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1.
J Am Chem Soc ; 146(5): 3052-3064, 2024 02 07.
Artículo en Inglés | MEDLINE | ID: mdl-38279916

RESUMEN

Fluorine NMR is a highly sensitive technique for delineating the conformational states of biomolecules and has shown great utility in drug screening and in understanding protein function. Current fluorinated protein tags leverage the intrinsic chemical shift sensitivity of the 19F nucleus to detect subtle changes in protein conformation and topology. This chemical shift sensitivity can be amplified by embedding the fluorine or trifluoromethyl reporter within a pyridone. Due to their polarizability and rapid tautomerization, pyridones exhibit a greater range of electron delocalization and correspondingly greater 19F NMR chemical shift dispersion. To assess the chemical shift sensitivity of these tautomeric probes to the local environment, 19F NMR spectra of all possible monofluorinated and trifluoromethyl-tagged versions of 2-pyridone were recorded in methanol/water mixtures ranging from 100% methanol to 100% water. 4-Fluoro-2-pyridone and 6-(trifluoromethyl)-2-pyridone (6-TFP) displayed the greatest sensitivity of the monofluorinated and trifluoromethylated pyridones, exceeding that of known conventional CF3 reporters. To evaluate the utility of tautomeric pyridone tags for 19F NMR of biomolecules, the alpha subunit of the stimulatory G protein (Gsα) and human serum albumin (HSA) were each labeled with a thiol-reactive derivative of 6-TFP and the spectra were recorded as a function of various adjuvants and drugs. The tautomeric tag outperformed the conventional tag, 2-bromo-N-(4-(trifluoromethyl)phenyl)acetamide through the improved resolution of several functional states.


Asunto(s)
Flúor , Metanol , Humanos , Flúor/química , Espectroscopía de Resonancia Magnética/métodos , Conformación Proteica , Agua , Piridonas
2.
Phytochem Anal ; 33(2): 226-238, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-34363263

RESUMEN

INTRODUCTION: Praxelis genus comprises 24 species, however, only two species of this genus have been chemically investigated. Here we investigated Praxelis sanctopaulensis, a native plant from Brazil, that occurs mainly in Cerrado regions. OBJECTIVE: The goal was to identify the specialised metabolites from P. sanctopaulensis, and compare with those described from Praxelis and Chromolaena species. METHODS: The phytochemical study of P. sanctopaulensis was performed through different chromatography techniques, including high-performance liquid chromatography (HPLC), gas chromatography flame ionisation detector (GC-FID), and ultra-high-performance liquid chromatography high-resolution tandem mass spectrometry (UHPLC-HRMS/MS). The structures of the compounds were established based on spectroscopic analysis, total correlated spectroscopy (TOCSY), hydrogen decoupling and computational calculations was used to an unequivocal structural elucidation of a new sesquiterpene. The antioxidant activity was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP), and antimicrobial assay was performed by the microdilution method. Comparison of the flavonoids described P. sanctopaulensis was carried out using principal component analysis. RESULTS: The phytochemical investigation of P. sanctopaulensis led to the isolation of a pair of diastereomers, praxilone A and praxilone B. Seven known compounds were isolated from this species, another 14 fatty acids were detected in hexane fraction, and 26 compounds were identified from ethyl acetate fraction. All these compounds are being described for the first time in this species, with the exception of viridifloric acid. The ethyl acetate fraction showed potent antioxidant activity. CONCLUSIONS: Forty-seven compounds are described from P. sanctopaulensis. The combination of different techniques of nuclear magnetic resonance (NMR) spectroscopy and computational calculations allowed the unequivocal structure elucidation of a new cadinene. The clustering analysis showed similarities between the flavonoids identified in P. sanctopaulensis and in Chromolaena species.


