Using Chiral Auxiliaries to Mimic the Effect of Chiral Media on the Structure of Lanthanide(III) Complexes Common in Bioimaging and Diagnostic MRI.

[Ln·DOTA]- complexes and systems derived therefrom are commonly used in MRI and optical bioimaging. These lanthanide(III) complexes are chiral, and, in solution, they are present in four forms, with two sets of enantiomers, with the ligand donors arranged in either a square antiprismatic, SAP, or twisted square antiprismatic geometry, TSAP. This complicated speciation is found in laboratory samples. To investigate speciation in biological media, when Ln·DOTA-like complexes interact with chiral biomolecules, six Eu·DOTA-monoamide complexes were prepared and investigated by using 1D and 2D 1H NMR. To emulate the chirality of biological media, the amide pendant arm was modified with one or two chiral centers. It is known that a chiral center on the DOTA scaffold significantly influences the properties of the system. Here, it was found that chirality much further away from the metal center changes the available conformational space and that both chiral centers and amide cis/trans isomerism may need to be considered─a fact that, for the optically enriched materials, led to the conclusion that eight chemically different forms may need to be considered, instead of the four forms necessary for DOTA. The results reported here clearly demonstrate the diverse speciation that must be considered when correlating an observation to a structure of a lanthanide(III) complex.

SimpleNMR: An interactive graph network approach to aid constitutional isomer verification using standard 1D and 2D NMR experiments.

Despite progress in computer automated solutions, constitutional isomer verification by NMR using one- and two-dimensional data sets is still, in the main, a manual, user-intensive activity that is challenging for a number of reasons. These include the problem of simultaneously keeping track of the information from a number of separate NMR experiments and the difficulty of another researcher subsequently verifying the assignments made without having to independently repeat the whole analysis. This paper describes a graphical interactive approach that overcomes some of these problems. By using concepts used to visualise graph networks, we have been able to represent the NMR data in a manner that highlights directly the link between the different NMR experiments and the molecule of interest. Furthermore, by making the graph networks interactive, a user can easily validate and correct the assignment and understand the decisions made in arriving at the solution. We have developed a usable proof-of-concept computer program, 'simpleNMR', written in Python to illustrate the ideas and approach.

Chelating chloride using binuclear lanthanide complexes in water.

Halide recognition by supramolecular receptors and coordination complexes in water is a long-standing challenge. In this work, we report chloride binding in water and in competing media by pre-organised binuclear kinetically inert lanthanide complexes, bridged by flexible -(CH2)2- and -(CH2)3- spacers, forming [Ln2(DO3A)2C-2] and [Ln2(DO3A)2C-3], respectively. These hydrophilic, neutral lanthanide coordination complexes are shown to bind chloride with apparent association constants of up to 105 M-1 in water and in buffered systems. Hydroxide bridging was observed in these complexes at basic pH, which was proven to be overcome by chloride. Thus, these lanthanide complexes show promise towards chloride recognition in biology and beyond. The results described here have clearly identified a new area of anion coordination chemistry that is ripe for detailed exploration.

Solution-state behaviour of algal mono-uronates evaluated by pure shift and compressive sampling NMR techniques.

Sodium salts of the algal uronic-acids, d-mannuronic acid (HManA) and l-guluronic acid (HGulA) have been isolated and characterised in solution by nuclear magnetic resonance (NMR) spectroscopy. A suite of recently-described NMR experiments (including pure shift and compressive sampling techniques) were used to provide confident assignments of the pyranose forms of the two uronic acids at various pD values (from 7.5 to 1.4). The resulting high resolution spectra were used to determine several previously unknown parameters for the two acids, including their pKa values, the position of their isomeric equilibria, and their propensity to form furanurono-6,3-lactones. For each of the three parameters, comparisons are drawn with the behaviour of the related D-glucuronic (HGlcA) and D-galacturonic acids (HGalA), which have been previously studied extensively. This paper demonstrates how these new NMR spectroscopic techniques can be applied to better understand the properties of polyuronides and uronide-rich macroalgal biomass.

Tuning the anion binding properties of lanthanide receptors to discriminate nucleoside phosphates in a sensing array.

