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Phase relations in the pseudo-binary systems RFeO 3 -R 2 Ti 2 O 7 (R: Lu, Ho and Dy), RGaO 3 -R 2 Ti 2 O 7 (R: Lu and Er), LuAlO 3 -Lu 2 Ti 2 O 7 and RAO 3 -R 2 Ti 2 O 7 (R: Lu and Yb. A: Cr and Mn) at elevated temperatures in air were determined by means of a classic quenching method. There exist Lu(Fe 1−x Ti x )O 3+x/2 , R(Ga 1−x Ti x )O 3+x/2 (R: Lu and Er) and Lu(Al 1−x Ti x )O 3+x/2 (2/3≤ x≤3/4) having the Yb(Fe 1−x Ti x )O 3+x/2 -type of crystal structure (x=0.72, space group: R 3 m , a(A)=17.9773 and c(A)=16.978 as a hexagonal setting) in these pseudo binary systems. Eighteen compounds R(A 1−x Ti x )O 3+x/2 (R: Lu-Sm and Y, A: Fe, Ga and Al) were newly synthesized and their lattice constants as a hexagonal setting were measured by means of the X-ray powder diffraction method. The R occupies the octahedral site and both A and Ti does the trigonalbipyramidal one in these compounds. Relation between lattice constants for the rhombic R(A 1−x Ti x )O 3+x/2 and the monoclinic In(A 1−x Ti x )O 3+x/2 are as follows, a h ≈5 x b m , c h ≈3 x c m x sin β and a m =3 1/2 x b m , where a h and c h are the lattice constants as a hexagonal setting for R(A 1−x Ti x )O 3+x/2 and a m , b m , c m and β are those of the monoclinic In(A 1−x Ti x )O 3+x/2 . Crystal structural relationships among α-InGaO 3 (hexagonal, high pressure form, space group: P 63/ mmc ), InGaO 3 (rhombic, hypothetical), (RAO 3 ) n (BO) m and RAO 3 (ZnO) m (R: Lu-Ho, Y and In, A: Fe, Ga, and Al, B: divalent cation element, m, n: natural number), the orthorhombic-and monoclinic In(A 1−x Ti x )O 3+x/2 (A: Fe, Ga, Al, Cr and Mn) and the hexagonal-and rhombic R(A 1−x Ti x )O 3+x/2 (R: Lu-Sm and Y, A: Fe, Ga and Al) are schematically presented. We concluded that the crystal structures of both the α-InGaO 3 (high pressure form, hexagonal, space group: P 63/ mmc ) and the hypothetical InGaO 3 (rhombic) are the key structures for constructing the crystal structures of these compounds having the cations with CN=5.

In the structure of the title compound, cooperative C—H⋯O=C, C—H⋯π and offset π–π inter­actions generate supra­molecular nanotubes which accommodate the 2,3-di­chloro­benzene solvent mol­ecules., The asymmetric unit of the title compound, C56H50N6O8S2·3C6H4Cl2, contains two half-mol­ecules of the parent, A and B, which both have crystallographic inversion symmetry, together with three 2,3-di­chloro­benzene mol­ecules of solvation. Mol­ecules A and B are conformationally similar, with dihedral angles between the central naphthalenedi­imide ring and the peripheral naphthalene and benzyl rings of 2.43 (7), 81.87 (7)° (A) and 3.95 (7), 84.88 (7)° (B), respectively. The conformations are stabilized by the presence of intra­molecular π–π inter­actions between the naphthalene ring and the six-membered di­imide ring of the central naphthalenedi­imide moiety, with ring centroid-to-centroid distances of 3.5795 (8) Å (A) and 3.5640 (8) Å (B). In the crystal, C—H⋯O hydrogen bonds link the mol­ecules into infinite supra­molecular chains along the c axis. These chains are inter­connected through C—H⋯π and offset π–π inter­actions, generating supra­molecular nanotubes which are filled by 1,2-di­chloro­benzene mol­ecules.

