Martin Köckerling

The Influence of Hydrogen‐Bond Defects on the Properties of Ionic Liquids

Ionic liquids (ILs) are salts with uncommonly low melting points that are formed by a combination of specific cations and anions; they display distinctive properties and can be used in a variety of applications. The working temperature range of an ionic liquid is set by the melting point and the boiling or decomposition point. In particular, the melting point (Tm) varies substantially between different ILs for reasons presently not fully understood, but which we explore herein. We show that the melting points of imidazolium ionic liquids can be decreased by about 100 K if an extended ionic and hydrogen-bond network is disrupted by localized interactions, which can also be hydrogen bonds. Evidence for the presence of ion–ion interactions through hydrogen bonds was reported by Dymek et al., Avent et al., and Elaiwi et al. some time ago. It is reasonable to assume that the interesting features of the melting points must be related to the formation of structures in the solid and the liquid phases of the ILs. Extended hydrogen-bond networks in the liquid phase were reported with possible implications for both the structure and solvent properties of the ILs. Dupont et al. described pure imidazolium ILs as hydrogenbonded polymeric supramolecules. Antonietti et al. suggested that these supramolecular solvent structures represent an interesting molecular basis of molecular recognition and self-organization processes. However, in all of these examples it is suggested that hydrogen bonds strengthen the structure of ILs leading to properties similar to those of molecular liquids. This idea is also the basis of most of the structure– property relations discussed in the literature including quantitative structure–property relationships (QSPR) methods to correlate the melting points of ILs based on “molecular descriptors” derived from quantum chemical calculations. Such empirical correlations suffer from the fact that large experimental data sets are required and that the statistical methods used are rather complex. In addition, no interpretation of these fundamental physical properties at the molecular level is provided. Krossing et al. have developed a simple predictive framework to calculate the melting point of a given ionic liquid based on lattice and solvation free energies. They showed that ILs are liquid under standard ambient conditions because the liquid state is thermodynamically favorable, owing to the large size and conformational flexibility of the ions involved. This leads to small lattice enthalpies and large entropy changes that favor the liquid state. For such studies substituted imidazolium, pyrrolidinium, pyridinium, and ammonium cations have been used along with fluorometalate, triflate, and bis(trifluoromethylsulfonyl)imide anions. Unfortunately, Krossing s results do not correlate with experimentally obtained melting points for protic ionic liquids (PILs) reported byMarkusson et al. The reason for the large deviations of the predicted from the experimental melting points is probably related to the general trend of increasing Tm with the increasing size of the anions. We do not intend to present another framework for predicting ionic liquid properties here. Instead we want to demonstrate that in addition to the large size and conformational flexibility of the ions, local defects such as directional hydrogen bonds can significantly decrease the melting points of ionic liquids. For eight imidazolium-based ionic liquids we show that these defects can increase their working temperature range by up to 100 K and thus expand the spectrum of potential applications. This was suggested previously by Fumino et al. based on spectroscopic measurements and DFT calculations on IL aggregates. They assumed that local and directional types of interactions present defects in the Coulomb system which may lower the melting points, viscosities, and enthalpies of vaporization. In contrast, based on quantum chemical calculations, Hunt claimed that an increase in the melting points and viscosities upon methylation at C(2) stem from reduced entropy. Noack et al. showed very recently that neither the “defect hypothesis” of Fumino et al. nor the “entropy hypothesis” of Hunt alone can explain the changes in the physicochemical properties. However, in all these studies the data base was not sufficiently large and other effects such as volume changes could not be excluded for the ILs under investigation. [*] Dipl.-Chem. C. Roth, Dr. K. Fumino, Dr. D. Paschek, Prof. Dr. R. Ludwig Universit t Rostock, Institut f r Chemie Abteilung f r Physikalische Chemie Dr. Lorenz Weg 1, 18059 Rostock (Germany) Fax: (+49)381-498-6517 E-mail: ralf.ludwig@uni-rostock.de

Synthesis, structure, and bonding of weakly coordinating anions based on CN adducts.

