Synthesis of Honeycomb-Structured Beryllium Oxide via Graphene Liquid Cells.

Using high-resolution transmission electron microscopy and electron energy-loss spectroscopy, we show that beryllium oxide crystallizes in the planar hexagonal structure in a graphene liquid cell by a wet-chemistry approach. These liquid cells can feature van-der-Waals pressures up to 1 GPa, producing a miniaturized high-pressure container for the crystallization in solution. The thickness of as-received crystals is beyond the thermodynamic ultra-thin limit above which the wurtzite phase is energetically more favorable according to the theoretical prediction. The crystallization of the planar phase is ascribed to the near-free-standing condition afforded by the graphene surface. Our calculations show that the energy barrier of the phase transition is responsible for the observed thickness beyond the previously predicted limit. These findings open a new door for exploring aqueous-solution approaches of more metal-oxide semiconductors with exotic phase structures and properties in graphene-encapsulated confined cells.

Photo-Uncaging of a Microtubule-Targeted Rigidin Analogue in Hypoxic Cancer Cells and in a Xenograft Mouse Model.

Marine alkaloid rigidins are cytotoxic compounds known to kill cancer cells at nanomolar concentrations by targeting the microtubule network. Here, a rigidin analogue containing a thioether group was "caged" by coordination of its thioether group to a photosensitive ruthenium complex. In the dark, the coordinated ruthenium fragment prevented the rigidin analogue from inhibiting tubulin polymerization and reduced its toxicity in 2D cancer cell line monolayers, 3D lung cancer tumor spheroids (A549), and a lung cancer tumor xenograft (A549) in nude mice. Photochemical activation of the prodrug upon green light irradiation led to the photosubstitution of the thioether ligand by water, thereby releasing the free rigidin analogue capable of inhibiting the polymerization of tubulin. In cancer cells, such photorelease was accompanied by a drastic reduction of cell growth, not only when the cells were grown in normoxia (21% O2) but also remarkably in hypoxic conditions (1% O2). In vivo, low toxicity was observed at a dose of 1 mg·kg-1 when the compound was injected intraperitoneally, and light activation of the compound in the tumor led to 30% tumor volume reduction, which represents the first demonstration of the safety and efficacy of ruthenium-based photoactivated chemotherapy compounds in a tumor xenograft.

Synthesis, Spectroscopic Characterization, and Redox Reactivity of a Cyclic (Alkyl) Amino Carbene-Derived Arsamethine Cyanine Dye.

In our efforts to prepare a diarsenic allotrope supported by two cyclic alkyl amino carbene (CAAC) ligands we stumbled upon the synthesis of the first carbene-supported chloroarsinidene 3, which has been fully characterized by a combination of NMR spectroscopic and XRD methods. Although further reduction of 3 was not possible, we found that addition of a second equivalent of CAAC in refluxing toluene afforded the first example of a crystallographically characterized arsamethine cyanine dye (4). The arsenic(I) dye is structurally similar to phosphorus analogues, and contains an arsenide anion with two stereochemically active lone pairs supported by two iminium ligands. The UV/Visible spectrum and redox chemistry of 4 were also explored. Upon reduction with one equivalent of KC8 , 3 is reduced to the originally targeted CAAC2 As2 allotrope 6, whereas oxidation provides access to the first example of an arsenic(II) radical dication (5).

Novel Topologically Complex Scaffold Derived from Alkaloid Haemanthamine.

The generation of natural product-like compound collections has become an important area of research due to low hit rates found with synthetic high-throughput libraries. One method of generating compounds occupying the areas of chemical space not accessible to synthetic planar heterocyclic structures is the utilization of natural products as starting materials. In the current work, using a ring-closing iodoalkoxylation reaction, alkaloid haemanthamine was transformed into a unique structural framework possessing an intricate ring system and a large number of stereocenters. The structure of the new compound was confirmed with an X-ray analysis. A small number of derivatives of this new compound were synthesized as a demonstration of the possibility of generating a large natural product-like compound collection based on the new structural framework.

Photochemically Switching Diamidocarbene Spin States Leads to Reversible Büchner Ring Expansions.