Fluorescent responses and conformational changes against pH were studied on four new water-soluble 1-pyrene and 1-methylpyrene bichromophores, (ttha1py)H4, (edta1mpy)H2, (dtpa1mpy)H3 and (ttha1mpy)H4, with the objective of modifying pH–fluorescence profiles and other solution properties of 1-pyrene bichromophores, (edta1py)H2 and (dtpa1py)H3, developed previously by our group; the abbreviations with acidic protons stand for pyrenyl moieties interlinked by an EDTA, DTPA (diethylenetriaminepentacetic acid) or TTHA (triethylenetetraminehexaacetic acid) chain through amide linkages. The new derivatives exhibit emission bands of monomeric pyrene and an intense structureless excimer band; the latter responds to pH sensitively. The pH dependence of the emission intensity of the DTPA and TTHA derivatives is well correlated with species distribution determined by potentiometry. In every derivative, the completely deprotonated species Ln− is the most efficient for excimer emission, followed by the corresponding monoprotonated species LH(n−1)−. In the latter, the acidic hydrogen is located on the central amine, as confirmed by 1H NMR. The resulting hydrogen bond between amino nitrogen atoms makes the aliphatic chain rigid. Further protonation stretches the interlinking chain due to electrostatic repulsion. These conformational changes with protonation result in fluorescent on–off cycles against pH window. The switching cycles of the methylpyrene derivatives are reverse to those of the corresponding pyrene derivatives, as the CH2 spacer between the amide and aromatic groups defines the orientation of pyrene rings. The sensitiveness of amide group to environment leads to a sharp change in excimer emission above pH ∼11. The combined functions of amide and amino groups lead to the novel pH-responses.

The title compound possesses twofold rotation symmetry, with the planes of the phthalimide moieties inclined to one another by 73.53 (7)° and by 78.62 (9)° to that of the urea unit. In the crystal, mol­ecules are linked via N—H⋯O and O—H⋯O hydrogen bonds, forming a three-dimensional framework structure., The whole mol­ecule of the title compound, C17H10N4O5·2H2O, is generated by twofold rotation symmetry and it crystallized as a dihydrate. The planes of the phthalimide moieties and the urea unit are almost normal to one another, with a dihedral angle of 78.62 (9)°. In the crystal, mol­ecules are linked by N—H⋯O and O—H⋯O hydrogen bonds, forming a three-dimensional framework structure. The crystal packing also features C—H⋯O hydrogen bonds and slipped parallel π–π inter­actions [centroid–centroid distance = 3.6746 (15) Å] involving the benzene rings of neighbouring phthalimide moieties.

Five hydrazone derivatives of streptomycin were synthetized (D0h, D1ph, D2bt, D3dctf, D4ag) and characterized by IR, 1H and 13C NMR spectroscopy, mass spectrometry and elemental analysis. Protonation constants were determined by potentiometry for all derivatives. D1ph and D2bt derivatives were investigated as receptors of dicarboxylates and adenine nucleotides in aqueous solution by potentiometric and 1H NMR titrations. D1ph and D2bt derivatives have the highest affinity with AMP and ATP, respectively, which shows that electrostatic forces are not always the dominant factor in binding of streptomycin derivatives with nucleotides, but the conformational fit between them. Calculated structures at the DFT level of the D1ph derivative bonded with either AMP or ADP showed that the complexes are stabilized by the formation of multiple interactions with the receptors. The antibiotic activity of the derivatives was explored and compared with native streptomycin.

Dicationic N-methylated at pyridyl or quinolyl moieties derivatives of three isomers of N,N'-bis(pyridyl)pyridine-2,6-dicarboxamide (o-, m-, and p-1) and of N,N'-bis(3-quinolyl)pyridine-2,6-dicarboxamide (4) strongly bind anions in MeCN (log K in the range 3.5-6.5) with pronounced selectivity for Cl(-) and also bind neutral urea and amide guests with log K in the range 1.1-2.8. Crystal structures of the triflate salts of m-1, p-1, and 4 show that amide NH and pyridinium o-CH groups are directed inside the receptor cleft with their four protons forming a circle of radius ca. 2.35 A optimal for inclusion of Cl(-). The binding of anions to these protons is evident from the crystal structure of a mixed triflate/chloride salt of p-1, calculated (DFT/B3LYP 6-31G**) structures of 1:1 complexes of all receptors with Cl(-), and results of (1)H NMR titrations. In the crystal structure of o-1 pyridinium N-Me(+) groups are directed inside the receptor cleft impeding the anion complexation, but calculations demonstrate that simple rotation of pyridinium rings in opposite directions by ca. 30 degrees creates a cavity to which the Cl(-) ion can fit forming 4 hydrogen bonds to amide NH and aliphatic CH groups of N-Me(+). The results of (1)H NMR titrations confirm this type of binding in solution. Anions quench the intense fluorescence of 4, which allows their fluorescent sensing in the muM range. A new methodology for determination of anion binding constants to strongly acidic receptors by inhibitory effects of anions on the receptor deprotonation by an external base has been developed. High affinity and selectivity of anion complexation by dicationic pyridine-2,6-dicarboxamides is attributed to the rigid preorganized structure of receptors, the high acidity of NH and CH groups, and the electrostatic charge effect.