The development of synthetic receptors for the selective binding and discrimination of anions in water requires an understanding of how anions interact with these synthetic receptors. Molecules designed to differentiate nucleoside phosphate anions (e.g. ATP, ADP, GTP, GDP, UDP) under physiological conditions could underpin exciting new sensing tools for biomedical research and drug discovery, but it is very challenging due to the similarities in anion structure, size and charge. We present a series of lanthanide-based anion receptors and establish key structural elements that impact on nucleoside phosphate anion binding and sensing. Structural evidence of anion binding using X-ray crystallographic and NMR data, supported by DFT calculations indicate the binding modes between the lanthanide complexes and certain phosphoanions, revealing a bidentate (α-, γ-) binding mode to ATP. We further use four of the receptors to allow discrimination of eight nucleoside phosphate anions in the first array-based assay using lanthanide complexes, taking advantage of the multiple emission bands and long emission lifetimes associated with luminescent lanthanide complexes.

Coherence transfer delay optimisation in PSYCOSY experiments.

PSYCOSY is an f1 broadband homonuclear decoupled version of the COSY nuclear magnetic resonance pulse sequence. Here, we investigate by a combination of experimental measurements, spatially distributed spin dynamics simulations, and analytical predictions the coherence evolution delay necessary in PSYCOSY experiments to ensure intensity discrimination in favour of the correlations typically arising from short range (n J, n ≤ 3) 1 H-1 H couplings and show that, in general, a coherence evolution delay of around 35 ms is optimum.

Reliable, high-quality suppression of NMR signals arising from water and macromolecules: application to bio-fluid analysis.

Analysis of metabolites in biofluids using nuclear magnetic resonance often requires the suppression of obscuring signals arising from water and macromolecules. This paper analyses the limitations of the pulse sequence most commonly used to achieve such suppression (presat-CPMG) and proposes new pulse sequences that do not share those limitations. The utility of these improved pulse sequences is demonstrated in a metabolomic study of multiple sclerosis (MS) patients.

A novel Pt(iv) mono azido mono triazolato complex evolves azidyl radicals following irradiation with visible light.

The platinum(iv) azido complex trans,trans,trans-[PtIV(N3)2(OH)2(py)2] (1) undergoes cycloaddition with 1,4-diphenyl-2-butyne-1,4-dione (2) under mild, catalyst-free conditions, affording a number of mono and bis click products. The major mono click product (3) exists in MeCN as an equilibrium mixture between two species; 3a and 3b rapidly interconvert through nucleophilic attack of the axial Pt-OH group at the adjacent Ph-CO group. The kinetic and thermodynamic parameters for this interconversion have been measured by selective saturation-transfer NMR spectroscopic experiments and are consistent with cyclisation at the Pt centre. Complex 3b was also characterised by X-ray crystallography. Visible light irradiation (440-480 nm) of 3 in d3-MeCN produces azidyl radicals (N3˙), as demonstrated by EPR spin-trapping with DMPO; no generation of hydroxyl radicals was observed. 1H-195Pt HMBC NMR confirmed that the photoproducts were PtIV rather than PtII species, and HPLC was consistent with these being [3-N3]+ species; no facile photoejection of the triazolato ligand was observed, consistent with MS/MS fragmentation of 3. When 3 was irradiated in the presence of 5'-GMP, no 5'-GMP photoproducts were observed, suggesting that complex 3 is likely to exhibit significantly simplified biological activity (release of azidyl radicals but not DNA binding) compared with complex 1.

Aggregation of Rare Earth Coordination Complexes in Solution Studied by Paramagnetic and DOSY NMR.

The degree of aggregation of neutral, 9-coordinate rare earth coordination complexes has been shown to affect their ligand field, as revealed by diffusion-ordered NMR spectroscopy (DOSY-NMR) measurements on Y(III) complexes, paramagnetic NMR analyses of Yb and Tb analogues and emission spectral studies with the EuIII systems. In non-polar media a lipophilic tris-isopropyl complex, [Ln.L2 ] tends to aggregate in chloroform and dichloromethane giving rise to oligomers, whereas in acetic and trifluoroacetic acid the more polar parent complex, [Ln.L1 ], also aggregates, profoundly affecting the pseudocontact shift and the form of the Eu emission spectrum. Such behaviour has important implications in the design of responsive spectral probes.

