Chemical Shift Separation Research Articles

Diastereotopic fluorine substituents as 19F NMR probes of screw-sense preference in helical foldamers

Ligating simple amino alcohol or amino ester monomers containing enantiotopic fluorine substituents to the C-terminus of a helical peptide places the fluorine atoms in diastereotopic environments, and gives two distinct and easily identifiable signals in the (19)F NMR spectrum. In the case of a dynamically inverting helix built from achiral monomers, the chemical shift separation between the (19)F signals provides a simple means of analysing the ratio of screw-sense conformers in the oligomer, in cases where an asymmetric bias leads to a screw-sense preference.

Spin-Transfer Pathways in Paramagnetic Lithium Transition-Metal Phosphates from Combined Broadband Isotropic Solid-State MAS NMR Spectroscopy and DFT Calculations

Substituted lithium transition-metal (TM) phosphate LiFe(x)Mn(1-x)PO(4) materials with olivine-type structures are among the most promising next generation lithium ion battery cathodes. However, a complete atomic-level description of the structure of such phases is not yet available. Here, a combined experimental and theoretical approach to the detailed assignment of the (31)P NMR spectra of the LiFe(x)Mn(1-x)PO(4) (x = 0, 0.25, 0.5, 0.75, 1) pure and mixed TM phosphates is developed and applied. Key to the present work is the development of a new NMR experiment enabling the characterization of complex paramagnetic materials via the complete separation of the individual isotropic chemical shifts, along with solid-state hybrid DFT calculations providing the separate hyperfine contributions of all distinct Mn-O-P and Fe-O-P bond pathways. The NMR experiment, referred to as aMAT, makes use of short high-powered adiabatic pulses (SHAPs), which can achieve 100% inversion over a range of isotropic shifts on the order of 1 MHz and with anisotropies greater than 100 kHz. In addition to complete spectral assignments of the mixed phases, the present study provides a detailed insight into the differences in electronic structure driving the variations in hyperfine parameters across the range of materials. A simple model delimiting the effects of distortions due to Mn/Fe substitution is also proposed and applied. The combined approach has clear future applications to TM-bearing battery cathode phases in particular and for the understanding of complex paramagnetic phases in general.

MATPASS/CPMG: A sensitivity enhanced magic-angle spinning sideband separation experiment for disordered solids

A Carr–Purcell Meiboom–Gill (CPMG) sensitivity-enhanced spinning sideband separation experiment is presented. The experiment combines the idea of magic-angle turning and phase-adjusted sideband separation (MATPASS), allowing for isotropic/anisotropic chemical shift separation of disordered solids with line widths far greater than the magic-angle spinning frequency. The use of CPMG enhances the sensitivity of the wide-line spectra by an order of magnitude via multiple-echo acquisition. The MATPASS/CPMG protocol involves acquisition of time-domain data using a MAT/CPMG pulse sequence followed by f1 shearing during data processing to arrive at the PASS representation. Such a protocol has √2 higher sensitivity than the conventional PASS method because all CPMG echo signals are used for the final PASS spectrum. Application of this method is demonstrated using a GeSe4 glass sample with both 77Se isotropic line widths and chemical shift anisotropy that far exceed the spinning frequency. The sideband separation allows for the measurement of chemical shift anisotropy of the disordered solids.

Fragment density functional theory calculation of NMR chemical shifts for proteins with implicit solvation

Fragment density functional theory (DFT) calculation of NMR chemical shifts for several proteins (Trp-cage, Pin1 WW domain, the third IgG-binding domain of Protein G (GB3) and human ubiquitin) has been carried out. The present study is based on a recently developed automatic fragmentation quantum mechanics/molecular mechanics (AF-QM/MM) approach but the solvent effects are included by using the PB (Poisson-Boltzmann) model. Our calculated chemical shifts of (1)H and (13)C for these four proteins are in excellent agreement with experimentally measured values and represent clear improvement over that from the gas phase calculation. However, although the inclusion of the solvent effect also improves the computed chemical shifts of (15)N, the results do not agree with experimental values as well as (1)H and (13)C. Our study also demonstrates that AF-QM/MM calculated results accurately reproduce the separation of α-helical and β-sheet chemical shifts for (13)C(α) atoms in proteins, and using the (1)H chemical shift to discriminate the native structure of proteins from decoys is quite remarkable.

