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The interaction of pinanediol with 2-fluorophenylboronic acid and several other substituted phenylboronic acids was studied in 40% vol. aqueous acetonitrile by 1H and 11B NMR, potentiometric and spectrophotometric titrations at variable pH values. The experimental results reveal the formation of a very stable trigonal ester (Ktrig ≈ 2 × 104 M-1) and a significantly less stable tetrahedral hydroxocomplex (Ktet ≈ 5 × 103 M-1) in contrast to the traditionally observed inverted order of stabilities KtrigKtet. Comparison of the crystal structure of the trigonal ester isolated from aqueous acetonitrile with the DFT simulated structure of the respective hydroxocomplex shows that an unusual order of stabilities KtrigKtet is observed in spite of the existence of the usual strain release effect in the O-B-O angle considered responsible for the typically observed increased stability of the tetrahedral hydroxocomplex. A complementary study of the stability of the six-membered cyclic boronate esters of chromotropic acid demonstrated the order Ktrig ≪ Ktet although the strain was absent in these esters. The results for m-, p-substituted phenylboronic acids show that the stability of both five- and six-membered trigonal esters formed with pinanediol and chromotropic acid, respectively, is insensitive to electronic effects but the electron accepting substituents stabilize the hydroxocomplexes. It follows from the whole set of results that Ktet can be much larger than Ktrig in the absence of the strain, but with a sufficiently acidic diol, and that the presence of the strain does not necessarily make Ktet larger than Ktrig for a less acidic diol with a purely saturated hydrocarbon backbone. Thus, the electronic effects manifested in the acidity of the diol appear to be more significant than the strain release effect in determining the Ktet/Ktrig ratio.

Metallobacitracins are complexes with an extensive antimicrobial and biological activity. In this work, we investigated the metal complexation of bacitracin with several divalent metal ions in aqueous solution. The binding constants of Zn(2+), Cd(2+), Hg(2+), Cu(2+), Ni(2+), Pd(2+), Fe(2+), Mn(2+) and Mg(2+) to bacitracin were measured by UV/Vis spectroscopy, isotermic titration calorimetry (ITC) and potentiometry while the complexes were studied by Circular Dichroism and Nuclear Magnetic Resonance (15N HSQC) for Zn(2+), Cd(2+) and Hg(2+) at different pH. By UV/Vis spectroscopy the affinity is in the range 104 to 105 M−1 at pH 6 and follows the order Ni(2+) > Cd(2+) > Hg(2+) > Zn(2+) > Fe(2+). By potentiometry, the binding constants were determined in the pH range 2–12. Microcalorimetry shows that the stoichiometry of metallobacitracins investigated is 1:1 with binding constants in the range 105–102 M−1 at pH 6 and with an order of stability of Ni(2+) > Cd(2+) > Zn(2+) > Hg(2+); ΔS, ΔH and ΔG parameters were also determined. NMR spectroscopy lets us establish the binding site of the metal ion when comparing 15N HSQC of free bacitracin and complex in natural abundance; these findings agree with calorimetric results. Chemical shift changes in complexes containing Zn(2+) and Cd(2+) exhibit a similar behavior despite pH differences. Conversely, there is not a significant change for Hg(2+) complex. The obtained data contribute to understand the mechanism of the biological activity of the metallobacitracins and give the guideline for the design of more powerful metalloantibiotics.

Two new chlorodiorganotin(IV) dithiocarbamate complexes with general formula {(R2SnCl)dtc} (dtc = R1R2NCS2−, R1 = Bn, R2 = naphtylimide; 3, R = n-Bu; 4, R = Ph) have been prepared from sodium N-[2-(benzylamino)ethyl]naphthalene-1,8-dicarboximide dithiocarbamate 2. The bis-dithiocarbamete 3d (R2Sn(dtc)2, R = n-Bu) was obtained as the thermodynamic product during the titration process (vide infra). All compounds were characterized by mass spectrometry, IR, 1H and 13C NMR spectroscopy. The chlorodiorganotin(IV) dithiocarbamate complexes 3–4 also were characterized by 119Sn NMR spectroscopy and single crystal X-ray diffraction analysis. The crystallographic study of these complexes showed the existence of C H…π, S…π and π…π intramolecular interactions, indicating that the naphthylimide aromatic fragment stabilized the complexes. Complexes 3 and 4 were studied as host for anions (CH3CO2−, F−, H2PO4−) in CDCl3 by UV–Vis and 119Sn NMR spectrometric titrations. The tested anions cause the displacement of the chloride ligand of the metallic centre. The excess of F− or H2PO4− induce the self-assembly of diorganotin(IV) dithiocarbamate to bis-dithiocarbamates R2Sn(dtc)2 (3d) instead of the breaking of the S Sn covalent bond. Quantum mechanical calculations at DFT level (B3LYP/def2-TZVP) were performed to obtain the thermodynamic parameters of the reactions involved in the anion addition to the complexes.

