Contribution of Non-Covalent Interactions and Electronic Effects on the Conformational Landscape and Tautomeric Equilibria of Molecules and Molecular Complexes: Structural and Dynamical Data from Rotational Spectroscopy

This thesis concerns the study of complex conformational surfaces and tautomeric equilibria of molecules and molecular complexes by quantum chemical methods and rotational spectroscopy techniques. In particular, the focus of this research is on the effects of substitution and noncovalent interactions in determining the energies and geometries of different conformers, tautomers or molecular complexes. The Free-Jet Absorption Millimeter Wave spectroscopy and the Pulsed-Jet Fourier Transform Microwave spectroscopy have been applied to perform these studies and the obtained results showcase the suitability of these techniques for the study of conformational surfaces and intermolecular interactions. The series of investigations of selected medium-size molecules and complexes have shown how different instrumental setups can be used to obtain a variety of results on molecular properties. The systems studied, include molecules of biological interest such as anethole and molecules of astrophysical interest such as N-methylaminoethanol. Moreover halogenation effects have been investigated on halogen substituted tautomeric systems (5-chlorohydroxypyridine and 6-chlorohydroxypyridine), where it has shown that the position of the inserted halogen atom affects the prototropic equilibrium. As for fluorination effects, interesting results have been achieved investigating some small complexes where a molecule of water is used as a probe to reveal the changes on the electrostatic potential of different fluorinated compounds: 2-fluoropyridine, 3-fluoropyridine and penta-fluoropyridine. While in the case of the molecular complex between water and 2-fluoropyridine and 3-fluoropyridine the geometry of the complex with one water molecule is analogous to that of pyridine with the water molecule linked to the pyridine nitrogen, the case of pentafluoropyridine reveals the effect of perfluorination and the water oxygen points towards the positive center of the pyridine ring. Additional molecular adducts with a molecule of water have been analyzed (benzylamine-water and acrylic acid-water) in order to reveal the stabilizing driving forces that characterize these complexes

Structure, Dynamics, and Accurate Laboratory Rotational Frequencies of the Acrylonitrile–Methanol Complex

The hydrogen-bonded complex between acrylonitrile (CH2=CHCN) and methanol has been characterized spectroscopically in the millimeter wave range (59.6-74.4 GHz) using a free jet absorption millimeter wave spectrometer. Precise values of the rotational and centrifugal distortion constants were obtained from the measured frequencies of the complex of acrylonitrile with CH3OH and CD3OD. The analysis of the splittings of the rotational lines due to the hindered internal rotation of the methanol methyl group led to the determination of a V-3 value of 221.9(7) and 218(5) cm(-1) for the complexes of CH3OH and CD3OD, respectively, and these values are about 40% lower than that of free methanol. The structure of the observed conformation is in agreement with the global minimum determined at the MP2/aug-cc-pVTZ level of calculation, and the counterpoise corrected intermolecular binding energy, obtained at the same theoretical level, is D-e = 26.3 kJ mol(-1)We thank the University of Bologna for funding (RFO). C.C. acknowledges the Spanish Government (MINECO, Project Code CTQ2017-89150-R) for a postdoctoral contract. W.D.G. acknowledges support from the Swedish Research Council (Vetenskapsradet), Grant Number 2019-04332. We thank R. A. Boto and J. Contreras-Garcia for the availability of the NCI 2D plot script

A Competition between Relative Stability and Binding Energy in Caffeine Phenyl-Glucose Aggregates: Implications in Biological Mechanisms

Hydrogen bonds and stacking interactions are pivotal in biological mechanisms, although their proper characterisation within a molecular complex remains a difficult task. We used quantum mechanical calculations to characterise the complex between caffeine and phenyl-β-D-glucopyranoside, in which several functional groups of the sugar derivative compete with each other to attract caffeine. Calculations at different levels of theory (M06-2X/6-311++G(d,p) and B3LYP-ED=GD3BJ/def2TZVP) agree to predict several structures similar in stability (relative energy) but with different affinity (binding energy). These computational results were experimentally verified by laser infrared spectroscopy, through which the caffeine·phenyl-β-D-glucopyranoside complex was identified in an isolated environment, produced under supersonic expansion conditions. The experimental observations correlate with the computational results. Caffeine shows intermolecular interaction preferences that combine both hydrogen bonding and stacking interactions. This dual behaviour had already been observed with phenol, and now with phenyl-β-D-glucopyranoside, it is confirmed and maximised. In fact, the size of the complex’s counterparts affects the maximisation of the intermolecular bond strength because of the conformational adaptability given by the stacking interaction. Comparison with the binding of caffeine within the orthosteric site of the A2A adenosine receptor shows that the more strongly bound caffeine·phenyl-β-D-glucopyranoside conformer mimics the interactions occurring within the receptor.Grants PGC2018-098561 and PID2021-127918NB-I00 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”. Grant IT1491-22 funded by the Basque Government