X-Ray Structural Characterization of the Bis-Guanine Derivative of a Cisplatin Analogue Having Just One Proton on Each Coordinated Nitrogen and a Head-to-Head Conformation: [Pt{(±)-N,N′-Dimethyl-2,3-diaminobutane}(9-ethyl-guanine)2]dinitrate

The X-ray structural and NMR characterization of a bis-guanine derivative of a cisplatin analogue designed to reduce the rate of the Pt-N7 rotation of the coordinated guanine nucleobases by more than 1-million-fold is reported. The [Pt{(+/-)-Me(2)dab}(9-EtG)(2)](NO(3))(2) (Me(2)dab = N,N'-dimethyl-2,3-diaminobutane, 9-EtG = 9-ethyl-guanine) complex crystallizes in the P2(1)/n space group, and the crystal contains a racemic mixture of complex molecules. The data were collected at 120 +/- 2 K, and the crystal and molecular structure (comprising one disordered nitrate) were resolved and refined to conventional agreement factors of R1 = 0.0270 and wR2 = 0.0565. The guanine ligands assume the less common head-to-head (HH) orientation, disclosing full details of the intramolecular relationships between cis guanines and between guanine and cis amine. Moreover, an understanding has been gained of the steric factors determining induction of asymmetry (from carbons to adjacent nitrogen atoms) and puckering of the chelate ring (delta or lambda for R,S,S,R or S,R,R,S configurations at the N,C,C,N chelate-ring atoms, respectively) within the Me(2)dab ligand. The chemical shift separation between H8 signals of the two HT atropisomers and between the two H8 signals of the single HH atropisomer can be explained in terms of canting of the nucleobases relative to the coordination plane and in terms of the different relationships between the H8 proton of one guanine and the shielding zone of the cis guanine. Furthermore, for each configuration of the Me(2)dab ligand (R,S,S,R or S,R,R,S), the NMR data indicate that the handedness of canting is similar for the two guanines in all three (two HT and one HH) conformers (R canting for R,S,S,R and L canting for S,R,R,S configuration).

Multiparametric Optimization of 31P NMR Spectroscopic Analysis of Phospholipids in Crude Tissue Extracts. 1. Chemical Shift and Signal Separation

(31)P NMR spectroscopy is known to be a fast and accurate method for analyzing phospholipid extracts from biological samples without prior separation. However, the number of phospholipid classes and subclasses that can be quantitated separately in (31)P NMR spectra of tissue extracts is critically dependent on a variety of experimental conditions. For solvent systems resulting in the formation of two phases, the effects of varying water and methanol content on chemical shift and line width of phospholipid signals have been previously determined. However, little attention has been paid to the influence that other extract components may exert on signal separation. We present, for the first time, a systematic and comprehensive study of (31)P NMR chemical shift as a function of four experimental parameters: (i) extract concentration, (ii) concentration of chelating agent, (iii) pH value of the aqueous component of the solvent system, and (iv) temperature of the NMR measurement. This multiparametric study provides methodological guidelines for predictable and reproducible manipulation of (31)P NMR spectra of brain phospholipids. It also provides a database for rational and efficient optimization of phospholipid spectra from other body tissues, cultured cells, and phospholipid-containing biofluids.

Behavior of Two Almost Identical Spins during the CPMG Pulse Sequence

Multiple-spin-echo experiments have found wide use in nuclear magnetic resonance spectroscopy. In particular, the Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence is used to determine transverse relaxation times T(2). Herein it is demonstrated, both theoretically and experimentally, that for a pair of almost identical spins-1/2 the experimental setup can have a profound effect on the observed spin dynamics. It is shown that, in the case of dipolar relaxation, the measured T(2) values can roughly vary between the limits of identical and unlike spins, just depending on the repetition rate of pi pulses with respect to chemical shift separation. Such an effect can, in the extreme narrowing regime, amount to a 50% difference.

