Solution Structure Of Complex Research Articles

New dioxadiaza- and trioxadiaza-macrocycles containing one dibenzofuran unit with two amino pendant arms: synthesis, protonation and complexation studies

New dioxadiaza- and trioxadiaza-macrocycles containing one rigid dibenzofuran unit (DBF) and N-(2-aminoethyl) pendant arms were synthesized, N,N'-bis(2-aminoethyl)-[17](DBF)N(2)O(2) (L(1)) and N,N'-bis(2-aminoethyl)-[22](DBF)N(2)O(3) (L(2)), respectively. The binding properties of both macrocycles to metal ions and structural studies of their metal complexes were carried out. The protonation constants of both compounds and the stability constants of their complexes with Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), and Pb(2+) were determined at 298.2 K, in aqueous solutions, and at ionic strength 0.10 mol dm(-3) in KNO(3). Mononuclear complexes with both ligands were formed, and dinuclear complexes were only found for L(2). The thermodynamic binding affinities of the metal complexes of L(2) are lower than those of L(1) as expected, but the Pb(2+) complexes of both macrocycles exhibit close stability constant values. On the other hand, the binding affinities of Cd(2+) and Pb(2+) for L(1) are very high, when compared to those of Co(2+), Ni(2+) and Zn(2+). These interesting properties were explained by the presence of the rigid DBF moiety in the backbone of the macrocycle and to the special match between the macrocyclic cavity size and the studied larger metal ions. To elucidate the adopted structures of complexes in solution, the nickel(II) and copper(II) complexes with both ligands were further studied by UV-vis-NIR spectroscopy in DMSO-H(2)O 1 : 1 (v/v) solution. The copper(II) complexes were also studied by EPR spectroscopy in the same mixture of solvents. The crystal structure of the copper complex of L(1) was also determined. The copper(II) displays an octahedral geometry, the four nitrogen atoms forming the equatorial plane and two oxygen atoms, one from the DBF unit and the other one from the ether oxygen, in axial positions. One of the ether oxygens of the macrocycle is out of the coordination sphere. Our results led us to suggest that this geometry is also adopted by the Co(2+) to Zn(2+) complexes, and only the larger Cd(2+) and Pb(2+) manage to form complexes with the involvement of all the oxygen atoms of the macrocyclic backbone.

An Asymptotic Framework for Finite Hydraulic Fractures Including Leak‐Off

The dynamics of hydraulic fracture, described by a system of nonlinear integro‐differential equations, is studied through the development and application of a multiparameter singular perturbation analysis. We present a new single expansion framework which describes the interaction between several physical processes, namely viscosity, toughness, and leak‐off. The problem has nonlocal and nonlinear effects which give a complex solution structure involving transitions on small scales near the tip of the fracture. Detailed solutions obtained in the crack tip region vary with the dominant physical processes. The parameters quantifying these processes can be identified from critical scaling relationships, which are then used to construct a smooth solution for the fracture depending on all three processes. Our work focuses on plane strain hydraulic fractures on long time scales, and this methodology shows promise for related models with additional time scales, fluid lag, or different geometries, such as radial (penny‐shaped) fractures and the classical Perkins–Kern–Nordgren (PKN) model.

Bcr-Abl Binding Modes of Dasatinib, Imatinib and Nilotinib: An NMR Study.