The addition of alkali or silver salts of dicyanoamide (dca), tricyanomethanide (tcm) and tetracyanoborate (tcb) to a solution of B(C(6)F(5))(3) in diethyl ether affords salts containing very voluminous B(C(6)F(5))(3) adduct anions of the type [E(CN)(n)(-)] x [B(C(6)F(5))(3)](n): E = N (dca_nb with n = 1, 2; b = B(C(6)F(5))(3)); E = C (tcm_nb with n = 1, 2, 3), and E = B (tcb_nb with n = 1, 2, 3, 4). Salts bearing these anions such as B[(CN) x B(C(6)F(5))(3)](4)(-) (= [B(CN)(4)(-)] x [B(C(6)F(5))(3)](4)), C[(CN) x B(C(6)F(5))(3)](3)(-) (= [C(CN)(3)(-)] x [B(C(6)F(5))(3)](3)), and N[(CN) x B(C(6)F(5))(3)](2)(-) (=[N(CN)(2)(-)] x [B(C(6)F(5))(3)](2)) can be prepared in good yields. They are thermally stable up to over 200 degrees C and dissolve in polar organic solvents. Depending on the stoichiometry mono-, di-, tri-, or tetraadduct formation is observed. The solid state structures of dca_2b, tcm_3b and tcb_4b salts show only long cation...anion contacts and thereby weak interactions, large anion volumes and only small distortions of the dca, tcm or tcb core enwrapped between B(C(6)F(5))(3) groups. That is why these anions can be regarded as weakly coordinating anions. On the basis of B3LYP/6-31+G(d) computations the energetics, structural trends and charge transfer of the adduct anion formation were studied. Since tcm_3b and tcb_4b are easily accessible and can also be prepared in large quantities, these anions may be utilized as a true alternative to other widely used weakly coordinating anions. Moreover, for both steric and electronic reasons it seems reasonable to expect that as counterions for cationic early transition metal catalysts such anions may show reduced ion pairing and hence increased catalytic activity.

Stability and selectivity of a multiphase membrane, consisting of dimethylpolysiloxane on an ionic liquid, used in the separation of solutes from aqueous mixtures by pervaporation

A novel ionic liquid ([(C3H7)4N][B(CN)4]) was immobilized and coated by silicon in a ceramic nanofiltration module; this multiphase membrane shows a high selectivity (separation factor up to 177) and stability (over nine months) during separation of 1,3-propanediol from aqueous mixtures by vacuum pervaporation.

First intermolecular palladium catalyzed arylation of an unfunctionalized aromatic hydrocarbon

Abstract Azulene is arylated by iodobenzene and by 4-nitro-chlorobenzene under palladium catalysis at the electron-rich 1-position.

X-ray crystal structure of tetrakis(1-methylcytosine)copper(II) perchlorate dihydrate: effect of 1-methyl substitution on cytosine on the spectral and redox behaviour

Abstract Copper(II) tetrakis-complexes of cytosine (cyt), 1-methylcytosine (1-mcyt) and cytidine (cyd) have been isolated and their spectral and electrochemical properties investigated. The X-ray crystal structure of tetrakis(1-mcyt)copper(II) perchlorate dihydrate has been successfully determined. The co-ordination geometry around copper in the complex corresponds to square-based 4+4′ co-ordination. In addition to the preferential CuN3 bonds, there is significant interaction between copper(II) and the exocyclic O2 of 1-mcyt rings. The mutually cis 1-mcyt rings are present in a head-tail-head-tail arrangement, which is stabilised by a network of bifurcated hydrogen-bonding between the exocyclic amine hydrogen atoms and the oxygen atoms of the adjacent carbonyl groups. The aqueous solution spectra of the complexes are slightly different from solid state spectra revealing that the solid state structures undergo slight changes on dissolution in water. The electronic and EPR spectral and electrochemical results are consistent with the retention of the solid state structure even in solution. The EPR spectra exhibit N-superhyperfine lines corresponding to the coordination of four N3 atoms of cytosines. The higher g‖ values indicate decreased covalency in the metalligand bond and the range of g‖/A‖ quotient (119–121 cm) confirms the presence of CuN4 square-planar co-ordination geometry even in solution. The plot of ipc and E1/2 values versus 1-mcyt concentration for the electrochemical titration of Cu(ClO4)2 with 1-mcyt reveals an inflection point indicating the formation of 1:4 species in solution. The trend in E1/2 values of the complexes shows that the incorporation of electron releasing methyl group/ribose moiety at N1 position of cytosine ring enhances the stabilisation of Cu(II), in spite of the steric demand from OC2.

