Solving Interoperability in Translational Health. Perspectives of Students from the International Partnership in Health Informatics Education (IPHIE) 2016 Master Class.

BACKGROUND: In the summer of 2016 an international group of biomedical and health informatics faculty and graduate students gathered for the 16th meeting of the International Partnership in Health Informatics Education (IPHIE) masterclass at the University of Utah campus in Salt Lake City, Utah. This international biomedical and health informatics workshop was created to share knowledge and explore issues in biomedical health informatics (BHI). OBJECTIVE: The goal of this paper is to summarize the discussions of biomedical and health informatics graduate students who were asked to define interoperability, and make critical observations to gather insight on how to improve biomedical education. METHODS: Students were assigned to one of four groups and asked to define interoperability and explore potential solutions to current problems of interoperability in health care. RESULTS: We summarize here the student reports on the importance and possible solutions to the "interoperability problem" in biomedical informatics. Reports are provided from each of the four groups of highly qualified graduate students from leading BHI programs in the US, Europe and Asia. CONCLUSION: International workshops such as IPHIE provide a unique opportunity for graduate student learning and knowledge sharing. BHI faculty are encouraged to incorporate into their curriculum opportunities to exercise and strengthen student critical thinking to prepare our students for solving health informatics problems in the future.

Electronic Excited States of Tungsten(0) Arylisocyanides.

W(CNAryl)6 complexes containing 2,6-diisopropylphenyl isocyanide (CNdipp) are powerful photoreductants with strongly emissive long-lived excited states. These properties are enhanced upon appending another aryl ring, e.g., W(CNdippPh(OMe2))6; CNdippPh(OMe2) = 4-(3,5-dimethoxyphenyl)-2,6-diisopropylphenylisocyanide (Sattler et al. J. Am. Chem. Soc. 2015, 137, 1198-1205). Electronic transitions and low-lying excited states of these complexes were investigated by time-dependent density functional theory (TDDFT); the lowest triplet state was characterized by time-resolved infrared spectroscopy (TRIR) supported by density functional theory (DFT). The intense absorption band of W(CNdipp)6 at 460 nm and that of W(CNdippPh(OMe2))6 at 500 nm originate from transitions of mixed ππ*(C≡N-C)/MLCT(W → Aryl) character, whereby W is depopulated by ca. 0.4 e(-) and the electron-density changes are predominantly localized along two equatorial molecular axes. The red shift and intensity rise on going from W(CNdipp)6 to W(CNdippPh(OMe2))6 are attributable to more extensive delocalization of the MLCT component. The complexes also exhibit absorptions in the 300-320 nm region, owing to W → C≡N MLCT transitions. Electronic absorptions in the spectrum of W(CNXy)6 (Xy = 2,6-dimethylphenyl), a complex with orthogonal aryl orientation, have similar characteristics, although shifted to higher energies. The relaxed lowest W(CNAryl)6 triplet state combines ππ* excitation of a trans pair of C≡N-C moieties with MLCT (0.21 e(-)) and ligand-to-ligand charge transfer (LLCT, 0.24-0.27 e(-)) from the other four CNAryl ligands to the axial aryl and, less, to C≡N groups; the spin density is localized along a single Aryl-N≡C-W-C≡N-Aryl axis. Delocalization of excited electron density on outer aryl rings in W(CNdippPh(OMe2))6 likely promotes photoinduced electron-transfer reactions to acceptor molecules. TRIR spectra show an intense broad bleach due to ν(C≡N), a prominent transient upshifted by 60-65 cm(-1), and a weak down-shifted feature due to antisymmetric C≡N stretch along the axis of high spin density. The TRIR spectral pattern remains unchanged on the femtosecond-nanosecond time scale, indicating that intersystem crossing and electron-density localization are ultrafast (<100 fs).

Dihydrogen activation by cobaloximes with various axial ligands.