Following the discovery that point mutations in the kinase domain of Bcr-Abl reduce the binding affinity of imatinib and lead to drug resistance in CML patients, efforts have been directed towards the discovery of new drugs which inhibit these resistant enzymes. Two such agents are dasatinib and nilotinib. Whereas, like imatinib, x-ray analysis of crystal structures of nilotinib in complex with the Abl kinase domain reveal that this agent binds to an inactive, DFG-out conformation of the enzyme, similar studies have shown that dasatinib binds to the catalytically active state of the enzyme (Tokarski et al, Cancer Res. 2006). However, based upon in silico methods using homology models of the imatinib-binding inactive conformation of Abl some reports claim that dasatinib is capable of binding to both the active and inactive forms of the enzyme. To help address this conundrum we have employed nuclear magnetic resonance (NMR) spectroscopy to study the different conformational characteristics and dynamic changes of the Abl protein obtained upon adding ligands.Selectively isotope labelled (15N and 13C) Abl kinase in the unphosphorylated state was produced according to published methods (Strauss et al, J. Biomolecular NMR 2005). Chemical shift data of the protein in solution were recorded by NMR spectroscopy, both with and without ligand. By measuring residual dipolar couplings (RDC) between the back-bone amide nitrogen and hydrogen atoms of amino-acid residues in the vicinity of the conserved DFG-motif (residues 370 – 410), the conformational states and equilibria of the activation loop of the kinase were established. Upon adding imatinib to the unliganded Abl, both chemical shift and RDC data show characteristic signals for residues M388, Y393 and G398, which are entirely consistent with the conformational equilibrium moving to the inactive state, in which the activation loop adopts the DFG-out conformation. In the case of nilotinib, NMR spectroscopy revealed chemical shift patterns and couplings involving the same three residues confirming that the drug binds to the same inactive conformation as imatinib, both in solution as well as in the crystalline state. In contrast, upon adding dasatinib to Abl, NMR data of the complex show distinctly different chemical shifts and RDC values, confirming that the protein assumes a different conformational state, with the activation loop adopting the active conformation, in accordance with the crystallographic evidence. Even upon adding dasatinib to a complex of imatinib with Abl in the inactive conformation, the kinase conformation changed to a state indistinguishable to that observed upon adding dasatinib to unliganded protein.In conclusion, these studies show that the three Abl kinase inhibitors all interact with the protein in solution with the same binding modes as observed in x-ray crystallographic studies, but show no evidence for dasatinib binding to the inactive “DFG-out” conformation. This case study also demonstrates the power of NMR spectroscopy in evaluating solution structures of ligand-protein complexes. Further experiments are in progress evaluating other structurally different Abl kinase inhibitors.

Complex of Calmodulin with a Ryanodine Receptor Target Reveals a Novel, Flexible Binding Mode

Calmodulin regulates ryanodine receptor-mediated Ca(2+) release through a conserved binding site. The crystal structure of Ca(2+)-calmodulin bound to this conserved site reveals that calmodulin recognizes two hydrophobic anchor residues at a novel "1-17" spacing that brings the calmodulin lobes close together but prevents them from contacting one another. NMR residual dipolar couplings demonstrate that the detailed structure of each lobe is preserved in solution but also show that the lobes experience domain motions within the complex. FRET measurements confirm the close approach of the lobes in binding the 1-17 target and show that calmodulin binds with one lobe to a peptide lacking the second anchor. We suggest that calmodulin regulates the Ca(2+) channel by switching between the contiguous binding mode seen in our crystal structure and a state where one lobe of calmodulin contacts the conserved binding site while the other interacts with a noncontiguous site on the channel.

A Molecular Dynamics Study and Free Energy Analysis of Complexes between the Mlc1p Protein and Two IQ Motif Peptides

The Mlc1p protein from the budding yeast Saccharomyces cerevisiae is a Calmodulin-like protein, which interacts with IQ-motif peptides located at the yeast’s myosin neck. In this study, we report a molecular dynamics study of the Mlc1p-IQ2 protein-peptide complex, starting with its crystal structure, and investigate its dynamics in an aqueous solution. The results are compared with those obtained by a previous study, where we followed the solution structure of the Mlc1p-IQ4 protein-peptide complex by molecular dynamics simulations. After the simulations, we performed an interaction free-energy analysis using the molecular mechanics Poisson-Boltzmann surface area approach. Based on the dynamics of the Mlc1p-IQ protein-peptide complexes, the structure of the light-chain-binding domain of myosin V from the yeast S. cerevisiae is discussed.

Mononuclear diastereopure non-heme Fe(II) complexes of pentadentate ligands with pyrrolidinyl moieties: Structural studies, and alkene and sulfide oxidation

Mononuclear iron(II) complexes of enantiopure Py(ProOH) 2 ( 2) and Py(ProPh 2OH) 2 ( 3) ligands have been prepared with FeCl 2 and Fe(OTf) 2 · 2MeCN. Both ligands coordinate to the metal in a pentadentate fashion. Next to the meridional N, N′, N-coordination of the ligand, additional coordination of the oxygen atoms of both hydroxyl groups to the metal is found in complexes 4– 7. Complex [FeCl( 2)](Cl) ( 4) shows an octahedral geometry as determined by X-ray diffraction and is formed as a single diastereoisomer. The solution structures of complexes 4– 7 were characterized by means of UV–Vis, IR, ESI-MS, conductivity and CD measurements. The catalytic potential of these complexes in the oxidation of alkenes and sulfides in the presence of H 2O 2 is presented.

