Nanoscale Dodecahedral and Fullerene-Type Organoboroxine and Borazine Cages from Planar Building Units.

Boroxine- and borazine-cage analogs to C20, C60, and C70 were calculated and compared in terms of structure, strain indicators, and physical properties relevant to nanoscale applications. The results show C60 and C70 type cages are less strained than the smaller congener, primarily due to minimized bending in the B-arylene-B segments. The smallest cage calculated has a diameter of 2.4 nm, which increases up to 4.9 nm by either variation of the polyhedron (C20 < C60 < C70-type cage) or organic spacer elongation between boron centers. All calculated cages are porous (apertures ranging from 0.6 to 1.9 nm). Molecular electrostatic potential and Hirshfeld population analysis revealed both nucleophilic and electrophilic sites in the interior and exterior cage surfaces. HOMO-LUMO gaps range from 3.98 to 4.89 eV and 5.10-5.18 eV for the boroxine- and borazine-cages, respectively. Our findings provide insights into the design and properties of highly porous boroxine and borazine cages for nanoscience.

Structures and Reactivities of Cocrystals Involving Diboronic Acids and Bipyridines: In Situ Linker Reaction and 1D-to-2D Dimensionality Change via Crystal-to-Crystal Photodimerization.

Cocrystallizations of diboronic acids [1,3-benzenediboronic acid (1,3-bdba), 1,4-benzenediboronic acid (1,4-bdba) and 4,4'-biphenyldiboronic acid (4,4'-bphdba)] and bipyridines [1,2-bis(4-pyridyl)ethylene (bpe) and 1,2-bis(4-pyridyl)ethane (bpeta)] generated the hydrogen-bonded 1 : 2 cocrystals [(1,4-bdba)(bpe)2 ] (1), [(1,4-bdba)(bpeta)2 ] (2), [(1,3-bdba)(bpe)2 (H2 O)2 ] (3) and [(1,3-bdba)(bpeta)2 (H2 O)] (4), wherein 1,3-bdba involved hydrated assemblies. The linear extended 4,4'-bphdba exhibited the formation of 1 : 1 cocrystals [(4,4'-bphdba)(bpe)] (5) and [(4,4'-bphdba-me)(bpeta)] (6). For 6, a hemiester was generated by an in-situ linker transformation. Single-crystal X-ray diffraction revealed all structures to be sustained by B(O)-H⋅⋅⋅N, B(O)-H⋅⋅⋅O, Ow -H⋅⋅⋅O, Ow -H⋅⋅⋅N, C-H⋅⋅⋅O, C-H⋅⋅⋅N, π⋅⋅⋅π, and C-H⋅⋅⋅π interactions. The cocrystals comprise 1D, 2D, and 3D hydrogen-bonded frameworks with components that display reactivities upon cocrystal formation and within the solids. In 1 and 3, the C=C bonds of the bpe molecules undergo a [2+2] photodimerization. UV radiation of each compound resulted in quantitative conversion of bpe into cyclobutane tpcb. The reactivity involving 1 occurred via 1D-to-2D single-crystal-to-single-crystal (SCSC) transformation. Our work supports the feasibility of the diboronic acids as formidable structural and reactivity building blocks for cocrystal construction.

Nanoconfinement of a Pharmaceutical Cocrystal with Praziquantel in Mesoporous Silica: The Influence of the Solid Form on Dissolution Enhancement.