Fluorine-18 Radiolabeling and Radiopharmacological Characterization of a Benzodioxolylpyrimidine-based Radiotracer Targeting the Receptor Tyrosine Kinase EphB4

Members of the Eph receptor tyrosine kinase family play essential roles in the pathogenesis of cancer and are therefore promising candidates for molecular imaging by positron emission tomography (PET), for example. In this regard, radiochemical access to novel PET radiotracers derived from potent inhibitors that target the EphB4 kinase domain and which bear a benzodioxolylpyrimidine structural motif was developed. A synthetic route was established for a new fluorine‐18‐containing radiotracer and for the desired precursor based on a high‐affinity benzodioxolylpyrimidine receptor tyrosine kinase inhibitor lead structure. The radiotracer [18F]15 was obtained in 16 % radiochemical yield with a specific activity of ∼7 GBq μmol−1 and >95 % radiochemical purity. Due to the implication of EphB4, particularly in the progression, angiogenesis, and metastasis of melanoma, EphB4‐overexpressing human melanoma cells were generated and used as a novel in vitro model for radiopharmacological evaluation of the radiotracer. We demonstrate that the corresponding non‐radioactive reference compound regained its functionality as an inhibitor for both EphB4 receptor tyrosine kinase and Src kinase. EphB4 was significantly inhibited at compound concentrations >1 μM. Cellular uptake studies with [18F]15 revealed substantial uptake in both EphB4‐overexpressing and control cells. Moreover, NMRI nu/nu mice bearing both EphB4‐overexpressing tumors and control tumors were used for radiopharmacological characterization by biodistribution studies ex vivo and by dynamic small‐animal PET experiments in vivo. Despite the high metabolic stability of the novel radiotracer observed in vivo, no substantial binding or accumulation in EphB4‐overexpressing and control tumors was observed. Nevertheless, we point out that the approach presented herein gives convenient access to novel 18F‐labeled benzodioxolylpyrimidines and is a promising strategy for the further development of novel radiotracers for imaging Eph receptor tyrosine kinases in cancer.

2,3-Diaryl-substituted indole based COX-2 inhibitors as leads for imaging tracer development

A series of 2,3-diaryl-substituted indoles containing a fluorine or methoxy group was synthesized via Fischer indole synthesis, McMurry cyclization, or Bischler–Mohlau reaction to identify potential leads for positron emission tomography (PET) radiotracer development as well as for optical imaging. All 2,3-diaryl-substituted indoles possess autofluorescent properties with an emission maximum in a range of 443–492 nm, which is acceptable for biological studies in vitro and, in part, in vivo. The molecular structure of compounds 3a and 3j was confirmed by X-ray crystal structure analysis. COX inhibitory activity was evaluated by a fluorescence-based and enzyme immunoassay-based assay. Redox activity of all target compounds was also determined. All synthesized 2,3-diaryl-substituted indoles are inhibitors of COX-2 enzyme in the low micromolar range. Compounds 3e, 3f, 3g and 3m displayed a 30–40% inhibition of COX-2 at 0.1 μM concentration while compounds 3f and 3g also exhibited COX-1 inhibitory activity. Various compounds like 3g showed substantial antioxidative potential (RDIENE = 2.85, RHAVA = 1.98), an effect that was most measurable with methoxy-substituted compounds. With respect to PET radiotracer synthesis, OMe-containing compound 3j was selected as a promising candidate for carbon-11 labeling, and F-containing compound 3m as a lead for the development of a fluorine-18 labeled derivative.

