Strong Bases Design: Key Techniques and Stability Issues.

Theoretical design of molecular superbases has been attracting researchers for more than twenty years. General approaches were developed to make the bases potentially stronger, but less attention was paid to the stability of the predicted structures. Hence, only a small fraction of the theoretical research has led to positive experimental results.

pH Indicators for Strong Molecular Bases: A Theoretical Approach.

The transition points in hexamethylphosphoramide are theoretically studied for a series of acid-base indicators. Three new indicators with multiple transition points and deeply colored low-nucleophilic anions are designed. A general basicity scale is established for highly basic hexamethylphosphoramide solutions, expanding beyond the basicity of the strongest currently known molecular bases.

Metal-(Acyclic Diaminocarbene) Complexes Demonstrate Nanomolar Antiproliferative Activity against Triple-Negative Breast Cancer.

Invited for the cover of this issue are Tatiyana Serebryanskaya, Mikhail Kinzhalov and co-workers at St. Petersburg State University, the Research Institute for Physical Chemical Problems, Belarusian State University, Togliatti State University and Blokhin National Medical Research Center of Oncology. The image depicts the shield of Pallas Athena with the structure of a palladium carbene complex that protects against triple-negative breast cancer.

Metal-(Acyclic Diaminocarbene) Complexes Demonstrate Nanomolar Antiproliferative Activity against Triple-Negative Breast Cancer.

Hydrolytically stable Pd and Pt complexes supported by acyclic diaminocarbene ligands represent a novel class of structural organometallic anticancer agents exhibiting nanomolar antiproliferative activity in a panel of cancer cell lines (IC 0.07-0.81 μM) and up to 300-fold selectivity for cancer cells over normal primary fibroblasts.

From ferrocene to decasubstituted enantiopure ferrocene-1,1'-disulfoxide derivatives.

The functionalization of (,)-,'-di--butylferrocene-1,1'-disulfoxide by deprotolithiation-electrophilic trapping sequences was studied towards polysubstituted, enantiopure derivatives for which the properties were determined. While the 2,2'-disubstituted ferrocene derivatives were obtained as expected, subsequent functionalization of the 2,2'-di(phenylthio) and 2,2'-bis(trimethylsilyl) derivatives occurred primarily at the 4- or 4,4'-positions. This unusual regioselectivity was discussed in detail in light of p values and structural data.

Strong Bases Design: Predicted Limits of Basicity.

Brønsted superbases have wide applications in organic chemistry due to their ability to activate C-H bonds. The strongest neutral bases to date are substituted aminophosphazenes developed in the late 1980s by Reinhard Schwesinger. Since then, much effort has been expended to create even stronger neutral bases.

Synthesis of Polysubstituted Ferrocenesulfoxides.

The purpose of the study is to design synthetic methodologies, especially directed deprotometalation using polar organometallic reagents, to access polysubstituted ferrocenesulfoxides. From enantiopure 2-substituted (SiMe, PPh) --butylferrocenesulfoxides, a third substituent was first introduced at the 5 position (SiMe, I, D, C(OH)Ph, Me, PPh, CHNMe, F) and removal of the trimethylsilyl group then afforded 2-substituted ferrocenesulfoxides unreachable otherwise. Attempts to apply the "halogen dance" reaction to the ferrocenesulfoxide series led to unexpected results although rationalized in light of calculated p values.

Deprotometalation-Iodolysis and Direct Iodination of 1-Arylated 7-Azaindoles: Reactivity Studies and Molecule Properties.

Five protocols were first compared for the copper-catalyzed C-N bond formation between 7-azaindole and aryl/heteroaryl iodides/bromides. The 1-arylated 7-azaindoles thus obtained were subjected to deprotometalation-iodolysis sequences using lithium 2,2,6,6-tetramethylpiperidide as the base and the corresponding zinc diamide as an in situ trap. The reactivity of the substrate was discussed in light of the calculated atomic charges and the p values.

Mesoionic tetrazolium-5-aminides: Synthesis, molecular and crystal structures, UV-vis spectra, and DFT calculations.

Tetrazolium-5-aminides have been prepared by the -butylation of 5-aminotetrazole and its -methyl derivatives by the BuOH/HClO system followed by the treatment of the tetrazolium salts by alkali. The mesoionic compounds have been found to show a higher reactivity of the exocyclic N atom in comparison with 5-aminotetrazoles. The compounds reacted with 1,2-dibromoethane and 5-(methylsulfonyl)-1-phenyl-1-tetrazole with substitution of bromine and methylsulfonyl groups giving the corresponding tetrazolium salts or conjugate aminides.