Protonation of an aminoglycoside antibiotic kanamycin A sulfate was studied by potentiometric titrations at variable ionic strength, sulfate concentration and temperature. From these results the association constants of differently protonated forms of kanamycin A with sulfate and enthalpy changes for protonation of each amino group were determined. The protonation of all amino groups of kanamycin A is exothermic, but the protonation enthalpy does not correlate with basicity as in a case of simple polyamines. The sites of stepwise protonation of kanamycin A have been assigned by analysis of 1 H– 13 C–HSQC spectra at variable pH in D 2 O. Plots of chemical shifts for each H and C atom of kanamycin A vs. pH were fitted to the theoretical equation relating them to p K a values of ionogenic groups and it was observed that changes in chemical shifts of all atoms in ring C were controlled by ionization of a single amino group with p K a 7.98, in ring B by ionization of two amino groups with p K a 6.61 and 8.54, but in ring A all atoms felt ionization of one group with p K a 9.19 and some atoms felt ionization of a second group with p K a 6.51, which therefore should belong to amino group at C3 in ring B positioned closer to the ring A while higher p K a 8.54 can be assigned to the group at C1. This resolves the previously existed uncertainty in assignment of protonation sites in rings B and C.

In the title compound, C14H10N2O2, the phtalimide and 2-pyridylmethyl units are almost perpendicular, with an interplanar angle of 85.74 (2)°. In the crystal, molecules are linked by weak C—H...O interactions, forming chains running along the b axis. The packing is further stabilized by offset π–π interactions between adjacent pyridine rings, with a centroid–centroid distance of 3.855 (2) Å.

A protonated cation salt of title compound C36H48N8O12 crystallized in the monoclinic space group with cell parameters a = 11.4721(8)A, b = 23.1049(16)A, c = 21.0730(14)A, β = 99.0040(10)° and Z = 4; the final residual factor was 0.0582 with 9694 reflections. A cyclophane conformation was determinated by an interplay between the ridigidy of amide and phenyl groups and the presence of intramolecular hydrogen bonds and C-H…π interactions.

Five hydrazone derivatives of streptomycin were synthetized (D0h, D1ph, D2bt, D3dctf, D4ag) and characterized by IR, 1H and 13C NMR spectroscopy, mass spectrometry and elemental analysis. Protonation constants were determined by potentiometry for all derivatives. D1ph and D2bt derivatives were investigated as receptors of dicarboxylates and adenine nucleotides in aqueous solution by potentiometric and 1H NMR titrations. D1ph and D2bt derivatives have the highest affinity with AMP and ATP, respectively, which shows that electrostatic forces are not always the dominant factor in binding of streptomycin derivatives with nucleotides, but the conformational fit between them. Calculated structures at the DFT level of the D1ph derivative bonded with either AMP or ADP showed that the complexes are stabilized by the formation of multiple interactions with the receptors. The antibiotic activity of the derivatives was explored and compared with native streptomycin.

Two bis crown ether receptors were synthesized and tested as host molecules for protonated forms of alkyl amines and amino acid esters. Molecular recognition studies were conducted in CH2Cl2:MeOH (92:8) by spectrophotometric UV/Vis titrations andby spectrometric 1H NMR titrations in CDCl3. The calculated binding constants are in the range 102-105 M-1. A high affinity for L-amino acid methyl ester derivatives was found. A theoretical study at the DFT level of the synthesized receptor and some analog ligands with three different ammonium ions helps to rationalize the experimentally found trends.