Asunto(s)
Asteraceae , Sesquiterpenos , Antioxidantes/química , Antioxidantes/farmacología , Cromatografía Líquida de Alta Presión , Cromatografía de Gases y Espectrometría de Masas , Hidrógeno , Espectroscopía de Resonancia Magnética , Extractos Vegetales/química
3.
Bioorg Med Chem ; 32: 115991, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33440318

RESUMEN

A novel series of arylcarbamate-N-acylhydrazones derivatives have been designed and synthesized as potential anti-cholinesterase agents. In vitro studies revealed that these compounds demonstrated selective for butyrylcholinesterase (BuChE) with potent inhibitory activity. The compounds 10a-d, 12b and 12d were the most potent BuChE inhibitors with IC50 values of 0.07-2.07 µM, highlighting the compound 10c (IC50 = 0.07 µM) which showed inhibitory activity 50 times greater than the reference drug donepezil (IC50 = 3.54 µM). The activity data indicates that the position of the carbamate group in the aromatic ring has a greater influence on the inhibitory activity of the derivatives. The enzyme kinetics studies indicate that the compound 10c has a non-competitive inhibition against BuChE with Ki value of 0.097 mM. Molecular modeling studies corroborated the in vitro inhibitory mode of interaction and show that compound 10c is stabilized into hBuChE by strong hydrogen bond interaction with Tyr128, π-π stacking interaction with Trp82 and CH⋯O interactions with His438, Gly121 and Glu197. Based on these data, compound10cwas identified as low-cost promising candidate for a drug prototype for AD treatment.


Asunto(s)
Carbamatos/farmacología , Inhibidores de la Colinesterasa/farmacología , Diseño de Fármacos , Hidrazonas/farmacología , Acetilcolinesterasa/metabolismo , Animales , Butirilcolinesterasa/metabolismo , Carbamatos/síntesis química , Carbamatos/química , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Electrophorus , Caballos , Hidrazonas/síntesis química , Hidrazonas/química , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad
4.
Bioorg Med Chem Lett ; 30(14): 127244, 2020 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-32527546

RESUMEN

Paracoccidioidomycosis is an endemic mycosis in Latin America for which there is a high mortality rate and limited treatment options. There are no specific drugs to treat the systemic disease. Thus, there is a need for further studies focused on the development of specific drugs. In this work we synthesized new hybrids pyrimido[4,5-d]pyridazinone-N-acylhydrazone (5a-p) by simple methodologies with good yields. The antifungal activity of compounds was evaluated against P. brasiliensis (Pb18) and Candida spp. Compounds 5a, 5f, 5i, 5 k, 5m and 5n showed significant inhibition against Pb18 with MIC of 0.125 to 64 µg mL-1. Compound 5a is the most promising, showing potent fungicidal profile with MFC of 0.5 µg mL-1, synergic effect with amphotericin B, besides showing no toxicity against HeLa and Vero cells.


Asunto(s)
Antifúngicos/farmacología , Candida/efectos de los fármacos , Hidrazonas/farmacología , Paracoccidioides/efectos de los fármacos , Piridazinas/farmacología , Animales , Antifúngicos/síntesis química , Antifúngicos/química , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Células HeLa , Humanos , Hidrazonas/síntesis química , Hidrazonas/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Piridazinas/síntesis química , Piridazinas/química , Relación Estructura-Actividad , Células Vero
5.
Org Lett ; 21(16): 6325-6328, 2019 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-31353911

RESUMEN

An efficient one-pot method is described for the highly regioselective synthesis of α-ketoamide N-arylpyrazoles from secondary ß-enamino diketones. For this, the key intermediate, 4-acyl 3,5-dihydroxypyrrolone, was generated in situ and underwent bimolecular nucleophilic substitution at C-5 by arylhydrazine, with subsequent heterocyclization at the carbonyl carbon of the acyl group. This strategy allowed for regiochemical control of α-ketoamide N-arylpyrazoles from ß-enamino diketones and arylhydrazines.