The first organocopper tetrazole derivative: synthesis and characterization.

1-(5-Amino-3-azapentyl)tetrazole dihydrochloride (HL·2HCl) was prepared by heterocyclization of diethylenetriamine with triethyl orthoformate and sodium azide followed by treatment with potassium carbonate and hydrochloric acid. The reaction of CuCl2, HL·2HCl and triethylamine (NEt3) in a molar ratio of 1 : 1 : 3 in water was found to generate a novel organometallic tetrazole derivative Cu2L2Cl2. This compound is present as a binuclear centrosymmetric molecular complex, in which C-deprotonated tetrazole L acts as a chelating ligand via the two amino N and tetrazole ring C coordination sites and the two copper atoms are linked together through two tetrazole ring N(4)-C(5) bridges.

Azide Binding Controlled by Steric Interactions in Second Sphere. Synthesis, Crystal Structure, and Magnetic Properties of [Ni(II)2(L)(μ(1,1)-N3)][ClO4] (L = Macrocyclic N6S2 Ligand).

The dinuclear Ni(II) complex [Ni2(L(2))][ClO4]2 (3) supported by the 28-membered hexaaza-dithiophenolate macrocycle (L(2))(2-) binds the N3(-) ion specifically end-on yielding [Ni2(L(2))(μ(1,1)-N3)][ClO4] (7) or [Ni2(L(2))(μ(1,1)-N3)][BPh4] (8), while the previously reported complex [Ni2L(1)(μ(1,3)-N3)][ClO4] (2) of the 24-membered macrocycle (L(1))(2-) coordinates it in the end-to-end fashion. A comparison of the X-ray structures of 2, 3, and 7 reveals the form-selective binding of complex 3 to be a consequence of its preorganized, channel-like binding pocket, which accommodates the azide anion via repulsive CH···π interactions in the end-on mode. In contrast to [Ni2L(1)(μ(1,3)-N3)][ClO4] (2), which features a S = 0 ground state, [Ni2(L(2))(μ(1,1)-N3)][BPh4] (8) has a S = 2 ground state that is attained by competing antiferromagnetic and ferromagnetic exchange interactions via the thiolato and azido bridges with a value for the magnetic exchange coupling constant J of 13 cm(-1) (H = -2JS1S2).

Copper(II) tetrafluoroborate complexes with the N(3),N(4)-bridging coordination of 1-(tert-butyl)-1H-tetrazole: synthesis, crystal structure and magnetic properties.

1-(tert-Butyl)-1H-tetrazole (L) reacts with copper(ii) tetrafluoroborate hexahydrate to give the complexes [Cu2L8(H2O)2](BF4)4 (1) or [Cu3L6(H2O)6](BF4)6 (2) depending on the reaction conditions. These complexes, as well as compound L, were characterized using single crystal X-ray analysis. Complex 1 was found to comprise a dinuclear complex cation [Cu2L8(H2O)2](4+) (the Ci symmetry point group), with six tetrazole ligands L showing monodentate N(4)-coordination, and two ligands L providing two tetrazole ring N(3),N(4) bridges between the copper(ii) cations; water molecules complete the distorted octahedral coordination of the metal ions.

Deproto-metallation of N-arylated pyrroles and indoles using a mixed lithium-zinc base and regioselectivity-computed CH acidity relationship.

The synthesis of N-arylated pyrroles and indoles is documented, as well as their functionalization by deprotonative metallation using the base in situ prepared from LiTMP and ZnCl2·TMEDA (1/3 equiv). With N-phenylpyrrole and -indole, the reactions were carried out in hexane containing TMEDA which regioselectively afforded the 2-iodo derivatives after subsequent iodolysis. With pyrroles and indoles bearing N-substituents such as 2-thienyl, 3-pyridyl, 4-methoxyphenyl and 4-bromophenyl, the reactions all took place on the substituent, at the position either adjacent to the heteroatom (S, N) or ortho to the heteroatom-containing substituent (OMe, Br).

Deprotometalation-iodolysis and computed CH acidity of 1,2,3- and 1,2,4-triazoles. Application to the synthesis of resveratrol analogues.

