Copper (II) complexes possessing alkyl-substituted polypyridyl ligands: Structural characterization and in vitro antitumor activity.

In an effort to find alternatives to the antitumor drug cisplatin, a series of copper (II) complexes possessing alkyl-substituted polypyridyl ligands have been synthesized. Eight new complexes are reported herein: µ-dichloro-bis{2,9-di-sec-butyl-1,10-phenanthrolinechlorocopper(II)} {[(di-sec-butylphen)ClCu(µ-Cl)2CuCl(di-sec-butylphen)]}(1), 2-sec-butyl-1,10-phenanthrolinedichlorocopper(II) {[mono-sec-butylphen) CuCl2} (2), 2,9-di-n-butyl-1,10-phenanthrolinedichlorocopper(II) {[di-n-butylphen) CuCl2}(3), 2-n-butyl-1,10-phenanthrolinedichlorocopper(II) {[mono-n-butylphen) CuCl2} (4), 2,9-di-methyl-1,10-phenanthrolineaquadichlorocopper(II) {[di-methylphen) Cu(H2O)Cl2}(5), µ-dichloro-bis{6-sec-butyl-2,2'-bipyridinedichlorocopper(II)} {(mono-sec-butylbipy) ClCu(µ-Cl)2CuCl(mono-sec-butylbipy)} (6), 6,6'-di-methyl-2,2'-bipyridinedichlorocopper(II) {6,6'-di-methylbipy) CuCl2} (7), and 4,4'-dimethyl-2,2'-bipyridinedichlorocopper(II) {4,4'-di-methylbipy) CuCl2} (8). These complexes have been characterized via elemental analysis, UV-vis spectroscopy, and mass spectrometry. Single crystal X-ray diffraction experiments revealed the complexes synthesized with the di-sec-butylphen ligand (1) and mono-sec-butylbipy ligand (6) crystallized as dimers in which two copper(II) centers are bridged by two chloride ligands. Conversely, complexes 2, 7, and 8 were isolated as monomeric species possessing distorted tetrahedral geometries, and the [(di-methylphen)Cu(H2O)Cl2] (5) complex was isolated as a distorted square pyramidal monomer possessing a coordinating aqua ligand. Compounds 1-8 were evaluated for their in vitro antitumor efficacy. Compounds 1, 5, and 7 in particular were found to exhibit remarkable activity against human derived lung cancer cells, yet this class of copper(II) compounds had minimal cytotoxic effect on non-cancerous cells. In vitro control experiments indicate the activity of the copper(II) complexes most likely does not arise from the formation of CuCl2 and free polypyridyl ligand, and preliminary solution state studies suggest these compounds are generally stable in biological buffer. The results presented herein suggest further development of this class of copper-based drugs as potential anti-cancer therapies should be pursued.

Anionic and zwitterionic carboranyl N-heterocyclic carbene Au(i) complexes.

The syntheses of the first carboranyl N-heterocyclic carbene complexes with transition metals are reported. Both unsymmetrical mono-anionic and symmetrical dianionic NHCs readily react with ClAuSMe2 to afford unusual zwitterionic and anionic Au(i) dimethyl sulfide adducts. The compounds are characterized by NMR, mass spectrometry, and single crystal X-ray diffraction studies. Percent buried volume (%Vbur) calculations indicate that replacement of an adamantyl group by a hydride substituted icosahedral carborane anion results in a 3.7% increase in %Vbur.

Band Structure Engineering by Substitutional Doping in Solid-State Solutions of [5-Me-PLY(O,O)]2B(1-x)Be(x) Radical Crystals.

We report the substitutional doping of solid-state spiro-bis(5-methyl-1,9-oxido-phenalenyl)boron radical ([2]2B) by co-crystallization of this radical with the corresponding spiro-bis(5-methyl-1,9-oxido-phenalenyl)beryllium compound ([2]2Be). The pure compounds crystallize in different space groups ([2]2B, P1̅, Z = 2; [2]2Be, P21/c, Z = 4) with distinct packing arrangements, yet we are able to isolate crystals of composition [2]2B(1-x)Be(x), where x = 0-0.59. The phase transition from the P1̅ to the P21/c space group occurs at x = 0.1, but the conductivities of the solid solutions are enhanced and the activation energies reduced for values of x = 0-0.25. The molecular packing is driven by the relative concentration of the spin-bearing ([2]2B) and spin-free ([2]2Be) molecules in the crystals, and the extended Hückel theory band structures show that the progressive incorporation of spin-free [2]2Be in the lattice of the [2]2B radical (overall bandwidth, W = 1.4 eV, in the pure compound) leads to very strong narrowing of the bandwidth, which reaches a minimum at [2]2Be (W = 0.3 eV). The results provide a graphic picture of the structural transformations undergone by the lattice, and at certain compositions we are able to identify distinct structures for the [2]2B and [2]2Be molecules in a single crystalline phase.

