Synthesis and Solid-State Characterization of Self-Assembled Macrocyclic Molecular Rotors of Bis(dithiocarbamate) Ligands with Diorganotin(IV)

Two bis­(dithiocarbamate) (bdtc) metallamacrocyclic compounds, <b>1</b> and <b>2</b>, and the deuterated analogues <b>1</b>-<i>d</i>₈ and <b>1</b>-<i>d</i>₂₀ were readily prepared through self-assembly processes involving the corresponding secondary bis­(diamines), with two equivalents each of CS₂ and dimethyltin­(IV) dichloride. Solid-state characterization using FTIR, PXRD, and TGA indicated that the solid phases of both macrocycles were amorphous solids. For compound <b>1</b>, a crystalline phase could only be obtained in the form of a dichloromethane solvate; however, the corresponding crystal lattice was unstable and collapsed rapidly under ambient conditions. The bdtc ligands containing <i>para</i>-disubstituted phenylene (compound <b>1</b>) and bicyclo[2.2.2]­octane groups (compound <b>2</b>) showed rotational motion within the macrocyclic assemblies in the solid state. For compound <b>1</b>, the internal rotation of the phenylene groups was examined first by ¹³C NMR CPMAS spectroscopy using the <b>1</b>-<i>d</i>₂₀ derivative in which the hydrogen atoms of the pendant phenyl groups had been substituted with deuterium atoms and also by ²H NMR spin echo experiments using the <b>1</b>-<i>d</i>₈ derivative in which the rotating phenylene groups have been deuterated. Line shape analysis using a log-Gaussian distribution model indicated that the central phenylene rings experience fast 2-fold flip reorientations over the sp²–sp³ carbon atom axes, overcoming an activation energy of <i>E</i>_a = 10 kcal/mol with a preexponential factor <i>A</i> = 3.9 × 10¹⁴ s^–1. For compound <b>2</b>, the ¹³C CPMAS experiments suggested that the bicyclo[2.2.2]­octane moieties also undergo fast internal dynamics, which is in agreement with the higher symmetry of these fragments when compared to the phenylene spacers

Synthesis and Solid-State Characterization of Self-Assembled Macrocyclic Molecular Rotors of Bis(dithiocarbamate) Ligands with Diorganotin(IV)

Two bis­(dithiocarbamate) (bdtc) metallamacrocyclic compounds, <b>1</b> and <b>2</b>, and the deuterated analogues <b>1</b>-<i>d</i>₈ and <b>1</b>-<i>d</i>₂₀ were readily prepared through self-assembly processes involving the corresponding secondary bis­(diamines), with two equivalents each of CS₂ and dimethyltin­(IV) dichloride. Solid-state characterization using FTIR, PXRD, and TGA indicated that the solid phases of both macrocycles were amorphous solids. For compound <b>1</b>, a crystalline phase could only be obtained in the form of a dichloromethane solvate; however, the corresponding crystal lattice was unstable and collapsed rapidly under ambient conditions. The bdtc ligands containing <i>para</i>-disubstituted phenylene (compound <b>1</b>) and bicyclo[2.2.2]­octane groups (compound <b>2</b>) showed rotational motion within the macrocyclic assemblies in the solid state. For compound <b>1</b>, the internal rotation of the phenylene groups was examined first by ¹³C NMR CPMAS spectroscopy using the <b>1</b>-<i>d</i>₂₀ derivative in which the hydrogen atoms of the pendant phenyl groups had been substituted with deuterium atoms and also by ²H NMR spin echo experiments using the <b>1</b>-<i>d</i>₈ derivative in which the rotating phenylene groups have been deuterated. Line shape analysis using a log-Gaussian distribution model indicated that the central phenylene rings experience fast 2-fold flip reorientations over the sp²–sp³ carbon atom axes, overcoming an activation energy of <i>E</i>_a = 10 kcal/mol with a preexponential factor <i>A</i> = 3.9 × 10¹⁴ s^–1. For compound <b>2</b>, the ¹³C CPMAS experiments suggested that the bicyclo[2.2.2]­octane moieties also undergo fast internal dynamics, which is in agreement with the higher symmetry of these fragments when compared to the phenylene spacers

Transition Metal-Free Selective Double sp³ C–H Oxidation of Cyclic Amines to 3‑Alkoxyamine Lactams

The first chemical method for selective dual sp³ C–H functionalization at the alpha-and beta positions of cyclic amines to their corresponding 3-alkoxyamine lactams is reported. Unlike traditional C_α–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 C_α–H oxidation but also the subsequent functionalization of the unreactive β-methylene group in an unprecedented tandem fashion and using environmentally friendly reactants