Molecular Mimicry in Mercury Toxicology

Molecular mimicry occurs when one molecular entity is "mistaken" for another by cellular or other biological processes, and is thought to arise from structural similarities between the two molecules in question. It has been postulated by others to be important in the mechanism of uptake of toxic metal species into living tissues. A widely accepted example is the transport of methylmercury-cysteine species, which are thought to mimic the amino acid methionine. We have used mass spectrometry and mercury L(III)-edge X-ray absorption spectroscopy to understand the solution structure of complexes between methylmercury and cysteine. With a view to understanding the basis of the suggested molecular mimicry mechanisms, we have used computational chemistry to compare the structure of methionine with that of the dominant solution species L-cysteinato(methyl)mercury(II), and the structure of cystine with that of mercury(II) bis-L-cysteineate. We conclude that the structural similarities between metal compounds and natural products are insufficient to support a mechanism based on molecular mimicry, but instead, mechanisms involving a less-specific mimicry based on similarity with the L(alpha) region of the amino acid part of the molecule.

Diastereopure Fe(II) and Zn(II) Complexes Derived from a Tridentate N,N‘,N-Bis(methyl-l-prolinate)-Substituted Pyridine Ligand

A series of mononuclear iron(II) and zinc(II) complexes of the new chiral Py(ProMe)2 ligand (Py(ProMe)2 = 2,6-bis[[(S)-2-(methyloxycarbonyl)-1-pyrrolidinyl]methyl]pyridine) have been prepared. The molecular geometry in the solid state (X-ray crystal structures) of the complexes [FeCl2(Py(ProMe)2)] (1), [ZnCl2(Py(ProMe)2)] (2), [Fe(OTf)2(Py(ProMe)2)] (3), [Fe(Py(ProMe)2)(OH2)2](OTf)2 (4), and [Zn(OTf)(Py(ProMe)2)](OTf) (5) are reported. They all show a meridional NN'N coordination of the Py(ProMe)2 ligand. The bis-chloride derivatives 1 and 2 represent neutral isostructural five-coordinated complexes with a distorted geometry around the metal center. Unusual seven-coordinate iron(II) complexes 3 and 4 having a pentagonal bipyramidal geometry were obtained using weakly coordinating triflate anions. The reaction of Zn(OTf)2 with the Py(ProMe)2 ligand afforded complex 5 with a distorted octahedral geometry around the zinc center. All complexes were formed as single diastereoisomers. In the case of complexes 3-5, the oxygen atoms of both carbonyl groups of the ligand are also coordinated to the metal. The stereochemistry of the coordinated tertiary amine donors in complexes 3-5 is of opposite configuration as in complexes 1 and 2 as a result of the planar penta-coordination of the ligand Py(ProMe)2. Complexes 1, 2, and 5 have an overall -configuration at their metal center, while the Fe(II) ion in complexes 3 and 4 has the opposite delta-configuration (crystal structures and CD measurements). The magnetic moments of iron complexes 1, 3, and 4 correspond to that of high-spin d6 Fe(II) complexes. The solution structures of complexes 1-5 were characterized by means of UV-vis, IR, conductivity, and CD measurements and their electrochemical behavior. These studies showed that the coordination environment of 1 and 2 observed in the solid state is maintained in solution. In coordinating solvents, the triflate anion (3, 5) or water (4) co-ligands of complexes 3-5 are replaced by solvent molecules with retention of the original pentagonal bipyramidal and octahedral geometry, respectively.

A justification for using NMR model‐free methods when investigating the solution structures of rhombic paramagnetic lanthanide complexes

The detailed analysis of the 1H NMR hyperfine shifts according to the model-free methods shows that the semi-rigid monometallic complexes [Ln(L)(NO3)3] (Ln = Eu-Yb) are isostructural in solution. The associated separation of contact and pseudo-contact contributions to the hyperfine NMR shifts in each rhombic lanthanide complex at room temperature provides paramagnetic susceptibility tensors whose principal magnetic axes match the expected symmetry requirements. Moreover, both axial (Delta chi(ax)) and rhombic (Delta chi(rh)) paramagnetic anisotropies display satisfactory linear dependence on Bleaney's factors, a correlation predicted by the approximate high-temperature expansion of the magnetic susceptibility limited to T(-2). Consequently, the simple, and chemically attracting NMR model-free methods are not limited to axial systems, and can be safely used for the investigation of the solution structures of any lanthanide complexes. Molecular-based structural criteria for the reliable estimation of paramagnetic susceptibility tensors by NMR are discussed, together with the assignment of the labels of the crystal-field and magnetic axes within Bleaney's approach.