Iron Salts with the Tetracyanidoborate Anion: [FeIII(H2O)6][B(CN)4]3, Coordination Polymer [FeII(H2O)2{κ2N[B(CN)4]}2], and [FeII(DMF)6][B(CN)4]2

The reaction of Fe(OH)(3) with tetracyanidoboronic acid, H[B(CN)(4)]·xH(2)O, in water leads to the first examples of tetracyanidoborates with a triply charged metal cation, [Fe(III)(H(2)O)(6)][B(CN)(4)](3) (1). Using elemental iron powder as starting material, [Fe(II)(H(2)O)(2){κ(2)ΝB(CN)(4)]}(2)] (2) is obtained. Anhydrous iron(II) tetracyanidoborate, which is synthesized by heating of 2, is soluble in dry dimethylformamide. After evaporation of the DMF solvent, single crystals of the third title compound, [Fe(II)(DMF)(6)][B(CN)(4)](2) (3), are obtained. Compound 3 is the first metal tetracyanidoborate soluble in nonpolar solvents. The title compounds have been characterized by single-crystal X-ray diffraction (1 rhombohedral, R3c (no. 167), a = 14.9017(7) Å, c = 20.486(1) Å, Z = 6; 2 tetragonal, I42d (no. 122), a = 12.3662(3) Å, c = 9.2066(4) Å, Z = 4; 3 triclinic, P1 (no. 2), a = 8.6255(3) Å, b = 11.0544(4) Å, c = 12.2377(5) Å, Z = 1). The metal ions in all three compounds are octahedrally coordinated. Whereas 1 and 3 are built up from isolated complex ions, 2 comprises a coordination polymer, in which the Fe(II) ion is coordinated by two oxygen atoms of two water molecules in a trans orientation and four nitrogen donor atoms of the [B(CN)(4)](-) groups, which bridge between neighboring iron ions. The iron(III) ion in 3 is in a perfect octahedral environment, which is formed by the O atoms of 6 molecules of water. The single-crystal X-ray structures, vibrational spectra, thermal properties, solubilities, and electrochemical characteristics are reported and compared with those of other known tetracyanidoborates.

X-Ray absorption spectroscopic studies on copper-containinghydrotalcite

EXAFS and XANES spectra have been recorded at the copper K-absorption edge on hydrotalcite samples, which contain 10 mol% copper, in order to determine the local environment of the copper ions. The vanishingly small magnitude of the pre-edge peak in the XANES region of the spectra indicates a centrosymmetric coordination of copper. The analysis of the EXAFS region results in a set of four oxygen ligands, 1.98 Aapart from copper as well as two oxygen ligands, which are 0.26 Afurther apart. This is consistent with an octahedron, elongated by Jahn–Teller effects. The best fit of the third coordination shell is obtained with 4.6 aluminium or magnesium ions at a distance of 3.05 Afrom the copper.

Diaryl-Substituted (Dihydro)pyrrolo[3,2,1-hi]indoles, a Class of Potent COX-2 Inhibitors with Tricyclic Core Structure

A new compound class of diaryl-substituted heterocycles with tricyclic dihydropyrrolo[3,2,1-hi]indole and pyrrolo[3,2,1-hi]indole core structures has been designed and was synthesized by a modular sequence of Friedel-Crafts acylation, amide formation, and McMurry cyclization. This synthesis route represents a novel and versatile access toward dihydropyrrolo[3,2,1-hi]indoles and is characterized by good chemical yields and high modularity. From a set of 19 derivatives, 11 candidates were selected for determination of their COX inhibition potency and were found to be selective inhibitors with high affinity to COX-2 (IC50 ranging from 20-2500 nM and negligible inhibition of COX-1). The binding mode of the novel inhibitors in the active side of COX-2 was calculated in silico using the protein-ligand docking program GOLD by application of the molecular structures of two compounds derived from X-ray crystallography. Two novel compounds with high affinity to COX-2 (6k = 70 nM, 8e = 60 nM) have a fluoro substituent, making them promising candidates for the development of (18)F-radiolabeled COX-2 inhibitors for imaging purposes with positron emission tomography (PET).