RESUMEN En este proyecto de tesis se presenta el estudio de reconocimiento molecular de aniones por nuevos derivados aromáticos del antibiótico natural espiramicina, que es un compuesto perteneciente a la familia de los macrólidos y que presenta muchas de las características adecuadas para funcionar como un buen receptor de aniones, ya que posee dos aminoazúcares cargados positivamente en pH ácido, así como grupos hidrofóbicos e hidrofílicos y una gran cantidad de centros quirales. Sin embargo, carece de grupos aromáticos que le confieran propiedades fotofísicas de absorción y que pudieran favorecer interacciones  con las unidades aromáticas de los aniones estudiados AMP, ADP y ATP. Se llevó a cabo la síntesis de cuatro nuevos derivados de espiramicina 1a-d introduciendo aminas con fragmentos aromáticos tales como: bencilo (1a), 2-metil-piridina (1b), 1-metil-natftilo (1c) y 1-metil-pirenilo (1d) mediante reacción de aminación reductiva del grupo aldehído de la espiramicina. Los derivados fueron completamente caracterizados mediante RMN (1H, 13C) y espectrometría de masas (HRMS). La adición de fragmentos aromáticos a la espiramicina se hizo con la finalidad de estudiar las propiedades fotofísicas de los nuevos derivados por la técnica espectrofotométrica UV-visible. Posteriormente, se llevaron a cabo estudios para la determinación de las constantes de protonación (pKa´s) de los derivados 1a-c por la técnica de potenciometría. Adicionalmente, las constantes de protonación calculadas para el derivado 1b fueron asignadas mediante titulación potenciométrica seguida por RMN 1H en D2O. Se realizaron estudios de reconocimiento molecular por potenciometría para la determinación de las constantes de asociación de 1a-c con huéspedes aniónicos de estructura diversa; en donde, el compuesto 1a reconoció selectivamente a los aniones fosfatados en el siguiente orden ADP > ATP > AMP > pirofosfato > fosfato, con constantes de magnitud log K = 4.82 - 3.34. Por otro lado, también se observó la asociación de 1a con dicarboxilatos, observándose una mayor afinidad por pimelato sobre adipato (log K = 4.80 v y 4.56, respectivamente). La tendencia de selectividad para los complejos formados por 1b con la misma serie de aniones fue: pirofosfato > fosfato > ATP > AMP > ADP (log K = 4.16- 2.67); mientras que con la serie de ácidos dicarboxílicos la selectividad fue: succinato > adipato > pimelato > suberato (log K = 3.27 – 3.03). Finalmente, para el receptor 1c sólo se estudió la serie de nucleótidos de adenina, cuya tendencia para la complejación fue: ATP > ADP > AMP (log K = 6.40 – 4.10). Adicionalmente, por ITC se determinaron los parámetros termodinámicos para la formación del complejo 1b-ATP. No obstante, por medio de UV-visible no fue posible determinar las constantes de asociación entre los derivados 1c-d con los nucleótidos de adenina. Se llevaron a cabo titulaciones por RMN 1H y 31P en D2O entre el derivado 1b con los aniones ATP y ADP con el fin de conocer los sitios de interacción en los complejos formados. Los valores de CIS calculados indicaron que dichos complejos se forman principalmente por interacciones de puente de hidrógeno entre los grupos amino protonados del receptor y los grupos fosfato de los nucleótidos, lo cual fue confirmado mediante estudios de química computacional a nivel de mecánica molecular. De este trabajo se concluye que el derivado bencil espiramicina 1a, mostró mayor afinidad hacia ATP y pirofosfato; mientras que el derivado 2-picolil espiramicina 1b mejoró su capacidad en el reconocimiento molecular únicamente hacia el pirofosfato y el derivado naftil espiramicina 1c potencializó su afinidad hacia ATP, todas ellas en comparación con las reportadas por espiramicina. El derivado 1a también mostró constantes de asociación más altas hacia los aniones dicarboxilato, como adipato y pimelato en comparación con las obtenidas por espiramicina. Cabe destacar que estas constantes se obtuvieron mediante la técnica de potenciometría, la cual nos permitió trabajar con mezclas acuosas para disolver mejor los derivados, arrojando valores de constantes más confiables. La técnica de ITC únicamente permitió trabajar con compuestos solubles en agua, por lo cual