We have investigated the effect of axial ligands on the ability of cobaloximes to catalyze the generation of transferable hydrogen atoms from hydrogen gas and have learned that the active catalyst contains one and only one axial ligand. We have, for example, shown that Co(dmgBF2)2 coordinates only one Ph3P and that the addition of additional Ph3P (beyond 1 equiv) to solvated Co(dmgBF2)2 does not affect its catalytic turnover for H• transfer from H2.

Lewis acid promoted titanium alkylidene formation: off-cycle intermediates relevant to olefin trimerization catalysis.

Two new precatalysts for ethylene and α-olefin trimerization, (FI)Ti(CH2SiMe3)2Me and (FI)Ti(CH2CMe3)2Me (FI = phenoxy-imine), have been synthesized and structurally characterized by X-ray diffraction. (FI)Ti(CH2SiMe3)2Me can be activated with 1 equiv of B(C6F5)3 at room temperature to give the solvent-separated ion pair [(FI)Ti(CH2SiMe3)2][MeB(C6F5)3], which catalytically trimerizes ethylene or 1-pentene to produce 1-hexene or C15 olefins, respectively. The neopentyl analogue (FI)Ti(CH2CMe3)2Me is unstable toward activation with B(C6F5)3 at room temperature, giving no discernible diamagnetic titanium complexes, but at -30 °C the following can be observed by NMR spectroscopy: (i) formation of the bis-neopentyl cation [(FI)Ti(CH2CMe3)2](+), (ii) α-elimination of neopentane to give the neopentylidene complex [(FI)Ti(═CHCMe3)](+), and (iii) subsequent conversion to the imido-olefin complex [(MeOAr2N═)Ti(OArHC═CHCMe3)](+) via an intramolecular metathesis reaction with the imine fragment of the (FI) ligand. If the reaction is carried out at low temperature in the presence of ethylene, catalytic production of 1-hexene is observed, in addition to the titanacyclobutane complex [(FI)Ti(CH(CMe3)CH2CH2)](+), resulting from addition of ethylene to the neopentylidene [(FI)Ti(═CHCMe3)](+). None of the complexes observed spectroscopically subsequent to [(FI)Ti(CH2CMe3)2](+) is an intermediate or precursor for ethylene trimerization, but notwithstanding these off-cycle pathways, [(FI)Ti(CH2CMe3)2](+) is a precatalyst that undergoes rapid initiation to generate a catalyst for trimerizing ethylene or 1-pentene.

Metal-drug synergy: new ruthenium(II) complexes of ketoconazole are highly active against Leishmania major and Trypanosoma cruzi and nontoxic to human or murine normal cells.

In our ongoing search for new metal-based chemotherapeutic agents against leishmaniasis and Chagas disease, six new ruthenium-ketoconazole (KTZ) complexes have been synthesized and characterized, including two octahedral coordination complexes-cis,fac-[Ru(II)Cl2(DMSO)3(KTZ)] (1) and cis-[Ru(II)Cl2(bipy)(DMSO)(KTZ)] (2) (where DMSO is dimethyl sulfoxide and bipy is 2,2'-bipyridine)-and four organometallic compounds-[Ru(II)(η(6)-p-cymene)Cl2(KTZ)] (3), [Ru(II)(η(6)-p-cymene)(en)(KTZ)][BF4]2 (4), [Ru(II)(η(6)-p-cymene)(bipy)(KTZ)][BF4]2 (5), and [Ru(II)(η(6)-p-cymene)(acac)(KTZ)][BF4] (6) (where en is ethylenediamine and acac is acetylacetonate); the crystal structure of 3 is described. The central hypothesis of our work is that combining a bioactive compound such as KTZ and a metal in a single molecule results in a synergy that can translate into improved activity and/or selectivity against parasites. In agreement with this hypothesis, complexation of KTZ with Ru(II) in compounds 3-5 produces a marked enhancement of the activity toward promastigotes and intracellular amastigotes of Leishmania major, when compared with uncomplexed KTZ, or with similar ruthenium compounds not containing KTZ. Importantly, the selective toxicity of compounds 3-5 toward the leishmania parasites, in relation to human fibroblasts and osteoblasts or murine macrophages, is also superior to the selective toxicities of the individual constituents of the drug. When tested against Trypanosoma cruzi epimastigotes, some of the organometallic complexes displayed activity and selectivity comparable to those of free KTZ. A dual-target mechanism is suggested to account for the antiparasitic properties of these complexes.