Pushing the Sensitivity Envelope of Lanthanide-Based Magnetic Resonance Imaging (MRI) Contrast Agents for Molecular Imaging Applications

Contrast in magnetic resonance imaging (MRI) arises from changes in the intensity of the proton signal of water between voxels (essentially, the 3D counterpart of pixels). Differences in intervoxel intensity can be significantly enhanced with chemicals that alter the nuclear magnetic resonance (NMR) intensity of the imaged spins; this alteration can occur by various mechanisms. Paramagnetic lanthanide(III) complexes are used in two major classes of MRI contrast agent: the well-established class of Gd-based agents and the emerging class of chemical exchange saturation transfer (CEST) agents. A Gd-based complex increases water signal by enhancing the longitudinal relaxation rate of water protons, whereas CEST agents decrease water signal as a consequence of the transfer of saturated magnetization from the exchangeable protons of the agent. In this Account, we survey recent progress in both areas, focusing on how MRI is becoming a more competitive choice among the various molecular imaging methods. Compared with other imaging modalities, MRI is set apart by its superb anatomical resolution; however, its success in molecular imaging suffers because of its intrinsic insensitivity. A relatively high concentration of molecular agents (0.01-0.1 mM) is necessary to produce a local alteration in the water signal intensity. Unfortunately, the most desirable molecules for visualization in molecular imaging are present at much lower concentrations, in the nano- or picomolar range. Therefore, augmenting the sensitivity of MRI agents is key to the development of MR-based molecular imaging applications. In principle, this task can be tackled either by increasing the sensitivity of the reporting units, through the optimization of their structural and dynamic properties, or by setting up proper amplification strategies that allow the accumulation of a huge number of imaging reporters at the site of interest. For Gd-based agents, high sensitivities can be attained by exploiting a range of nanosized carriers (micelles, liposomes, microemulsions, and the like, as well as biological structures such as apoferritin and lipoproteins) properly loaded with Gd-based chelates. Furthermore, the sensitivity of Gd-based agents can be markedly affected either by their interactions with biological structures or by their cellular localization. For CEST agents, a huge sensitivity enhancement has been obtained by using the water molecules contained in the inner cavity of liposomes as the exchangeable source of protons for magnetization transfer. Several "tricks" (for example, the use of multimeric lanthanide(III) shift reagents, changes in the shape of the liposome container, and so forth) have been devised to improve the chemical shift separation between the intraliposomal water and the "bulk" water resonances. Overall, excellent sensitivity enhancements have been obtained for both classes of agents, enabling their use in MR molecular imaging applications.

A novel technique to monitor carboxypeptidase G2 expression in suicide gene therapy using 19F magnetic resonance spectroscopy

Development and evaluation of new anticancer drugs are expedited when minimally invasive biomarkers of pharmacokinetic and pharmacodynamic behaviour are available. Gene-directed enzyme prodrug therapy (GDEPT) is a suicide gene therapy in which the anticancer drug is activated in the tumor by an exogenous enzyme previously targeted by a vector carrying the gene. GDEPT has been evaluated in various clinical trials using several enzyme/prodrug combinations. The key processes to be monitored in GDEPT are gene delivery and expression, as well as prodrug delivery and activation. {4-[bis(2-chloroethyl)amino]-3,5-difluorobenzoyl}-L-glutamic acid, a prodrug for the GDEPT enzyme carboxypeptidase-G2 (CPG2; K(m) = 1.71 microM; k(cat) = 732 s(-1)), was measured with (19)F magnetic resonance spectroscopy (MRS). The 1 ppm chemical shift separation found between the signals of prodrug and activated drug (4-[bis(2-chloroethyl)amino]-3,5-difluorobenzoic acid) is sufficient for the detection of prodrug activation in vivo. However, these compounds hydrolyze rapidly, and protein binding broadens the MR signals. A new CPG2 substrate was designed with hydroxyethyl instead of chloroethyl groups (K(m) = 3.5 microM, k(cat) = 747 s(-1)). This substrate is nontoxic and stable in solution, has a narrow MRS resonance in the presence of bovine and foetal bovine albumin, and exhibits a 1.1 ppm change in chemical shift upon cleavage by CPG2. In cells transfected to express CPG2 in the cytoplasm (MDA MB 361 breast carcinoma cells and WiDr colon cancer cells), well-resolved (19)F MRS signals were observed from clinically relevant concentrations of the new substrate and its nontoxic product. The MRS conversion half-life (470 min) agreed with that measured by HPLC (500 min). This substrate is, therefore, suitable for evaluating gene delivery and expression prior to administration of the therapeutic agent.

