Experimental and computational study of the mechanism of the reaction of ketones with bromoform

U оvој dоktоrskој disеrtаciјi ispitаn је, i еkspеrimеntаlnо i rаčunаrski, mеhаnizаm rеаkciје kеtоnа sа brоmоfоrmоm. Еkspеrimеntаlnо ispitајući оvај mеhаnizаm rаzviјеna је i оptimizоvаnа nоvа „one-pot“ mеtоdа zа sintеzu α,β-nеzаsićеnih kаrbоksilnih kisеlinа. Меtоdа оbuhvаtа rеаkciјu kеtоnа sа brоmоfоrmоm i litiјum-hidrоksidоm u аlkоhоlnim rаstvаrаčimа i vоdоm kао kо-rаstvаrаčеm kоја је kаtаlizоvаnа fаznim kаtаlizаtоrimа (TEBA, 18-C-6). Rеаkciја sе izvоdi nа sоbnој tеmpеrаturi u tоku 24 čаsа. Kоnjugоvаnе kisеlinе nаstајu iz cikličnih i аrоmаtičnih kеtоnа, dоk α-brоmkаrbоksilnе kisеlinе nаstајu iz еtil-4-оksо-pipеridin-1-kаrbоksilаtа i tеrc-butil-4-оksо-pipеridin-1-kаrbоksilаtа. Prоrаčuni su rаđеni nа sistеmu ciklоhеksаnоn-brоmоfоrm dа bi sе оbјаsnilо оtvаrаnjе еpоksidnоg prstеnа nuklеоfilnоm rеаkciјоm dihаlоgеnеpоksidа. U оvој rеаkciјi, nаstајаnjе dibrоmеpоksidа је klјučnа fаzа kоја оdrеđuје udео i stеrеоhеmiјu prоizvоdа. Svаkа rеаkciоnа shеmа sаdrži еpоksid kао klјučni intеrmеdiјеr. Prеtpоstаvlјеnа su i prоučаvаnа tri rеаkciоnа mеhаnizmа kојim nаstајu 1-ciklоhеksеnkаrbоksilnа kisеlinа, 1-hidrоksiciklоhеksаnkаrbоksilnа kisеlinа 1-brоmciklоhеksаnkаrbоksilnа kisеlinа, kао prоizvоdi. Prоrаčuni pоkаzuјu dа su svа tri rеаkciоnа putа еgzоtеrmnа. Rеаkciоni put kојim nаstаје 1¬ ciklо-hеksеnkаrbоksilnа kisеlinа kао prоizvоd је nајvеrоvаtniјi i nе uklјučuје intеrmеdiјеr. Svim sintеtizоvаnim kisеlinаmа оdrеđеnа је in vitro аntiprоlifеrаtivnа аktivnоst prеmа HeLa ćеliјskim liniјаmа. U nаmеri dа sе оdrеdi i nеpоžеlјnа citоtоksičnоst оvih јеdinjеnjа, оdrеđеnа је citоtоksičnа аktivnоst prеmа nеstimulisаnim i stimulisаnim ćеliјаmа PBMC. Vеćinа sintеtizоvаnih kisеlinа pоkаzuје slаbо аntiprоlifеrаtivnо dејstvо i imајu IC50 od 122,2 do 192 μM. Nајаktivniја је 1- ciklо-dоdеcеnkаrbоksilnа kisеlinа (IC50=122 μM prеmа HeLa ćеliјаmа). Ispitivаnе kisеlinе pоkаzuјu tаkоđе vеоmа slаbu аktivnоst prеmа ćеliјаmа limfоcitа (PBMC i PBMC+PHA) sа IC50 > 200 μM.In this Thesis, the mechanism of reaction of bromoform with ketones was examined by experimental and computing. A new one-pot reaction for synthesis of α,β-unsaturated carboxylic acids was developed. Phase-transfer catalyzed (PTC) reactions of ketones with bromoform and aqueous lithium hydroxide in alcoholic solvent with TEBA or 18-C-6 as catalyst, result in the formation of α,β-unsaturated carboxylic acids. The reaction was performed at room temperature for 24 h. Corresponding conjugated acids were obtained from cyclic or aromatic ketones, while bromo acids were obtained from 4 oxo-piperidine-1-carboxylic acid ethyl ester and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester. To elucidate the ring opening nucleophilic reactions of dihaloepoxides the extensive calculations were done on a model system cyclohexanone - bromoform. In this reaction the formation of dibromoepoxide is postulated as a key step determining distribution and stereochemistry of products. Every reaction scheme involves epoxide as a key intermediate. Three major products, 1¬ cyclohexene-1-carboxylic acid, 1-bromocyclohexane carboxylic acid and 1-hydroxy¬cyclohexane carboxylic acid could be obtained by three different competing reaction pathways. Calculations showed that all pathways are exothermic. Reaction pathway for synthesis of 1¬ cyclohexene-1-carboxylic acid is most convenient, and does not include any intermediate. The antiproliferative activity of obtained acids toward malignant cell lines was evaluated in this work, too. With the aim to determine the undesirable cytotoxic effect of investigated compounds on immune competent cells the normal peripheral blood mononuclear cells were used as target cells, too. The majority of synthesized conjugated acids exert moderate antiproliferative activity in vitro toward HeLa, having IC50 values from 122.20 to 192 μM. The most active compound is 1-cyclododecene-1-carboxylic acid, (IC50=122 μM toward HeLa cells). All examined compounds did not affect proliferation of healthy human blood peripheral mononuclear cells (PBMC and PBMC+PHA), IC50 > 200 Μ

