Comprehensive Study on Structure−Activity Relationships of Rifamycins: Discussion of Molecular and Crystal Structure and Spectroscopic and Thermochemical Properties of Rifamycin O

The mechanism of action of rifamycins against bacterial DNA-dependent RNA polymerase has been explained on the basis of the spatial arrangement of four oxygens which can form hydrogen bonds with the enzyme. Structural descriptors are derived from X-ray diffraction crystal structures of 25 active and nonactive rifamycins. Principal component analysis is used to find the combination of structural parameters which better discriminate between active and nonactive rifamycins. Two possible mechanisms of molecular rearrangement are described which can convert nonactive into active conformations. The energy involved for conformational rearrangements is studied by molecular modeling techniques. Methyl C34 is found to play a key role for determining the geometry of the pharmacophore. Rifamycin O, reported to be active, is obtained by oxidation of rifamycin B and is studied by X-ray single-crystal diffractometry, by solution IR and NMR spectroscopy, and by thermal analysis. Surprisingly the oxidation process is totally stereospecific, and an explanation is given based on solution spectroscopic evidence. The conformation found in the solid state is typical of nonactive compounds, and molecular mechanics calculations show that a molecular rearrangement to the active conformation would require about 15 kcal/mol. Thermal analysis confirms that rifamycin O has a sterically constrained conformation. Therefore, it is likely that the antibiotic activity of rifamycin O is due either to chemical modification prior to reaching the enzyme or to conformational activation

From Local Control to Collective Response: Fabrication of Responsive Organometallic Crystalline Materials by Careful Design of Functionalities and Tailoring of the Intermolecular Interactions

The two aminobenzoic acid isomers 4-amino-3-hydroxybenzoic acid and 3-amino-4-hydroxybenzoic acid have been used to synthesize the corresponding half-sandwich Ru­(II) complexes [(<i>p</i>-cymene)­Ru­(κN-ligand)­X₂] (X = Cl, I). The solid state structures of all the complexes have been elucidated by single-crystal X-ray analysis. In all the cases, the complexes give rise to wheel-and-axle shaped supramolecular entities based on the dimerization of the carboxylic functionalities, with extended hydrogen bond networks involving the NH₂, OH, and X groups. The nature of the halogen ligand strongly influences the host–guest properties of the crystalline materials. In fact, the chloride complexes crystallize as nonsolvates and result as inert toward the uptake of volatile organic compounds. Diversely, the replacement of Cl with I gives rise to systems with remarkable efficiency in exchanging volatile guests (acetone) by fast and reversible solid–vapor processes based on the breaking and reforming of hydrogen bonds

Guest Molecules Play Tug of War in a Breathing MOF: The Stepwise Monitoring of an Elastic Framework Deformation via SC-SC Transformations

Metal–organic frameworks (MOFs) keep attracting the attention of many research groups worldwide who are aiming at using them as crystalline sponges, thus loading their porous structures with any kind of molecules of interest. Among other desiderata, framework flexibility is the golden property that an MOF must have to adapt its structure throughout the loading and release process of guest molecules. Here, we highlight the flexibility of a breathing MOF by soaking the crystals of the mixed-ligand MOF PUM168 into different solvents, ranging from acetonitrile (ACN) to THF and diethyl ether, revealing a systematic framework twisting observed via single-crystal-to-single-crystal transformations during the DMF–solvent exchange. Reversible chemical pathways have successfully been reported and confirmed via FT-IR and 1H NMR. Soaking in ACN resulted in the most effective strategy in terms of the solvent-exchange activation of the pristine MOF, leading to a complete extrusion of the native solvent from the structure while keeping the porous channels widely open

Coordination of <i>c</i><i>yclo</i>-Octasulfur and <i>c</i><i>yclo</i>-Heptaselenium to Dinuclear Rhenium(I) Systems

