Kinetically Inert Macrocyclic Europium(III) Receptors for Phosphate.

The significant role that phosphate plays in environmental water pollution and biomedical conditions such as hyperphosphatemia highlights the need to develop robust receptors that can sequester the anion effectively and selectively from complex aqueous media. Toward that goal, four macrocyclic tris-bidentate 1,2-hydroxypyridonate (HOPO) europium(III) complexes containing either a cyclen, cyclam, TACN, or TACD ligand cap were synthesized and evaluated as phosphate receptors. The solubility of EuIII-TACD-HOPO in water was insufficient for luminescent studies. Whereas EuIII-cyclen-HOPO is eight coordinate with two inner-sphere water molecules, both EuIII-cyclam-HOPO and EuIII-TACN-HOPO are nine coordinate with three inner-sphere water molecules, suggesting that the two coordination states are very close in energy. As observed previously with linear analogues of tripodal HOPO complexes, there is no relationship between the number of inner-sphere water molecules and the affinity of the complex for phosphate. Whereas all three complexes do bind phosphate, EuIII-cyclen-HOPO has the highest affinity for phosphate with the anion displacing both of its inner-sphere water molecules. On the other hand, only one or two of the three inner-sphere water molecules of EuIII-TACN-HOPO and EuIII-cyclam-HOPO are displaced by phosphate, respectively. All three complexes are highly selective for phosphate over other anions, including arsenate. All three complexes are highly stable. EuIII-cyclen-HOPO and, to a lesser extent, EuIII-TACN-HOPO are more kinetically inert than the linear EuIII-Ser-HOPO. EuIII-cyclam-HOPO, on the other hand, is not. This study highlights the significant effect that minor changes in the ligand cap can have on both the ligand exchange rate and affinity for phosphate of tripodal 1,2-dihydroxypyridinonate complexes.

Exploiting the Fluxionality of Lanthanide Complexes in the Design of Paramagnetic Fluorine Probes.

Fluorine-19 MRI is increasingly being considered as a tool for biomolecular imaging, but the very poor sensitivity of this technique has limited most applications. Previous studies have long established that increasing the sensitivity of 19F molecular probes requires increasing the number of fluorine nuclei per probe as well as decreasing their longitudinal relaxation time. The latter is easily achieved by positioning the fluorine atoms in close proximity to a paramagnetic metal ion such as a lanthanide(III). Increasing the number of fluorine atoms per molecule, however, is only useful inasmuch as all of the fluorine nuclei are chemically equivalent. Previous attempts to achieve this equivalency have focused on designing highly symmetric and rigid fluorinated macrocyclic ligands. A much simpler approach consists of exploiting highly fluxional lanthanide complexes with open coordination sites that have a high affinity for phosphated and phosphonated species. Computational studies indicate that LnIII-TREN-MAM is highly fluxional, rapidly interconverting between at least six distinct isomers. In neutral water at room temperature, LnIII-TREN-MAM binds two or three equivalents of fluorinated phosphonates. The close proximity of the 19F nuclei to the LnIII center in the ternary complex decreases the relaxation times of the fluorine nuclei up to 40-fold. Advantageously, the fluorophosphonate-bound lanthanide complex is also highly fluxional such that all 19F nuclei are chemically equivalent and display a single 19F signal with a small LIS. Dynamic averaging of fluxional fluorinated supramolecular assemblies thus produces effective 19F MR systems.

Design and applications of metal-based molecular receptors and probes for inorganic phosphate.

Inorganic phosphate has numerous biomedical functions. Regulated primarily by the kidneys, phosphate reaches abnormally high blood levels in patients with advanced renal diseases. Since phosphate cannot be efficiently removed by dialysis, the resulting hyperphosphatemia leads to increased mortality. Phosphate is also an important component of the environmental chemistry of surface water. Although required to secure our food supply, inorganic phosphate is also linked to eutrophication and the spread of algal blooms with an increasing economic and environmental burden. Key to resolving both of these issues is the development of accurate probes and molecular receptors for inorganic phosphate. Yet, quantifying phosphate in complex aqueous media remains challenging, as is the development of supramolecular receptors that have adequate sensitivity and selectivity for use in either blood or surface waters. Metal-based receptors are particularly well-suited for these applications as they can overcome the high hydration enthalpy of phosphate that limits the effectiveness of many organic receptors in water. Three different strategies are most commonly employed with inorganic receptors for anions: metal extrusion assays, responsive molecular receptors, and indicator displacement assays. In this review, the requirements for molecular receptors and probes for environmental applications are outlined. The different strategies deployed to recognize and sense phosphate with metal ions will be detailed, and their advantages and shortfalls will be delineated with key examples from the literature.

Effect of Thiol Molecular Structure on the Sensitivity of Gold Nanoparticle-Based Chemiresistors toward Carbonyl Compounds.

