Hugo Morales-Rojas

Macrocyclic Diorganotin Complexes of γ-Amino Acid Dithiocarbamates as Hosts for Ion-Pair Recognition

The dimethyl-, di-n-butyl-, and diphenyltin(IV) dithiocarbamate (dtc) complexes [{R2Sn(L-dtc)}x] 1-7 (1, L = L1, R = Me; 2, L = L1, R = n-Bu; 3, L = L2, R = Me, x = infinity; 4, L = L2, R = n-Bu; 5, L = L3, R = Me, x = 2; 6, L = L3, R = n-Bu, x = 2; 7, L = L3, R = Ph, x = 2) have been prepared from a series of secondary amino acid (AA) homologues as starting materials: N-benzylglycine (alpha-AA derivative = L1), N-benzyl-3-aminopropionic acid (beta-AA derivative = L2), and N-benzyl-4-aminobutyric acid (gamma-AA derivative = L3). The resulting compounds have been characterized by elemental analysis, mass spectrometry, IR and NMR ((1)H, (13)C, and (119)Sn) spectroscopy, thermogravimetric analysis, and X-ray crystallography, showing that in all complexes both functional groups of the heteroleptic ligands are coordinated to the tin atoms. By X-ray diffraction analysis, it could be shown that [{Me2Sn(L2-dtc)}x] (3) is polymeric in the solid state, while the complexes derived from L3 (5-7) have dinuclear 18-membered macrocyclic structures of the composition [{R2Sn(L3-dtc)}2]. For the remaining compounds, it could not be established with certainty whether the structures are macrocyclic or polymeric. A theoretical investigation at the B3LYP/SBKJC(d,p) level of theory indicated that the alpha-AA-dtc complexes might have trinuclear macrocyclic structures. The macrocyclic complexes 5-7 have a double-calix-shaped conformation with two cavities large enough for the inclusion of aliphatic and aromatic guest molecules. They are self-complementary for the formation of supramolecuar synthons that give rise to 1D molecular arrangements in the solid state. Preliminary recognition experiments with tetrabutylammonium acetate have shown that the [{R2Sn(L3-dtc)}2] macrocycles 6 and 7 might interact simultaneously with anions (AcO(-)), which coordinate to the tin atoms, and organic cations (TBA(+)), which accommodate within the hydrophobic cavity (ion-pair recognition).

On molecular complexes derived from amino acids and nicotinamides in combination with boronic acids

Cocrystallization experiments of three representative aromatic boronic acids, namely phenylboronic acid (PBA), 1,4-benzenediboronic acid (BDBA) and 4-iodophenylboronic acid (IPBA), with a series of essential amino acids, nicotinamide (NA) and isonicotinamide (INA) gave a total of nine molecular complexes of the compositions: PBA–PRO (1 : 1), PBA–PRO–H2O (1 : 1 : 1), α-BDBA–PRO (1 : 2), β-BDBA–PRO (1 : 2), α-IPBA–PRO (1 : 1), β-IPBA–PRO (1 : 1), BDBA–INA (1 : 2), IPBA–INA (1 : 1) and IPBA–NA (1 : 1), where PRO = L-proline. Of these, α-BDBA–PRO/β-BDBA–PRO and α-IPBA–PRO/β-IPBA–PRO were true polymorphs. Experiments varying the solvent in the screening process showed that the formation of the polymorphs is influenced strongly by the presence/absence of water. For the cocrystalline phases with L-proline, the structural characterization revealed that the molecular components were connected into high-dimensional hydrogen bonded networks. As expected, the charge-assisted –B(OH)2⋯carboxylate heterosynthon is dominant and was found to display varying degrees of distortion from planarity. The α-IPBA–PRO/β-IPBA–PRO polymorphs displayed a similar crystal packing, with differences only in one direction of the crystal lattice (AAAA versus ABAB stacking). The cocrystals with nicotinamide and isonicotinamide exhibited 1D or 2D hydrogen bonded layers, which were formed through (B)O–H⋯pyridine, B(OH)2⋯amide, amide⋯amide and/or single-bridged (B)O–H⋯O(H)B interactions. Comparison between the crystal structures of IPBA–INA and IPBA–NA revealed that the position of the heteroatom in the (iso)nicotinamide not only controlled the final crystalline form but also produced different hydrogen bonding interactions. In vitro toxicology studies showed that the cell viability is conserved when human kidney or hepatic cells are treated even with high concentrations of the boronic acids examined herein. However, some boronic acids exhibited teratogenicity in chicken embryos.

Interrelation of the dissolution behavior and solid-state features of acetazolamide cocrystals

&NA; The thermal behavior, phase stability, indicative stability and intrinsic dissolution rates of a series of cocrystals and cocrystal hydrates derived from the pharmaceutically active ingredient acetazolamide (ACZ) and 2‐aminobenzamide (2ABAM), 2,3‐dihydroxybenzoic acid (23DHBA), 2‐hydroxybenzamide (2HBAM), 4‐hydroxybenzoic acid (4HBA), nicotinamide (NAM) and picolinamide (PAM) as cocrystal formers have been evaluated. Upon heating in an inert atmosphere most of the cocrystals tested demonstrated first the elimination of the crystal former, followed by ACZ degradation. Only in cocrystals with NAM was melting observed. Under controlled temperature and relative humidity conditions all cocrystals tested were stable. However, phase stability tests in a medium simulating physiological conditions (HCl 0.01 N, pH 2.0) indicated that cocrystals ACZ‐NAM‐H2O and ACZ‐PAM gradually transform into ACZ. All cocrystals examined gave enhanced intrinsic dissolution rates when compared to pure ACZ and the largest dissolution rate constants were measured for the cocrystals that transformed in the phase stability test (approximate two‐fold increase of the dissolution rate constants). The series of cocrystals examined herein exhibits an inverse correlation between the intrinsic dissolution rates and the melting/decomposition temperatures as well as the dimension of the hydrogen‐bonded ACZ aggregates found in the corresponding crystal structure, indicating that solid‐state stability is the major influence on dissolution performance. Graphical abstract Figure. No caption available.

CCDC 1574801: Experimental Crystal Structure Determination

Related Article: Gonzalo Campillo-Alvarado, Eva C. Vargas-Olvera, Herbert Hopfl, Angel D. Herrera-Espana, Obdulia Sanchez-Guadarrama, Hugo Morales-Rojas, Leonard R. MacGillivray, Braulio Rodriguez-Molina, Norberto Farfan|2018|Cryst.Growth Des.|||doi:10.1021/acs.cgd.7b01368

CCDC 1574802: Experimental Crystal Structure Determination

Related Article: Gonzalo Campillo-Alvarado, Eva C. Vargas-Olvera, Herbert Hopfl, Angel D. Herrera-Espana, Obdulia Sanchez-Guadarrama, Hugo Morales-Rojas, Leonard R. MacGillivray, Braulio Rodriguez-Molina, Norberto Farfan|2018|Cryst.Growth Des.|||doi:10.1021/acs.cgd.7b01368

CCDC 1574800: Experimental Crystal Structure Determination

Related Article: Gonzalo Campillo-Alvarado, Eva C. Vargas-Olvera, Herbert Hopfl, Angel D. Herrera-Espana, Obdulia Sanchez-Guadarrama, Hugo Morales-Rojas, Leonard R. MacGillivray, Braulio Rodriguez-Molina, Norberto Farfan|2018|Cryst.Growth Des.|18|2726|doi:10.1021/acs.cgd.7b01368