6.
Future Microbiol ; 14: 587-598, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31148472

RESUMEN

Aim: 17 new 4-methoxynaphthalene-N-acylhydrazones were synthesized in order to evaluate their biological action against important pathogens. Methods: In vitro susceptibility assays of compounds were performed against Paracoccidioidesbrasiliensis and Mycobacterium tuberculosis. Results: Compounds 4a, 4b and 4k were the most potent against P. brasiliensis, two with minimum inhibitory concentrations of ≤1 µg ml-1 and exhibited pharmacological synergy with amphotericin B. The compounds also showed activity against M. tuberculosis, with 4c and 4k being the more promising. Compound 4k showed good synergistic antimycobacterium activity with ethambutol. None of the compounds tested showed toxicity. Conclusion: We highlight the compound 4k, as a potential agent for the treatment of patients co-infected with paracoccidioidomycosis and tuberculosis.


Asunto(s)
Antibacterianos/farmacología , Antifúngicos/farmacología , Coinfección/tratamiento farmacológico , Mycobacterium tuberculosis/efectos de los fármacos , Paracoccidioides/efectos de los fármacos , Paracoccidioidomicosis/tratamiento farmacológico , Tuberculosis/tratamiento farmacológico , Anfotericina B/farmacología , Antibacterianos/síntesis química , Antifúngicos/síntesis química , Combinación de Medicamentos , Descubrimiento de Drogas , Sinergismo Farmacológico , Etambutol/farmacología , Humanos , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/patogenicidad , Paracoccidioides/patogenicidad
7.
Beilstein J Org Chem ; 15: 818-829, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31019574

RESUMEN

The presence of strong stereoelectronic interactions involving the substituents in cis-2-substituted cyclohexanes may lead to results different from those expected. In this work, we studied the conformational behavior of cis-2-fluoro- (F), cis-2-chloro- (Cl), cis-2-bromo- (Br) and cis-2-iodocyclohexylamine (I) by dynamic NMR and theoretical calculations. The experimental data pointed to an equilibrium strongly shifted toward the ea conformer (equatorial amine group and axial halogen), with populations greater than 90% for F, Cl and Br in both dichloromethane-d 2 and methanol-d 4. Theoretical calculations (M06-2X/6-311++G(2df,2p)) were in agreement with the experimental, with no influence of the solvent or the halogen on the equilibrium. A principal component analysis of natural bond orbital energies pointed to the σ*C-X and σC-H orbitals and the halogen lone pairs (LPX) as the most significant for the hyperconjugative interactions that influenced the equilibrium. The σC-H → σ*C-X hyperconjugation and the interactions involving the LPX counterbalance each other, explaining the non-influence of the halogen on the conformational equilibrium. These interactions are responsible for the strong preference for the ea conformer in cis-2-halocyclohexylamines, being strong enough to restrain the shift in the equilibrium due to other factors such as steric repulsion or solvent effects.

8.
Chem Biodivers ; 16(5): e1800644, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30843651

RESUMEN

The phytochemical investigation of Grazielia gaudichaudeana aerial parts yielded 15 compounds, including diterpenes, triterpenes, sterols and flavonoids. With exception to ent-kaurenoic acid diterpenes, the compounds isolated are being described for the first time in this species. Some unusual 1 H-NMR chemical shifts of 18-nor-ent-labdane (7-9) led us carry out a conformational analysis by theoretical calculations in order to support the experimental data. Moreover, due to the limitation of studies focused on pharmacological potential of Grazielia gaudichaudeana, the present study was carried out to investigate the antioxidant, antiproliferative, antiviral, antileishmanial and antimicrobial activities from the extract, fractions and isolated compounds obtained from this species. Ethyl acetate fraction showed significant activity in the antiproliferative assay, with GI50 range of 3.9 to 27.2 µg mL-1 . Dichloromethane fraction, rich in diterpenoids, inhibited all human tumor cell lines tested, and the nor-labdane 7 showed potent cytotoxic activity against glioma and ovary cancer cell lines.