The discovery of thermal and photochemical control by Woodward and Hoffmann revolutionized how we understand chemical reactivity. Similarly, we now describe the first example of a carbene that exhibits differing thermal and photochemical reactivity. When a singlet ground-state N,N'-diamidocarbene 1 was photolyzed at 380 nm, excitation to a triplet state was observed. The triplet-state electronic structure was characteristic of the expected biradical σ1pπ1 spin configuration according to a combination of spectroscopic and computational methods. Surprisingly, the triplet state of 1 was found to engage a series of arenes in thermally reversible Büchner ring expansion reactions, marking the first examples where both cyclopropanation and ring expansion of arenes were rendered reversible. Not only are these photochemical reactions different from the known thermal chemistry of 1, but the reversibility enabled us to perform the first examples of photochemically induced arene exchange/expansion reactions at a single carbon center.

Stepwise Reduction of an α-Phosphonio-Carbocation to a Crystalline Phosphorus Radical Cation and an Acridinyl-Phosphorus Ylide.

We have synthesized the dicationic α-phosphonio-carbocation 1(2+) , which can be regarded as a two-electron oxidized phosphorus ylide. Carbocation 1(2+) exhibits two reversible reduction waves at -0.28 and -0.90 V (vs. Fc(+) /Fc) indicating that both the radical cation 1(.+) and the neural phosphorus ylide 1 can be generated. Indeed, reduction of 1(2+) with Zn afforded 1(.+) as a dark green solid that was characterized by XRD and EPR spectroscopy, and reduction with Mg(Ant)⋅(THF)3 gave 1, which was characterized by (1) H and (31) P NMR spectroscopy. Computational analyses reveal the stepwise population of a C-P π bonding orbital upon reduction of 1(2+) .

Metal-free stabilization of monomeric antimony(I): a carbene-supported stibinidene.

A diamidocarbene was coordinated to an antimony(III) dichloride Lewis acid. Subsequent reduction with magnesium gave a monomeric, formally antimony(I) fragment that is supported by the diamidocarbene. Spectroscopic, crystallographic, and computational analyses demonstrated that the carbene ligand engages the antimony(I) center in π-backbonding resulting in a short (2.068(7) Å) Sb-C interaction that is comparable to those observed in known stibaalkenes.

Photochemical reactions of a diamidocarbene: cyclopropanation of bromonaphthalene, addition to pyridine, and activation of sp3 C-H bonds.

We report unprecedented photochemistry for the diamidocarbene 1. Described within are the double cyclopropanation of 1-bromonaphthalene, the double addition to pyridine, and remarkably, the insertion into the unactivated sp3 C-H bonds of cyclohexane, tetramethylsilane, and n-pentane to give compounds 2-6, respectively. All compounds have been fully characterized, and the solid state structure of 4 was obtained using single crystal electron diffraction.

Synthesis, crystal structure determination, and spectroscopic analyses of 1-chloro-2-(2,6-diisopropylphenyl)-4,4-dimethyl-2-azaspiro[5.5]undecane-3,5-dione: an unyielding precursor to a cyclic (alkyl)(amido)carbene.

The synthesis, single-crystal X-ray structure, and 1H and 13C NMR spectrocopic analyses of an unyielding precursor molecule to a cyclic (alkyl)(amido)carbene, 1-chloro-2-(2,6-diisopropylphenyl)-4,4-dimethyl-2-azaspiro[5.5]undecane-3,5-dione, C24H34ClNO2 (1), is reported. Despite the use of several bases, 1 could not be deprotonated to afford the corresponding carbene. The crystal structure of 1 was compared to the crystal structures of two structurally similar HCl adducts of stable carbenes (compounds 4 and 5), which revealed no significant differences in the geometries about the `carbene' C atoms. To better understand the reactivity differences observed for 1 when compared to 4 and 5, modified percent buried volume (%Vbur) calculations were performed. These calculations revealed that the H atom bound to the carbene C atom is the most sterically hindered in compound 1 when compared to 4 and 5 (%Vbur = 84.9, 81.3, and 79.3% for 1, 4, and 5, respectively). Finally, close inspection of the quadrant-specific %Vbur values indicated that the approach of a deprotonating base to the H atom bound to the carbene C atom is significantly blocked in 1 (69.9%) when compared to 4 and 5 (50.4 and 56.5%, respectively).

Mechanical reconfiguration of stereoisomers.

Poly(methyl acrylate) of varying molecular weight was grown from the enantiopure ditopic initiator (R)- or (S)-1,1'-binaphthyl-2,2'-bis-(2-bromoisobutyrate). Subjecting CH(3)CN solutions of high-molecular-weight derivatives (M(N) > 25 kDa) to sonication at 0 degrees C resulted in >95% racemization after 24 h, as determined by circular dichroism; no appreciable racemization was observed in low-molecular-weight derivatives. Control experiments excluded the possibility of a thermal racemization mechanism.