By substitution reactions of the coordinated THF ligands of Re2(μ-X)2(CO)6(THF)2 by elemental chalcogens (S8 and red selenium), the complexes Re2(μ-X)2(CO)6(S8) (X = Br, 1; I, 2), and Re2(μ-X)2(CO)6(Se7), (X = I, 3; Br, 4) have been prepared. Binuclear compound 3 was crystallographically established to be a coordination compound of cyclo-heptaselenium, two adjacent selenium atoms of the Se7 ligand [Se−Se distance, 2.558(3) Å] being bonded to rhenium(I), at an average Re−Se distance of 2.586(3) Å, and the nonbonding Re···Re distance being 4.077(3) Å. Spectroscopic evidence of the existence of these chalcogen complexes in solution is reported. The Re2(μ-X)2(CO)6(S8) complexes undergo S8 displacement by THF, while the coordinated Se7 moiety is less readily displaced from 3

Preparation and Reactivity of Mixed-Ligand Ruthenium(II) Hydride Complexes with Phosphites and Polypyridyls

Chloro complexes [RuCl(N-N)P3]BPh4 (1−3) [N-N = 2,2‘-bipyridine, bpy; 1,10-phenanthroline, phen; 5,5‘-dimethyl-2,2‘-bipyridine, 5,5‘-Me2bpy; P = P(OEt)3, PPh(OEt)2 and PPh2OEt] were prepared by allowing the [RuCl4(N-N)]·H2O compounds to react with an excess of phosphite in ethanol. The bis(bipyridine) [RuCl(bpy)2{P(OEt)3}]BPh4 (7) complex was also prepared by reacting RuCl2(bpy)2·2H2O with phosphite and ethanol. Treatment of the chloro complexes 1−3 and 7 with NaBH4 yielded the hydride [RuH(N-N)P3]BPh4 (4−6) and [RuH(bpy)2P]BPh4 (8) derivatives, which were characterized spectroscopically and by the X-ray crystal structure determination of [RuH(bpy){P(OEt)3}3]BPh4 (4a). Protonation reaction of the new hydrides with Brønsted acid was studied and led to dicationic [Ru(η2-H2)(N-N)P3]2+ (9, 10) and [Ru(η2-H2)(bpy)2P]2+ (11) dihydrogen derivatives. The presence of the η2-H2 ligand was indicated by a short T1min value and by the measurements of the JHD in the [Ru](η2-HD) isotopomers. From T1min and JHD values the H−H distances of the dihydrogen complexes were also calculated. A series of ruthenium complexes, [RuL(N-N)P3](BPh4)2 and [RuL(bpy)2P](BPh4)2 (P = P(OEt)3; L = H2O, CO, 4-CH3C6H4NC, CH3CN, 4-CH3C6H4CN, PPh(OEt)2], was prepared by substituting the labile η2-H2 ligand in the 9, 10, 11 derivatives. The reactions of the new hydrides 4−6 and 8 with both mono- and bis(aryldiazonium) cations were studied and led to aryldiazene [Ru(C6H5NNH)(N-N)P3](BPh4)2 (19, 21), [{Ru(N-N)P3}2(μ-4,4‘-NHNC6H4−C6H4NNH)](BPh4)4 (20), and [Ru(C6H5NNH)(bpy)2P](BPh4)2 (22) derivatives. Also the heteroallenes CO2 and CS2 reacted with [RuH(bpy)2P]BPh4, yielding the formato [Ru{η1-OC(H)O}(bpy)2P]BPh4 and dithioformato [Ru{η1-SC(H)S}(bpy)2P]BPh4 derivatives

Tautomerization of Methyldiazene to Formaldehyde-Hydrazone in Ruthenium and Osmium Complexes

Mixed-ligand hydrazine complexes [M(CO)(RNHNH2)P4](BPh4)2 (1, 2) [M = Ru, Os; R = H, CH3, C6H5; P = P(OEt)3] with carbonyl and triethyl phosphite were prepared by allowing hydride [MH(CO)P4]BPh4 species to react first with HBF4·Et2O and then with hydrazines. Depending on the nature of the hydrazine ligand, the oxidation of [M(CO)(RNHNH2)P4](BPh4)2 derivatives with Pb(OAc)4 at −30 °C gives acetate [M(κ1-OCOCH3)(CO)P4]BPh4 (3a), phenyldiazene [M(CO)(C6H5NNH)P4](BPh4)2 (3c, 4c), and methyldiazene [M(CO)(CH3NNH)P4](BPh4)2 (3b, 4b) derivatives. Methyldiazene complexes 3b and 4b undergo base-catalyzed tautomerization of the CH3NNH ligand to formaldehyde-hydrazone NH2NCH2, giving the [M(CO)(NH2NCH2)P4](BPh4)2 (5, 6) derivatives. Complexes 5 and 6 were characterized spectroscopically and by the X-ray crystal structure determination of the [Ru(CO)(NH2NCH2){P(OEt)3}4](BPh4)2 (5) derivative. Acetone-hydrazone [M(CO){NH2NC(CH3)2}P4](BPh4)2 (7, 8) complexes were also prepared by allowing hydrazine [M(CO)(NH2NH2)P4](BPh4)2 derivatives to react with acetone