Optimizacija sinteze i in vitro proučavanje antimikrobnog dejstva α,β-nezasićenih i α-bromkarboksilnih kiselina

A series of α,β-unsaturated and α-bromo carboxylic acids were identified as potent antimicrobial agents. The antimicrobial activity was evaluated using the broth microdilution method. All acids 1-12 exhibited a significant activity against nine laboratory control strains of bacteria and two strains of yeast Candida albicans. The tested acids were efficiently prepared by optimized phase-transfer-catalyzed (PTC) reactions of ketones with bromoform and aqueous lithium hydroxide in alcoholic solvent with triethylbenzyl ammonium chloride (TEBA) as catalyst.U ovom radu je prikazano in vitro ispitivanje antimikrobnog dejstva serije α,β-nezasićenih i α-bromkarboksilnih kiselina i pokazano je da su one potencijalno dobri antimikrobni agensi. Sve kiseline 1-12 pokazale su značajnu aktivnost prema devet sojeva bakterija i dva soja gljivica Candida albicans. Ispitivane kiseline sintetisane su u optimizovanoj reakciji ketona sa bromoformom i litijum-hidroksidom u smesi rastvarača (terc-butanol/voda). Kao katalizator za prenos između faza upotrebljen je trietilbenzilamonijum-hlorid (TEBA)

Glutarimidi - biološka aktivnost, opšti postupci za sintezu i fizičko-hemijske karakteristike