Searching for new chemotherapies for tropical diseases: ruthenium-clotrimazole complexes display high in vitro activity against Leishmania major and Trypanosoma cruzi and low toxicity toward normal mammalian cells.

Eight new ruthenium complexes of clotrimazole (CTZ) with high antiparasitic activity have been synthesized, cis,fac-[Ru(II)Cl(2)(DMSO)(3)(CTZ)] (1), cis,cis,trans-[Ru(II)Cl(2)(DMSO)(2)(CTZ)(2)] (2), Na[Ru(III)Cl(4)(DMSO)(CTZ)] (3), Na[trans-Ru(III)Cl(4)(CTZ)(2)] (4), [Ru(II)(η(6)-p-cymene)Cl(2)(CTZ)] (5), [Ru(II)(η(6)-p-cymene)(bipy)(CTZ)][BF(4)](2) (6), [Ru(II)(η(6)-p-cymene)(en)(CTZ)][BF(4)](2) (7), and [Ru(II)(η(6)-p-cymene)(acac)(CTZ)][BF(4)] (8) (bipy = bipyridine; en = ethlylenediamine; acac = acetylacetonate). The crystal structures of compounds 4-8 are described. Complexes 1-8 are active against promastigotes of Leishmania major and epimastigotes of Trypanosoma cruzi. Most notably, complex 5 increases the activity of CTZ by factors of 110 and 58 against L. major and T. cruzi, with no appreciable toxicity to human osteoblasts, resulting in nanomolar and low micromolar lethal doses and therapeutic indexes of 500 and 75, respectively. In a high-content imaging assay on L. major-infected intraperitoneal mice macrophages, complex 5 showed significant inhibition on the proliferation of intracellular amastigotes (IC(70) = 29 nM), while complex 8 displayed some effect at a higher concentration (IC(40) = 1 µM).

A new class of transition metal pincer ligand: tantalum complexes that feature a [CCC] X3-donor array derived from a terphenyl ligand.

A new class of [CCC] X(3)-donor pincer ligand for transition metals has been constructed via cyclometalation of a 2,6-di-p-tolylphenyl ([Ar(Tol(2))]) derivative. Specifically, addition of PMe(3) to [Ar(Tol(2))]TaMe(3)Cl induces elimination of methane and formation of the pincer complex, [κ(3)-Ar(Tol'(2))]Ta(PMe(3))(2)MeCl (Tol' = C(6)H(3)Me), which may also be obtained by treatment of Ta(PMe(3))(2)Me(3)Cl(2) with [Ar(Tol(2))]Li. Solutions of [κ(3)-Ar(Tol'(2))]Ta(PMe(3))(2)MeCl undergo ligand redistribution with the formation of [κ(3)-Ar(Tol'(2))]Ta(PMe(3))(2)Me(2)and [κ(3)-Ar(Tol'(2))]Ta(PMe(3))(2)Cl(2), which may also be synthesized by the reactions of [κ(3)-Ar(Tol'(2))]Ta(PMe(3))(2)MeCl with MeMgBr and ZnCl(2), respectively. Reduction of [κ(3)-Ar(Tol'(2))]Ta(PMe(3))(2)Cl(2) with KC(8) in benzene gives the benzene complex [κ(3)-Ar(Tol'(2))]Ta(PMe(3))(2)(η(6)-C(6)H(6)) that is better described as a 1,4-cyclohexadienediyl derivative. Deuterium labeling employing Ta(PMe(3))(2)(CD(3))(3)Cl(2) demonstrates that the pincer ligand is created by a pair of Ar-H/Ta-Me sigma-bond metathesis transformations, rather than by a mechanism that involves α-H abstraction by a tantalum methyl ligand.

