Energy Transfer from Magnetic Iron Oxide Nanoparticles: Implications for Magnetic Hyperthermia.

Magnetic iron oxide nanoparticles (IONPs) have gained momentum in the field of biomedical applications. They can be remotely heated via alternating magnetic fields, and such heat can be transferred from the IONPs to the local environment. However, the microscopic mechanism of heat transfer is still debated. By X-ray total scattering experiments and first-principles simulations, we show how such heat transfer can occur. After establishing structural and microstructural properties of the maghemite phase of the IONPs, we built a maghemite model functionalized with aminoalkoxysilane, a molecule used to anchor (bio)molecules to oxide surfaces. By a linear response theory approach, we reveal that a resonance mechanism is responsible for the heat transfer from the IONPs to the surroundings. Heat transfer occurs not only via covalent linkages with the IONP but also through the solvent hydrogen-bond network. This result may pave the way to exploit the directional control of the heat flow from the IONPs to the anchored molecules-i.e., antibiotics, therapeutics, and enzymes-for their activation or release in a broader range of medical and industrial applications.

Thermal and Structural Characterization of Two Crystalline Polymorphs of Tafamidis Free Acid.

Tafamidis, chemical formula C14H7Cl2NO3, is a drug used to delay disease progression in adults suffering from transthyretin amyloidosis, and is marketed worldwide under different tradenames as a free acid or in the form of its meglumine salt. The free acid (CAS no. 594839-88-0) is reported to crystallize as distinct (polymorphic) crystal forms, the thermal stability and structural features of which remained thus far undisclosed. In this paper, we present-by selectively isolating highly pure batches of Tafamidis Form 1 and Tafamidis Form 4-the full characterization of these solids, in terms of crystal structures (determined using state-of-the-art structural powder diffraction methods) and spectroscopic and thermal properties. Beyond conventional thermogravimetric and calorimetric analyses, variable-temperature X-ray diffraction was employed to measure the highly anisotropic response of these (poly)crystalline materials to thermal stimuli and enabled the determination of the linear and volumetric thermal expansion coefficients and of the related indicatrix. Both crystal phases are monoclinic and contain substantially flat and π-π stacked Tafamidis molecules, arranged as centrosymmetric dimers by strong O-H···O bonds; weaker C-H···N contacts give rise, in both polymorphs, to infinite ribbons, which guarantee the substantial stiffness of the crystals in the direction of their elongation. Complete knowledge of the structural models will foster the usage of full-pattern quantitative phase analyses of Tafamidis in drug and polymorphic mixtures, an important aspect in both the forensic and the industrial sectors.

Quinone-related hexacyclic by-products in the production process of exemestane.

Exemestane, a 3rd-generation aromatase inhibitor, is clinically used in the treatment of breast cancer in postmenopausal women. The key step of the industrial synthetic process, i.e., a dehydrogenation to introduce the Δ1-unsaturation, is normally performed with quinones such as p-chloranil or DDQ. We observed the formation of two different hexacyclic by-products, depending on the quinone used in the oxidation step. These compounds arise from an initial [4+2] cycloaddition between the precursor 6-methylenandrost-4-ene-3,17-dione and the quinone reagent, followed by a twofold dehydrohalogenation (with p-chloranil) or dehydrogenation (with DDQ). The structures of these unprecedented hexacyclic adducts were determined by a combination of mass spectrometry, NMR techniques and crystallographic analysis.

AAZTA: An Ideal Chelating Agent for the Development of 44 Sc PET Imaging Agents.

Unprecedented fast and efficient complexation of ScIII was demonstrated with the chelating agent AAZTA (AAZTA=1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine) under mild experimental conditions. The robustness of the 44 Sc(AAZTA)- chelate and conjugated biomolecules thereof is further shown by in vivo PET imaging in healthy and tumor mice models. The new results pave the way towards development of efficient Sc-based radiopharmaceuticals using the AAZTA chelator.

Nanostructured Drugs Embedded into a Polymeric Matrix: Vinpocetine/PVP Hybrids Investigated by Debye Function Analysis.

Microcrystalline vinpocetine, coground with cross-linked polyvinylpyrrolidone, affords hybrids containing nanosized drug nanocrystals, the size and size distributions of which depend on milling times and drug-to-polymer weight ratios. Using an innovative approach to microstructural characterization, we analyzed wide-angle X-ray total scattering data by the Debye function analysis and demonstrated the possibility to characterize pharmaceutical solid dispersions obtaining a reliable quantitative view of the physicochemical status of the drug dispersed in an amorphous carrier. The microstructural properties derived therefrom have been successfully employed in reconciling the enigmatic difference in behavior between in vitro and in vivo solubility tests performed on nanosized vinpocetine embedded in a polymeric matrix.

