Itzia I. Padilla-Martínez

Carbon­yl–carbonyl, carbon­yl–π and carbon­yl–halogen dipolar inter­actions as the directing motifs of the supra­molecular structure of ethyl 6-chloro-2-oxo-2H-chromene-3-carboxyl­ate and ethyl 6-bromo-2-oxo-2H-chromene-3-carboxyl­ate

The title compounds, C(12)H(9)ClO(4), (I), and C(12)H(9)BrO(4), (II), are isomorphous and crystallize in the monoclinic space group P2(1)/c. Both compounds present an anti conformation between the 3-carboxy and the lactone carbonyl groups. Both carbonyl groups are out of the plane defined by the remaining chromene atoms, by 8.37 (6) and 17.57 (6) degrees for (I), and by 9.07 (8) and 18.96 (18) degrees for (II), owing to their involvement in intermolecular interactions. In both compounds, layers of centrosymmetric hydrogen-bonded dimers are developed in the [-5 -2 22] plane through C-H...O interactions, involving both carbonyl groups as acceptors. Two families of dimers stack through C=O...C=O, C=O...pi and C-X...C=O (X = Cl and Br) dipolar interactions, as well as a C-H...pi interaction, developing the three-dimensional structure along the c axis.

N–H…O Assisted Structural Changes Induced on Ketoenamine Systems

The tautomeric equilibrium between the ketoenamine and enolimine forms for a series of arylimines (1a–1c) derived from salicylaldehyde and enaminones (2a–2f) derived from benzoylacetone and substituted anilines has been analyzed in solution by 1H NMR and UV-vis spectroscopy, while IR and X-ray diffraction analyses were used in the solid state. The X-ray diffraction analysis of 1a, 2a–2c and 2e–2f showed that the most stable tautomer is the ketoenamine and all enaminones present intramolecular NH…O hydrogen bonds forming a six member ring in which the keto form is favored. In addition, the VT-NMR analysis for 2b in solvents of different polarities evidenced the behavior of the tautomeric equilibrium, showing that in DMF and acetone at low temperature, the enolimine tautomer is more stable.

Benzazole‐N(SINGLE BOND)BH3 adducts. Reductive transposition of 2‐benzimidazole, 2‐benzothiazole, and 2‐benzoxazole N(SINGLE BOND)BH3 adducts to 1,3,2‐benzimidazaborole, 1,3,2‐benzoxaborole, and 1,3,2‐benzothiazaborole

1,3,2-Benzimidazaborole, 1,3,2-benzoxaborole, and 1,3,2-benzothiazaborole were synthesized from the corresponding 2-benzazole N(SINGLE BOND)BH3 and 2-benzazole S(SINGLE BOND)BH3 adducts through a reductive transposition from the isolobal fragment X(SINGLE BOND)C(sp2) (DOUBLE BOND) N(sp2) (SINGLE BOND) B(sp3) (X (DOUBLE BOND) N, O, S) to the fragment X(SINGLE BOND)B(sp2) (DOUBLE BOND) N(sp2) (SINGLE BOND) C(sp3). N(SINGLE BOND)BH3 substitution shifts to lower frequencies 4-H, C-3a, and C-7a resonances. The X-ray diffraction analysis of 2-(o-methoxyphenyl)benzothiazole N(SINGLE BOND)BH3 adduct is reported. Two new tetracyclic boron-bridged compounds were observed as by-products (6,9-(ethyl)-diaza-2-oxa-1-bora[3,4,7,8]-dibenzobycyclo[4.3.0]-nona-3,7-diene, 6d, and 8-aza-9-oxa-2-thia-1-bora-[3,4,7,8]dibenzobycyclo[3.4.0]nona-3,7-diene, 15d, when 2-(o-methoxyphenyl)-1-ethylbenzimidazole-BH36b and 2-(o-methoxyphenyl)-benzothiazole-BH315b adducts were heated.