Formation of a cationic alkylidene complex via formal hydride abstraction: synthesis and structural characterization of [W(PMe3)4(η2-CHPMe2)H]X (X = Br, I).

W(PMe(3))(4)(η(2)-CH(2)PMe(2))H reacts with aryl halides to give the alkylidene complex, [W(PMe(3))(4)(η(2)-CHPMe(2))H](+), which reacts with LiAlD(4) to give selectively W(PMe(3))(4)(η(2)-CHDPMe(2))H, in which the deuterium resides in the methylene group; subsequent migration of deuterium from the methylene group provides a means to measure the rate constant for the formation of the 16-electron species [W(PMe(3))(5)] from W(PMe(3))(4)(η(2)-CH(2)PMe(2))H.

Structural characterization of TaMe3Cl2 and Ta(PMe3)2Me3Cl2, a pair of five and seven-coordinate d0 tantalum methyl compounds.

The trimethylphosphine complex Ta(PMe(3))(2)Me(3)Cl(2) has been synthesized by addition of PMe(3) to TaMe(3)Cl(2). The molecular structures of both TaMe(3)Cl(2) and Ta(PMe(3))(2)Me(3)Cl(2) have been determined by X-ray diffraction thereby demonstrating that, in the solid state, these complexes respectively adopt trigonal bipyramidal and capped trigonal prismatic geometries.

Carbon-sulfur bond cleavage and hydrodesulfurization of thiophenes by tungsten.

The reactions of W(PMe(3))(4)(η(2)-CH(2)PMe(2))H, W(PMe(3))(5)H(2), W(PMe(3))(4)H(4) and W(PMe(3))(3)H(6) towards thiophenes reveal that molecular tungsten compounds are capable of achieving a variety of transformations that are relevant to hydrodesulfurization. For example, sequential treatment of W(PMe(3))(4)(η(2)-CH(2)PMe(2))H with thiophene and H(2) yields the butanethiolate complex, W(PMe(3))(4)(SBu(n))H(3), which eliminates but-1-ene at 100 °C. Likewise, sequential treatment of W(PMe(3))(4)(η(2)-CH(2)PMe(2))H with benzothiophene and H(2) yields W(PMe(3))(4)(SC(6)H(4)Et)H(3), which releases ethylbenzene at 100 °C. Moreover, W(PMe(3))(4)(η(2)-CH(2)PMe(2))H desulfurizes dibenzothiophene to form a dibenzometallacyclopentadiene complex, [(κ(2)-C(12)H(8))W(PMe(3))](µ-S)(µ-CH(2)PMe(2))(µ-PMe(2))[W(PMe(3))(3)].

Synthesis and structural characterization of tris(2-oxo-1-tert-butylimidazolyl) and tris(2-oxo-1-methylbenzimidazolyl)hydroborato complexes: a new class of tripodal oxygen donor ligand.

A new class of tripodal L(2)X ligands that feature three oxygen donors, namely the tris(2-oxo-1-tert-butylimidazolyl) and tris(2-oxo-1-methylbenzimidazolyl)hydroborato ligands, [To(Bu(t))] and [To(MeBenz)], has been synthesized via the reactions of NaBH(4) with the respective imidazolone. Structural and spectroscopic studies indicate that both [To(Bu(t))] and [To(MeBenz)] are significantly more sterically demanding but less electron donating than the related [O(3)] donor ligand, [CpCo{P(O)(OEt)(2)}(3)].

Synthesis of polynitroxides based on nucleophilic aromatic substitution.

The scope and limitations of the synthesis of polynitroxides by nucleophilic substitution of electron-deficient fluorinated aromatic compounds are described. The method provides a facile route to the formation of polynitroxides exhibiting strong electron exchange between nitroxide groups.

Cleaving carbon-carbon bonds by inserting tungsten into unstrained aromatic rings.