Synthesis and reactivity of a zwitterionic palladium allyl complex supported by a perchlorinated carboranyl phosphine.

A zwitterionic palladium complex of a phosphine bearing a perchlorinated carba-closo-dodecaborate anion as a ligand substituent is reported. A single-crystal X-ray diffraction study reveals that, in the solid state, one of the chlorides of the carborane cage occupies a coordination site of the square-planar complex. However, in solution, the P-carborane bond of the ligand is rapidly rotating at temperatures as low as -90 °C, which demonstrates the carborane substituent's weak coordinative ability even though this anion is covalently linked to the phosphine ligand. The complex is thermally stable and catalyzes the vinyl addition polymerization of norbornene.

Synthesis of unsymmetrical N-carboranyl NHCs: directing effect of the carborane anion.

The syntheses of unsymmetrical N-heterocyclic carbenes (NHCs) that contain a single N-bound icosahedral carborane anion substituent are reported. Both anionic C-2 and doubly deprotonated dianionic C-2/C-5 NHC lithium complexes are isolated. The latter species is formed selectively, which reveals a surprising directing effect conveyed by icosahedral carborane anion substituents.

Enhanced electrical conductivity in a substitutionally doped spiro-bis(phenalenyl)boron radical molecular solid.

We report the crystallization of a subsitutionally doped organic conductor based on a host lattice composed of spiro-bis(phenalenyl)boron radicals. Co-crystallization of solutions of spiro-bis(9-oxidophenalenone)boron radical [PLY(O,O)]2B mixed with selected amounts of spiro-bis(9-oxidophenalenone)beryllium [PLY(O,O)]2Be leads to the formation of a series of solid-state solutions of composition [PLY(O,O)]2B(1-x)Be(x). The dopant molecules [PLY(O,O)]2Be serve to introduce holes into the lattice of spins provided by the [PLY(O,O)]2B radicals and lead to a systematic increase in the conductivity while decreasing the activation energy of the conduction process and leaving the solid-state structure relatively unperturbed. While the energies of the hole sites are expected to be high, the results are consistent with the interpretation of the electronic structure of [PLY(O,O)]2B in terms of the resonating valence bond model.

Synthesis of tetrachalcogenide-substituted phenalenyl derivatives: preparation and solid-state characterization of bis(3,4,6,7-tetrathioalkyl-phenalenyl)boron radicals.

We report the synthesis and properties of a series of spiro-bis(3,4,6,7-tetrachalcogenide-substituted-phenalenyl)boron salts and two of the corresponding tetrathioalkyl-substituted spiro-bis(phenalenyl)boron radicals [tetrathiomethyl (10) and tetrathioethyl (11)] in which all of the active positions of the phenalenyl (PLY) nucleus are functionalized. In the solid state, radicals 10 and 11 exist as a weak π-dimers due to the steric congestion of the thioalkyl groups in the superimposed PLY units. As a result, the spins are localized in the isolated (nonsuperimposed) PLY rings, and the structure, magnetic susceptibility measurements, and band structure calculations confirm that these PLY units are unable to undergo strong intermolecular interaction as a result of the orientation of the thioalkyl groups.

Click-like reactions with the inert HCB11Cl11(-) anion lead to carborane-fused heterocycles with unusual aromatic character.

The chlorinated carba-closo-dodecaborate anion HCB11Cl11(-) is an exceptionally stable molecule and has previously been reported to be substitutionally inert at the B-Cl vertices. We present here the discovery of base induced cycloaddition reactions between this carborane anion and organic azides that leads to selective C and B functionalization of the cluster. A single crystal X-ray diffraction study reveals bond lengths in the heterocyclic portion of the ring that are shortened, which suggests electronic delocalization. Molecular orbital analysis of the ensuing heterocycles reveals that two of the bonding orbitals of these systems resemble two of the doubly occupied π-MOs of a simple 5-membered Hückel-aromatic, even though they are entangled in the carborane skeleton. Nucleus independent chemical shift analysis indicates that both the carborane cluster portion of the molecule and the carborane fused heterocyclic region display aromatic character. Computational methods indicate that the reaction likely follows a stepwise addition cyclization pathway.

Hydrogen bonding versus hyperconjugation in condensed-phase carbocations.