Nanoconfinement is a recent strategy to enhance solubility and dissolution of active pharmaceutical ingredients (APIs) with poor biopharmaceutical properties. In this work, we combine the advantage of cocrystals of racemic praziquantel (PZQ) containing a water-soluble coformer (i.e., increased solubility and supersaturation) and its confinement in a mesoporous silica material (i.e., increased dissolution rate). Among various potential cocrystalline phases of PZQ with dicarboxylic acid coformers, the cocrystal with glutaric acid (PZQ-GLU) was selected and successfully loaded by the melting method into nanopores of SBA-15 (experimental pore size of 5.6 nm) as suggested by physical and spectroscopic characterization using various complementary techniques like N2 adsorption, powder X-ray diffraction (PXRD), infrared spectroscopy (IR), solid-state NMR (ss-NMR), differential scanning calorimetry (DSC), and field emission-scanning electron microscopy (FE-SEM) analysis. The PZQ-GLU phase confined in SBA-15 presents more mobility according to ss-NMR studies but still retains its cocrystal-like features in the IR spectra, and it also shows depression of the melting transition temperature in DSC. On the contrary, pristine PZQ loaded into SBA-15 was found only in the amorphous state, according to the aforementioned studies. This dissimilar behavior of the composites was attributed to the larger crystal lattice of PZQ over the PZQ-GLU cocrystal (3320.1 vs 1167.9 Å3) and to stronger intermolecular interactions between PZQ and GLU, facilitating the confinement of a more mobile solid-like phase in the constrained channels. Powder dissolution studies under extremely nonsink conditions (SI = 0.014) of the confined PZQ-GLU and amorphous PZQ phases embedded in mesoporous silica showed transient supersaturation behavior when dissolving in simulated gastric fluid (HCl pH 1.2 at 37 ± 0.5 °C) in a similar fashion to the bare cocrystal PZQ-GLU. A comparison of the area under the curve (AUC0-90 min) of the dissolution profiles afforded a dissolution advantage of 2-fold (p < 0.05) of the new solid phases over pristine racemic PZQ after 90 min; under these conditions, the solubilized API reprecipitated as the recently discovered PZQ hemihydrate (PZQ-HH). In the presence of a cellulosic polymer, sustained solubilization of PZQ from composites SBA-15/PZQ or SBA-15/PZQ-GLU was observed, increasing AUC0-90 min up to 5.1-fold in comparison to pristine PZQ. The combination of a confined solid phase in mesoporous silica and a methylcellulose polymer in the dissolution medium effectively maintained the drug solubilized during times significant to promote absorption. Finally, powder dissolution studies under intermediate nonsink conditions (SI = 1.99) showed a fast release profile from the nanoconfined PZQ-GLU phase in SBA-15, which reached rapid saturation (95% drug dissolved at 30 min); the amorphous PZQ composite and bare PZQ-GLU also displayed an immediate release of the API but at a lower rate (69% drug dissolved at 30 min). In all of these cases, a large dissolution advantage was observed from any of the novel solid phases over PZQ.

Molecular Cage Assembly by Sn-O-Sn Bridging of Di-, Tri- and Tetranuclear Organotin Tectons: Extending the Spacing in Double Ladder Structures.

Hydrolysis reactions of di- and trinuclear organotin halides yielded large novel cage compounds containing Sn-O-Sn bridges. The molecular structures of two octanuclear tetraorganodistannoxanes showing double-ladder motifs, viz., [{Me3 SiCH2 (Cl)SnCH2 YCH2 Sn(OH)CH2 SiMe3 }2 (µ-O)2 ]2 [1, Y=p-(Me)2 SiC6 H4 -C6 H4 Si(Me)2 ] and [{Me3 SiCH2 (I)SnCH2 YCH2 Sn(OH)CH2 SiMe3 }2 (µ-O)2 ]2 ⋅0.48 I2 [2⋅0.48 I2 , Y=p-(Me)2 SiC6 H4 -C6 H4 Si(Me)2 ], and the hexanuclear cage-compound 1,3,6-C6 H3 (p-C6 H4 Si(Me)2 CH2 Sn(R)2 OSn(R)2 CH2 Si(Me)2 C6 H4 -p)3 C6 H3 -1,3,6 (3, R=CH2 SiMe3 ) are reported. Of these, the co-crystal 2⋅0.48 I2 exhibits the largest spacing of 16.7 Šreported to date for distannoxane-based double ladders. DFT calculations for the hexanuclear cage and a related octanuclear congener accompany the experimental work.

Further Approaches in the Design of Antitumor Agents with Response to Cell Resistance: Looking toward Aza Crown Ether-dtc Complexes.