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 this work the interaction of halide anions and simple aromatic compounds with a bichromophoric fluorescent dyad derived from 1,8-naphthalimide (NAPIM) and 5-(dimethylamino)naphthalene-1-sulfonyl (DANS) was studied using electronic spectroscopy, 1H, and 19F NMR spectroscopy and quantum chemistry modeling (b3lyp/def2-TZVP). The NAPIM-DANS dyad interacts with electron-rich guests with binding constants in the range of 6 × 103 to 8 × 103 M−1 in CHCl3. The formed complexes are stabilized through aryl C–H … anion and aryl C–H … π interactions.

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.

The chlorodiphenyltin(IV) dithiocarbamate complexes 1–5 with general formula {(Ph2SnCl)dtc} (dtc = R1R2NCS2−; 1, R1 = Bn, R2 = 9-anthrylmethyl; 2, R1 = Bn, R2 = 9-phenanthrylmethyl; 3, R1 = Bn, R2 = 1-pyrenylmethyl; 4, R1 = 1-naphthylmethyl, R2 = 1-pyrenylmethyl; 5, R1 = R2 1-pyrenylmethyl) have been tested as host for anions and neutral amines in acetonitrile by spectrophotometric UV/Vis titrations. In addition, the titrations of the complexes 1 and 5 were studied in chloroform by 1H and 119Sn NMR spectroscopy. It was found that anions as acetate, benzoate, and dihydrogen phosphate cause a displacement of the dithiocarbamate ligands of metallic center independently of the aromatic nature of the substituents on the nitrogen atom functioning as chemodosimeters in which the indicator is displaced. However, some aliphatic amines and aromatic methylene amines and its aromatic analogs can act as guests with binding constants in the range of 103 to 106 M−1. Also, in these cases compound 5 functions as chemodosimeter without displacement of the indicator. According to 1H, 13C, 119Sn NMR data and using DFT (B3LYP) and Poisson–Boltzmann (PB) to model the solvent, structures of the complexes are proposed in which the hydrophobic and π–π interactions are suggested as the dominant interactions.

Four new homoditopic bis[chlorodiorganotin(IV) and triorganotin(IV) dithiocarbamate] complexes derived from naphthalene diimide (NDI) with general formula NDI-[(CH2)2-N(CH2Ph)(CS2SnR2X)]2, 3: R = n-Bu, X = Cl; 4: R = Me, X = Cl; 5: R = Ph, X = Cl; 6: R = X = Me; were prepared from triethylammonium ((1,3,6,8-tetraoxo-1,3,6,8-tetrahydrobenzo[lmn][3,8]phenanthroline-2,7-diyl)bis(ethane-2,1-diyl))bis(benzylcarbamodithioate) 2. All compounds were characterized by IR, as well as 1H and 13C NMR spectroscopy. The complexes 3–6 also were characterized by 119Sn NMR spectroscopy. In addition, complex 3 was further characterized by single-crystal X-ray diffraction analysis. The crystallographic study performed on complex 3 showed that the tin atom has a coordination geometry intermediate between square-pyramid and a trigonal-bipyramidal, with τ value of 0.69. In addition the presence of cooperative C H…π, C H…S, C H…O and S…π intramolecular interactions in the crystal structure of 3 was observed. The interaction of complexes 3–6 with anions (CH3CO2−, F−, H2PO4−) in CDCl3 was studied by UV/Vis, fluorescence and 119Sn NMR titrations. The addition of the foregoing anions to complexes 3-6 lead to the displacement of the chloride ligand at the tin(IV) atom. However, an the excess of F− or H2PO4− induced the self-assembly of complexes 3 and 5 in their corresponding binuclear metallomacrocycles.

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.

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.