Separating the coherence transfer from chemical shift evolution in high-resolution pure shift COSY NMR.

Recent developments in data sampling and processing techniques have made it possible to acquire 2-dimensional NMR spectra of small molecules at digital resolutions in both dimensions approaching the intrinsic limitations of the equipment and sample on a realistic timescale. These developments offer the possibility of enormously increased effective resolution (peak dispersion) and the ability to effectively study samples where peak overlap was previously a limiting factor. Examples of such spectra have been produced for a number of 2-dimensional techniques including TOCSY and HSQC. In this paper, we investigate some of the problems in applying such techniques to COSY spectra and suggest a modification to the classic experiment that alleviates some of these problems.

Compressed NMR: Combining compressive sampling and pure shift NMR techniques.

Historically, the resolution of multidimensional nuclear magnetic resonance (NMR) has been orders of magnitude lower than the intrinsic resolution that NMR spectrometers are capable of producing. The slowness of Nyquist sampling as well as the existence of signals as multiplets instead of singlets have been two of the main reasons for this underperformance. Fortunately, two compressive techniques have appeared that can overcome these limitations. Compressive sensing, also known as compressed sampling (CS), avoids the first limitation by exploiting the compressibility of typical NMR spectra, thus allowing sampling at sub-Nyquist rates, and pure shift techniques eliminate the second issue "compressing" multiplets into singlets. This paper explores the possibilities and challenges presented by this combination (compressed NMR). First, a description of the CS framework is given, followed by a description of the importance of combining it with the right pure shift experiment. Second, examples of compressed NMR spectra and how they can be combined with covariance methods will be shown.

Lanthanide Complexes that Respond to Changes in Cyanide Concentration in Water.

Cyanide ions are shown to interact with lanthanide complexes of phenacylDO3A derivatives in aqueous solution, giving rise to changes in the luminescence and NMR spectra. These changes are the consequence of cyanohydrin formation, which is favored by the coordination of the phenacyl carbonyl group to the lanthanide center. These complexes display minimal affinity for fluoride and can detect cyanide at concentrations less than 1 µm. By contrast, lanthanide complexes with DOTAM derivatives display no affinity for cyanide in water, but respond to changes in fluoride concentration.

Amorphism and Thermal Decomposition of Salicylsalicylic Acid-A Cautionary Tale.

Salicylsalicylic acid ("Salsalate") is a non-steroidal anti-inflammatory drug with anti-rheumatic properties, whose amorphous form offers the potential for enhanced dissolution rates and improved bioavailability compared with its crystalline counterpart. It has been reported to form a stable glassy phase on heating and rapid quenching. A number of the existing studies of the solid-state structure of salsalate and of its thermal decomposition contain information that is difficult to reconcile. In this article, we review much of the existing literature in light of our own recent studies using solution-state nuclear magnetic resonance, mass spectrometry, and solid-state infrared spectroscopy, and conclude that much of the literature data relating to melting and the glassy state is questionable due to failure to take into account the effects of thermal decomposition.

Fluoride Binding and Crystal-Field Analysis of Lanthanide Complexes of Tetrapicolyl-Appended Cyclen.

Lanthanide complexes of tetrapicolyl cyclen displayed remarkably high affinities for fluoride (log K≈5) in water, and were shown to form 1:1 complexes. The behaviour of these systems can be rationalised by changes to the magnitude of the crystal-field parameter, B20 . However, such changes are not invariably accompanied by a change in sign of this parameter: for early lanthanides, the N8 donor set with a coordinated axial water molecule ensures that the magnetic anisotropy has the opposite sense to that observed in the analogous dehydrated lanthanide complexes.

Luminescence of a binuclear europium complex bearing a 4-nitrophenolate chromophore: a different way of seeing pH dependence.

A europium complex derived from NP-(DO3A)2 exhibits pH-dependent europium-centred luminescence following excitation of the nitrophenolate chromophore. Such behaviour is not observed with an analogous mononuclear complex, suggesting coordination of both lanthanide ions to the phenolate oxygen in the emissive species.