Asunto(s)
Asteraceae/química , Diterpenos/química , Antiinfecciosos/química , Antiinfecciosos/aislamiento & purificación , Antiinfecciosos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Antioxidantes/química , Antiprotozoarios/química , Antiprotozoarios/aislamiento & purificación , Antiprotozoarios/farmacología , Asteraceae/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Hongos/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Leishmania/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Extractos Vegetales/química
9.
Future Microbiol ; 14: 235-245, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30663901

RESUMEN

AIM: Novel 4-methoxy-naphthalene derivatives were synthesized based on hits structures in order to evaluate the antifungal activity against Paracoccidioides spp. METHODS: Antifungal activity of compounds was evaluated against P. brasiliensis and most promising compounds 2 and 3 were tested against eight clinically important fungal species. RESULTS: Compound 3 was the more active compound with MIC 8 to 32 µg.ml-1 for Paracoccidioides spp without toxicity monkey kidney and murine macrophagecells. Carbohydrazide 3 showed good synergistic antifungal activity with amphotericin B against P. brasiliensis specie. Titration assay of carbohydrazide 3 with PbHSD enzyme demonstrates the binding ligand-protein. Molecular dynamics simulations show that ligand 3 let the PbHSD protein more stable. CONCLUSION: New carbohydrazide 3 is an attractive lead for drug development to treat paracoccidioidomycoses.


Asunto(s)
Antifúngicos/farmacología , Naftalenos/farmacología , Paracoccidioides/efectos de los fármacos , Paracoccidioidomicosis/tratamiento farmacológico , Anfotericina B/farmacología , Animales , Antifúngicos/uso terapéutico , Chlorocebus aethiops , Combinación de Medicamentos , Sinergismo Farmacológico , Homoserina Deshidrogenasa/metabolismo , Hidrazinas/farmacología , Macrófagos/efectos de los fármacos , Ratones , Pruebas de Sensibilidad Microbiana , Simulación de Dinámica Molecular , Naftalenos/síntesis química , Naftalenos/uso terapéutico , Paracoccidioides/patogenicidad , Estabilidad Proteica , Células Vero/efectos de los fármacos
10.
Spectrochim Acta A Mol Biomol Spectrosc ; 204: 174-179, 2018 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-29933152

RESUMEN

The Raman spectral profile of p-methylcarbohydrazonethioamide (MCHT) is completely changed due to strong SERS effects upon bonding onto gold nanoparticles surface, but some vibrational modes are further enhanced in the presence of Hg(II) ions. The lack of SERS response for most common metal ions indicates that the coordinating groups are interacting with the gold nanoparticles surface and not available for binding metal ions in solution, except for mercury ions. The selective enhancement of some vibrational modes is consistent with significant conformational changes upon binding of Hg(II) ion onto the AuNP@MCHT hybrid, as confirmed by TEM/EDS measurements, demonstrating its potentiality as a highly selective and sensitive SERS substrate.

11.
RSC Adv ; 8(9): 4773-4778, 2018 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-35539545

RESUMEN

Four methodologies are reported for the regioselective synthesis of four series of regioisomer isoxazoles from cyclocondensation of ß-enamino diketones and hydroxylamine hydrochloride. Regiochemical control was achieved by varying reaction conditions and substrate structure. The mild reaction conditions used to access 4,5-disubstituted, 3,4-disubtituted, and 3,4,5-trisubstituted regioisomer isoxazoles, as well as the pharmacological and synthetic potential of the products, make these novel methodologies very powerful.