Efficient and General Synthesis of 5-(Alkoxycarbonyl)methylene-3-oxazolines by Palladium-Catalyzed Oxidative Carbonylation of Prop-2-ynylamides

A variety of prop-2-ynylamides have been carbonylated under oxidative conditions to give oxazolines, oxazolines with chelating groups, and bisoxazolines bearing an (alkoxycarbonyl)methylene chain at the 5 position in good yields. The cyclization−alkoxycarbonylation process was carried out in alcoholic media at 50−70 °C and under 24 bar pressure of 3:1 carbon monoxide/air in the presence of catalytic amounts of 10% Pd/C or PdI2 in conjunction with KI. Cyclization occurred by anti attack of an oxygen function on the palladium-coordinated triple bond, followed by stereospecific alkoxycarbonylation, strictly resulting in E-stereochemistry. The structures of representative oxazolines and bisoxazolines have been determined by X-ray diffraction analysis

Synthesis and Reactivity of Trihydridostannyl Complexes of Ruthenium and Osmium

Trichlorostannyl complexes M(SnCl3)(Tp)L(PPh3) (1, 2) and M(SnCl3)(Cp)L(PPh3) (5, 6) [M = Ru, Os; L = P(OMe)3 (a), P(OEt)3 (b), PPh(OEt)2 (c), PPh3 (d)] were prepared by allowing chloro complexes MCl(Tp)L(PPh3) and MCl(Cp)L(PPh3) to react with an excess of SnCl2·2H2O in ethanol. Treatment of trichlorostannyl complexes 1, 2, 5, and 6 with NaBH4 in ethanol yielded tin trihydride derivatives M(SnH3)(Tp)L(PPh3) (3, 4) and M(SnH3)(Cp)L(PPh3) (7, 8). Reaction of these complexes with CCl4 gave the trichlorostannyl precursors 1, 2, 5, and 6. Hydridochlorostannyl intermediates Os(SnH2Cl)(Tp)[P(OMe)3](PPh3) (9a) and Os(SnHCl2)(Tp)[P(OMe)3](PPh3) (10a) were also obtained. Reaction of trihydridostannyl complexes M(SnH3)(Tp)L(PPh3) (3, 4) with CO2 (1 atm) led to hydridobis(formate) derivatives M[SnH{OC(H)O}2](Tp)L(PPh3) (11). In contrast, reaction of the related complexes M(SnH3)(Cp)L(PPh3) (7, 8) with CO2 (1 atm) led to the binuclear OH-bridging bis(formate) derivatives [M[Sn{OC(H)O}2(μ-OH)](Cp)L(PPh3)]2 (12, 13). A reaction path for the formation of 12 and 13, involving the mononuclear tin hydride complex M[SnH{OC(H)O}2](Cp)L(PPh3), is discussed. The X-ray crystal structure of 12b is reported. Chlorobis(methyl)stannyl Ru(SnClMe2)(Cp)[P(OEt)3](PPh3) (15b) and trimethylstannyl complexes M(SnMe3)(Tp)[P(OMe)3](PPh3) (14a) and M(SnMe3)(Cp)[P(OEt)3](PPh3) (16b, 17b) were prepared by allowing trichlorostannyl compounds 1, 2, 5, and 6 to react with MgBrMe in diethyl ether. Trialkynylstannyl derivatives M[Sn(CCR)3}(Tp)L(PPh3) (18, 19) and Ru[Sn(CCR)3}(Cp)[P(OEt)3](PPh3) (20b) (R = Ph, p-tolyl) were also prepared from the reaction of trichlorostannyl complexes 1, 2, 5, and 6 with Li+(CCR)− in thf. The complexes were characterized by spectroscopy and by X-ray crystal structure determination of Ru(SnClMe2)(Cp)[P(OEt)3](PPh3) (15b)