The dianionic aza crown ether-dtc N,N'-bis(dithiocarbamate)-1,10-diaza-18-crown-6 (L2-) is a versatile ligand capable of yielding binuclear complexes with group 10 elements, also known as Ni-triade, [µ-(κ2-S,-S'-L)M2(PPh3)4]Cl2 (M = Pd (1), Pt (2)), [µ-(κ2-S,-S'-L)M2(PPh3)4](BPh4)2 (M = Pd (3), Pt (4)), and µ-(κ-S,-S'-L)Ni2(PPh3)2Cl2 (5), and has proven to be an excellent option to the design of metal-based drugs able to provide multiple response to cell resistance. Palladium and platinum complexes, 1 and 2, were tested for cytotoxicity in the human cervix carcinoma cell line HeLa-229, the human ovarian carcinoma cell line A2780, and the cisplatin-resistant mutant A2780cis, finding significant activity toward all three cancer cell lines, with low micromolar IC50 values, comparable to cisplatin. Markedly, against the cisplatin resistant cell line A2780cis, compound 2 exhibits better cytotoxic activity than the clinical drug (IC50 = 2.3 ± 0.2 µM for 2 versus 3.6 ± 0.5 µM for cisplatin). Moreover, an enhancement of the antitumor response is achieved when adding an equimolar amount of alkali metal chloride (NaCl or KCl) to the medium, for instance, testing compound 1 against the cisplatin-resistant A2780cis cells, the IC50 decreases from 9.3 ± 0.4 to 7.4 ± 0.3 and 5.4 ± 0.1 µM, respectively, after addition of the salt solution. For the platinum derivative 2, the IC50 improves by ca. 40% reaching 1.3 ± 0.1 µM when potassium chloride is added. Likewise, the resistant factor found for 2 (RF = 1) confirms that this complex circumvents cisplatin-resistance in A2780cis and is improved with the addition of potassium chloride (RF = 0.65). The presence of the aza crown ether moiety as linker in the systems studied herein is a key point since, in addition to allowing and facilitating interaction with alkali metal ions, this unit is flexible enough to adapt to a variety of environments, as confirmed by the X-ray crystal structures described, where different conformations and ways to fold in are found. In order to gain insight into the electronic and structural facts involved in the interaction of complex 2 with the alkali metal ions, a DFT study was performed, and the description of the molecular electrostatic potentials (MEPs) is also presented.

Exploiting Boron Coordination: B←N Bond Supports a [2+2] Photodimerization in the Solid State and Generation of a Diboron Bis-Tweezer for Benzene/Thiophene Separation.

B←N coordination supports a [2+2] photodimerization in the solid state. The bond is defined by an orthogonal interaction between stilbazole and a phenylboronic ester to enable a stereocontrolled and rapid photoreaction. The cyclobutane photoproduct affords a novel diboron bis-tweezer adduct that is used to separate a mixture of benzene and thiophene upon crystallization.

Molecular Tectonics with Di- and Trinuclear Organotin Compounds.

Di- and trinuclear organotin(IV) complexes, in which the metal atoms are separated by large aromatic connectors, are useful building blocks for self-assembly. This is demonstrated by the preparation of [1+1], [2+2], and [2+3] macrocyclic and cage-type structures in combination with organic aromatic dicarboxylates. The linkage of the metal atoms by organic binders and the option of varying the number of reactive M-X sites generate versatile building blocks enabling molecular tectonics instead of the node-based strategy generally employed in metallo-supramolecular self-assembly.

The direct and highly diastereoselective synthesis of 3,4-epoxy-2-piperidones. Application to the total synthesis and absolute configurational assignment of 3α,4α-epoxy-5ß-pipermethystine.

