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- Unravelling the structure of peroxides with antiparasitic activity: the relative impact of a trioxolane or a tetraoxane pharmacophore on the overall molecular structurePublication . Amado, Patrícia; Jesus, A. J. Lopes; Paixão, José A.; Fausto, Rui; Cristiano, Maria De LurdesPlasmodium falciparum artemisinin-resistance boosted the quest for novel plasmodial "fast killers," uncovering antimalarial candidates OZ439 and E209, whose peroxide precursors are 1,2,4-trioxolane (1) and 1,2,4,5-tetraoxane (2), differing solely in the pharmacophore (trioxolane or tetraoxane). Combining X-ray crystallography and vibrational spectroscopy, along with Hirsh-feld surface analysis and calculations (CE-B3LYP/6-31G(d,p)) of pairwise interaction energies of intermolecular contacts existing in the crystal structure, may deepen the understanding of relative reactivity and properties of these endoperoxides classes. In the crystal, the tetraoxane ring in 2 and the trioxolane-adamantyl fragment in 1 are disordered, with molecules 1 and 2 existing as two distinct, stable conformations. Whereas the dominant C-H center dot center dot center dot O H-bonds in 1 connect an adamantyl C-H and O1 or O2 of the trioxolane ring, in 2 they involve the carbonyl oxygen, acting as a double acceptor from phenyl ring C-H groups. C-H center dot center dot center dot O and C-H center dot center dot center dot pi H-bonds define the molecular packing of 2, while C-H center dot center dot center dot H-C van der Waals interactions determine the packing of 1. The dispersive component dominates the interaction energies calculated for the most representative molecular pairs.
- Palladium-catalysed reduction of heteroaromatic naphthyl ethers: structural effects on reactivityPublication . Frija, L.; Cristiano, Maria Lurdes Santos; Guimarães, Emanuel M. O.; Martins, Nelson C.; Loureiro, Rui M. S.; Bickley, Jamie F.Tetrazolyl and benzisothiazolyl naphthylmethylic ethers 3 and 4(a–e) are stable crystalline compounds that can be synthesised in high yields by reaction of the corresponding naphthyl methanols (1a–e) with the derivatizing agents 2a and 2b. Experimental conditions for palladium-catalysed hydrogenolysis of ethers 3, 4, with a hydrogen donor and with molecular hydrogen, were investigated. Analysis of the structure and reactivity indicates that naphthylmethylic ethers 3 and 4 are structurally similar to the corresponding benzyloxyderivatives around the ether bond but exhibit different reactivity. Structural analysis for these compounds is based on crystallographic structure determinations, for 5-(2-naphthylmethoxy)-1-phenyltetrazole (3a) and 3-(2-naphthylmethoxy)-1,2-benzisothiazole 1,1-dioxide (4a), and molecular orbital DFT(B3LYP)/6-311G(d) calculations, for all ethers. It can be concluded from this investigation that 5-chloro-1-phenyltetrazole 2a acts as a better derivatizing agent for naphthyl methanols than 3-chloro-1,2-benzisothiazole-11-dioxide 2b, this contrasting with what has been observed with phenols, allylic and benzylic alcohols.
- Ultrasensitive gold micro-structured electrodes enabling the detection of extra-cellular long-lasting potentials in astrocytes populationsPublication . Mestre, Ana L. G.; Cerquido, Monica; INÁCIO, PEDRO; Asgarifar, Sanaz; Lourenco, Ana S.; Lurdes S. Cristiano, M.; Aguiar, Paulo; Medeiros, Maria C. R.; Araújo, Inês; Ventura, Joao; Gomes, Henrique L.Ultra-sensitive electrodes for extracellular recordings were fabricated and electrically characterized. A signal detection limit defined by a noise level of 0.3-0.4 mu V for a bandwidth of 12.5 Hz was achieved. To obtain this high sensitivity, large area (4 mm(2)) electrodes were used. The electrode surface is also micro-structured with an array of gold mushroom-like shapes to further enhance the active area. In comparison with a flat gold surface, the micro-structured surface increases the capacitance of the electrode/electrolyte interface by 54%. The electrode low impedance and low noise enable the detection of weak and low frequency quasi-periodic signals produced by astrocytes populations that thus far had remained inaccessible using conventional extracellular electrodes. Signals with 5 mu V in amplitude and lasting for 5-10 s were measured, with a peak-to-peak signal-to-noise ratio of 16. The electrodes and the methodology developed here can be used as an ultrasensitive electrophysiological tool to reveal the synchronization dynamics of ultra-slow ionic signalling between non-electrogenic cells.