The cleavage of C-H and C-C bonds by transition metal centres is of fundamental interest and plays an important role in the synthesis of complex organic molecules from petroleum feedstocks. But while there are many examples for the oxidative addition of C-H bonds to a metal centre, transformations that feature oxidative addition of C-C bonds are rare. The paucity of transformations that involve the cleavage of C-C rather than C-H bonds is usually attributed to kinetic factors arising from the greater steric hindrance and the directional nature of the sp(n) hybrids that form the C-C bond, and to thermodynamic factors arising from the fact that M-C bonds are weaker than M-H bonds. Not surprisingly, therefore, most examples of C-C bond cleavage either avoid the kinetic limitations by using metal compounds in which the C-C bond is held in close proximity to the metal centre, or avoid the thermodynamic limitations by using organic substrates in which the cleavage is accompanied by either a relief of strain energy or the formation of an aromatic system. Here, we show that a tungsten centre can be used to cleave a strong C-C bond that is a component of an unstrained 6-membered aromatic ring. The cleavage is enabled by the formation of an unusual chelating di(isocyanide) ligand, which suggests that other metal centres with suitable ancillary ligands could also accomplish the cleavage of strong C-C bonds of aromatic substrates and thereby provide new ways of functionalizing such molecules.

Multiple modes for coordination of phenazine to molybdenum: ring fusion promotes access to eta4-coordination, oxidative addition of dihydrogen and hydrogenation of aromatic nitrogen compounds.

Mo(PMe(3))(6) reacts with phenazine (PhzH) to give (eta(6)-C(6)-PhzH)Mo(PMe(3))(3), (mu-eta(6),eta(6)-PhzH)[Mo(PMe(3))(3)](2) and (eta(4)-C(4)-PhzH)(2)Mo(PMe(3))(2), each of which displays previously unknown coordination modes for phenazine. Both mononuclear (eta(6)-C(6)-PhzH)Mo(PMe(3))(3) and dinuclear (mu-eta(6),eta(6)-PhzH)[Mo(PMe(3))(3)](2) react with H(2) at room temperature to give the respective dihydride complexes, (eta(4)-C(4)-PhzH)Mo(PMe(3))(3)H(2) and (mu-eta(6),eta(4)-PhzH)[Mo(PMe(3))(3)][Mo(PMe(3))(3)H(2)]. A comparison of (eta(6)-C(6)-PhzH)Mo(PMe(3))(3) with the anthracene (AnH) and acridine (AcrH) counterparts, (eta(6)-AnH)Mo(PMe(3))(3) and (eta(6)-C(6)-AcrH)Mo(PMe(3))(3), indicates that oxidative addition of H(2) is promoted by incorporation of nitrogen substituents into the central ring. Furthermore, comparison of (eta(6)-C(6)-PhzH)Mo(PMe(3))(3) with the quinoxaline (QoxH) analogue, (eta(6)-C(6)-QoxH)Mo(PMe(3))(3), indicates that ring fusion also promotes oxidative addition of H(2). The mononitrogen quinoline (QH) and acridine compounds, (eta(6)-C(6)-QH)Mo(PMe(3))(3) and (eta(6)-C(6)-AcrH)Mo(PMe(3))(3), which respectively possess two and three fused six-membered rings, exhibit a similar trend, with the former being inert towards H(2), while the latter reacts rapidly to yield (eta(4)-C(4)-AcrH)Mo(PMe(3))(3)H(2). Ring fusion also promotes hydrogenation of the heterocyclic ligand, with (eta(6)-C(6)-AcrH)Mo(PMe(3))(3) releasing 9,10-dihydroacridine upon treatment with H(2) in benzene at 95 degrees C. Furthermore, catalytic hydrogenation of acridine to a mixture of 9,10-dihydroacridine and 1,2,3,4-tetrahydroacridine may be achieved by treatment of (eta(6)-C(6)-AcrH)Mo(PMe(3))(3) with acridine and H(2) at 95 degrees C.