The substrate-controlled asymmetric total synthesis and absolute configurational assignment of biologically active 3α,4α-epoxy-5ß-pipermethystine, a minor component in the aerial parts of kava, has been achieved by featuring, as a key step, the environmentally friendly and direct synthesis of 2,3-epoxyamides from allyl amines. By using the chiron approach, first a carbohydrate-derived dehydropiperidine was prepared and subjected to a stereoselective tandem C-H/C[double bond, length as m-dash]C oxidation reaction. In this attempt, the required α,α-trans-epoxy-2-piperidone skeleton of the kava metabolite precursor was not achieved, although the tandem oxidation was highly stereoselective. However, starting from non-carbohydrate 3-hydroxy-4,5-dehydropiperidine, and using the same tandem oxidation, the target intermediate was obtained in high yield and complete unprecedented anti-stereoselectivity. Since the proposed mechanistic course of this tandem oxidation implies the transient formation of an α,ß-unsaturated amide followed by the subsequent epoxidation reaction, this second approach supports the previously established biotransformation proposal of (-)-pipermethystine to (-)-3α,4α-epoxy-5ß-pipermethystine.

Transition Metal-Free Selective Double sp(3) C-H Oxidation of Cyclic Amines to 3-Alkoxyamine Lactams.

The first chemical method for selective dual sp(3) C-H functionalization at the alpha-and beta positions of cyclic amines to their corresponding 3-alkoxyamine lactams is reported. Unlike traditional Cα-H oxidation of amines to amides mediated by transition metals, the present protocol, which involves the use of NaClO2/TEMPO/NaClO in either aqueous or organic solvent, not only allows the Cα-H oxidation but also the subsequent functionalization of the unreactive ß-methylene group in an unprecedented tandem fashion and using environmentally friendly reactants.

Variation of the Molecular Conformation, Shape, and Cavity Size in Dinuclear Metalla-Macrocycles Containing Hetero-Ditopic Dithiocarbamate-Carboxylate Ligands from a Homologous Series of N-Substituted Amino Acids.

A homologous series of dithiocarbamate ligands derived from N-substituted amino acids was reacted with different diorganotin dichlorides to give 18 diorganotin complexes. Spectroscopic and mass spectrometric analysis evidenced the formation of assemblies with six-coordinate tin atoms embedded in skewed-trapezoidal bipyramidal coordination environments of composition C2SnS2O2. Single-crystal X-ray diffraction analysis for three of the compounds revealed a one-dimensional polymeric structure for the complex with the ligand derived from 5-aminopentanoic acid, which through further intermolecular Sn···O interactions generated an overall two-dimensional coordination polymer containing 40-membered hexanuclear tin macrocycles. On the contrary, the ligands derived from 6-aminohexanoic and 8-aminooctanoic acid provided the expected 22- and 26-membered dinuclear macrocyclic structures. Density functional theory calculations for a representative series of macrocyclic complexes of composition [Me2SnLx]2 with Lx = ¯S2CN(Me)-(CH2)x-COO¯ (x = 3-12) enabled a detailed analysis of the variations in the molecular conformation, shape, and cavity size of the macrocycles in dependence of the aliphatic spacer. Because of odd-even effects, the difunctional ligands can adopt either a curved or a twisted-pincer shape, while the SnSxO4-x (x = 0-4) moieties can act either as linear or angular tectons with varying connectivity angles.

The Stabilizing Role of the Intramolecular C-H···O Hydrogen Bond in Cyclic Amides Derived From α-Methylbenzylamine.

A series of five-, six-, seven-, and eight-membered lactams containing the chiral auxiliary α-methylbenzylamine were structurally analyzed and further studied by DFT calculations with the purpose to examine with detail the previously detected intramolecular C-H···O hydrogen-bonding interaction formed between the hydrogen atom of the α-methylbenzylamine and the carbonyl group of the cyclic amide. The main objective was to establish whether its presence does have a tangible relevance in their spatial arrangement in solution and in the solid state or is a simple and not stabilizing interaction.

Further evidence on the favorable role of the anomeric effect on the cleavage of HepDirect and cyclophosphamide prodrugs.