- Vibrational spectra and structure of 1-phenyltetrazole and 5-chloro-1-phenyltetrazolePublication . Bugalho, Susana C. S.; Lapinski, L.; Cristiano, Maria Lurdes Santos; Frija, L.; Fausto, R.Infrared spectra of 1-phenyltetrazole (C7N4H6) and 5-chloro-1-phenyltetrazole (C7N4H5Cl) isolated in argon matrixes (T ¼ 8 K) and in the solid state (at room temperature) were studied. DFT(B3LYP)/6-31G* calculations predict the minimum energy conformation of 1-phenyltetrazole as being non-planar, with the two rings (phenyl and tetrazole) twisted by 298. For 5-chloro-1- phenyltetrazole, the optimized dihedral angle between the two rings is larger (488). The theoretically calculated IR spectra of both compounds fit well the spectra observed experimentally. This allowed a reliable assignment of observed IR absorption bands.
- 3-Hydroxy-2,6-dinitroacetophenone: an unusual substitution pattern resulting from nitration of 3-hydroxyacetophenonePublication . Cristiano, Maria Lurdes Santos; Johnstone, Robert A. W.; Pratt, M. J.Nitration of 3-hydroxyacetophenone gives 2,6-dinitro-3-hydroxyacetophenone, C8H6N206, in which the nitro groups have entered the sterically least favourable positions in the aromatic nucleus. None of the expected substitution in the 4-position was observed. The two nitro groups flanking the carbonyl side chain are different in that one is in the plane of the aryl ring but the other is twisted well out of the plane.
- Structural investigation of nitrogen-linked saccharinate–tetrazolePublication . Gómez-Zavaglia, A.; Ismael, Amin; Cabral, Lília; Kaczor, A.; Paixão, J. A.; Fausto, R.; Cristiano, Maria Lurdes SantosThe molecular structure of nitrogen-linked saccharinate–tetrazole, N-(1,1-dioxo-1,2-benzisothiazol-3-yl)-amine-1H-tetrazole (BAT), was investigated in the crystalline state using X-ray crystallography and infrared and Raman spectroscopies, and isolated in argon matrix by infrared spectroscopy. Interpretation of the experimental results was supported by quantum chemical calculations undertaken at the DFT(B3LYP)/6-311++G(3df,3pd) level of theory. In the neat crystalline solid (space group C2/c, a = 21.7493(3) Å, b = 8.85940(10) Å, c = 10.76900(10) Å, b = 103.3300(10) deg; Z = 8), BAT units exist in the (1H)-tetrazole aminosaccharin tautomeric form, with the NH spacer establishing a hydrogen bond to the nitrogen in position-4 of the tetrazole group of a neighbour molecule, and the NH group of the tetrazole fragment forming a bifurcated H-bond to the saccharyl nitrogen of the same molecule and to one of the oxygen atoms of a second neighbour molecule. On the other hand, according to both the matrix isolation infrared studies and the theoretical calculations, the isolated BAT molecule exists preferentially as the (1H)-tetrazole iminosaccharin tautomer, where the main stabilizing interaction is the intramolecular H-bond established between the NH group of the saccharyl ring and the tetrazole nitrogen atom in position 4. A detailed conformational analysis of the studied molecule and full assignment of the vibrational spectra for both the matrix-isolated compound and crystalline sample were undertaken.
- Structure and IR Spectra of 3(5)-Aminopyrazoles and UV-induced tautomerization in argon matrixPublication . Secrieru, Alina; Lopes, Susy; Cristiano, Maria L. S.; Fausto, RuiThe prototropic tautomerism in 3(5)-aminopyrazoles was investigated by matrix isolation infrared (IR) spectroscopy, supported by DFT(B3LYP)/6-311++G(d,p) calculations. In consonance with the experimental data, the calculations predict tautomer 3-aminopyrazole (3AP) to be more stable than the 5-aminopyrazole (5AP) tautomer (calculated energy difference: 10.7 kJ mol−1 ; Gibbs free energy difference: 9.8 kJ mol−1 ). The obtained matrix isolation IR spectra (in both argon and xenon matrices) were interpreted, and the observed bands were assigned to the tautomeric forms with help of vibrational calculations carried out at both harmonic and anharmonic levels. The matrix-isolated compound (in argon matrix) was then subjected to in situ broadband UV irradiation (λ > 235 nm), and the UV-induced transformations were followed by IR spectroscopy. Phototautomerization of the 3AP tautomer into the 5AP form was observed as the strongly prevalent reaction.