Modification of the Supramolecular Hydrogen-Bonding Patterns of Acetazolamide in the Presence of Different Cocrystal Formers: 3:1, 2:1, 1:1, and 1:2 Cocrystals from Screening with the Structural Isomers of Hydroxybenzoic Acids, Aminobenzoic Acids, Hydroxybenzamides, Aminobenzamides, Nicotinic Acids, Nicotinamides, and 2,3-Dihydroxybenzoic Acids

Acetazolamide (ACZ) has been combined via liquid-assisted grinding in water with a library of cocrystal formers derived from benzoic and nicotinic acid, which provided novel cocrystals with 2-hydroxybenzamide, 2-aminobenzamide, picolinamide, and 2,3-dihydroxybenzoic acid. The cocrystalline phases were identified first by XRPD analysis and then structurally characterized by IR spectroscopy and single-crystal X-ray diffraction analysis. These cocrystals and the previously reported cocrystalline phases obtained from 4-hydroxybenzoic acid and nicotinamide constitute a series of six cocrystals of varied stoichiometric ratios (3:1, 2:1, 1:1, and 1:2), which allowed for a profound analysis of the structural and chemical factors that govern their formation. The structural analysis has shown that the ACZ molecules participate in the dominant hydrogen-bonding patterns within the crystal structures: three cocrystal structures exhibit extended supramolecular aggregates of ACZ having channels, pores, or semispherical voids, in which the cocrystal formers are included as guest molecules, and can, therefore, be described as inclusion or clathrate complexes. One cocrystal can be considered as a pillared or intercalation compound, and the remaining two cocrystals are true two-component 2D or 3D networks. In addition, a variety of alternative preparative methods (liquid-assisted grinding, neat grinding, reaction crystallization, solution-mediated phase transformation, and solution crystallization) have been employed, showing that four of the six cocrystals required the presence of water for successful cocrystal formation

Modification of the Supramolecular Hydrogen-Bonding Patterns of Acetazolamide in the Presence of Different Cocrystal Formers: 3:1, 2:1, 1:1, and 1:2 Cocrystals from Screening with the Structural Isomers of Hydroxybenzoic Acids, Aminobenzoic Acids, Hydroxybenzamides, Aminobenzamides, Nicotinic Acids, Nicotinamides, and 2,3-Dihydroxybenzoic Acids

Acetazolamide (ACZ) has been combined via liquid-assisted grinding in water with a library of cocrystal formers derived from benzoic and nicotinic acid, which provided novel cocrystals with 2-hydroxybenzamide, 2-aminobenzamide, picolinamide, and 2,3-dihydroxybenzoic acid. The cocrystalline phases were identified first by XRPD analysis and then structurally characterized by IR spectroscopy and single-crystal X-ray diffraction analysis. These cocrystals and the previously reported cocrystalline phases obtained from 4-hydroxybenzoic acid and nicotinamide constitute a series of six cocrystals of varied stoichiometric ratios (3:1, 2:1, 1:1, and 1:2), which allowed for a profound analysis of the structural and chemical factors that govern their formation. The structural analysis has shown that the ACZ molecules participate in the dominant hydrogen-bonding patterns within the crystal structures: three cocrystal structures exhibit extended supramolecular aggregates of ACZ having channels, pores, or semispherical voids, in which the cocrystal formers are included as guest molecules, and can, therefore, be described as inclusion or clathrate complexes. One cocrystal can be considered as a pillared or intercalation compound, and the remaining two cocrystals are true two-component 2D or 3D networks. In addition, a variety of alternative preparative methods (liquid-assisted grinding, neat grinding, reaction crystallization, solution-mediated phase transformation, and solution crystallization) have been employed, showing that four of the six cocrystals required the presence of water for successful cocrystal formation

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

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

Nitazoxanide Cocrystals in Combination with Succinic, Glutaric, and 2,5-Dihydroxybenzoic Acid