Difluprednate: more than meets the eye.

Difluprednate, a FDA approved topical corticosteroid indicated for the treatment of inflammation and pain associated with ocular surgery, affords three polymorphic crystal forms (one hexagonal, sg. P65, and two distinct orthorhombic, both sg.'s P212121, phases), whose preparation, thermal stability ranges, crystal structures and stereochemical preferences are here reported. Using DSC, single-crystal structural analysis and less conventional ab-initio X-ray powder diffraction methods, the rich structural and thermal behavior of three difluprednate polymorphs have been clarified, and the validity of previous complex and sometimes contradicting literature reports has been challenged. Complementary solution state NMR provided (1)H, (13)C and (19)F chemical shifts full assignment of the corresponding signals. These results allow us to precisely describe the selective isolation pathways toward three distinct crystal phases, and to define their structural and analytical data necessary for identification and easy and accurate quantification, by modern Rietveld analysis, of complex difluprednate polymorphic mixtures, often obtained as a result of poorly controlled (co)-precipitation methods.

Drastic effect of lattice propionitrile molecules on the spin-transition temperature of a 2,2'-dipyridylamino/s-triazine-based iron(II) complex.

Reaction of iron(II) selenocyanate (obtained from Fe(ClO4)2 and KNCSe) with 2-(N,N-bis(2-pyridyl)amino)-4,6-bis(pentafluorophenoxy)-(1,3,5)triazine (L1(F)) in propionitrile produces the compound [Fe(L1(F))2(NCSe)2]·2CH3CH2CN (1(NCSe)·2PrCN), which shows spin-crossover (SCO) properties characterized by a T(1/2) of 283 K and a ΔT80 (i.e., temperature range within which 80% of the transition considered occurs) of about 65 K. Upon air exposure, 1(NCSe)·2PrCN gradually converts to a new SCO species that exhibits different properties, as reflected by T(1/2) = 220 K and ΔT80 = 70 K. Various characterization techniques, namely, IR spectroscopy, thermogravimetric analysis, and thermodiffractometric studies, reveal that the new phase is obtained through the loss of the lattice propionitrile molecules within several days upon air exposure or several hours upon heating above 390 K.

Triple helicates with golden strands: self-assembly of M2Au6 complexes from gold(I) metallaligands and iron(II), cobalt(II) or zinc(II) cations.

Alkynyl gold(I) metallaligands [(AuC≡Cbpyl)2(µ-diphosphine)] (bpyl=2,2'-bipyridin-5-yl; diphosphine=Ph2P(CH2)(n)PPh2, [n=3 (L(Pr)), 4 (L(Bu)), 5 (L(Pent)), 6 (L(Hex))], dppf (L(Fc)), Binap (L(Binap)) and Diop (L(Diop))) react with MX2 (M=Fe, Zn, X=ClO4; M=Co, X=BF4) to give triple helicates [M2(L(R))3]X4. These complexes, except those containing the semirigid L(Binap) metallaligand, present similar hydrodynamic radii (determined by diffusion NMR spectroscopy measurements) and a similar pattern in the aromatic region of their (1)H NMR spectra, which suggests that in solution they adopt a compact structure where the long and flexible organometallic strands are folded. The diastereoselectivity of the self-assembly process was studied by using chiral metallaligands, and the absolute configuration of the iron(II) complexes with L(Binap) and L(Diop) was determined by circular dichroism spectroscopy (CD). Thus, (R)-L(Binap) or (S)-L(Binap) specifically induce the formation of (Δ,Δ)-[Fe2((R)-L(Binap))3](ClO4)4 or (Λ,Λ)-[Fe2((S)-L(Binap))3](ClO4)4, respectively, whereas (R,R)- or (S,S)-L(Diop) give mixtures of the ΔΔ- and ΛΛ-diastereomers. The ΔΔ helicate diastereomer is dominant in the reaction of Fe(II) with (R,R)-L(Diop), whereas the ΛΛ isomer predominates in the analogous reaction with (S,S)-L(Diop). The photophysical properties of the new dinuclear alkynyl complexes and the helicates have been studied. The new metallaligands and the [Zn2(L(R))3](4+) helicates present luminescence from [π→π*] excited states mainly located in the C≡Cbpyl units.

Mixed-ligand Cu(II)-vanillin Schiff base complexes; effect of coligands on their DNA binding, DNA cleavage, SOD mimetic and anticancer activity.