Separation of isotropic chemical and second-order quadrupolar shifts by multiple-quantum double rotation NMR

Using a two-dimensional multiple-quantum (MQ) double rotation (DOR) experiment the contributions of the chemical shift and quadrupolar interaction to isotropic resonance shifts can be completely separated. Spectra were acquired using a three-pulse triple-quantum z-filtered pulse sequence and subsequently sheared along both the ν 1 and ν 2 dimensions. The application of this method is demonstrated for both crystalline (RbNO 3) and amorphous samples (vitreous B 2O 3). The existence of the two rubidium isotopes ( 85Rb and 87Rb) allows comparison of results for two nuclei with different spins ( I = 3/2 and 5/2), as well as different dipole and quadrupole moments in a single chemical compound. Being only limited by homogeneous line broadening and sample crystallinity, linewidths of approximately 0.1 and 0.2 ppm can be measured for 87Rb in the quadrupolar and chemical shift dimensions, enabling highly accurate determination of the isotropic chemical shift and the quadrupolar product, P Q . For vitreous B 2O 3, the use of MQDOR allows the chemical shift and electric field gradient distributions to be directly determined—information that is difficult to obtain otherwise due to the presence of second-order quadrupolar broadening.

NMR and X-ray Structural Characterization of a Cisplatin Analogue Able To Slow Down the Pt−N7 Rotation of a Coordinated Guanine Base by a Billion-Fold Times: 2,2′-Bipiperidine(dimethylmalonato)platinum(II) Complex

The synthesis and the NMR and X-ray structural characterization of a cisplatin analogue designed to reduce the Pt-N7 rotation of a coordinated guanine base by a billion times are reported. The [Pt(dmm){(+/-)-bip}] (dmm=dimethylmalonato; bip=2,2'-bipiperidine) complex crystallizes in the C2/m space group, which contemplates a mirror plane bisecting the bip and dmm ligands. Because the bip moiety (R, R or S, S configuration at the 2,2'-carbon atoms) does not have planes of symmetry, the requirements of the crystal symmetry are satisfied by a statistical disorder made of bip molecules of R, R or S, S configurations alternating at the same crystallographic site. Such an unexpected arrangement has been permitted by a "quasi planarity" of the bip ligand [maximum deviation from the mean plane through the C and N atoms of 0.2927(9) A], which allows bip molecules of different chiralities to fit in the same space. The bip array of heavy atoms is overlaid, from both sides, by a layer of "quasi axial" (C)H and (N)H atoms (six per side). Those on one side are hydrogen-bonded to the dmm oxygen atoms of another complex molecule joined in a pair. The distance between the average platinum coordination planes is as short as 3.498(1) A, comparable to those found in crystals of the [PtCl 2(bipy)] complex (bipy=2,2'-bipyridine) and of graphite, in which, however, all atoms of each unit are rigorously coplanar and there are no out-of-plane hydrogen atoms. The NMR data show a net chemical shift separation between geminal methylene protons, with the "quasi axial" protons being always at higher field with respect to the "quasi equatorial" ones. This is in accordance with a rigid bip ligand frame and the inability of the bip methylene protons adjacent to the coordinated nitrogen to rotate away from a cis-G base (G=guanine) during G rotation around the Pt-N7 bond.