Hyperconjugative stabilization of positive charge in tertiary carbocations is the textbook explanation for their stability and low frequency νCH bands in their IR spectra have long been taken as confirming evidence. While this is substantiated in the gas phase by the very close match of the IR spectrum of argon-tagged t-butyl cation with that calculated under C(s) symmetry, the situation in condensed phases is much less clear. The congruence of νCH(max) of t-Bu(+) in superacid media (2830 cm(-1)) with that in the gas phase (2834 cm(-1)) has recently been shown to be accidental. Rather, νCH(max) varies considerably as a function of counterion in a manner that reveals the presence of significant C-H···anion hydrogen bonding. This paper addresses the question of the relative importance of hyperconjugation versus H-bonding. We show by assigning IR spectra in the νCH region to specific C-H bonds in t-butyl cation that the low frequency νCH(max) band in the IR spectrum of t-butyl cation, long taken as direct evidence for hyperconjugation, appears to be due mostly to H-bonding. The appearance of similar low frequency νCH bands in the IR spectra of secondary alkyl carboranes such as i-Pr(CHB11Cl11), which have predominant sp(3) centres rather than sp(2) centres (and are therefore less supportive of hyperconjugation), also suggests the dominance of H-bonding over hyperconjugation.

Hexathiophenalenyliums cations: syntheses, structures, and redox chemistry.

Preparations of two hexathiophenalenylium compounds as stable salts from the reaction of 3,4,6,7-tetrathio-9-hydroxyphenalenone with Lawesson's reagent have been reported. The presence of three disulfide linkages on the periphery of the core phenalenyl unit is confirmed by X-ray crystallographic characterizations. Electrochemical cell potentials are lower than those of related dithio- and tetrathio-bridged phenalenyl radicals, and the hexathiophenalenyl radical shows a strong electron paramagnetic resonance (EPR) signal in the solid state.

Extreme oxatriquinanes and a record C-O bond length.

Oxatriquinanes are fused, tricyclic oxonium ions that are known to have exceptional stability compared to simple alkyl oxonium salts. C-O bonds in ethers are generally ∼1.43 Å in length, but oxatriquinane has been found to have C-O bond lengths of 1.54 Å. A search of the Cambridge Structural Database turned up no bona fide C-O bond length exceeding this value. Computational modelling of oxatriquinane alongside other alkyl oxonium ions indicated that the electronic consequences of molecular strain were primarily responsible for the observed bond elongation. We also show that substitution of the oxatriquinane ring system with alkyl groups of increasing steric demand pushes the C-O bond to unheard of distances, culminating in a tert-butyl derivative at a predicted 1.60 Å. Chemical synthesis and an X-ray crystallographic study of these compounds validated the results of the modelling work and, finally, an extraordinary 1.622 Å C-O bond was observed in 1,4,7-tri-tert-butyloxatriquinane.

Evidence for C-H hydrogen bonding in salts of tert-butyl cation.

Environmentally sensitive: A combination of C-H anion hydrogen bonding and hyperconjugative charge delocalization explains the sensitivity of the IR spectrum of the tert-butyl cation to its anion (see high-resolution X-ray structure with a CHB(11)Cl(11)(-) counterion). The νCH vibration of the cation scales linearly with the basicity of carborane anions on the νNH scale. The same also holds for the C(6)H(7)(+) benzenium ion.

The R3O+···H+ hydrogen bond: toward a tetracoordinate oxadionium(2+) ion.

Oxatriquinanes are tricyclic oxonium ions which are known to possess remarkable solvolytic stability compared to simple alkyl oxonium salts. Their rigid, hemispherical structure presents an oxygen at the apex of three fused five-membered rings. While trivalent oxygen species like these have been well described in the literature, the ability of oxygen to enter into a fourth covalent bonding relationship has been visited in theory and suggested by the outcome of certain reactions conducted in superacidic media, but has never been established by the characterization of a stable, persistent R(3)OH(2+) or R(4)O(2+) ion. In this study, the nucleophilicity of the oxatriquinane oxygen was evaluated first by a series of protonation studies using the Brønsted superacid H(CHB(11)Cl(11)) both in the solid state and in liquid HCl solution. The interaction of the oxatriquinane oxygen with a bridging carbocation was also examined. A strong case could be made for the occurrence of hydrogen bonding between H(CHB(11)Cl(11)) and oxatriquinane using IR spectroscopy. Under the most forcing protonation conditions, the oxatriquinane ring is cleaved to give a bridged, dicationic, protonated tetrahydrofuran-carbenium ion.

Vibrations of a chelated proton in a protonated tertiary diamine.