π-Stacking Isomerism in Polycyclic Aromatic Hydrocarbons: The 2-Naphthalenethiol Dimer

Producción Científicaπ-Stacking is a common descriptor for face-to-face attractive forces between aromatic hydrocarbons. However, the physical origin of this interaction remains debatable. Here we examined π-stacking in a model homodimer formed by two thiol-substituted naphthalene rings. Two isomers of the 2-naphthalenethiol dimer were discovered using rotational spectroscopy, sharing a parallel-displaced crossed orientation and absence of thiol–thiol hydrogen bonds. One of the isomers presents C2 symmetry, structurally analogous to the global minimum of the naphthalene dimer. The experimental data were rationalized with molecular orbital calculations, revealing a shallow potential energy surface. Noncovalent interactions are dominated by dispersion forces according to SAPT energy decomposition. In addition, the reduced electronic density shows a diffuse and extended region of inter-ring interactions, compatible with the description of π-stacking as a competition between dispersion and Pauli repulsion forces

Material solidoen deskonposizio termikoan igortzen diren molekula txikien determinazioa mikrouhin-espektroskopiaren bidez

The qualitative determination of small molecules that reach the gas phase after the thermal decomposition of solar cell materials, have been carried out by means of microwave spectroscopy (MW). In this case, the evidence of small molecule tracers after the thermal decomposition of pervoskites (CH3NH3PbI3) has been proved thanks to the combination between rotational spectroscopy and supersonic expansion. The results are in good agreement with those previously obtained from other techniques, and this demostrates the ability of microwave spectroscopy to perform satisfactorly as analytical tool.; Mikrouhin-espektroskopiaren (MW) oinarriak eta sistema esperimentalen oinarrizko funtsak emanez, materialen deskonposizio termikoetan gas eran igortzen diren molekula txikien determinazio kualitatiboa burutu daitekeela frogatu da. Adibide modura, errotazio-espektroskopiaren eta hedapen supersonikoaren konbinaketaren bidezko etorkizuneko eguzki-zeluletan erabil daitekeen metilamonio berun triioduroa (CH3NH3PbI3) perovskiten deskonposizio termikoan sortzen diren molekula txikien determinazio zehatza egin da. Lortutako emaitzak aurretik bestelako teknikekin lortutako emaitzekin bat datozela ikusi da, prozedura honen baliagarritasuna erakutsiz eta mikrouhin-espektroskopia teknika analitiko moduan erabil daitekeela erakutsiz

1,4-disubstituted-1,2,3-triazole compounds induce ultrastructural alterations in leishmania amazonensis promastigote: An in vitro antileishmanial and in silico pharmacokinetic study

Funding Information: This research was funded by the Coordination for the Improvement of Higher Education Personnel (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior do Brazil; CAPES) grant number Finance Code 001; and the Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro (Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro; FAPERJ) grant number E-26/010.001759/2019. The APC was funded by the Oswaldo Cruz Institute (Instituto Oswaldo Cruz; IOC). Dr. Fernando Almeida-Souza is a postdoctoral researcher fellow of CAPES grant number 88887.363006/2019-00. Dra. Ana Lucia Abreu-Silva is a research productivity fellow of National Scientific and Technological Development Council (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico; CNPq) grant number 309885/2017-5.The current standard treatment for leishmaniasis has remained the same for over 100 years, despite inducing several adverse effects and increasing cases of resistance. In this study we evaluated the in vitro antileishmanial activity of 1,4-disubstituted-1,2,3 triazole compounds and carried out in silico predictive study of their pharmacokinetic and toxicity properties. Ten compounds were analyzed, with compound 6 notably presenting IC50: 14.64 ± 4.392 µM against promastigotes, IC50: 17.78 ± 3.257 µM against intracellular amastigotes, CC50: 547.88 ± 3.256 µM against BALB/c peritoneal macrophages, and 30.81-fold selectivity for the parasite over the cells. It also resulted in a remarkable decrease in all the parameters of in vitro infection. Ultrastructural analysis revealed lipid corpuscles, a nucleus with discontinuity of the nuclear membrane, a change in nuclear chromatin, and kinetoplast swelling with breakdown of the mitochondrial cristae and electron-density loss induced by 1,4-disubstituted-1,2,3-triazole treatment. In addition, compound 6 enhanced 2.3-fold the nitrite levels in the Leishmania-stimulated macrophages. In silico pharmacokinetic prediction of compound 6 revealed that it is not recommended for topical formulation cutaneous leishmaniasis treatment, however the other properties exhibited results that were similar or even better than miltefosine, making it a good candidate for further in vivo studies against Leishmania parasites.publishersversionpublishe

The Role of Non-Covalent Interactions on Cluster Formation: Pentamer, Hexamers and Heptamer of Difluoromethane