Fluorine-19 NMR Chemical Shift Probes Molecular Binding to Lipid Membranes

The binding of amphiphilic molecules to lipid bilayers is followed by 19F NMR using chemical shift and line shape differences between the solution and membrane-tethered states of -CF 3 and -CHF 2 groups. A chemical shift separation of 1.6 ppm combined with a high natural abundance and high sensitivity of 19F nuclei offers an advantage of using 19F NMR spectroscopy as an efficient tool for rapid time-resolved screening of pharmaceuticals for membrane binding. We illustrate the approach with molecules containing both fluorinated tails and an acrylate moiety, resolving the signals of molecules in solution from those bound to synthetic dimyristoylphosphatidylcholine bilayers both with and without magic angle sample spinning. The potential in vitro and in vivo biomedical applications are outlined. The presented method is applicable with the conventional NMR equipment, magnetic fields of several Tesla, stationary samples, and natural abundance isotopes.

2H 2O quadrupolar splitting used to measure water exchange in erythrocytes

The 2H NMR resonance from HDO (D = 2H) in human red blood cells (RBCs) suspended in gelatin that was held stretched in a special apparatus was distinct from the two signals that were symmetrically arranged on either side of it, which were assigned to extracellular HDO. The large extracellular splitting is due to the interaction of the electric quadrupole moment of the 2H nuclei with the electric field gradient tensor of the stretched, partially aligned gelatin. Lack of resolved splitting of the intracellular resonance indicated greatly diminished or absent ordering of the HDO inside RBCs. The separate resonances enabled the application of a saturation transfer method to estimate the rate constants of transmembrane exchange of water in RBCs. However both the theory and the practical applications needed modifications because even in the absence of RBCs the HDO resonances were maximally suppressed when the saturating radio-frequency radiation was applied exactly at the central frequency between the two resonances of the quadrupolar HDO doublet. More statistically robust estimates of the exchange rate constants were obtained by applying two-dimensional exchange spectroscopy (2D EXSY), with back-transformation analysis. A monotonic dependence of the estimates of the efflux rate constants on the mixing time, t mix, used in the 2D EXSY experiment were seen. Extrapolation to t mix = 0, gave an estimate of the efflux rate constant at 15 °C of 31.5 ± 2.2 s −1 while at 25 °C it was ∼50 s −1. These values are close to, but less than, those estimated by an NMR relaxation-enhancement method that uses Mn 2+ doping of the extracellular medium. The basis for this difference is thought to include the high viscosity of the extracellular gel. At the abstract level of quantum mechanics we have used the quadrupolar Hamiltonian to provide chemical shift separation between signals from spin populations across cell membranes; this is the first time, to our knowledge, that this has been achieved.

Two-dimensional J-spectra with absorption-mode lineshapes

Two-dimensional J-spectroscopy offers the possibility of a complete separation of chemical shifts and J-couplings. However, the usefulness of the experiment is considerably reduced by the fact that peaks in the spectra have the phase-twist lineshape. We present a simple new spectroscopic method for recording J-spectra in which the peaks are both in the absorption mode and retain their natural intensities, albeit at the cost of a considerable reduction in the signal-to-noise ratio. No special data-processing is required. The method is tested on quinine, and the steroid dehydroisoandrosterone.

Ranking the effect of [1A(ax), 1B(eq)] versus [1A(eq), 1B(ax)] cyclohexane ring substitution on the 1H chemical shifts of γ-methylene cyclohexane ring protons using 2,2-disubstituted adamantanes as models

When two different substituents are placed in the nonbridgehead position of adamantane, the two [1A(ax), 1B(eq)] and [1A(eq), 1B(ax)] cyclohexane chair conformers are modeled and features of their NMR spectra can be studied from a single spectrum at 298 K. The effect of [1A(ax), 1B(eq)] and [1A(eq), 1B(ax)] cyclohexane ring substitution on the 1H resonance separation within the γ-CH 2s of cyclohexane ring is compared for various substituent pairs; this aim is approached by measuring the 1H chemical shift separation within the 4′,9′-H and 8′,10′-H methylenes from the 1H NMR spectrum of the model 2A,2B-disubstituted adamantane at 298 K.