Fluoride ion recognition by chelating and cationic boranes.

Because of the ubiquity of fluoride ions and their potential toxicity at high doses, researchers would like to design receptors that selectively detect this anion. Fluoride is found in drinking water, toothpaste, and osteoporosis drugs. In addition, fluoride ions also can be detected as an indicator of uranium enrichment (via hydrolysis of UF(6)) or of the chemical warfare agent sarin, which releases the ion upon hydrolysis. However, because of its high hydration enthalpy, the fluoride anion is one of the most challenging targets for anion recognition. Among the various recognition strategies that are available, researchers have focused a great deal of attention on Lewis acidic boron compounds. These molecules typically interact with fluoride anions to form the corresponding fluoroborate species. In the case of simple triarylboranes, the fluoroborates are formed in organic solvents but not in water. To overcome this limitation, this Account examines various methods we have pursued to increase the fluoride-binding properties of boron-based receptors. We first considered the use of bifunctional boranes, which chelate the fluoride anion, such as 1,8-diborylnaphthalenes or heteronuclear 1-boryl-8-mercurio-naphthalenes. In these molecules, the neighboring Lewis acidic atoms can cooperatively interact with the anionic guest. Although the fluoride binding constants of the bifunctional compounds exceed those of neutral monofunctional boranes by several orders of magnitude, the incompatibility of these systems with aqueous media limits their utility. More recently, we have examined simple triarylboranes whose ligands are decorated by cationic ammonium or phosphonium groups. These cationic groups increase the electrophilic character of these boranes, and unlike their neutral analogs, they are able to complex fluoride in aqueous media. We have also considered cationic boranes, which form chelate complexes with fluoride anions. Our work demonstrates that Coulombic and chelate effects are additive and can be combined to boost the anion affinity of Lewis acidic hosts. The boron compounds that we have investigated present a set of photophysical and electrochemical properties that can serve to signal the fluoride-binding event. We can also apply this approach to cyanide complexation and are continuing our investigations in that area.

Quinobis(imidazolylidene): synthesis and study of an electron-configurable bis(N-heterocyclic carbene) and its bimetallic complexes.

Reaction of bromanil with N,N'-dimesitylformamidine followed by deprotonation with NaN(SiMe(3))(2) afforded 1,1',3,3'-tetramesitylquinobis(imidazolylidene) (1), a bis(N-heterocyclic carbene) (NHC) with two NHC moieties connected by a redox active p-quinone residue, in 72 % yield of isolated compound. Bimetallic complexes of 1 were prepared by coupling to FcN(3) (2) or FcNCS (3; Fc=ferrocenyl) or coordination to [M(cod)Cl] (4 a or 4 b, where M=Rh or Ir, respectively; cod=1,5-cyclooctadiene). Treatment of 4 a and 4 b with excess CO(g) afforded the corresponding [M(CO)(2)Cl] complexes 5 a and 5 b, respectively. Analysis of 2-5 by NMR spectroscopy and X-ray diffraction indicated that the electron-deficient quinone did not significantly affect the inherent spectral properties or coordination chemistry of the flanking imidazolylidene units, as compared to analogous NHCs. Infrared spectroscopy and cyclic voltammetry revealed that decreasing the electron density at ML(n) afforded an increase in the stretching energy and a decrease in the reduction potential of the quinone, indicative of metal-quinone electronic interaction. Differential pulse voltammetry and chronoamperometry of the metal-centered oxidations in 2-4 revealed two single, one-electron peaks. Thus, the metal atoms bound to 1 are oxidized at indistinguishable potentials and do not appear electronically coupled. However, the metal-quinone interaction was used to increase the electron density at coordinated metal atoms. Infrared spectroelectrochemistry revealed that the average nu(CO) values for 5 a and 5 b decreased by 14 and 15 cm(-1), respectively, upon reduction of the quinone embedded within 1. These shifts correspond to 10 and 12 cm(-1) decreases in the Tolman electronic parameter of this ditopic ligand.

N,N'-diamidoketenimines via coupling of isocyanides to an N-heterocyclic carbene.

Treatment of an N-heterocyclic carbene that features two amide groups N-bound to the carbene nucleus with various organic isocyanides afforded a new class of ketenimines in yields of up to 96% (isolated). DFT analyses revealed that the carbene exhibits a unique, low-lying LUMO, which may explain the atypical reactivity observed.

