A Computational Study of 2-Selenobarbituric Acid: Conformational Analysis, Enthalpy of Formation, Acidity and Basicity.

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Pyrolytic elimination of ethylene from ethoxyquinolines and ethoxyisoquinolines: a computational study

This work reports a thermo-kinetic study on unimolecular thermal decomposition of some ethoxyquinolines and ethoxyisoquinolines derivatives (1-ethoxyisoquinoline (1-EisoQ), 2-ethoxyquinoline (2-EQ), 3-ethoxyquinoline (3-EQ), 3-ethoxyisoquinoline (3-EisoQ), 4-ethoxyquinoline (4-EQ), 4-ethoxyisoquinoline (4-EisoQ), 5-ethoxyquinoline (5-EQ), 5-ethoxyisoquinoline (5-EisoQ), 8-ethoxyquinoline (8-EQ) and 8-ethoxyisoquinoline (8-EisoQ)) using density functional theory DFT (BMK, MPW1B95, M06-2X) and ab initio complete basis set-quadratic Becke3 (CBS-QB3) calculations. In the course of the decomposition of the investigated systems, ethylene is eliminated with the production of either keto or enol tautomer. The six-membered transition state structure encountered in the path of keto formation is much lower in energy than the four-membered transition state required to give enol form. Rate constants and activation energies for the decomposition of 1-EisoQ, 2-EQ, 3-EQ, 3-EisoQ, 4-EQ, 4-EisoQ, 5-EQ, 5-EisoQ, 8-EQ, and 8-EisoQ have been estimated at different temperatures and pressures using conventional transition state theory combined with Eckart tunneling and the unimolecular statistical Rice–Ramsperger–Kassel–Marcus theories. The tunneling correction is significant at temperatures up to 1000 K. Rate constants results reveal that ethylene elimination and keto production are favored kinetically and thermodynamically over the whole temperature range of 400–1200 K and the rates of the processes under study increase with the rising of pressure up to 1 atm.This paper is dedicated to the soul of the late Prof. Dr. Ahmed El-Nahas, without whom this project would never have been possible.Scopu

Quantum chemical study of tautomerization in select pharmaceuticals

Prototropička tautomerizacija je ravnotežna reakcija pomaka protona s kiselog centra molekule na bazični, uz istovremeni pomak π-elektrona u suprotnom smjeru. Molekule koje posjeduju -CH-C(=O)-NH- fragment postoje u tri tautomerna oblika: keto, enol i iminol. Među takvim molekulama nalazi se značajan broj lijekova. Tautomeri se međusobno razlikuju po fizikalno-kemijskim osobinama, stoga je karakterizacija tautomerne smjese važna za razumijevanje farmakokinetike i farmakodinamike lijekova, kao i za postupke proizvodnje i oblikovanja. Udio svakog tautomera u ravnotežnoj smjesi ovisi o njihovim relativnim stabilnostima. Gibbsova energija molekule može se odrediti in silico, koristeći računalne programe bazirane na zakonima kvantne mehanike. U ovom radu ispitane su stabilnosti tautomera 15 molekula farmaceutika. Keto oblik najstabilniji je u svim slučajevima. Iminolni oblik većine molekula dovoljno je stabilan kako bi se smatrao značajnim dijelom ravnotežne smjese, za razliku od enola čiji se udio zbog nestabilnosti može zanemariti. Supstituenti na amidnom dušiku i α-ugljiku utječu na energije tautomera: najjači su stabilizatori elektron-akceptorske skupine, aromatski sustavi i strukture koje omogućuju uspostavu produžene konjugacije. Stabilnost se može povećati i uspostavom intramolekulske vodikove veze. Ispitivani lijekovi koriste se u terapiji velikog broja pacijenata širom svijeta. Karakterizacija tautomera pomoći će u produbljivanju razumijevanja njihovih fizikalno-kemijskih osobina te u izgradnji srodnih lijekova poboljšanih svojstava.Prototropic tautomerization is an equilibrium reaction that includes a proton shift from the acidic centre of a molecule to the basic centre, with the simultaneous shift of π-electrons in the opposite direction. Molecules possessing the -CH-C(=O)-NH- fragment exist in three tautomeric forms: keto, enol and iminol. Among such molecules is a large number of pharmaceuticals. Tautomers differ in physico-chemical properties. The characterisation of the tautomeric equilibrium is thus important for the understanding of pharmacokinetics and pharmacodynamics of drugs, as well as for their manufacturing and formulation. The percentage of each tautomer in the equilibrium depends on their relative stabilities. The Gibbs energy of a molecule can be determined in silico, using computer programs based on the laws of quantum mechanics. In this thesis the stabilities of tautomers of 15 molecules were examined. Keto form is the most stable in all cases. Iminolic form of most molecules is stable enough to be considered a significant part of the tautomeric mix, while the enolic form is very unstable, so its presence can be deemed negligible. Substituents on the amidic nitrogen and the α-carbon affect the energies of tautomers: electron-accepting groups, aromatic structures and conjugated systems possess the strongest stabilizing effect. Stability of tautomers can also be increased by the formation of an intramolecular hydrogen bond. The analyzed pharmaceuticals are widely used for treatment of patients all over the world. Characterization of their tautomers will help increase the understanding of their physico-chemical properties and aid in design of related drugs with improved features