On the basis of previous conformational and configurational studies of 4-aryl-substituted cyclophosph(on)ates derived from d-xylofuranose derivatives, wherein it was proposed that the anomeric effect is involved in the spontaneous isomerization of the P atom and the C4 carbon, and consequently, this unusual behavior was associated with the cleavage of the HepDirect prodrugs. We synthesized an analogous series of 2-amino-2-oxo-1,3,2-dioxaphosphorinanes and performed a conformational and configurational analysis in solution and the solid state followed by an examination of their mutagenic activity. The results showed that the 2-amino-2-oxo-1,3,2-dioxaphosphorinanes with the largest mutagenic activity contain either a 4-methoxyphenyl or 4-fluorophenyl group at C4 carbon and presented a major chair conformation, which is prone to weaken the C4-O3 bond via the anomeric effect and facilitates the cleavage for the release of the biologically active metabolite.

2,6-Dihy-droxy-4-oxo-2-(pyridin-1-ium-3-yl)-4H-1,3,2-benzodioxaborinin-2-ide 0.67-hydrate.

The asymmetric unit of the title compound, C12H10BNO5·0.67H2O, contains three independent pyridinylboronic acid esters adopting zwitterionic forms and two water mol-ecules. The six-membered heterocyclic rings in the boronic esters have half-chair conformations and the deviations of the B atoms from the boronate mean planes range from 0.456 (3) to 0.657 (3) Å. All of the B atoms have tetra-hedral coordination environments, with B-O and B-C bond lengths of 1.446 (4)-1.539 (3) and 1.590 (5)-1.609 (5) Å, respectively. In the crystal, the ester and water mol-ecules are linked into a three-dimensional network by a large number of O-H⋯O, N-H⋯O and C-H⋯O hydrogen bonds. The crystal packing is further accomplished by π-π inter-actions, with centroid-centroid distances of 3.621 (4)-3.787 (4) Å.

Benzene-1,3,5-tri-carb-oxy-lic acid-pyridinium-2-olate (1/3).

The asymmetric unit of the title compound, C9H6O6·3C5H5NO, contains one benzene-1,3,5-tri-carb-oxy-lic acid mol-ecule (BTA) and three pyridin-2-ol mol-ecules each present in the zwitterion form. In the crystal, these entities are linked through O-H⋯O(-) and N(+)-H⋯O(-) hydrogen bonds, forming sheets parallel to (10-1). These layers contain macrocyclic rings of composition [BTA]2[pyol]6 and with graph-set notation R (6) 8(44), which are stacked along c through π-π inter-actions [inter-centroid distances = 3.536 (2)-3.948 (3) Å]. They are inter-connected by N(+)-H⋯O(-) hydrogen-bonded chains of pyridin-2-ol mol-ecules running parallel to c, forming a three-dimensional network. There are also C-H⋯O hydrogen bonds present which reinforce the three-dimensional structure.

Bis[(1RS,2RS)-4,4'-(1-aza-niumyl-2-hy-droxy-ethane-1,2-di-yl)dipyridinium] tris-[tetra-chloridopalladate(II)].

The asymmetric unit of the title compound, (C12H16N3O)2[PdCl4]3, consists of a 4,4'-(1-aza-niumyl-2-hy-droxy-ethane-1,2-di-yl)dipyridinium dication and one and a half tetra-chloridopalladate(II) anions; the latter has inversion symmetry. In the cation, the pyridinium rings attached to the central 1-aza-niumyl-2-hy-droxy-ethane fragment show an anti conformation, as indicated by the central C-C-C-C torsion angle of -178.1 (4)°, and they are inclined to one another by 25.7 (2)°. In the crystal, the cations and anions are linked through N-H⋯Cl and O-H⋯Cl hydrogen bonds. There are also π-π contacts [centroid-centroid distance = 3.788 (3) Å] and a number of C-H⋯O and C-H⋯Cl inter-actions are present, consolidating the formation of a three-dimensional structure.

(1RS,2RS)-4,4'-(1-Aza-niumyl-2-hy-droxy-ethane-1,2-di-yl)dipyridinium tetra-chlorido-platinate(II) chloride.