In vivo carbon‐13 magnetization transfer effect. Detection of aspartate aminotransferase reaction

One of the most remarkable achievements of in vivo NMR spectroscopy has been the detection of rapid enzyme-catalyzed exchange reactions using phosphorus-31 magnetic resonance spectroscopy-based magnetization transfer experiments. In this paper, we report, for the first time, the in vivo carbon magnetization transfer (CMT) effect and in vivo detection of the CMT effects of the alpha-ketoglutarate <--> glutamate and the oxaloacetate <--> aspartate reactions, both of which are catalyzed by aspartate aminotransferase. By saturating the carbonyl carbon of alpha-ketoglutarate at 206 ppm in alpha-chloralose anesthetized adult rat brain, the unidirectional glutamate --> alpha-ketoglutarate flux was determined to be 78 +/- 9 mumol/g/min (mean +/- SD, n = 11) following i.v. infusion of [1,6-(13)C(2)]D-glucose. Contribution from aspartate aminotransferase-catalyzed partial reactions to the observed CMT effects was emphasized. Because of the large chemical shift separation between the alpha-carbons of the amino acids and the carbonyl carbons of the corresponding cognate keto acids, the spillover of the saturation radiofrequency pulses to the alpha-carbon resonances was negligible. The results indicate that the magnetization transfer effects of aspartate aminotransferase-catalyzed reactions can be used as new biomarkers accessible to non-invasive in vivo magnetic resonance spectroscopy techniques.

NMR quantum computing: applying theoretical methods to designing enhanced systems.

Density functional theory results for chemical shifts and spin-spin coupling constants are presented for compounds currently used in NMR quantum computing experiments. Specific design criteria were examined and numerical guidelines were assessed. Using a field strength of 7.0 T, protons require a coupling constant of 4 Hz with a chemical shift separation of 0.3 ppm, whereas carbon needs a coupling constant of 25 Hz for a chemical shift difference of 10 ppm, based on the minimal coupling approximation. Using these guidelines, it was determined that 2,3-dibromothiophene is limited to only two qubits; the three qubit system bromotrifluoroethene could be expanded to five qubits and the three qubit system 2,3-dibromopropanoic acid could also be used as a six qubit system. An examination of substituent effects showed that judiciously choosing specific groups could increase the number of available qubits by removing rotational degeneracies in addition to introducing specific conformational preferences that could increase (or decrease) the magnitude of the couplings. The introduction of one site of unsaturation can lead to a marked improvement in spectroscopic properties, even increasing the number of active nuclei.

Magnetic Resonance Diagnostics: A New Technology for High-Throughput Clinical Diagnostics

Magnetic resonance diagnostics (MRD) uses automated, high-throughput nuclear magnetic resonance (NMR) spectroscopy for the rapid identification and quantification of small-molecule metabolites in biofluid mixtures (blood, urine, saliva, cerebrospinal fluid, and others). Specifically, MRD involves using a high-field (400 MHz) NMR instrument equipped with a small-volume flow probe and robotic sample handler to rapidly load biofluid samples and to collect their 1H NMR spectra. Spectral deconvolution software automatically assigns individual peaks to particular compounds and calculates concentrations from peak areas. MRD uses the principle of chemical shift separation to physically separate and identify individual compounds directly from 1H NMR spectra, thus avoiding chromatographic separation steps (e.g., HPLC, gas chromatography, and capillary electrophoresis). MRD is useful for rapid (<2 min per sample) qualitative and quantitative assessment of small-molecule metabolites. NMR spectroscopy is not new to the field of clinical chemistry. Indeed several important applications have already been demonstrated in the area of diagnosis and therapeutic monitoring of metabolic disorders (1)(2)(3)(4), in toxicologic and renal testing (5)(6), and in the profiling of blood lipoproteins and cholesterol (7). An emerging approach to enable high-throughput in vivo toxicology is called metabonomics, which uses high-resolution NMR to rapidly evaluate the metabolic status of an animal (8)(9). A key limitation to all of these NMR approaches is that they depend on manual sample handling and/or manual (i.e., expert) spectral analysis. This has made most NMR approaches to clinical analyses far too slow or too costly for routine chemical profiling or high-throughput screening. Because MRD is fully automated (sample handling, spectral collection, and spectral analysis are all handled by robots or computers), this technique offers the potential for high-throughput, comprehensive, and inexpensive chemical analysis of a wide range of biofluid samples. To demonstrate the potential …

