM) and the non-covalent interactions (NCI) framework. Although both interactions are crucial for the stabilization of the conformer geometries, the observed positive JFH spin-spin coupling constant (SSCC) is mainly resultant from the trans conformer, which has a large calculated positive SSCC, and is transmitted through steric interactions involving the F lone pairs and the σSH bonding orbital.
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Depending on the catalyst used, N-methylation of indole with dimethylcarbonate (DMC)-an environmentally friendly alkylation agent-yields different products. With 1,4-diazabicyclo[2.2.2]octane (DABCO), the reaction forms only N-methylated indole, but with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), both N-methylated and N-methoxycarbonylated indole are formed. Using direct ESI(+)-MS monitoring to collect actual snapshots of the changing ionic composition of the reaction solution, we report on the interception and characterization of key intermediates for such reactions. Although a mechanism has been proposed with methoxycarbonylated base as the key intermediate for both DBU and DABCO, the ESI(+)-MS data and B3LYP-D3/6-311+G** calculations suggest that the reaction of DMC with indole under either DABCO or DBU catalysis follows contrasting mechanisms.
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Steric, electrostatic and hyperconjugative effects were evaluated in the natural bond orbital framework as candidate sources of the preferred geometry of hydroperoxides. Stabilising 1,2-δ+H-δ-O electrostatic interactions and nO â σ*OR hyperconjugative interactions were found to be the driving force for the preferred anticlinal or perpendicular geometries, respectively. There is an interesting interplay between these two effects: when one increases, the other decreases. On the other hand, steric effects showed negligible contributions to the conformational behaviour of the studied molecules. Also, HO-OR bond dissociation energy appeared to be dependent on ROË radical stability, which is governed by hyperconjugation.
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In this work, the stereoselective heterogeneous hydrogenation of a tetrasubstituted indolizine was studied. Partial hydrogenation products were obtained in three steps from a substituted pyridine-2-carboxaldehyde prepared from commercial pyridoxine hydrochloride. The hydrogenation of the indolizine ring was shown to be diastereoselective, forming trans-6b and cis-9. Theoretical calculations (ab initio and DFT) were used to rationalize the unusual trans stereoselectivity for 6b, and a keto-enol tautomerism under kinetic control has been proposed as the source of diastereoselectivity.
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We report counter-intuitive axial preferences in non-stereochemically biased, selectively fluorinated methoxycyclohexanes. These pseudo-anomeric effects are apparent when electronegative CF2 groups are placed at the C-2, C-4 and C-6 positions of the cyclohexane ring to render the C-3/5 axial hydrogen atoms electropositive. The electrostatic interaction between these axial hydrogen atoms and the -OMe oxygen is stabilising. The effect is explored using high-level ab initio and DFT calculations in the framework of NBO, QTAIM and NCI analysis across a range of derivatives, and experimentally (19 F{1 H}-NMR at -80 °C) for some illustrative examples. The effect is significant in energy terms for a weak interaction, and illustrates a new stereoelectronic aspect attributed to selective fluorine substitution in organic chemistry.
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A visible-light-promoted photochemical protocol is reported for the coupling of aryldiazoacetates with boronic acids. This photochemical reaction shows great enhancement compared to the same protocol performed in the absence of light. Except for a few cases, the room temperature coupling in the dark (thermal process) generally does not work. When it does, it is likely to also involve free carbenes as key intermediates. Alternatively, photochemical reactions show a broad scope, can be performed under air and tolerate a wide variety of functional groups. Reaction-evolution monitoring, DFT calculations and control experiments have been used to evaluate the main aspects of this intricate mechanistic scenario. Biologically active molecules Adiphenine, Benactyzine and Aprophen have been prepared as examples of synthetic applications.