Vibrational spectra of the conjugate acid of Me(2)NCH(2)CH(2)CH(2)CH(2)NMe(2) (N,N,N',N'-tetramethylputrescine) have been examined in the gaseous and crystalline phases using Infrared Multiple Photon Dissociation (IRMPD) spectroscopy, Inelastic Neutron Scattering (INS), and high pressure Raman spectroscopy. A band observed near 530 cm(-1) is assigned to the asymmetric stretch of the bridging proton between the two nitrogens, based on deuterium substitution and pressure dependence. The NN distance measured by X-ray crystallography gives a good match to DFT calculations, and the experimental band position agrees with the value predicted from theory using a 2-dimensional potential energy surface. The reduced dimensionality potential energy surface, which treats the ion as though it possesses a linear NHN geometry, shows low barriers to proton transit from one nitrogen to the other, with zero point levels close to the barrier tops. In contrast, two other related systems containing strong hydrogen bonds do not exhibit the same spectroscopic signature of a low barrier hydrogen bond (LBHB). On the one hand, the IRMPD spectra of the conjugate acid ions of the amino acid N,N,N',N'-tetramethylornithine (in which the two nitrogens have different basicities) show fewer bands and no comparable isotopic shifts in the low frequency domain. On the other hand, the IRMPD spectrum of the shorter homologue Me(2)NCH(2)CH(2)CH(2)NMe(2) (N,N,N',N'-tetramethyl-1,3-propanediamine), for which the NHN bond angle deviates substantially from linearity, displays more than one band in the 1100-1400 cm(-1) domain, which vanish as a consequence of deuteration.

Synthesis, structure, and physical properties of a partial π-stacked phenalenyl-based neutral radical molecular conductor.

We report the synthesis, crystallization, and solid-state characterization of the 3,7-ethoxy-substituted spirobiphenalenyl-boron neutral radical 22. The radical is distinguished by its low disproportionation energy and one-dimensional structure. We show that our strategy of substitution of OEt group at the active positions of the phenalenyl units changes the crystal packing from its previously known OMe analogue and the solid-state properties are dictated by the partial π-stack structure and the oxygen atoms at the 3,7-positions and can be best rationalized in terms of the resonating valence bond model. Magnetic susceptibility measurements show that in the solid state the radical remains paramagnetic but there is significant spin-spin interaction between the molecules. Band structure calculations reflect efficient overlap between the molecules along the π stack and show evidence of interactions between the spin-bearing oxygen atoms. The room temperature electrical conductivity (σ(RT)=2.0×10(-2) S cm(-1)) of 22 is higher than that observed in previously known one-dimensional phenalenyl radicals.

Planar subporphyrin borenium cations.

Subporphyrin borenium cations with a carborane counterion have been prepared by treatment of B-methoxy subporphyrins with the silylium reagent Et(3)Si(CH(6)B(11)Br(6)). In contrast to the distinctly domed subphthalocyanine borenium cation, a nearly planar structure with sp(2) hybridized boron is found in the X-ray structure of the triphenylsubporphyrin borenium cation. The cations exhibit absorption and fluorescence spectra that are quite similar to those of B-methoxy subporphyrins. B-phenyl subporphyrins were prepared in good yield by reaction of subporphyrin borenium cations with phenyllithium.

Hysteretic spin and charge delocalization in a phenalenyl-based molecular conductor.

We have investigated the solid-state electronic structure and properties of a phenalenyl-based butyl-substituted neutral radical, 3, that shows a hysteretic phase transition just above room temperature. We quantitatively analyzed the electron density distribution of this radical throughout both branches of the hysteretic phase transition using solid-state X-ray structures and found two distinct electronic states in the hysteresis loop that accompanies the phase transition. The bistability of the two electronic states was observed through a number of measurements, including IR transmittance spectra of single crystals in the vicinity of the phase transition. By comparing the changes in the crystal structures of 3 and the related ethyl-substituted radical 1 (which exhibits no hysteresis) at various temperatures, we show that the change in the interplanar π-π distance within dimers is the most important structural parameter in determining the physical properties of the radicals. The large change in the C-H···π interaction in 3 occurs in concert with the spin redistribution during the phase transition, but these factors are not responsible for the hysteresis effect. We suggest that the presence of a high-temperature state inside the hysteretic loop during the cooling cycle is due to thermodynamic stability, while the existence of the low-temperature state during the heating cycle is due to the presence of a large energy barrier between the two states (estimated to be greater than 100 kJ/mol) that results from the large-amplitude motion of the phenalenyl rings and the associated lattice reorganization energy that is required at the phase transition.

Identification and mechanism of ABA receptor antagonism.

The phytohormone abscisic acid (ABA) functions through a family of fourteen PYR/PYL receptors, which were identified by resistance to pyrabactin, a synthetic inhibitor of seed germination. ABA activates these receptors to inhibit type 2C protein phosphatases, such as ABI1, yet it remains unclear whether these receptors can be antagonized. Here we demonstrate that pyrabactin is an agonist of PYR1 and PYL1 but is unexpectedly an antagonist of PYL2. Crystal structures of the PYL2-pyrabactin and PYL1-pyrabactin-ABI1 complexes reveal the mechanism responsible for receptor-selective activation and inhibition, which enables us to design mutations that convert PYL1 to a pyrabactin-inhibited receptor and PYL2 to a pyrabactin-activated receptor and to identify new pyrabactin-based ABA receptor agonists. Together, our results establish a new concept of ABA receptor antagonism, illustrate its underlying mechanisms and provide a rational framework for discovering novel ABA receptor ligands.