12.
Artículo en Inglés | MEDLINE | ID: mdl-28652239

RESUMEN

This work evaluated new potential inhibitors of the enzyme homoserine dehydrogenase (HSD) of Paracoccidioides brasiliensis, one of the etiological agents of paracoccidioidomycosis. The tertiary structure of the protein bonded to the analogue NAD, and l-homoserine was modeled by homology. The model with the best output was subjected to gradient minimization, redocking, and molecular dynamics simulation. Virtual screening simulations with 187,841 molecules purchasable from the Zinc database were performed. After the screenings, 14 molecules were selected and analyzed by the use of absorption, distribution, metabolism, excretion, and toxicity criteria, resulting in four compounds for in vitro assays. The molecules HS1 and HS2 were promising, exhibiting MICs of 64 and 32 µg · ml-1, respectively, for the Pb18 isolate of P. brasilensis, 64 µg · ml-1 for two isolates of P. lutzii, and also synergy with itraconazole. The application of these molecules to human-pathogenic fungi confirmed that the HSD enzyme may be used as a target for the development of drugs with specific action against paracoccidioidomycosis; moreover, these compounds may serve as leads in the design of new antifungals.


Asunto(s)
Antifúngicos/farmacología , Homoserina Deshidrogenasa/metabolismo , Paracoccidioides/efectos de los fármacos , Paracoccidioidomicosis/tratamiento farmacológico , Línea Celular Tumoral , Células HeLa , Humanos , Itraconazol/farmacología , Pruebas de Sensibilidad Microbiana/métodos , Paracoccidioides/metabolismo , Paracoccidioidomicosis/metabolismo
13.
J Phys Chem A ; 121(26): 4993-5004, 2017 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-28595011

RESUMEN

The rationalization of acid/base behavior is a central concern for chemistry and related fields. In this work, we describe an alternative approach toward the understanding of gas phase acidities based on the localized molecular orbital energy decomposition analysis (LMOEDA) method. Upon partitioning the molecules (and the corresponding anions) over the X-OH (or X-O-) bond, we have observed a perfect correlation between the interaction energy of the two fragments and the acidity, as given by the energy difference between the anion and the neutral molecule. On the basis of this correlation, acidities could be interpreted according to the energy components provided by LMOEDA, namely, electrostatic, exchange repulsion, polarization, and dispersion. For example, alkyl groups increase the gas phase acidities of alcohols mainly due to electrostatic and polarization interactions. Carboxylic acids are stronger acids than alcohols through the ability of oxygen to stabilize the extra charge formed in the anion (electrostatic interactions) and also through a decrease of exchange repulsions between the two fragments. Polarization interaction (orbital relaxation) also plays an important role. Electrostatic and polarization interactions dominate the enhanced acidity of sulfuric acid over ethanol. Electrostatic and polarization interactions are also responsible for the higher acidity of sulfuric over boric acid. The anomalous behavior of formic acid compared to acetic, propionic, and butyric acids is also explained. The examples worked in this report evince the still unexplored potential of energy decomposition to the comprehension of acid/base phenomena.

14.
Spectrochim Acta A Mol Biomol Spectrosc ; 174: 138-146, 2017 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-27889673

RESUMEN

This paper presents a study on the conformational preferences of phenylacetic acid (PA) and its halogenated analogues (FPA, CPA, BPA). To clarify the effects that rule these molecules' behaviour, theoretical calculations were used, for both the isolated phase and solution, combined with nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy. Most conformations of phenylacetic acid and its halogenated derivatives are stabilized through the hyperconjugative effect, which rules the conformational preference. NMR analyses showed that even with the variation in medium polarity, there was no significant change in the conformation population. Infrared spectroscopy showed similar results for all compounds under study. In most spectra, two bands were found through the carbonyl deconvolution, which is in accordance with the theoretical data. It was possible to prove that variation in the nature of the substituent in the ortho position had no significant influence on the conformational equilibrium.