Glutarimides, 2,6-dioxopiperidines, are compounds that rarely occur in natural sources, but so far isolated ones exert widespread pharmacological activities, which makes them valuable as potential pharmacotherapeutics. Glutarimides act as androgen receptor antagonists, anti-inflammatory, anxiolytics, antibacterials, and tumor suppressing agents. Some synthetic glutarimide derivatives are already in use as immunosuppressive and sedative (e.g., thalidomide) or anxiolytics (buspirone) drugs. The wide applicability of this class of compounds, justify the interest of scientists to explore new pathways for its syntheses. General methods for synthesis of six-membered imide ring are presented in this paper. These methods include: a) reaction of dicarboxylic acids with ammonia or primary amine, b) reactions of cyclization: amido-acids, diamides, dinitriles, nitrilo-acids, amidonitriles, amido-esters, amidoacyl-chlorides or diacyl-chlorides, c) addition of carbon-monoxide on alpha,beta-unsaturated amides, d) oxidation reactions, e) Michael addition of active methylen compounds on methacrylamide or conjugated amides. Some of the described methods are used for closing glutarimide ring in syntheses of pharmacological active compounds sesbanimide and aldose reductase inhibitors (ARI). Analyses of the geometry, as well as, the spectroscopic analyses (NMR and FT-IR) of some glutarimides are presented due to their broad spectrum of pharmacological activity. To elucidate structures of glutarimides, geometrical parameters of newly synthesized tert-pentyl-1-benzyl-4-methyl-glutarimide-3-carboxylate (PBMG) are analyzed and compared with the experimental data from X-ray analysis for glutarimide. Moreover, molecular electrostatic potential (MEP) surface which is plotted over the optimized geometry to elucidate the reactivity of PBMG molecule is analyzed. The electronic properties of glutarimide derivatives are explained on the example of thalidomide. The Frontier Molecular Orbital (FMO) and their energies are presented, as well as the energy gap between them.U ovom radu dat je prikaz metoda za sintezu šestočlanih cikličnih imida. Glutarimidi, 2,6-dioksopiperidini, su značajna biološka jedinjenja i deluju kao antagonisti adrenogenih receptora, antiinflamatorni agensi, anksiolitici, antivirotici, antibiotici i agensi koji sprečavaju rast pojedinih vrsta tumora. Prikazana je i njihova spektralna analiza (FT-IR i NMR), zbog potvrde stukture, kao i analiza graničnih molekulskih orbitala koja daje prikaz elektronskih svojstava ovih molekula, što je važno zbog njihove biološke aktivnosti. Da bi se predstavila hemijska reaktivnost glutarimida predstavljen je molekulski elektronski potencijal (MEP) iz prethodno optimizovane geometrije reprezentativnog primera terc-pentil-1- -benzil-4-metil-glutarimid-3-karboksilata (skraćenica PBMG). Elektronska svojstva su objašnjena na primeru talidomida

Spectroscopic and quantum chemical elucidation of newly synthesized 1-aryl-3-methyl-3-phenylpyrrolidine-2,5-diones as potential anticonvulsant agents

Novel succinimide derivatives were synthesized from 3-methyl-3-phenylsuccinic acid and substituted anilines under solvent-free conditions by using microwave irradiation. All obtained compounds were characterized by ultraviolet (UV), Fourier-transform infrared (FT-IR), H-1 and C-13 nuclear magnetic resonance (NMR) spectroscopy as well as by elemental analysis. The influence of the substituent electronic effects on spectroscopic data was analyzed by applying the Hammett equation. Moreover, a detailed interpretation and comparison of experimentally obtained and theoretically calculated FT-IR, UV and NMR spectra was performed. Density functional theory (DFT) calculated data of the investigated succinimides were obtained and analyzed in order to determine their structural, spectroscopic and electronic properties. Furthermore, ADMET factor profiling and in-silico prediction of potential biological activities of novel succinimide derivatives have been performed

Voltammetric and Quantum Investigation of Selected Succinimides

A series of succinimide derivatives were studied using the cyclic and square wave voltammetry. Density function theory was used in order to determinate which of the structural parameters influence the electrochemical activity. The quantum chemical calculations of the investigated succinimides were linked with the experimental electrochemical data and used to propose the oxidation mechanism. The most active among studied succinimides is 1,3-diphenylsuccinimide. The results obtained from the cyclic and square wave voltammetry and quantum chemical calculations indicate that the investigated compounds undergo oxidation by irreversible, diffusion controlled process including transfer of 1e(-) and 1 proton. The voltammetric and DFT results signify that the mechanism of electrochemical oxidation of all compounds involve the conversion of carbonyl-methyne-phenyl segment or methylene group in free radical. This conversion proceeds by the loss of one proton one electron process

Towards understanding intermolecular interactions in hydantoin derivatives: the case of cycloalkane-5-spirohydantoins tethered with a halogenated benzyl moiety