Combination of nitazoxanide (NTZ) with a total of 32 cocrystal formers gave cocrystals with succinic acid (NTZ-SUC, 2:1) and glutaric acid (NTZ-GLU, 1:1). Additionally, 2,5-dihydroxybenzoic acid provided a cocrystal solvate with acetonitrile (NTZ-25DHBA-CH₃CN, 1:1:1). All solid phases were characterized by X-ray powder diffraction analysis, IR spectroscopy, thermogravimetric analysis, differential scanning calorimetry, and single-crystal X-ray diffraction analysis. Single-crystal X-ray crystallography revealed that NTZ and the carboxylic acid cocrystal formers were linked in all three cocrystals through the same supramolecular heterodimeric synthon, C­(N)­NH···HOOC. Despite having different stoichiometries, the crystal structures of NTZ-SUC and NTZ-GLU showed similarities in the supramolecular organization, both containing two-dimensional layers formed by NTZ molecules, which were further interconnected by single (NTZ-SUC) and homodimeric entities (NTZ-GLU) of the cocrystal former. Basic physical stability tests showed that cocrystals NTZ-SUC and NTZ-GLU are stable at least for one month under standardized temperature/relative humidity stress conditions but decompose within 1 h into the corresponding physical phase mixtures, when exposed to aqueous solutions simulating physiological gastrointestinal conditions. Measurement of the dissolution rates gave small increases of the intrinsic dissolution rate constants when compared with NTZ. Pressure stability tests showed that the cocrystals support higher pressures (at least up to 60 kg/cm²) than NTZ

Modification of the Supramolecular Hydrogen-Bonding Patterns of Acetazolamide in the Presence of Different Cocrystal Formers: 3:1, 2:1, 1:1, and 1:2 Cocrystals from Screening with the Structural Isomers of Hydroxybenzoic Acids, Aminobenzoic Acids, Hydroxybenzamides, Aminobenzamides, Nicotinic Acids, Nicotinamides, and 2,3-Dihydroxybenzoic Acids

Acetazolamide (ACZ) has been combined via liquid-assisted grinding in water with a library of cocrystal formers derived from benzoic and nicotinic acid, which provided novel cocrystals with 2-hydroxybenzamide, 2-aminobenzamide, picolinamide, and 2,3-dihydroxybenzoic acid. The cocrystalline phases were identified first by XRPD analysis and then structurally characterized by IR spectroscopy and single-crystal X-ray diffraction analysis. These cocrystals and the previously reported cocrystalline phases obtained from 4-hydroxybenzoic acid and nicotinamide constitute a series of six cocrystals of varied stoichiometric ratios (3:1, 2:1, 1:1, and 1:2), which allowed for a profound analysis of the structural and chemical factors that govern their formation. The structural analysis has shown that the ACZ molecules participate in the dominant hydrogen-bonding patterns within the crystal structures: three cocrystal structures exhibit extended supramolecular aggregates of ACZ having channels, pores, or semispherical voids, in which the cocrystal formers are included as guest molecules, and can, therefore, be described as inclusion or clathrate complexes. One cocrystal can be considered as a pillared or intercalation compound, and the remaining two cocrystals are true two-component 2D or 3D networks. In addition, a variety of alternative preparative methods (liquid-assisted grinding, neat grinding, reaction crystallization, solution-mediated phase transformation, and solution crystallization) have been employed, showing that four of the six cocrystals required the presence of water for successful cocrystal formation

Nitazoxanide Cocrystals in Combination with Succinic, Glutaric, and 2,5-Dihydroxybenzoic Acid

Combination of nitazoxanide (NTZ) with a total of 32 cocrystal formers gave cocrystals with succinic acid (NTZ-SUC, 2:1) and glutaric acid (NTZ-GLU, 1:1). Additionally, 2,5-dihydroxybenzoic acid provided a cocrystal solvate with acetonitrile (NTZ-25DHBA-CH₃CN, 1:1:1). All solid phases were characterized by X-ray powder diffraction analysis, IR spectroscopy, thermogravimetric analysis, differential scanning calorimetry, and single-crystal X-ray diffraction analysis. Single-crystal X-ray crystallography revealed that NTZ and the carboxylic acid cocrystal formers were linked in all three cocrystals through the same supramolecular heterodimeric synthon, C­(N)­NH···HOOC. Despite having different stoichiometries, the crystal structures of NTZ-SUC and NTZ-GLU showed similarities in the supramolecular organization, both containing two-dimensional layers formed by NTZ molecules, which were further interconnected by single (NTZ-SUC) and homodimeric entities (NTZ-GLU) of the cocrystal former. Basic physical stability tests showed that cocrystals NTZ-SUC and NTZ-GLU are stable at least for one month under standardized temperature/relative humidity stress conditions but decompose within 1 h into the corresponding physical phase mixtures, when exposed to aqueous solutions simulating physiological gastrointestinal conditions. Measurement of the dissolution rates gave small increases of the intrinsic dissolution rate constants when compared with NTZ. Pressure stability tests showed that the cocrystals support higher pressures (at least up to 60 kg/cm²) than NTZ