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The intramolecular CF···HX (X = O or S) H-bond and JFH spin-spin coupling constants (SSCCs) in 2-fluorophenol and 2-fluorothiophenol were investigated experimentally by 1H and 19F NMR and theoretically in the framework of the natural bond orbital analysis. In contrast with recent findings from the literature, the results obtained in this work showed that an intramolecular H-bond is formed in the cis conformers and that it has an electrostatic origin. Such an intramolecular electrostatic H-bond is the interaction that rules the conformational preferences on these compounds. Moreover, the natural J-coupling analysis indicated that the JHF SSCC in 2-fluorophenol has its origin on LP(F)/σOH steric interactions and should be labeled as 4TSJHF. On the other hand, the analogue SSCC for 2-fluorothiophenol has its origin on the intramolecular H-bond LP(F) â σSH* hyperconjugative interaction and should be described as a 1hJFH SSCC.
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The active species of the Ishikawa´s reagent [N,N-diethyl-(1,1,2,3,3,3-hexafluoropropyl)amine] is a fluorinating hexafluoropropylamine used to convert alcohols into alkyl fluorides. On the other hand, it is also an example of model compound useful to probe conformational preferences using spectroscopic information from diastereotopic fluorines. Moreover, the possibility of experiencing both the generalized anomeric and gauche effects makes the Ishikawa´s reagent an ideal choice to study the governing stereoelectronic interactions of the conformational equilibrium of organofluorine compounds. The conformational equilibrium of the Ishikawa´s reagent was analyzed using NMR 3 J H,F coupling constant data in different solvents, since the orientation of the diastereotopic fluorines relative to H-2 and F-2 changes with the medium. In nonpolar cyclohexane solvent, the preferred conformation experiences a weaker steric and electrostatic repulsion. The conformational behavior changes in the more polar pyridine solution, where the double fluorine gauche effect takes place, since F-2 is preferably gauche to both diastereotopic fluorines. An analysis of the rotation around the N-C(F2) bond indicates the manifestation of anomeric interactions (n N â σ*C-F), which can be demonstrated by means of 19F chemical shifts. The results were rationalized with the aid of theoretical calculations and natural bond orbital (NBO) analysis, allowing for the evaluation of competing steric, electrostatic and hyperconjugative interactions.
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An earlier study demonstrated that hyperconjugation operates in hydrazides by analyzing the N-H stretching mode in gas phase infrared (IR) spectroscopy, and then observing two very distinct bands corresponding to isolated isomers experiencing or not the nN â σ*N-H electron delocalization. The present work reports a chemical method to obtain insight on the hyperconjugation in hydrazide derivatives from solution IR spectroscopy. The analogous amides did not show a νN-H red-shifted band, as the electron donor orbital in the above hyperconjugative interaction does not exist. In addition, the effect of electron withdrawing groups bonded to a nitrogen atom, namely the trifluoroacetyl and the methanesulfonyl groups, was analyzed on the conformational isomerism and on the ability to induce a stronger hyperconjugation in the resulting compounds.
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Hyperconjugative, steric, and electrostatic effects were evaluated as possible sources of the helicity in linear perfluorinated alkanes through analysis of natural bond orbitals and classical electrostatics. Contrary to previous rationalizations, which indicate dominating steric or electrostatic effects, this analysis indicates that hyperconjugative stabilization through σCC âσ*CF interactions are the underlying driving force for the origin of the observed helicity in perfluoroalkanes.
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The conformational behaviour of Ac-Ala-NHMe was studied in the gas-phase and in solution by theoretical calculations (B3LYP-D3/aug-cc-pVDZ level) and experimental (1)H NMR. The conformational preferences of this compound were shown to result from a complex interplay between the strengths of possible intramolecular hydrogen bonds, steric interactions, hyperconjugation, entropy effects and the overall dipole moments. The Ac-Ala-N(Me)2 derivative was studied in addition, to design a system akin to Ac-Ala-NHMe, but with disrupted intramolecular hydrogen bonds involving the -NHMe group, mimicking the effect of polar protic solvents.