15.
Eur J Med Chem ; 124: 340-349, 2016 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-27597410

RESUMEN

A new series of pyrazolo[3,4-d]pyridazin-7-one derivatives were synthesised and evaluated for their in vitro antileishmanial activity against Leishmania amazonensis promastigote and axenic amastigote forms. The results showed that the pyrazolo[3,4-d]-pyridazin-7-one-N-acylhydrazone-(bi)thiophene hybrids 5b, 6b and 6d exhibit better antileishmanial activity with IC50 84.96, 3.63 and 10.79 µM, against the promastigote form and IC50 32.71, 2.32 and >100 µM against the axenic amastigote form, respectively. The active compounds had their cytotoxicity tested against macrophages and fibroblast cells with a higher selectivity index than 10 for compounds 6b and 6d. Molecular docking studies were performed for all active compounds using the enzyme trypanothione reductase (TR) to investigate a possible action mechanism. The results suggested that active compounds had interactions with the residues of amino acids Gly 13, Thr 51, Thr 160, Gly 161, Tyr 198, Arg 287, Asp 327, Thr 335, which may inhibit the enzyme TR.


Asunto(s)
Diseño de Fármacos , Leishmania mexicana/efectos de los fármacos , Tiofenos/síntesis química , Tiofenos/farmacología , Animales , Técnicas de Química Sintética , Concentración 50 Inhibidora , Leishmania mexicana/enzimología , Ratones , Simulación del Acoplamiento Molecular , NADH NADPH Oxidorreductasas/química , NADH NADPH Oxidorreductasas/metabolismo , Pruebas de Sensibilidad Parasitaria , Conformación Proteica , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/metabolismo
16.
Oxid Med Cell Longev ; 2015: 394367, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26075034

RESUMEN

A series of thiosemicarbazone (TSC) p-substituted acetophenone derivatives were synthesized and chemically characterized. The p-substituents appended to the phenyl group of the TSC structures were hydrogen, fluor, chlorine, methyl, and nitro, producing compounds named TSC-H, TSC-F, TSC-Cl, TSC-Me, and TSC-NO2, respectively. The TSC compounds were evaluated for their capacity to induce mitochondrial permeability, to deplete mitochondrial thiol content, and to promote cell death in the K562 cell lineage using flow cytometry and fluorescence microscopy. TSC-H, TSC-F, and TSC-Cl exhibited a bell-shaped dose-response curve for the induction of apoptosis in K562 cells due to the change from apoptosis to necrosis as the principal mechanism of cell death at the highest tested doses. TSC-Me and TSC-NO2 exhibited a typical dose-response profile, with a half maximal effective concentration of approximately 10 µM for cell death. Cell death was also evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, which revealed lower toxicity of these compounds for peripheral blood mononuclear cells than for K562 cells. The possible mechanisms leading to cell death are discussed based on the observed effects of the new TSC compounds on the cellular thiol content and on mitochondrial bioenergetics.


Asunto(s)
Acetofenonas/farmacología , Glutatión/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Tiosemicarbazonas/farmacología , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Indoles/química , Indoles/farmacología , Células K562 , Espectrometría de Masas , Compuestos de Sulfhidrilo/metabolismo , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/química
17.
J Phys Chem A ; 119(10): 2111-21, 2015 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-25679501

RESUMEN

This study reports the results of ab initio and density functional theory (DFT) electronic structure calculations as well as (3)J(HH) experimental and calculated coupling constant data obtained in the investigation of the conformational equilibrium of 3-halo-derivatives of 1-methylpyrrolidin-2-one. The five-membered ring assumes an envelope conformation owing to the plane of formation of the O═C-N-R bond, with C4 forming the "envelope lid". When the conformation changes, the "lid" alternates between positions above and below the amide plane. The α-carbonyl halogen assumes two positions: a pseudo-axial and a pseudo-equatorial. In the gaseous phase, the calculations indicate that the pseudo-axial conformer is more stable and preferable going down the halogen family. Natural bond orbital analysis showed that electronic delocalization is significant only for the iodo derivative. In the other derivatives, the electrostatic repulsion between oxygen and the halogen determines the conformational equilibrium. When the solvated molecule was taken into account, the pseudo-equatorial conformer population increased with the relative permittivity of the solvent. This variation was strong in the fluoro derivative, and the preference was inverted. In the chlorine derivative, the two populations became closer in methanol and acetonitrile. In the bromine and iodine derivatives, the percentage of pseudo-equatorial conformer increased only slightly owing to the dipole moment of the conformation: the pseudo-equatorial conformation has a greater dipole moment and thus is stable in media with high relative permittivity.