Metal-assembled cobalt(II) resorc[4]arene-based cage molecules that reversibly capture organic molecules from water and act as NMR shift reagents.

The complex Co4 1(2)8- is a tetranuclear cobalt(II) cage compound that assembles in aqueous solutions above pH 4 and is capable of encapsulating a variety of organic guest molecules, for example, benzene, hexane, chlorobutane, butanol, and ethyl acetate. Ligand 1 is a resorc[4]arene-based molecule with iminodiacetate moieties appended to its upper rim. 1H NMR studies of Co4 1(2)8-.guest complexes demonstrate inclusion of nonpolar hydrocarbons, substituted phenyls, alcohols, halogen-containing hydrocarbons, and polar organic molecules. The complex Co4 1(2)8- acts as an NMR shift reagent and causes substantial upfield isotropic hydrogen shifts (-30 to -40 ppm) in the guest molecule and separation of the guest hydrogen chemical shifts by typically 12 ppm. The complex Co4 1(2)8- will encapsulate molecules with fewer than eight atoms in a linear chain, mono- and disubstituted benzenes, and polar molecules with greater than two carbon atoms. The solid-state structure of Ba4[Co4 1(2).C6H5C2H5] shows a disordered guest molecule encapsulated within the cavity of Co4 1(2)8-. The cavity dimensions, bond lengths, and bond angles of Ba4[Co4 1(2).C6H5C2H5] are very similar to those determined in Ba4[Co4 1(2).6H2O].

Multinuclear Metal Complexes and their Assembly into Cage Molecules

Current research efforts focus on using metal ions to bring organic molecules together and in so doing form structures that resemble large common materials, such as boxes, cages, grids, and channels. These metal-organic supramolecular structures are at the interface between molecular and macromolecular chemistry. As a contribution to this field of chemistry, we have focused on binding metal ions to cupped-shaped template molecules, which can be appended with functional groups. These resorcinarene-based molecules have four phenyl groups linked together into a ring and various functional groups attached to their upper rim. Some of the functional groups, bispyridylmethylamine (bpa) and iminodiacetic acid, are able to coordinate to metal ions. In the case of the bispyridylmethylamine resorcinarene, 2, a tetranuclear metal complex is formed when it is allowed to coordinate to copper(II). The copper centers surround the resorcinarene cavity and are not electronically coupled. In contrast to the Cu428+ complex, when cobalt(II) or iron(II) are allowed to coordinate to an iminodiacetic acid resorcinarene, 3, two resorcinarenes are bought together. The M432 8− (M = Co or Fe) complexes are tetranuclear metal(II) cage compounds that assemble in aqueous solutions above pH 4 and have a cavity. These molecules are capable of encapsulating a variety of organic guest molecules, for example, nonpolar hydrocarbons, substituted phenyls, alcohols, halogen containing hydrocarbons, and polar organic molecules. The cages act as NMR shift reagents and cause substantial up-field isotropic hydrogen shifts (−30 to −40 ppm for Co2+ and −5 to −15 ppm for Fe2+) in the guest molecule and separation of the guest hydrogen chemical shifts. The solid state structures of Ba4[M4 3 2guest] (guest = 6 H2O, bromobenzene, or ethylbenzene) show bond angles independent of whether the metal ion is cobalt or iron, and bond lengths typical of metal oxygen and nitrogen bonds. The encapsulated guest does not noticeably effect the cavity dimensions, bond lengths, and bond angles.