el derivado 1b fue el único que se estudió bajo esta técnica, determinándose los valores termodinámicos para el complejo 1b - ATP. Finalmente, por espectrofotometría con la técnica de UV-visible sólo fue posible trabajar con los derivados 1c-d, los cuales presentaron absorbancias significativas debido a la presencia de grandes grupos aromáticos. ABSTRACT In this work, the study of the anion molecular recognition by new derivatives of spiramycin is presented. Spiramycin is a natural antibiotic of the macrolide family and has many of the adequate characteristics to work as an efficient receptor for anions, including two aminosugar moieties with a positive charge at acidic pH, hydrophobic and hydrophilic groups as well as several chiral centers. However, spiramycin lacks aromatic groups that can confer photophysical properties of light emission/absorption or the ability to establish - interactions with anions such as AMP, ADP or ATP. The synthesis of four new derivatives 1a-d was carried out by reductive amination of the spiramycin aldehyde group to link aromatic moieties, such as benzyl (1a), 2-methyl-pyridyl (1b), 1-methyl-naphthyl (1c) and 1-methyl-pyrenyl (1d). The compounds 1a-d were fully characterized by 1H, and 13C NMR and mass spectrometry (HRMS). The aim of introducing aromatic fragments into the structure of spiramycin was to study the photophysical properties of the new derivatives by UV-vis spectrophotometry. Later, studies for the determination of protonation constants (pKa´s) of the derivatives by potentiometry were carried out. Additionally, the determined protonation constants for 1b were assigned unequivocally by 1H NMR titrations in D2O. Molecular recognition studies to determine the association constants between 1a-c with diverse anionic guests were carried out by potentiometry. Compound 1a selectively recognized phosphate anions in the order ADP > ATP > AMP > pyrophosphate, phosphate with association constant in the range log K = 4.82 - 3.34. In another side, the association of 1a with dicarboxylates also was observed, in this case a higher affinity for pimelate over adipate (log K = 4.80 and 4.56, respectively) was observed. The selectivity trend for the complexes formed between 1b and the same anion series was: pyrophosphate > phosphate > ATP > ADP > AMP (log K = 4.16 - 2.67); while with the studied dicarboxylates the selectivity followed the order: succinate > adipate > pimelate > suberate (log K = 3.27 – 3.03). Finally, receptor 1c was only studied with adenine nucleotides, which vii form complexes in the affinity trend: ATP > ADP > AMP (log K = 6.40 – 4.10). Besides, the thermodynamic parameters of the association between 1b-ATP were determined by ITC. The determination of association constants between the receptors 1c-d and nucleotides was not possible by UV-vis spectroscopy. In order to determine the interaction sites in the structure complexes formed between 1b derivative with ATP and ADP nucleotides, some 1H and 31P NMR titrations were performed. The calculated CIS values indicated that these complexes are formed by hydrogen bonds between the protonated amino groups of the receptor and phosphate moieties of the nucleotides, which was confirmed by molecular mechanic computational studies. In conclusion, compared with spiramycin, the benzyl spiramycin derivative 1a, has the highest affinity toward ATP and pyrophosphate; while 2-picolyl spiramycin, 1b improved its molecular recognition ability towards pyrophosphate and naphthyl spiramycin derivative 1c showed a higher affinity for ATP. Derivative 1a also showed higher association constants with dicarboxylates as pimelate and adipate in comparison with spyramycin. It´s essential to remark that constants obtained by potentiometry in aqueous solution in this study are trustworthy. Because of the ITC equipment only allows to work with substances totally dissolved in water; just the derivative 1b was studied by this technique, where the thermodynamic parameters for the 1b-ATP complex were determined. Finally, complexes with the derivatives 1c-d were analyzed by UV-Vis spectrophotometry due to the strong absorption of the aromatic groups present in the structure of the derivatives.