Theoretical, spectroscopic, and chromatographic study of the structure and properties of para-substituted 5-benzylidenebarbituric acid derivatives with electron-donor and electron-acceptor substituents

5-Benziliden barbiturati pokazuju različitu biološku aktivnost koja je znatno uslovljena fizičkim, hemijskim i strukturnim osobinama jedinjenja, kao i zanimljive optičke osobine koje su posledica donor-akceptorskih interakcija u molekulu. Sintetisana je serija para-supstituisanih derivata 5-benzilidenbarbiturne kiseline kao potencijalnih push-pull elektronskih sistema sa elektron-donorskim i elektron-akceptorskim supstituentima. Proučavane su donor-akceptorske interakcije, kao i potencijalna elektron-donorska sposobnost barbiturne kiseline u sintetisanim jedinjenjima koja do sada nije potvrđena u literaturi. Elektronske interakcije u jedinjenjima u osnovnom stanju proučavane su LFER analizom NMR podataka, zajedno sa analizom optimizovanih geometrija i izračunatih elektronskih gustina. LSER analizom i TD-DFT proračunima proučavane su ekscitacije i pobuđena stanja. Rezultati "hole-electron" analize i izračunatih ICT deskriptora tokom ekscitacije pokazuju da je p-N(CH3)2 derivat najbolji kandidat za push-pull sistem. Utvrđeno je da barbiturna kiselina može biti slab elektron-donor kada je kuplovana sa jakim elektron-akceptorom. Primenom RP TLC metode određeni su hromatografski parametri lipofilnosti sintetisanih jedinjenja u metanolu, n-propanolu, acetonu i tetrahidrofuranu. Ispitana je zavisnost između hromatografskih parametara lipofilnosti (RМ0 i m), softverski dobijenih vrednosti logP kao standardne mere lipofilnosti, farmakokinetičkih i toksikoloških parametara primenom linearne regresije, klasterske analize i analize glavnih komponenata. Retenciono ponašanje ispitivanih jedinjenja znatno je uslovljeno prirodom supstituenata kao i njihovim elektronskim efektima. Rezultati potvrđuju da se hromatografski parametri, RМ0 i m mogu koristiti za opisivanje lipofilnosti ispitivanih jedinjenja.5-Benzylidenebarbiturates show different biological activities that are significantly influenced by the physical, chemical, and structural properties of the compound, as well as interesting optical properties resulting from donor-acceptor interaction in the molecules. A series of para-substituted 5-benzylidenebarbituric acid derivatives as potential push-pull electronic systems with electron-donor and electron-acceptor substituents was synthesized. The potential electron-donor abilities of barbituric acid, which are still not established in the literature, and donor-acceptor interactions in the synthesized compounds were investigated. The electronic interactions in the ground state were investigated by LFER analysis on 13C NMR data together with the analysis of optimized geometries and calculated electron densities. The electron excitations and the nature of excited state were studied by LSER analysis and TDDFT calculations. The results of the “hole-electron” analysis and calculated ICT descriptors during the excitation show that the p-N(CH3)2 derivative is the best candidate for the push-pull system. It has been found that barbituric acid can be a weak electron-donor when coupled with a strong electron-acceptor. The chromatographic lipophilicity parameters of the synthesized compounds were determined by the RP TLC in methanol, n-propanol, acetone, and tetrahydrofuran. The relationship between chromatographic lipophilicity parameters (RМ0 and m), theoretically calculated logP values as a standard measure of lipophilicity, pharmacokinetic and toxicological parameters was examined using the linear regression, cluster analysis, and principal component analysis. The retention behavior of the investigated compounds is significantly conditioned by the nature of the substituents as well as their electronic effects. The results confirm that the chromatographic parameters (RМ0 and m) can be used to describe the lipophilicity of the investigated compounds