SOD mimics with varying coligand are momentous in developing potential chemotherapeutic drugs. Cu(II) based SOD mimics 1-4 [CuLH(OAc)(H(2)O)Y)] (LH = 2-((E)-(1,3-dihydroxy-2-methylpropan-2-ylimino)methyl)-6-methoxyphenol, OAc = CH(3)COO, 1: Y = H(2)O; 2: Y = phen (1,10-phenanthroline), 3: Y = tpimH (2,4,5-triphenylimidazole); 4: Y = tfbimH (2-(trifluoromethyl)benzimidazole) were synthesized and thoroughly characterized. Their interaction with CT-DNA showed different non-covalent binding behaviour. SOD activity of 2 was highest among 1-4 which was further validated by gel electrophoresis. The pBR322 plasmid strand break offered by 2 + O2·â» system reveals oxidative cleavage mechanism. In vitro antimicrobial activity of 1-4 was shown by percent inhibition data while in vitro anticancer activity of 1-4 was screened using 16 human carcinoma cell lines of different histological origin. Complex 2 showed higher efficacy towards 14 cell lines.

Structural and energetic aspects of a new bupropion hydrochloride polymorph.

Crystalline bupropion hydrochloride [(±)1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride], recently characterized as form 1, was found to undergo, upon storage at RT within months, a solid-solid conversion to a new polymorphic form, hereafter named form 2, containing a markedly different molecular conformer in the solid state. This new form, available only as a polycrystalline material, has been fully characterized using structural X-ray powder diffraction methods, coupled to thermoanalytical analyses. The relative stability of the two crystalline phases (forms 1 and 2) was compared by quantum mechanics calculations including density functional methods specific for solid state molecular systems. Bupropion hydrochloride form 2 crystallizes in the orthorhombic space group Pbca with Z=8, a=27.2853(5)Å, b=8.7184(3)Å, c=12.0422(3)Å, V=2864.7(1)ų, as centrosymmetric dimers, thanks to the presence of N-H…Cl interactions, and µ2-bridging chloride ions, each connected to two protonated amine moieties.

Pro-porous coordination polymers of the 1,4-bis((3,5-dimethyl-1H-pyrazol-4-yl)-methyl)benzene ligand with late transition metals.

Solvothermal reactions of the flexible, pyrazole-based 1,4-bis((3,5-dimethyl-1H-pyrazol-4-yl)methyl)benzene ligand (H(2)BDMPX) with late transition metal ions allowed the isolation of the four coordination compounds M(x)(BDMPX) (x = 1 for M = Zn, 1; Co, 2; Cd, 3; x = 2 for M = Cu, 4). The investigation of the thermal behavior assessed the high thermal robustness of these materials, which are stable in air at least up to 300 °C, with the Cd(II) derivative starting to decompose only around 500 °C. As retrieved by ab initio X-ray powder diffraction, the isomorphous compounds 1-3 possess a dense 3-D network featuring rhombic motifs hinged about rigid and parallel chains of tetrahedral MN(4) chromophores. As demonstrated by thermodiffractometric measurements, temperature increase triggers framework flexibility. The latter is at work also when N(2) adsorption is assayed at 77 K: 1 and 2 show permanent porosity, with BET and Langmuir specific surface areas of 515, 667 m(2)/g and 209, 384 m(2)/g, respectively. 1 and 2 thus represent an intriguing example of "porosity without pores", their pro-porous nature being explained in terms of the flexibility of the rhombic motifs, stimulated by the gas probe and facilitated by the nature of the ligand.

Study of the incorporation and release of the non-conventional half-sandwich ruthenium(II) metallodrug RAPTA-C on a robust MOF.

The highly porous and robust [Ni(8)(OH)(4)(OH(2))(2)(4,4'-(buta-1,3-diyne-1,4-diyl)bispyrazolato)(6)](n) MOF can be used as a proof of concept for the incorporation and release of the non-conventional [Ru(p-cymene)Cl(2)(pta)] RAPTA-C metallodrug.

Capture of nerve agents and mustard gas analogues by hydrophobic robust MOF-5 type metal-organic frameworks.