An N,N'-diamidocarbene: studies in C-H insertion, reversible carbonylation, and transition-metal coordination chemistry.

Treatment of dimethylmalonyl dichloride with N,N'-bis(2,6-diisopropylphenyl)-N-trimethylsilylformamidine followed by trimethylsilyl triflate (TMS.OTf) afforded the pyrimidinium salt [1H][OTf] in >99% yield. Subsequent deprotonation of this salt led to the formation of the corresponding free N-heterocyclic carbene (NHC) 1. Exhibiting a reactivity profile that is characteristic of traditional electrophilic carbenes, 1 was found to insert into a tertiary C-H bond and reversibly fix carbon monoxide (CO) under mild conditions to afford the first example of a diamidoketene. Remarkably, the aforementioned carbonylation reaction was found to be thermally reversible (K(eq) = 2.62 M(-1) at 30 degrees C; DeltaH degrees = -35.33 kJ mol(-1) and DeltaS degrees = -109.5 J mol(-1) K(-1)). NHC 1 also displayed nucleophilic characteristics. Treatment of 1 with [Ir(COD)Cl](2) (COD = 1,5-cyclooctadiene) afforded 1-[Ir(COD)Cl], a complex with bond lengths and angles that were in accord with known NHC analogues. Treatment of 1-[Ir(COD)Cl] with CO afforded the carbonyl complex 1-[Ir(CO)(2)Cl]. IR studies of this complex revealed a Tolman Electronic Parameter of 2057 cm(-1), a value similar to those for analogous metal complexes containing tricyclohexylphosphine.

Azide ion recognition in water-CHCl(3) using a chelating phosphonium borane as a receptor.

In H(2)O-CHCl(3), the phosphonium borane [ortho-(Mes(2)B)C(6)H(4)(PMePh(2))](+) selectively complexes azide anions to afford ortho-(Mes(2)(N(3))B)C(6)H(4)(PMePh(2)) in which the boron-bound azide anion is stabilized by an interaction with the adjacent phosphorus atom.

Cyclic (aryl)(amido)carbenes: pushing the π-acidity of amidocarbenes through benzannulation.

Cyclic(aryl)(amido)carbenes were synthesized, and studied via a combination of experimental and computational approaches. These carbenes undergo dimerization when isolation is attempted, however, are trapped with sulfur, selenium, and [Ir(cod)Cl]. The π-acidity, measured using 77Se NMR, revealed that these are the most electrophilic singlet carbenes reported to date whereas the TEP measured demonstrated that these carbenes are poor σ donors.

Fluoride ion chelation by a bidentate phosphonium/borane Lewis acid.

The phosphonium borane [1-Mes2B-2-MePh2P-(C6H4)]+ ([2]+) has been synthesized as an iodide salt by alkylation of 1-Mes2B-2-Ph2P-(C6H4) with MeI. This novel cationic borane complexes fluoride to afford the corresponding zwitterionic fluoroborate complex 1-FMes2B-2-MePh2P-(C6H4) (2-F) with a binding constant in MeOH exceeding that of 1-Mes2B-4-MePh2P-(C6H4) ([1]+) by at least 4 orders of magnitude. Structural and computational results indicate that the high fluorophilicity of [2]+ arises from both Coulombic and cooperative effects which lead to formation of a B-F-->P interaction with a F-->P distance of 2.666(2) A. These results, which are supported by NBO and AIM analyses, show that the latent phosphorus-centered Lewis acidity of the phosphonium moiety in [2]+ can be exploited to enhance fluoride binding via chelation.

A BODIPY boronium cation for the sensing of fluoride ions.

In the presence of iodide ions, the cationic p-dimethylaminopyridine adduct of 1,3,5,7,8-pentamethylpyrromethene-boron fluoride [-DMAP](+) reacts with fluoride ions to afford the corresponding brightly fluorescent difluoride -F.

Hybrid Lewis acid/hydrogen-bond donor receptor for fluoride.

[reaction: see text] To verify if hydrogen-bond donor groups can assist fluoride binding at the boron center of triaryl boranes, o-(dimesitylboryl)trifluoroacetanilide has been synthesized. Reaction of this new borane with [n-Bu(4)N][F] in acetone affords the corresponding fluoroborate complex whose stability constant exceeds that of [Mes(3)BF](-) by at least 2 orders of magnitude. Presumably, the higher fluoride affinity of o-(dimesitylboryl)trifluoroacetanilide results from the cooperativity of the Lewis acidic boron center and the hydrogen-bond donor trifluoroacetamide group.