A series of cycloalkane-5-spirohydantoins bearing a halogeno substituted benzyl group (X = Cl and Br) in position 3 has been synthesized and their structures (1-6) have been determined by a single crystal X-ray diffraction method. These compounds have multiple functional groups, which allow greater competition and/ or cooperation among the different intermolecular interactions in the formation of their crystal structures. The molecules are linked together by paired N-H... O hydrogen bonds in R22(8) rings, while the CH. O interactions lead to their further association into double chains. The contribution of the cycloalkyl ring depends on its conformational flexibility and the multiple C-H donor implications. In the case of compounds 1-4 bearing the cyclopentyl or the cyclohexyl ring, halogen bonding (X...O) interactions give rise to a supramolecular pseudo-hexagonal network. In addition, the C-H... X interactions with a higher degree of multifurcation at the halogen acceptor have an important role in the formation of the crystal structure. Regarding compounds 5 and 6 with the cycloheptane ring, the X. O interaction is absent, and along with the C-H. X interactions, these compounds realize an alternative crystal structure with an emphasis on the X. p interactions. The lattice energies of all these crystal structures, as well as the intermolecular pair energies, have been calculated using PIXEL and further partitioned into coulombic, dispersive, polarization and repulsive factors. The crystal structures have also been subjected to Hirshfeld surface analysis which reveals that approximately 75% of the close contacts correspond to relatively weak interactions. The application of both concepts has provided a new insight into the relationship between the molecular interactions and crystal structures of the hydantoin derivatives.This is the peer-reviewed version of the following article: Crystengcomm, 2017, 19, 3, 469-483 [https://dx.doi.org/10.1039/C6CE02210C][http://cer.ihtm.bg.ac.rs/handle/123456789/2204

Determination of ionization constants (PKA) of β-hydroxy-β-arylalkanoic acids using high-pressure liquid chromatography

pKa values of five β-hydroxy-β-arylalkanoic acids and ibuprofen were determined using the RP-HPLC method. Stationary phase was octadecyl modified (C-18) silica gel, and mobile phase was a mixture of methanol and one of nine different buffers (60:40, v/v). wspH values were measured after mixing methanol with an appropriate buffer. The mean retention time of each compound was plotted against wspH of each mobile phase. The inflection point of each sigmoidal curve represented wspK a of the compound. Using wspK a in already known equations for the specific methanol/buffer mixture, wwpK a values were calculated. Obtained pKa values for synthesized compounds were in a narrow range from 3.34-3.81 and pKa for ibuprofen was 4.45. Predicted pKa values for these compounds in SPARC software showed good correlation with experimental pKa values (R2=0.8048)

On the azo dyes derived from benzoic and cinnamic acids used as photosensitizersin dye-sensitized solar cells

In order to get a better insight into the relationship between molecular structure and photovoltaic performance, six monoazo dye molecules containing benzoic and cinnamic acid moieties were synthesized and their photovoltaic properties were studied. Three of them have not been previously used in solar cells. Spectroscopic measurements of the investigated compounds coupled with theoretical calculations were performed. Short-circuit current density, open-circuit voltage, and fill-factor were determined. It was found that a larger amount of short-circuit current density will be generated if the HOMO-LUMO energy gap is lower, determined by the stability of the molecule and the electronic effect of the donor moiety. Among both series of synthesized dye molecules, the highest obtained values of short-circuit current density were achieved with (2-hydroxynaphthalene-1-ylazo)benzoic acid and (2-hydroxynaphthalene-1-ylazo)cinnamic acid, and thus they were regarded as promising candidates for application in dye-sensitized solar cells

Determination of ionization constants (PKA) of β-hydroxy-β-arylalkanoic acids using high-pressure liquid chromatography

pKa values of five β-hydroxy-β-arylalkanoic acids and ibuprofen were determined using the RP-HPLC method. Stationary phase was octadecyl modified (C-18) silica gel, and mobile phase was a mixture of methanol and one of nine different buffers (60:40, v/v). wspH values were measured after mixing methanol with an appropriate buffer. The mean retention time of each compound was plotted against wspH of each mobile phase. The inflection point of each sigmoidal curve represented wspK a of the compound. Using wspK a in already known equations for the specific methanol/buffer mixture, wwpK a values were calculated. Obtained pKa values for synthesized compounds were in a narrow range from 3.34-3.81 and pKa for ibuprofen was 4.45. Predicted pKa values for these compounds in SPARC software showed good correlation with experimental pKa values (R2=0.8048)