In this communication, a series of observations and data analyses coherently confirms the suitability of the novel metal-organic framework (MOF) [Zn(4)(µ(4)-O)(µ(4)-4-carboxy-3,5-dimethyl-4-carboxy-pyrazolato)(3)] (1) in the capture of harmful volatile organic compounds (VOCs). It is worthy of attention that 1, whose crystal structure resembles that of MOF-5, exhibits remarkable thermal, mechanical, and chemical stability, as required if practical applications are sought. In addition, it selectively captures harmful VOCs (including models of Sarin and mustard gas, which are chemical warfare agents), even in competition with ambient moisture (i.e., under conditions mimicking operative ones). The results can be rationalized on the basis of Henry constant and adsorption heat values for the different essayed adsorbates as well as H(2)O/VOC partition coefficients as obtained from variable-temperature reverse gas chromatography experiments. To further strengthen the importance of 1, its performance in the capture of harmful VOCs has been compared with those of well-known materials, namely, a MOF with coordinatively unsaturated metal sites, [Cu(3)(btc)(2)] and the molecular sieve active carbon Carboxen. The results of this comparison show that coordinatively unsaturated metal sites (preferential guest-binding sites) are ineffective for the capture of VOCs in the presence of ambient moisture. Consequently, we propose that the driving force of the VOC-MOF recognition process is mainly dictated by pore size and surface hydrophobicity.

Cubic octanuclear Ni(II) clusters in highly porous polypyrazolyl-based materials.

Two highly porous coordination polymers, containing rare octanuclear hydroxo-nickel clusters and long bis-pyrazolyl spacers, are shown to possess, after mild thermal treatment, lattice cavities up to 72% of the total crystal volume.

Structures from powders: bupropion hydrochloride.

The crystal structure of bupropion hydrochloride, 1, was fully characterized from powdered crystalline samples, using the ab-initio XRPD technique and a global optimization strategy (simulated annealing), adopting, as starting model, the already known molecular structure of its ethanol solvate, 2. Bupropion hydrochloride crystallizes as a racemate in monoclinic system, space group P2(1)/c with Z=4, a=14.3406(3)A, b=8.7564(2)A, c=11.8801(2)A, beta=78.025(2) degrees , V=1459.34(5)A(3). In the crystals of 1 the molecules interact via strong NH[...]Cl contacts, generating dimeric entities with mu-Cl ions. Further stabilizing contacts, of the CH[...]O are at work, but differently organized in the 1 and 2 phases. The thermal behaviour of the product was assessed by differential scanning calorimetry.

Structural and thermodiffractometric analysis of coordination polymers. Part II: zinc and cadmium derivatives of the Bim ligand [Bim = bis(1-imidazolyl)methane].

New polynuclear coordination species containing the ditopic bis(1-imidazolyl)methane (Bim) ligand have been prepared as microcrystalline powders and structurally characterized by ab initio X-ray powder diffraction methods. [Zn(CH3COO)2(Bim)]n contains 1D chains with tetrahedral metal atoms bridged by Bim ligands; [CdBr2(Bim)]n shows a dense packing with hexacoordinated Cd(II) ions and mu-Br and mu-Bim bridges; at variance, the isomorphous [ZnCl2(Bim)]n and [ZnBr2(Bim)]n species contain cyclic dimers based on tetrahedral Zn(II) ions. Thermodiffractometric analysis allowed estimation of the linear thermal expansion coefficients and strain tensors derived there from. Bim-rich phases, with 2:1 ligand-to-metal ratio, were also isolated: ZnBr2(Bim)2(H2O)3 and [Cd(CH3COO)2(Bim)2]n containing cis and trans MN4O2 chromophores, respectively, show 1D polymers built upon M2Bim2 cycles, hinged on the metal ions. In all species the conformation of the Bim ligands is Cs (or nearly so), while in the few sparse reports of similar coordination polymers the alternative C2 one was preferentially observed.

Synthesis, solid-state NMR, and X-ray powder diffraction characterization of group 12 coordination polymers, including the first example of a C-mercuriated pyrazole.

Cadmium and mercury acetates have been reacted with pyrazole (Hpz) and 3,5-dimethylpyrazole (Hdmpz), affording distinct mixed-ligand species, selectively prepared upon slightly modifying the reaction conditions. Two polymorphs of [{Cd(mu-ac)2(Hpz)2}n], as well as the [{Cd(mu-ac)2(Hdmpz)2}n] species (Hac = acetic acid), were obtained by solution chemistry, while the two-dimensional [{Cd3(mu3-ac)4(mu-pz)2(Hpz)2}n] and [{Cd(mu-ac)(mu-pz)}n] polymers were prepared upon controlled thermal treatment of one of the [{Cd(mu-ac)2(Hpz)2}n] forms. Two mercury derivatives, [{Hg3(mu-ac)3(mu-pz)3}n] and [{Hg(ac)(mu-dmpz)}n], were also prepared, the latter containing one-dimensional chains of Hg(II) ions bridged by C-mercuriated Hdmpz ligands. All their crystal structures (but one) were determined by powder diffraction methods using conventional X-ray laboratory equipment, supported by 13C CPMAS NMR measurements. The latter method helped in assigning a C-metalated nature to an amorphous material of [Hg(ac)(pz)] formula, obtained by employing EtOH as a solvent. A few other Hdmpz-containing cadmium acetates were also prepared, but their polyphasic nature, evidenced by diffraction methods, hampered their complete structural characterization.