1-Aryl- and 2-aryl-1,2,3-triazoles were synthesized by N-arylation of the corresponding azoles using aryl iodides. The deprotometalations of 1-phenyl-1,2,3-triazole and -1,2,4-triazole were performed using a 2,2,6,6-tetramethylpiperidino-based mixed lithium-zinc combination and occurred at the most acidic site, affording by iodolysis the 5-substituted derivatives. Dideprotonation was noted from 1-(2-thienyl)-1,2,4-triazole by increasing the amount of base.

Cavitands incorporating a Lewis acid dinickel chelate function as receptors for halide anions.

The halide binding properties of the cavitand [Ni2(L(Me2H4))](2+) (4) are reported. Cavitand 4 exhibits a chelating N3Ni(μ-S)2NiN3 moiety with two square-pyramidal Ni(II)N3S2 units situated in an anion binding pocket of ∼4 Å diameter formed by the organic backbone of the (L(Me2H4))(2-) macrocycle. The receptor reacts with fluoride, chloride (in MeCN/MeOH), and bromide (in MeCN) ions to afford an isostructural series of halogenido-bridged complexes [Ni2(L(Me2H4))(μ-Hal)](+) (Hal = F(-) (5), Cl(-) (6), and Br(-) (7)) featuring a N3Ni(μ-S)2(μ-Hal)NiN3 core structure.

Encapsulation of the 4-mercaptobenzoate ligand by macrocyclic metal complexes: conversion of a metallocavitand to a metalloligand.

Complexation of the ambidentate ligand 4-mercaptobenzoate (4-SH-C6H4CO2H, H2mba) by the macrocyclic complex [Ni2L(μ-Cl)]ClO4 (L(2-) represents a 24-membered macrocyclic hexaazadithiophenolate ligand) has been examined. The monodeprotonated Hmba(-) ligand reacts with the Ni2 complex in a selective manner by substitution of the bridging chlorido ligand to produce μ1,3-carboxylato-bridged complex [Ni2L(Hmba)](+) (2(+)), which can be isolated as an air-sensitive perchlorate (2ClO4) or tetraphenylborate (2BPh4) salt. The reactivity of the new mercaptobenzoate complex is reminiscent of that of a "free" thiophenolate ligand.

Deproto-metallation using a mixed lithium-zinc base and computed CH acidity of 1-aryl 1H-benzotriazoles and 1-aryl 1H-indazoles.

1-Aryl-1H-benzotriazoles and -1H-indazoles were synthesized, and their deproto-metallation using the base prepared by mixing LiTMP with ZnCl2·TMEDA (1/3 equiv.) was studied. In the indazole series, reactions occurring at the 3 position were followed by ring opening, and functionalization of the substrate was only found possible (on the sulfur ring) using 2-thienyl as aryl group.

Computed CH acidity of biaryl compounds and their deprotonative metalation by using a mixed lithium/zinc-TMP base.

With the aim of synthesizing biaryl compounds, several aromatic iodides were prepared by the deprotonative metalation of methoxybenzenes, 3-substituted naphthalenes, isoquinoline, and methoxypyridines by using a mixed lithium/zinc-TMP (TMP=2,2,6,6-tetramethylpiperidino) base and subsequent iodolysis. The halides thus obtained, as well as commercial compounds, were cross-coupled under palladium catalysis (e.g.

Synthesis, characterization, and biological evaluation of new tetrazole-based platinum(II) and palladium(II) chlorido complexes--potent cisplatin analogues and their trans isomers.

Two series of tetrazole-containing platinum(II) and palladium(II) chlorido complexes, trans-[ML(2)Cl(2)] (M=Pt, Pd) and cis-[PtL(2)Cl(2)]·nH(2)O (n=0, 1), where L is 1- or 2-substituted 5-aminotetrazole, have been synthesized and thoroughly characterized. Configuration of platinum(II) complexes obtained from the reaction of 5-aminotetrazoles with K(2)PtCl(4) has been found to vary depending on the nature of tetrazole derivatives and reaction conditions. According to in vitro cytotoxic evaluation, only platinum complexes display noticeable antiproliferative effect, and their cytotoxicity depends strongly on their geometry and hydrophobicity of the carrier ligands.

2-tert-Butyl-5-(2-pyridyl)-2H-tetrazole as a chelating ligand in the direct synthesis of novel Cu(II) and heterobimetallic Cu(II)/Mn(II) complexes.