- Bond energy/eond order relationships for N-O linkages and a quantitative measure of ionicity: the rôle of nitro groups in hydrogen bondingPublication . Johnstone, Robert A. W.; Loureiro, Rui M. S.; Labat, G.; Cristiano, Maria Lurdes SantosThe nitro group is active in metabolic systems and can be found as an integral part of a number of useful curative drugs and many toxic substances. The basis for much of this activity is not fully understood. It is not necessarily caused directly by through-bond electronic effects but may also be due to direct H-bonding to nitro or to indirect interference by the nitro group with existing H-bonding. An unusual effect of a nitro substituent on kinetic results from urethane addition/elimination reactions (Scheme 1) has been ascribed to some form of self-association, which was neither specified nor quantified. To investigate self-association phenomena caused by a nitro group, a bond energy/bond order formula for N–O bonds has been developed and then used to interpret relative amounts of covalent and ionic contributions to total N–O bond energy. Calculated bond energies were then used to obtain enthalpies of formation for H-bonds to nitro groups in crystals and in solution. Similar results from solution data reveal that direct H-bonding to nitro is much weaker than in crystals, unless intramolecular H-bonding can occur. The results revealed that the 'self-association' effects observed for nitro substituents in urethanes (Scheme 1) were not caused by nitro participating directly in intermolecular bonding to NH of another urethane but by an indirect intramolecular action of the nitro group on pre-existing normal NH–O amide/amide type H-bonding.
- Molecular structure, vibrational spectra and photochemistry of 2-methyl-2 h -tetrazol-5-amine in solid argonPublication . Gómez-Zavaglia, A.; Reva, I. D.; Frija, L.; Cristiano, Maria Lurdes Santos; Fausto, R.In this work, the molecular structure, infrared spectrum and UV photochemistry of 2-methyl-2H-tetrazol-5-amine (2MTA) isolated in solid argon (10 K) were investigated. The experimental studies were supported by extensive DFT(B3LYP)/6-311++G(d,p) calculations. The infrared spectrum of matrix-isolated 2MTA was fully assigned and correlated with structural properties. Taking into consideration the observed frequency of the NH2 wagging mode, it is suggested that, in the matrixes, the amine group becomes slightly more planar than in the gas phase, due to matrix-packing effects. In situ UV irradiation (ì > 235 nm) of the matrixisolated 2MTA monomer is shown to induce three main primary photochemical processes: (1) tautomerization to mesoionic 3-methyl-1H-tetrazol-3-ium-5-aminide; (2) nitrogen elimination, with production of 1-methyl-1H-diazirene-3-amine; (3) ring cleavage leading to production of methyl azide and cyanamide. Following the primary photoproducts, secondary reactions were observed, leading to spectroscopic observation of methylenimine and isocyanidric acid.
- Photochemistry of 1-and 2-Methyl-5-aminotetrazoles: structural effects on reaction pathwaysPublication . Ismael, Amin; Fausto, R.; Cristiano, Maria Lurdes SantosThe influence of the position of the methyl substituent in 1- and 2-methyl-substituted 5-aminotetrazoles on the photochemistry of these molecules is evaluated. The two compounds were isolated in an argon matrix (15 K) and the matrix was subjected to in situ narrowband UV excitation at different wavelengths, which induce selectively photochemical transformations of different species (reactants and initially formed photoproducts). The progress of the reactions was followed by infrared spectroscopy, supported by quantum chemical calculations. It is shown that the photochemistries of the two isomers, 1-methyl-(1H)-tetrazole-5-amine (la) and 2-methyl-(2H)-tetrazole-5-amine (1b), although resulting in a common intermediate diazirine 3, which undergoes subsequent photoconversion into 1-amino-3-methylcarbodiimide (H2N-N=C=N-CH3), show marked differences: formation of the amino cyanamide 4 (H2N-N(CH3)-CE equivalent to N) is only observed from the photo cleavage of the isomer la, whereas formation of the nitrile imine 2 (H2N-C-=N+=N-CH3) is only obtained from photolysis of 1b. The exclusive formation of nitrile imine from the isomer lb points to the possibility that only the 2H-tetrazoles forms can give a direct access to nitrile imines, while observation of the amino cyanamide 4 represents a novel reaction pathway in the photochemistry of tetrazoles and seems to be characteristic of 1H-tetrazoles. The structural and vibrational characterization of both reactants and photoproducts has been undertaken.