Salts and Cocrystals of Benzocaine with Increased Dissolution Rate and Permeability Open New Avenues for Enhancing the Duration of Action

Benzocaine, a widely used local anesthetic, has some usage limitations due to its short duration of action, resulting in inconsistent clinical outcomes. In this study, the formation of salts and cocrystals is explored as a strategy to enhance the pharmacokinetic profile of benzocaine, aiming for a higher dissolution rate and permeability in vitro as well as to potentially increase its pharmacological effect and duration of action in vivo. A new cocrystal and nine new salts with two different categories of acids (carboxylic and sulfonic) were prepared and characterized: BH oxalate, BH naphthalenesulfonate, BH camphorsulfonate, BH maleate, BH mesylate, BH tartrate, BH benzenesulfonate, BH p-toluenesulfonate, BH esylate (BH: protonated benzocaine), and benzocaine–ligustrazine (cocrystal). Dissolution rate and permeability were improved for all newly synthesized forms. Indeed, every system was completely dissolved within 1 h, while benzocaine was dissolved at 54%, and it was still present in suspension after 4 h. Furthermore, permeability was increased 2-fold for benzocaine maleate and up to seven times for benzocaine camphorsulfonate, highlighting the potential of salification and cocrystallization to increase the in vivo performances of benzocaine

Preparation and Reactivity of Mixed-Ligand Ruthenium(II) Hydride Complexes with Phosphites and Polypyridyls

Chloro complexes [RuCl(N-N)P3]BPh4 (1−3) [N-N = 2,2‘-bipyridine, bpy; 1,10-phenanthroline, phen; 5,5‘-dimethyl-2,2‘-bipyridine, 5,5‘-Me2bpy; P = P(OEt)3, PPh(OEt)2 and PPh2OEt] were prepared by allowing the [RuCl4(N-N)]·H2O compounds to react with an excess of phosphite in ethanol. The bis(bipyridine) [RuCl(bpy)2{P(OEt)3}]BPh4 (7) complex was also prepared by reacting RuCl2(bpy)2·2H2O with phosphite and ethanol. Treatment of the chloro complexes 1−3 and 7 with NaBH4 yielded the hydride [RuH(N-N)P3]BPh4 (4−6) and [RuH(bpy)2P]BPh4 (8) derivatives, which were characterized spectroscopically and by the X-ray crystal structure determination of [RuH(bpy){P(OEt)3}3]BPh4 (4a). Protonation reaction of the new hydrides with Brønsted acid was studied and led to dicationic [Ru(η2-H2)(N-N)P3]2+ (9, 10) and [Ru(η2-H2)(bpy)2P]2+ (11) dihydrogen derivatives. The presence of the η2-H2 ligand was indicated by a short T1min value and by the measurements of the JHD in the [Ru](η2-HD) isotopomers. From T1min and JHD values the H−H distances of the dihydrogen complexes were also calculated. A series of ruthenium complexes, [RuL(N-N)P3](BPh4)2 and [RuL(bpy)2P](BPh4)2 (P = P(OEt)3; L = H2O, CO, 4-CH3C6H4NC, CH3CN, 4-CH3C6H4CN, PPh(OEt)2], was prepared by substituting the labile η2-H2 ligand in the 9, 10, 11 derivatives. The reactions of the new hydrides 4−6 and 8 with both mono- and bis(aryldiazonium) cations were studied and led to aryldiazene [Ru(C6H5NNH)(N-N)P3](BPh4)2 (19, 21), [{Ru(N-N)P3}2(μ-4,4‘-NHNC6H4−C6H4NNH)](BPh4)4 (20), and [Ru(C6H5NNH)(bpy)2P](BPh4)2 (22) derivatives. Also the heteroallenes CO2 and CS2 reacted with [RuH(bpy)2P]BPh4, yielding the formato [Ru{η1-OC(H)O}(bpy)2P]BPh4 and dithioformato [Ru{η1-SC(H)S}(bpy)2P]BPh4 derivatives