18.
Spectrochim Acta A Mol Biomol Spectrosc ; 137: 176-84, 2015 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-25218227

RESUMEN

The establishment of the most stable structures of eight membered rings is a challenging task to the field of conformational analysis. In this work, a series of 2-halocyclooctanones were synthesized (including fluorine, chlorine, bromine and iodine derivatives) and submitted to conformational studies using a combination of theoretical calculation and infrared spectroscopy. For each compound, four conformations were identified as the most important ones. These conformations are derived from the chair-boat conformation of cyclooctanone. The pseudo-equatorial (with respect to the halogen) conformer is preferred in vacuum and in low polarity solvents for chlorine, bromine and iodine derivatives. For 2-fluorocyclooctanone, the preferred conformation in vacuum is pseudo-axial. In acetonitrile, the pseudo-axial conformer becomes the most stable for the chlorine derivative. According to NBO calculations, the conformational preference is not dictated by electron delocalization, but by classical electrostatic repulsions.


Asunto(s)
Ciclooctanos/química , Halógenos/química , Cetonas/química , Conformación Molecular , Electrones , Espectrofotometría Infrarroja , Termodinámica
19.
Spectrochim Acta A Mol Biomol Spectrosc ; 129: 148-56, 2014 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-24727174

RESUMEN

The geometries involved in the conformational equilibria of 2,2-dichloro-N-cyclohexyl-N-methyl-acetamide (DCCMA) and 2-chloro-N,N-dicyclohexylacetamide (CDCA) were investigated. Theoretical calculations at the B3LYP/cc-pVDZ level of theory showed that gauche forms (ClCCO) are the most stable and the predominant conformers in isolated phase. Both compounds had the conformational behavior in solvents of different polarities estimated from theoretical calculations with the PCM (Polarizable Continuum Model), at the same level of theory, using infrared data from deconvolution of the carbonyl absorption bands and (13)C NMR spectra. Their IR spectra showed two carbonyl absorptions and that the conformer with the highest dipole moment had its population increased when the most polar solvents were used, in accordance with the theoretical calculation in solution. (1)JCH coupling constants were obtained from their NMR spectra, and revealed that there was population variation of conformers with solvent exchange. Experimental data (NMR and IR) as well as calculations including the solvent effects followed the same trend.


Asunto(s)
Acetamidas/química , Isomerismo , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Espectrofotometría Infrarroja
20.
Artículo en Inglés | MEDLINE | ID: mdl-22534556

RESUMEN

2-Halocycloheptanones (Halo=F, Cl, Br and I) were synthesized and their conformational analysis was performed through infrared spectroscopy data. The corresponding conformers geometries and energies were obtained by theoretical calculations at B3LYP/aug-cc-pVDZ level of theory in the isolated state and in solution. It was observed, by both approaches, that the conformational preferences were very sensitive to the solvent polarity, since its increase led to an increase in the population of the more polar conformer. An analysis of these conformational equilibria showed they suffer also the influence of stereoelectronic effects, like hyperconjugation and steric effects. These results were interpreted using natural bond orbital (NBO) analysis, which indicated that the electronic delocalization to the orbital π*(C=O) is directly involved in the stability increase of conformers I and II. The relative effect of the period of the halogen can also be noted, with changes in the conformational preferences and in the energies involved in the interactions of NBO.


Asunto(s)
Hidrocarburos Cíclicos/química , Hidrocarburos Halogenados/química , Cetonas/química , Modelos Moleculares , Conformación Molecular , Absorción , Solventes/química , Espectrofotometría Infrarroja , Termodinámica
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