The title compound, (C12H16N3O)[PtCl4]Cl, consists of a 4,4'-(1-aza-niumyl-2-hy-droxy-ethane-1,2-di-yl)dipyridinium trication, a square-planar tetra-chloridoplatinate(II) dianion and a chloride ion. In the cation, the pyridinium rings attached to the central 1-aza-niumyl-2-hy-droxy-ethane fragment have an anti conformation, as indicated by the central C-C-C-C torsion angle of -166.5 (6)°, and they are inclined to one another by 63.5 (4)°. In the crystal, the cations and anions are linked through N-H⋯Cl and O-H⋯Cl hydrogen bonds. There are also π-π contacts [centroid-centroid distances = 3.671 (4) and 3.851 (4) Å] and a number of C-H⋯Cl inter-actions present, consolidating the formation of a three-dimensional supra-molecular structure.

Cyclo-hexane-1,4-dicarb-oxy-lic acid-pyridinium-4-olate (1/1).

In the title adduct, C5H5NO·C8H12O4, the heterocycle exists in its zwitterionic form. The cyclo-hexane ring exhibits a chair conformation with the carb-oxy-lic acid groups in equatorial and axial orientations. In the crystal, mol-ecules are linked through charge-assisted O-H⋯O(-), N(+)-H⋯O(-) and N(+)-H⋯O hydrogen bonds, and an additional series of C-H⋯O contacts, giving a pleated two-dimensional hydrogen-bonded network parallel to (-204).

Bis{2-[2,5-bis-(pyridin-2-yl)-1H-imidazol-4-yl]pyridinium} tetra-cyanidoplatinate(II) tetra-hydrate.

The asymmetric unit of the title hydrated complex salt, (C18H14N5)2[Pt(CN)4]·4H2O, consists of one 2-[2,5-bis-(pyridin-2-yl)-1H-imidazol-4-yl]pyridinium cation, half a tetra-cyanidoplatinate(II) dianion, which is located about a crystallographic inversion center, and two water mol-ecules of crystallization. The Pt(II) atom has a square-planar coordination environment, with Pt-CCN distances of 1.992 (4) and 2.000 (4) Å. In the cation, there is an N-H⋯N hydrogen bond linking adjacent pyridinium and pyridine rings in positions 4 and 5. Despite this, the organic component is non-planar, as shown by the dihedral angles of 10.3 (2), 6.60 (19) and 15.66 (18)° between the planes of the central imidazole ring and the pyridine/pyridinium substituents in the 2-, 4- and 5-positions. In the crystal, cations and anions are linked via O-H⋯O, O-H⋯N and N-H⋯O hydrogen bonds, forming a three-dimensional network. Additional π-π, C-H⋯O and C-H⋯N contacts provide stabilization to the crystal lattice.

Direct chemical method for preparing 2,3-epoxyamides using sodium chlorite.

A direct method for preparing 2,3-epoxyamides from tertiary allylamines via a tandem C-H oxidation/double bond epoxidation using sodium chlorite is reported. Apparently, the reaction course consists of two steps: (i) allylic oxidation of the starting allylamine to corresponding unsaturated allylamide with sodium chlorite followed by (ii) epoxidation of the allylamide to the 2,3-epoxyamide mediated by hypochlorite ion, which is formed in situ by reduction of sodium chlorite. The reaction conditions tolerate the presence of free hydroxyl groups and typical functional groups such as TBS, aryl, alkyl, allyl, acetyl, and benzyl groups; however, when an activated aromatic ring (e.g., sesamol) is present in the substrate, the use of a scavenger is necessary.

2,4,5-Tris(pyridin-4-yl)-4,5-dihydro-1,3-oxazole.

In the title compound, C(18)H(14)N(4)O, the mol-ecules are disordered about a crystallographic twofold axis, leading to 50:50 disorder of the O- and N-atom sites within the oxazole ring. As a consequence, symmetry-related oxazole C-N and C-O bonds are averaged. The oxazole ring makes a dihedral angle of 6.920 (1)° with the pyridyl ring in the 2-position and 60.960 (2)° with the pyridyl rings in the 4- and 5-positions.