Design, synthesis and in vitro evaluation of (R)-4-(2-(tert-butylamino)-1-hydroxyethyl)-2-(hydroxymethyl)phenyl hydrogen phenylboronate: A novel salbutamol derivative with high intrinsic efficacy on the β2 adrenoceptor

We tested a set of boron containing arylethanolamine derivatives on the human and guinea pig β(2) adrenoceptor (β(2)AR) 3-D structures by docking methodology. The compound with the highest affinity based on docking analysis, (R)-4-(2-(tert-butylamino)-1-hydroxyethyl)-2-(hydroxymethyl)phenyl hydrogen phenylboronate (boronterol) was synthesized, characterized and tested in guinea pig tracheal rings at basal tone and with histamine-induced contractions. Boronterol was at least eightfold more potent than salbutamol as a smooth muscle relaxant drug (judged by the EC(50) values) and showed a similar maximal relaxant effect as isoproterenol. ICI118,551 showed competitive antagonism on the relaxing effect of boronterol. These results suggest the β(2)AR agonist action of boronterol.

Competition between OH⋯O and multiple halogen–dipole interactions on the formation of intramolecular three-centred hydrogen bond in 3-acyl coumarins

This paper describes the synthesis and structural study in solution, by NMR, and in the solid state, by X-ray analysis, of 6-substituted (H, NO2, OCH3, Cl, Br) 2-oxo-2H-chromene-3-carboxylic acid (2-hydroxy-ethyl) amides. The results were supported by ab initio calculations at RHF-631G** level of theory. The crystal structures of compounds 6-Cl and 6-Br show deviations from the predicted theoretical conformation and also from that observed in solution, pointing to the influence exerted by intermolecular interactions on the molecular structure and on intramolecular three-centred hydrogen bond formation (O2⋯H12⋯O1). The significance of the plethora of non-covalent interactions [C‒H⋯A (A = O, X, π), CO⋯CO, CO⋯π, C‒X⋯OC (X = halogen), Br⋯Br and π‒π stacking] is discussed.

Through space charge transfer and quadratic nonlinear optical (NLO) properties in alternated stacks of 2-amino-1,3-benzothiazole-ethylcoumarin-3-carboxylate charge transfer complexes: from the molecular to the bulk NLO response

The title compound is a charge transfer complex with an experimental low lying excitation located around 420 nm. It is used as a model compound for the investigation of a possible strategy towards NLO materials obtained by “through space” charge transfer. Its solid state structure (Pc space group) reveals non-centrosymmetric alternating chains of donor-acceptor entities, built from the two independent 2-amino-1,3-benzothiazole entities hydrogen-bonded in the crystal unit cell. Each independent chain gives rise to a one-dimensional charge transfer, and therefore a non-vanishing NLO response along the chain. The angle between the glide mirror and the charge transfer direction is close to the optimized value (61°) and leads to two extended lattices of high NLO capability over the whole extent of the crystal. Unfortunately, an angle of 175° is observed between the two lattices, because of the unexpected effect of the hydrogen bonding, thus cancelling most of the NLO response. The efficiency of the material is therefore limited to 0.15 times that of urea in second harmonic generation (SHG). Nevertheless, this investigation indicates that charge transfer complexes could be envisioned for an alternative approach to molecular materials with SHG capabilities.

Thermal [4 + 2] Cycloadditions of 3-Acetyl-, 3-Carbamoyl-, and 3-Ethoxycarbonyl-Coumarins with 2,3-Dimethyl-1,3-butadiene under Solventless Conditions: A Structural Study

The thermal [4+2] cycloadditions of 3-acetyl-, 3-carbamoyl, and 3-ethoxy-carbonylcoumarins with 2,3-dimethyl-1,3-butadiene under solvent free conditions are reported, as well as the epoxidation reactions of some adducts. Discussion is focused on the structural features of the Diels-Alder adducts and their epoxides, based upon NMR, X-ray, and mass spectral data, and supported by ab initio theoretical calculations.