Increasing both the sensitivity and selectivity of thiol-functionalized gold nanoparticle chemiresistors remains a challenging issue in the quest to develop real-time gas sensors. The effects of thiol molecular structure on such sensor properties are not well understood. This study investigates the effects of steric as well as electronic effects in a panel of substituted thiol-urea compounds on the sensing properties of thiolate monolayer-protected gold nanoparticle chemiresistors. Three series of urea-substituted thiols with different peripheral end groups were synthesized for the study and used to prepare gold nanoparticle-based chemiresistors. The responses of the prepared sensors to trace volatile analytes were significantly affected by the urea functional motifs. The largest response for sensing acetone among the three series was observed for the thiol-urea sensor featuring a tert-butyl end group. Furthermore, the ligands fitted with N, N'-dialkyl urea moieties exhibit a much larger response to carbonyl analytes than the more acidic urea series containing N-alkoxy-N'-alkyl urea and N, N'-dialkoxy urea groups with the same peripheral end groups. The results show that the peripheral molecular structure of thiolate-coated gold nanoparticles plays a critical role in sensing target analytes.

The Stability of the Complex and the Basicity of the Anion Impact the Selectivity and Affinity of Tripodal Gadolinium Complexes for Anions.

The affinities and selectivities of lanthanide complexes with open coordination sites for anions vary considerably with the chelate. In order to determine the effect of the stability of a lanthanide complex on its affinity for anions, five different complexes featuring different bidentate chelating moieties were synthesized, and their affinity for anions in water at neutral pH were evaluated by longitudinal relaxometry measurements. The chelates comprise both oxygen and nitrogen donors including maltol, 1,2-hydroxypyridinone, hydroxamic acid, pyridin-2-ylmethanol, and carbamoylmethylphosphonate diester. They were chosen to span a range of basicities all the while maintaining a similar tripodal tris-bidentate architecture, thereby allowing for a direct study of the role of the coordinating motif on the supramolecular recognition of anions by the corresponding GdIII complex. Overall, for ligands containing the same number of protonation steps, and therefore the same charge at neutral pH, the lower the acidity of the chelate (higher ∑pKa's), the less stable the corresponding GdIII complex, and the higher its affinity for anions. Regardless of the number of protonation steps, the more stable GdIII complexes form ternary or quaternary assemblies with coordinating anions. In contrast, the same anions readily displace the chelate of the least stable complexes, resulting instead in the formation of GdIII·anion precipitates. Irrespective of the chelate, in the absence of steric hindrance at the open coordination site, the affinity of GdIII complexes for anions follows the order phosphate > arsenate > bicarbonate > fluoride. Hence, the selectivity and affinity of GdIII complexes of tripodal tris-bidentate chelates for anions is a function of the stability of the GdIII complex and the basicity of the anion.

Quantitative profiling of carbonyl metabolites directly in crude biological extracts using chemoselective tagging and nanoESI-FTMS.

The extensive range of chemical structures, wide range of abundances, and chemical instability of metabolites present in the metabolome pose major analytical challenges that are difficult to address with existing technologies. To address these issues, one approach is to target a subset of metabolites that share a functional group, such as ketones and aldehydes, using chemoselective tagging. Here we report a greatly improved chemoselective method for the quantitative analysis of hydrophilic and hydrophobic carbonyl-containing metabolites directly in biological samples. This method is based on direct tissue or cells extraction with simultaneous derivatization of stable and labile carbonylated metabolites using N-[2-(aminooxy)ethyl]-N,N-dimethyl-1-dodecylammonium (QDA) and 13CD3 labeled QDA. We combined innovations of direct quenching of biological sample with frozen derivatization conditions under the catalyst N,N-dimethyl-p-phenylenediamine, which facilitated the formation of oxime stable-isotope ion pairs differing by m/z 4.02188 while minimizing metabolite degradation. The resulting oximes were extracted by HyperSep C8 tips to remove interfering compounds, and the products were detected using nano-electrospray ionization interfaced with a Thermo Fusion mass spectrometer. The quaternary ammonium tagging greatly increased electrospray MS detection sensitivity and the signature ions pairs enabled simple identification of carbonyl compounds. The improved method showed the lower limits of quantification for carbonyl standards to be in the range of 0.20-2 nM, with linearity of R2 > 0.99 over 4 orders of magnitude. We have applied the method to assign 66 carbonyls in mouse tumor tissues, many of which could not be assigned solely by accurate mass and tandem MS. Fourteen of the metabolites were quantified using authentic standards. We also demonstrated the suitability of this method for determining 13C labeled isotopologues of carbonyl metabolites in 13C6-glucose-based stable isotope-resolved metabolomic (SIRM) studies.

Metallointercalators-DNA Tetrahedron Supramolecular Self-Assemblies with Increased Serum Stability.