The role of non-covalent interactions (NCIs) has broadened with the inclusion of new types of interactions and a plethora of weak donor/acceptor partners. This work illustrates the potential of chirped-pulse Fourier transform microwave technique, which has revolutionized the field of rotational spectroscopy. In particular, it has been exploited to reveal the role of NCIs' in the molecular self-aggregation of difluoromethane where a pentamer, two hexamers and a heptamer were detected. The development of a new automated assignment program and a sophisticated computational screening protocol was essential for identifying the homoclusters in conditions of spectral congestion. The major role of dispersion forces leads to less directional interactions and more distorted structures than those found in polar clusters, although a detailed analysis demonstrates that the dominant interaction energy is the pairwise interaction. The tetramer cluster is identified as a structural unit in larger clusters, representing the maximum expression of bond between dimers.We thank MINECO (CTQ2017-89150-R), Basque Government (IT1162-19 and PIBA2018-11), the UPV/EHU (PPG17/10, GIU18/207), CSIC (2018FR0036, LINKA20249), University of Bologna (RFO), Fondazione CARISBO (2018/0353) and NSF (CHE-1903871 and CHE-2018427) for the financial support. C.C thanks MINECO for a Juan de la Cierva contract. L.E. was supported by Marie Curie fellowship PIOF-GA-2012-32840

ANALISIS KEMAMPUAN BERFIKIR ALJABAR DI KELAS VII SMP NEGERI 1 KRANGKENG KABUPATEN INDRAMAYU (Studi Survei di Kelas VII Tahun Akademik 2012/2013)

Setiati Rahayu, 2013. Analisis Kemampuan Berfikir Aljabar di Kelas VII di SMP Negeri 1 Krangkeng Kab. Indramayu (Studi Survei di Kelas VII Tahun Akademik 2012/2013) Untuk mengukur kemampuan berfikir aljabar seorang siswa diperlukan beberapa indikator. Terdapat beberapa indikator untuk memahami aljabar diantaranya memahami pengertian koefisien variabel suku sejenis, kemampuan melakuakan operasi hitung, kemampuan mengggunakan simbol matematika, kemampuan menggunakan bahasa sehari-hari, kemampuan menyederhanakan operasi aljabar, kemampuan menyatakan berbagai hubungan, kemampuan menggunakan diagram alur dan memahami konsep aljabar invers. Tujuan dalam penelitian ini untuk menganalisis kemampuan berfikir aljabar di kelas VII yang ditinjau dari operasi aljabar, penggunaan aljabar, masalah aljabar, dan pemahaman konsep aljabar saat menjawab soal-soal aljabar. Kemampuan siswa dalam memahami aljabar merupakan suatu kondisi yang terdapat dalam sekolah SMP tersebut. Aljabar adalah suatu cabang ilmu matematika yang menggunakan tandatanda dan huruf-huruf yang mewakili angka-angka. Banyaknya indikator yang menjadi indikator kemampuan aljabar, maka akan ada beberapa indikator yang akan menjadi komponen utama dalam kemampuan aljabar. Untuk mengetahui kemampuan siswa dalam memahami aljabar, tidak perlu semua indikator pada\ud materi aljabar diujikan dalam tes. Mengetahui sangat pentingnya komponen utama dalam materi aljabar untuk mengukur kemampuan berfikir aljabar seorang siswa maka peneliti mencoba menganalisis kemampuan berfikir aljabar siswa kelas VII di SMPN 1 Krangkeng. Teknik pengumpulan data yang digunakan dalam penelitian ini adalah tes. Populasi dalam penelitian ini adalah Kelas VII yang berjumlah (160 siswa). Sampel diambil dari kelas VIIB cluster random sampling. Untuk uji coba dilakukan di kelas VIIA yang berjumlah 32. Dari hasil penelitian diperoleh hasil sebagai berikut: 1) Aljabar di SMP N 1 Krangkeng cukup baik hal ini ditunjukan dengan nilai rata-rata 75. 2) Indikator kemampuan berfikir aljabar secara mekanisme dan indikator Kemampuan terbesar yang dicapai oleh siswa kelas VII SMP Negeri 1 Krangkeng tahun ajaran 2012/2013 dalam memahami aljabar adalah pada pengertian koefisien, variabel, konstanta, faktor, suku sejenis adalah sebesar 89.58% dan kemampuan yang kurang dikuasai oleh siswa kelas VII SMP Negeri 1 Krangkeng tahun ajaran 2012/2013 dalam memahami aljabar adalah memahami invers adalah sebesar 85.94%. 3) Dari delapan indicator kemampuan berfikir aljabar ada tiga komponen yang dominan yaitu menggunakan diagram alur, pengertian koefisien variable konstanta, faktor suku sejenis, dan menyederhanakan operasi aljaba