Structural, magnetic, and electrical characterization of new polycrystalline phases of nickel- and platinum-doped [(DT-TTF)n][Au(mnt)2] (n = 1, 2).

Doping of spin-ladder systems by isostructural paramagnetic complexes was attempted. Despite the close isostructural nature of the pure (DT-TTF)2[M(mnt)2] (M = Au, Ni, Pt) end-members, which present a ladder structure, doping of the spin-ladder (DT-TTF)2[Au(mnt)2] with either 5% or 25% [M(mnt)2]- (M = Ni, Pt) generates two (metrically) new phases. Their markedly different crystal structures have been determined using laboratory X-ray powder diffraction data. (DT-TTF)2[Au0.75Ni0.25(mnt)2] consists of a mixed-valence compound (of triclinic symmetry), which was only detected, pure or in a mixture of phases, when [Ni(mnt)2]- was used as a dopant. Differently, the stoichiometric 1:1 [DT-TTF][Au0.75Pt0.25(mnt)2] monoclinic phase was found when [Pt(mnt)2]- (in 5% and 25%) was employed as the doping agent. Remarkably, only in the 5% Pt doping experiment, the major component of the mixture was the ladder structure compound (DT-TTF)2[Au(mnt)2] doped with minor amounts of Pt. This 5% Pt-doped specimen shows an EPR signal (g = 2.0115, DeltaHpp = 114 G at 300 K) wider than the pure compound (DT-TTF)2[Au(mnt)2], denoting exchange between the donor spins and Pt(mnt)2- centers. The electrical transport properties of the 5% Pt-doped composition at high temperatures are comparable to those of (DT-TTF)2[Au(mnt)2] with room-temperature conductivity sigma300K = 13 S/cm and thermopower S300K = 46 microV/K, with a sharp transition at 223 K similar to that previously observed in the Cu analogue at 235 K.

Coordination frameworks containing the pyrimidin-4-olate ligand. Synthesis, thermal, magnetic, and ab initio XRPD structural characterization of nickel and zinc derivatives.

Extended coordination frameworks containing the pyrimidin-4-olate ligand (4-pymo) and Zn(II) and Ni(II) metal ions have been obtained by solid state reactions and have been fully characterized by spectroscopic, thermal, and magnetic measurements and by ab initio XRPD. The reaction of ZnO and 4-Hpymo at 140 degrees C gives a solid microcrystalline phase, Zn(4-pymo)(2) (1). Its 3D framework contains Zn(II) centers linked by 4-pymo ligands acting in two different coordination modes, namely, the N,N'- and the N,O-exo-bidentate ones, which result in a pseudotetrahedral ZnN(3)O chromophore. Thermal treatment of the "molecular" Ni(4-pymo)(2)(H(2)O)(4) complex (2) above 140 degrees C gives an anhydrous amorphous material analyzing as Ni(4-pymo)(2) (3a). Further heating of this material above 388 degrees C results in the formation of the microcrystalline layered Ni(4-pymo)(2) species (3b), in which Ni(II) centers are bridged by N,O-exo-bidentate 4-pymo ligands (assisted by longer Ni.N contacts). The thermal dependence of the magnetic susceptibility has been studied for the paramagnetic species 2 and 3a. 2 shows a weak antiferromagnetic interaction [J = -0.313(5) cm(-)(1)] transmitted through the multiple H-bonding interactions between the exocyclic pyrimidine and water oxygen atoms coordinated to the metal centers. 3a behaves as a 2D Heisenberg antiferromagnet with J = -4.11(3) cm(-)(1).

Synthesis and characterization of two polymorphic crystalline phases and an amorphous powder of nickel(II) bisimidazolate.

Nickel(II) bisimidazolate is polymorphic. Depending on the synthetic strategy adopted, two crystalline phases (alpha- and beta-Ni(im)(2)) or an amorphous material of the same composition can be prepared. The thermodynamically stable alpha-Ni(im)(2) phase, which can be prepared in water at elevated temperatures, contains a two-dimensional polymer (of nearly square meshes) with square-planar NiN(4) chromophores and exo-bidentate imidazolate ligands bridging nickel atoms that are ca. 5.73 A apart. The beta-Ni(im)(2) phase can be kinetically stabilized at lower temperatures, but the structural complexity and the lack of single crystals prevented its full structural characterization, even in the presence of an indexed powder diffraction pattern. The spectroscopic features of these crystalline phases are compared with those of the amorphous material.