Self-assembly of metallointercalators into DNA nanocages is a rapid and facile approach to synthesize discrete bioinorganic host/guest structures with a high load of metal complexes. Turberfield's DNA tetrahedron can accommodate one intercalator for every two base pairs, which corresponds to 48 metallointercalators per DNA tetrahedron. The affinity of the metallointercalator for the DNA tetrahedron is a function of both the structure of the intercalating ligand and the overall charge of the complex, with a trend in affinity [Ru(bpy)2(dppz)]2+ > [Tb-DOTAm-Phen]3+ ≫ Tb-DOTA-Phen. Intercalation of the metal complex stabilizes the DNA tetrahedron, resulting in an increase of its melting temperature and, importantly, a significant increase in its stability in the presence of serum. [Ru(bpy)2(dppz)]2+, which has a greater affinity for DNA than [Tb-DOTAm-Phen]3+, increases the melting point and decreases degradation in serum to a greater extent than the TbIII complex. In the presence of Lipofectamine, the metallointercalator@DNA nanocage assemblies substantially increase the cell uptake of their respective metal complex. Altogether, the facile incorporation of a large number of metal complexes per assembly, the higher stability in serum, and the increased cell penetration of metallointercalator@DNA make these self-assemblies well-suited as metallodrugs.

Imparting sensitivity and selectivity to a gold nanoparticle chemiresistor through thiol monolayer functionalization for sensing acetone.

Chemiresistor-based gas sensors for detection of target volatile organic compounds (VOCs) in air face common challenges of poor sensitivity and selectivity as well as suffering from interference by other constituent gases and/or humidity. This work demonstrates that functionalizing gold nanoparticles (AuNPs) with a designed thiol monolayer improves sensitivity and selectivity of the derived AuNPs gas sensor. We report the synthesis and application of a thiol ligand fitted with both a urea motif and a tert-butyl end group for functionalizing AuNPs. The AuNPs sensor prepared using the urea thiol ligand demonstrated significantly increased acetone sensing in comparison with tested commercially available thiol-functionalized AuNPs. The sensor worked under ambient temperature and high humidity conditions, and demonstrated a linear relationship between the sensor response and the common logarithm of analyte concentration.

Aldehyde Detection in Electronic Cigarette Aerosols.

Acetaldehyde, acrolein, and formaldehyde are the principal toxic aldehydes present in cigarette smoke and contribute to the risk of cardiovascular disease and noncancerous pulmonary disease. The rapid growth of the use of electronic cigarettes (e-cigarettes) has raised concerns over emissions of these harmful aldehydes. This work determines emissions of these aldehydes in both free and bound (aldehyde-hemiacetal) forms and other carbonyls from the use of e-cigarettes. A novel silicon microreactor with a coating phase of 4-(2-aminooxyethyl)-morpholin-4-ium chloride (AMAH) was used to trap carbonyl compounds in the aerosols of e-cigarettes via oximation reactions. AMAH-aldehyde adducts were measured using gas chromatography-mass spectrometry. 1H nuclear magnetic resonance spectroscopy was used to analyze hemiacetals in the aerosols. These aldehydes were detected in the aerosols of all e-cigarettes. Newer-generation e-cigarette devices generated more aldehydes than the first-generation e-cigarettes because of higher battery power output. Formaldehyde-hemiacetal was detected in the aerosols generated from some e-liquids using the newer e-cigarette devices at a battery power output of 11.7 W and above. The emission of these aldehydes from all e-cigarettes, especially higher levels of aldehydes from the newer-generation e-cigarette devices, indicates the risk of using e-cigarettes.

Acid/Base and H2PO4(-) Controllable High-Contrast Optical Molecular Switches with a Novel BODIPY Functionalized [2]Rotaxane.

A novel multifunctional mechanically interlocked switchable [2]rotaxane R4 containing two molecular stations and rotaxane arms terminated with boron-dipyrromethene (BODIPY) fluorophores and its derivatives were synthesized for the first time by CuAAC click reaction. The shuttling motion of macrocycle between the dibenzylammonium and triazolium recognition sites and the distance dependent photoinduced electron transfer process of R4 is demonstrated by utilizing external chemical stimuli (acid/base). Interestingly, the reversible self-assembly process of R4 was recognized by the acid-base molecular switch strategy. Notably, two symmetrical triazolium groups acted as molecular stations, H2PO4(-) receptors, and H-bonded donors. Both [2]rotaxane R4 and thread R2 demonstrated excellent optical responses and high selectivity toward H2PO4(-) ion. The specific motion and guest-host interactions of mechanically interlocked machines (MIMs) were also further explored by quantum mechanical calculations. The thread R2 also demonstrated to enable the detection of H2PO4(-) in RAW 264.7 cells successfully.