Electromagnetic susceptibility anisotropy and its importance for paramagnetic NMR and optical spectroscopy in lanthanide coordination chemistry.

The importance of the directional dependence of magnetic susceptibility in magnetic resonance and of electric susceptibility in the optical spectroscopy of lanthanide coordination complexes is assessed. A body of more reliable shift, relaxation and optical emission data is emerging for well-defined isostructural series of complexes, allowing detailed comparative analyses to be undertaken. Such work is highlighting the limitations of the current NMR shift and relaxation theories, as well as emphasising the absence of a compelling theoretical framework to explain optical emission phenomena.

Substituent effects on fluoride binding by lanthanide complexes of DOTA-tetraamides.

Fluoride binding by a series of europium and ytterbium complexes of DOTA-tetraamide ligands derived from primary, secondary and tertiary amides has been studied by NMR and luminescence spectroscopies. In all the systems studied, fluoride binding results in a change in the nature of the magnetic anisotropy at the metal centre from an easy axis, to an easy plane anisotropy. This results in reversal of the peaks in the NMR spectra, and in changes to the fine structure of the luminescence spectra. Furthermore, changes to the periphery of the binding cavity are implicated in determining the affinity constant for fluoride. There are clear differences in the entropic contribution to the free energy of activation between systems with benzylic amides and those with methylamides.

Spectroscopic and Crystal Field Consequences of Fluoride Binding by [Yb⋠DTMA](3+) in Aqueous Solution.

Yb⋅DTMA forms a ternary complex with fluoride in aqueous solution by displacement of a bound solvent molecule from the lanthanide ion. [Yb⋅DTMA⋅F](2+) and [Yb⋅DTMA⋅OH2 ](3+) are in slow exchange on the relevant NMR timescale (<2000 s(-1) ), and profound differences are observed in their respective NMR and EPR spectra of these species. The observed differences can be explained by drastic modification of the ligand field states due to the fluoride binding. This changes the magnetic anisotropy of the Yb(III) ground state from easy-axis to easy-plane type, and this change is easily detected in the observed magnetic anisotropy despite thermal population of more than just the ground state. The spectroscopic consequences of such drastic changes to the ligand field represent important new opportunities in developing fluoride-responsive complexes and contrast agents.

Axial fluoride binding by lanthanide DTMA complexes alters the local crystal field, resulting in dramatic spectroscopic changes.

Addition of fluoride to aqueous solutions of lanthanide complexes of DTMA results in the formation of ternary complexes of the form [F·Ln·DTMA](2+) in which an axial solvent molecule is displaced by fluoride. [F·Ln·DTMA](2+) and [H2O·Ln·DTMA](3+) are in exchange on a timescale of around 1 s. Dramatic changes are observed in both the NMR and luminescence spectra of the complexes: these are consistent with a change in the nature of the magnetic anisotropy at the paramagnetic lanthanide centre, itself arising from a change in the local crystal field. Study of paramagnetic lanthanide complexes with anisotropic electronic distributions reveals that, upon replacing water with fluoride, there is an inversion of the sign, and a significant reduction in the magnitude, of the crystal field term that defines the nature of the pseudocontact shift.

Challenging lanthanide relaxation theory: erbium and thulium complexes that show NMR relaxation rates faster than dysprosium and terbium analogues.

Measurements of the proton NMR paramagnetic relaxation rates for several series of isostructural lanthanide(III) complexes have been performed in aqueous solution over the field range 1.0 to 16.5 Tesla. The field dependence has been modeled using Bloch-Redfield-Wangsness theory, allowing values for the electronic relaxation time, Tle and the magnetic susceptibility, µeff, to be estimated. Anomalous relaxation rate profiles were obtained, notably for erbium and thulium complexes of low symmetry 8-coordinate aza-phosphinate complexes. Such behaviour challenges accepted theory and can be interpreted in terms of changes in Tle values that are a function of the transient ligand field induced by solvent collision and vary considerably between Ln(3+) ions, along with magnetic susceptibilities that deviate significantly from free-ion values.