Design of Multi-Target Compounds as AChE, BACE1, and Amyloid-β1-42 Oligomerization Inhibitors: In Silico and In Vitro Studies

Despite great efforts to develop new therapeutic strategies against Alzheimers disease (AD), the acetylcholinesterase inhibitors (AChEIs): donepezil, rivastigmine, and galantamine, have been used only as a palliative therapeutic approach. However, the pathogenesis of AD includes several factors such as cholinergic hypothesis, amyloid-β (Aβ) aggregation, and oxidative stress. For this reason, the design of compounds that target the genesis and progression of AD could offer a therapeutic benefit. We have designed a set of compounds (M-1 to M-5) with pharmacophore moieties to inhibit the release, aggregation, or toxicity of Aβ, act as AChEIs and have antioxidant properties. Once the compounds were designed, we analyzed their physicochemical parameters and performed docking studies to determine their affinity values for AChE, β-site amyloid-protein precursor cleaving enzyme 1 (BACE1), and the Aβ monomer. The best ligands, M-1 and M-4, were then synthesized, chemically characterized, and evaluated in vitro. The in vitro studies showed that these compounds inhibit AChE (M-1 Ki = 0.12 and M-4 Ki = 0.17 μM) and BACE1 (M-1 IC50 = 15.1 and M-4 IC50 = 15.4 nM). They also inhibit Aβ oligomerization and exhibit antioxidant activity. In addition, these compounds showed low cytotoxicity in microglial cells. For these reasons, they are promising for future use as drugs in AD mice transgenic models.

Three-center intramolecular hydrogen bonding in oxamide derivatives. NMR and X-ray diffraction study

This contribution describes the synthesis and structural investigation of the symmetric and non-symmetric oxamides N,N′-bis(2-hydroxyphenyl)oxamide 1, N,N′-bis(5-tert-butyl-2-hydroxyphenyl)oxamide 2, N,N′-bis(3,5-dimethyl-2-hydroxyphenyl)oxamide 3, N,N′-bis(2-hydroxybenzyl)oxamide 4, N,N′-diphenethyloxamide 5, N-(2-hydroxyphenyl)-N′-(2-methoxyphenyl)oxamide 6, N-(2-hydroxyphenyl)-N′-phenethyloxamide 7, (1S,2R)-(–)-N-(2-hydroxyphenylcarbamoylcarbonyl)norephedrine 8, (1R,2S)-(–)-N-(2-hydroxyphenylcarbamoylcarbonyl) 9, ethyl N-(2-hydroxyphenyl)oxalamate 10 and ethyl N-(2-methoxyphenyl)oxalamate 11. The structures were established by 1H, 13C, 15N and variable temperature NMR spectroscopy. Compounds 1–4 and 6–11 are stabilized by intramolecular three-center hydrogen bonding between the amide proton and two oxygen atoms. The 1H NMR Δδ/ΔT value of the amide proton correlates with the 15N NMR chemical shift. The X-ray diffraction molecular structures of 1 and 11 showed a planar conformation with trans configuration in the solid state, corresponding to the preferred conformation found in solution.

Solid State Structure and Solution Thermodynamics of Three-Centered Hydrogen Bonds (O∙∙∙H∙∙∙O) Using N-(2-Benzoyl-phenyl) Oxalyl Derivatives as Model Compounds

Intramolecular hydrogen bond (HB) formation was analyzed in the model compounds N-(2-benzoylphenyl)acetamide, N-(2-benzoylphenyl)oxalamate and N1,N2-bis(2-benzoylphenyl)oxalamide. The formation of three-center hydrogen bonds in oxalyl derivatives was demonstrated in the solid state by the X-ray diffraction analysis of the geometric parameters associated with the molecular structures. The solvent effect on the chemical shift of H6 [δH6(DMSO-d6)–δH6(CDCl3)] and Δδ(ΝΗ)/ΔT measurements, in DMSO-d6 as solvent, have been used to establish the energetics associated with intramolecular hydrogen bonding. Two center intramolecular HB is not allowed in N-(2-benzoylphenyl)acetamide either in the solid state or in DMSO-d6 solution because of the unfavorable steric effects of the o-benzoyl group. The estimated ΔHº and ΔSº values for the hydrogen bonding disruption by DMSO-d6 of 28.3(0.1) kJ·mol−1 and 69.1(0.4) J·mol−1·K−1 for oxalamide, are in agreement with intramolecular three-center hydrogen bonding in solution. In the solid, the benzoyl group contributes to develop 1-D and 2-D crystal networks, through C–H∙∙∙A (A = O, π) and dipolar C=O∙∙∙A (A = CO, π) interactions, in oxalyl derivatives. To the best of our knowledge, this is the first example where three-center hydrogen bond is claimed to overcome steric constraints.