Synthesis of New Bis(spiro-β-lactams) via Interaction of Methyl 1-Bromocycloalcanecarboxylates with Zinc and N,N′-Bis(arylmethylidene)benzidines

Interaction of the Reformatsky reagents, prepared from methyl 1-bromocyclopentane-1-carboxylate or methyl 1-bromocyclohexane-1-carboxylate, with N,N′-bis(arylmethylidene)benzidines has given rise to a set of intermediates as a result of nucleophilic addition to the C=N group of a substrate. Further intramolecular attack of the amide nitrogen atom onto the ester carbonyl group is responsible for the ring closure, which affords two series of spirocompounds: 2,2′-([1,1′-biphenyl]-4,4′-diyl)bis(3-aryl-2-azaspiro[3.4]octan-1-one) or 2,2′-([1,1′-biphenyl]-4,4′-diyl)bis(3-aryl-2-azaspiro[3.5]nonan-1-ones).

Doxycycline hydrate and doxycycline hydrochloride dihydrate – crystal structure and charge density analysis

High-resolution low-temperature X-ray diffraction experiments for doxycycline monohydrate and hydrochloride dihydrate have been performed. Translation-Libration-Screw (TLS) analysis for both crystal forms as well as the data from neutron diffraction experiment for hydrochloride combined with the Hansen-Coppens formalism resulted in precise charge density distribution models for both the zwitterionic monohydrate and a protonated hydrochloride crystal forms. Their detailed topological analysis suggested that the electron structure of doxycycline’s amide moiety undergoes significant changes during protonation due to formation of a very strong resonance-assisted hydrogen bond. A notably increased participation of amide nitrogen atom and hydrogen-accepting oxygen atom in the resonance upon doxycycline protonation was observed. A comparison of TLS- and neutron data-derived hydrogen parameters confirmed the experimental neutron data to be vital for proper description of intra- and inter-molecular interactions in this compound. Finally, calculated lattice and interaction energies quantified repulsive Dox-Dox interactions in the protonated crystal form of the antibiotic, relating with a good solubility of doxycycline hydrochloride relative to its hydrate.

Crystal structure and Hirshfeld surface analysis of N,N′-bis(2-nitrophenyl)glutaramide

The asymmetric unit of the title compound, C17H16N4O6, contains two independent molecules (A and B). The two benzene rings are twisted by an angle of 79.14 (7)° in molecule A, whereas, in molecule B, they are inclined by 19.02 (14)°. The conformations of the molecules are stabilized by intramolecular N—H...O hydrogen bonds between the amide nitrogen atom and the O atom of the ortho-nitro substituent on the phenyl ring, enclosing an S(6) ring motif. In the amide and aliphatic segments, all the N—H, C=O and C—H bonds are anti to each other. In the crystal, the A and B molecules are linked by intermolecular amide-to-amide N—H...O hydrogen bonds, resulting in chains running along the b-axis direction. The intermolecular interactions were analysed using Hirshfeld surface analysis. The two-dimensional fingerprint plots of the intermolecular contacts indicate that the major contributions are from H...H and O...H interactions.

Unexpected Resistance to Base-Catalyzed Hydrolysis of Nitrogen Pyramidal Amides Based on the 7-Azabicyclic[2.2.1]heptane Scaffold

Non-planar amides are usually transitional structures, that are involved in amide bond rotation and inversion of the nitrogen atom, but some ground-minimum non-planar amides have been reported. Non-planar amides are generally sensitive to water or other nucleophiles, so that the amide bond is readily cleaved. In this article, we examine the reactivity profile of the base-catalyzed hydrolysis of 7-azabicyclo[2.2.1]heptane amides, which show pyramidalization of the amide nitrogen atom, and we compare the kinetics of the base-catalyzed hydrolysis of the benzamides of 7-azabicyclo[2.2.1]heptane and related monocyclic compounds. Unexpectedly, non-planar amides based on the 7-azabicyclo[2.2.1]heptane scaffold were found to be resistant to base-catalyzed hydrolysis. The calculated Gibbs free energies were consistent with this experimental finding. The contribution of thermal corrections (entropy term, –TΔS‡) was large; the entropy term (ΔS‡) took a large negative value, indicating significant order in the transition structure, which includes solvating water molecules.