For the first time, a representative of the 2,5-disubstituted tetrazoles, namely, 2-tert-butyl-5-(2-pyridyl)-2H-tetrazole (L), has been found to participate in oxidative dissolution of copper powder in homometalic systems Cu0–L–NH4X–DMSO (X = Cl, SCN, ClO4) and heterobimetallic ones Cu0–Mn(OAc)2–L–NH4OAc–Solv (Solv = DMSO, DMF), providing the formation of molecular homometallic complexes [CuL2Cl2] (1), [CuL2(SCN)2] (2), and [CuL2(H2O)](ClO4)2 (3), heterobimetallic complex [Cu2MnL2(OAc)6] (4) from DMF solution and its mixture with complex [Cu2MnL2(OAc)6]·2DMSO (5) from DMSO solution. Free ligand L and complexes 1–4 were characterized by elemental analysis, IR spectroscopy, thermal and X-ray single crystal analyses, whereas complex 5 was characterized by X-ray analysis only. Compounds 1–3 are mononuclear complexes, with chelating coordination mode of L via the tetrazole ring N4 and pyridine ring N7 atoms.

Deproto-metallation and computed CH acidity of 2-aryl-1,2,3-triazoles.

2-Aryl-1,2,3-triazoles were synthesized by cyclization of the corresponding glyoxal arylosazones, generated from commercial arylhydrazines. The deproto-metallation of 2-phenyl-1,2,3-triazole was attempted using different 2,2,6,6-tetramethylpiperidino-based mixed lithium-metal (Zn, Cd, Cu, Co, Fe) combinations, giving results in the case of Zn, Cd, and Cu. The lithium-zinc combination was next selected to apply the deprotonation-iodination sequence to all the 2-aryl-1,2,3-triazoles synthesized.

Deprotonative metalation of chloro- and bromopyridines using amido-based bimetallic species and regioselectivity-computed CH acidity relationships.

A series of chloro- and bromopyridines have been deprotometalated by using a range of 2,2,6,6-tetramethylpiperidino-based mixed lithium-metal combinations. Whereas lithium-zinc and lithium-cadmium bases afforded different mono- and diiodides after subsequent interception with iodine, complete regioselectivities were observed with the corresponding lithium-copper combination, as demonstrated by subsequent trapping with benzoyl chlorides. The obtained selectivities have been discussed in light of the CH acidities of the substrates, determined both in the gas phase and as a solution in THF by using the DFT B3LYP method.

N-aryl pyrazoles: DFT calculations of CH acidity and deprotonative metallation using a combination of lithium and zinc amides.

A series of N-aryl and N-heteroaryl pyrazoles have been deproto-metallated using a 2,2,6,6-tetramethylpiperidino-based mixed lithium-zinc combination. Mono-, di-, and tri-iodides have been obtained after subsequent trapping with iodine, depending on the substrate and on the quantity of base used. The results have been discussed in the light of the CH acidities of the substrates, determined both in the gas phase and in THF solution using the DFT B3LYP method.

Copper(II) chloride and bromide complexes with 2-methyl-2H-tetrazol-5-amine: an X-ray powder diffraction study.

The complex catena-poly[[dibromidocopper(II)]-bis(mu-2-methyl-2H-tetrazol-5-amine)-kappa(2)N(4):N(5);kappa(2)N(5):N(4)], [CuBr(2)(C(2)H(5)N(5))(2)](n), (I), and the isotypic chloride complex catena-poly[[dichloridocopper(II)]-bis(mu-2-methyl-2H-tetrazol-5-amine)-kappa(2)N(4):N(5);kappa(2)N(5):N(4)], [CuCl(2)(C(2)H(5)N(5))(2)](n), (II), were investigated by X-ray powder diffraction at room temperature. The crystal structure of (I) was solved by direct methods, while the Rietveld refinement of (II) started from the atomic coordinates of (I). In both structures, the Cu atoms lie on inversion centres, adopting a distorted octahedral coordination of two halogen atoms, two tetrazole N atoms and two 5-amine group N atoms.

catena-Poly[cobalt(II)-di-μ-chlorido-κCl:Cl-μ-1,5-dimethyl-1H-tetra-zole-κN:N]: an X-ray powder investigation.

The asymmetric unit of the title compound, [CoCl(2)(C(3)H(6)N(4))](n), contains two Co atoms, both lying on inversion centres, two Cl atoms and one 1,5-dimethyl-tetra-zole ligand. The coordination polyhedra of both Co atoms adopt flattened octa-hedral geometry, with two N atoms from two ligands in axial positions and four Cl atoms in equatorial sites. Neighbouring Co atoms are linked together via two bridging Cl atoms and one tetra-zole ring to form polymeric chains running along the a axis.