Synthesis and evaluation of a radiometal-labeled macrocyclic chelator-derivatised thymidine analog

Several radiolabeled thymidine analogs as metabolic probes of cell proliferation were developed specifically addressing DNA synthesis. Thymidine analogs containing carboranylalkyl groups for neutron capture therapy at the N-3 position were found to be good substrates for cytosolic thymidine kinase 1 (TK1). According to this approach, a DO3A macrocycle in N-3 position was attached to thymidine. The 3-DO3A thymidine analog was labeled with 68Ga and 111In. Different lipophilicities of the corresponding radiometal-thymidines were detected via RP-HPLC. [111In]DO3A-thymidine ([111In]D3T) was evaluated for cellular uptake in different cell lines (HL60 and DoHH2). Cellular uptake was low in both cell lines. Phosphorylation of the radioconjugates by TK1 was negligible. Although stable complexation of radiometals to thymidine was obtained, introduction of the macrocycle DO3A reduced the affinity to cytosolic TK1 drastically. Low cellular uptake can be ascribed to missing substrate specificity of [111In]DO3A-thymidine for TK1. The absence of substrate specificity may be due to the bulky macrocyclic chelator and partial charges remaining on the coordination sphere due to a more complex solution structure.

Solution Structure of a Post-transition State Analog of the Phosphotransfer Reaction between the A and B Cytoplasmic Domains of the Mannitol Transporter IIMannitol of the Escherichia coli Phosphotransferase System

The solution structure of the post-transition state complex between the isolated cytoplasmic A (IIAMtl) and phosphorylated B (phospho-IIBMtl) domains of the mannitol transporter of the Escherichia coli phosphotransferase system has been solved by NMR. The active site His-554 of IIAMtl was mutated to glutamine to block phosphoryl transfer activity, and the active site Cys-384 of IIBMtl (residues of IIBMtl are denoted in italic type) was substituted by serine to permit the formation of a stable phosphorylated form of IIBMtl. The two complementary interaction surfaces are predominantly hydrophobic, and two methionines on IIBMtl, Met-388 and Met-393, serve as anchors by interacting with two deep pockets on the surface of IIAMtl. With the exception of a salt bridge between the conserved Arg-538 of IIAMtl and the phosphoryl group of phospho-IIBMtl, electrostatic interactions between the two proteins are limited to the outer edges of the interface, are few in number, and appear to be weak. This accounts for the low affinity of the complex (Kd approximately 3.7 mm), which is optimally tuned to the intact biological system in which the A and B domains are expressed as a single polypeptide connected by a flexible 21-residue linker. The phosphoryl transition state can readily be modeled with no change in protein-protein orientation and minimal perturbations in both the backbone immediately adjacent to His-554 and Cys-384 and the side chains in close proximity to the phosphoryl group. Comparison with the previously solved structure of the IIAMtl-HPr complex reveals how IIAMtl uses the same interaction surface to recognize two structurally unrelated proteins and explains the much higher affinity of IIAMtl for HPr than IIBMtl.

UV–visible spectroscopic study of the salicyladehyde benzoylhydrazone and its cobalt complexes

Salicyladehyde benzoylhydrazone (SBH) has three groups suitable for forming coordination bond with transition metal. The UV–vis absorption spectra of SBH and its Co(II) complexes in various media were studied by using the deconvolution method. It is found that the structure of complex in solution is different from those in solid crystals. The nature of complexes in solution depends on acidity of the phenolic proton of SBH and on the medium. In neutral or slightly acid medium, the SBH is a non-charged bidentate ligand. And the “free” hydroxyl group on the SBH molecule makes it possible to form hydrogen bonds in solution. In basic medium, the SBH is a mono, negatively charged tridentates ligand.

Pyridine and phosphonate containing ligands for stable lanthanide complexation. An experimental and theoretical study to assess the solution structure

We report an experimental and theoretical study of the stability and solution structure of lanthanide complexes with two novel ligands containing pyridine units and phosphonate pendant arms on either ethane-1,2-diamine (L2) or cyclohexane-1,2-diamine (L3) backbones. Potentiometric studies have been carried out to determine the protonation constants of the ligands and the stability constants of the complexes with Gd(III) and the endogenous metal ions Zn(II) and Cu(II). While the stability constant of the GdL2 complex is too high to be determined by direct pH-potentiometric titrations, the cyclohexyl derivative GdL3 has a lower and assessable stability (log K(GdL3)=17.62). Due to the presence of the phosphonate groups, various protonated species can be detected up to pH approximately 8 for both ligands and all metal ions studied. The molecular clusters [Ln(L)(H2O)](3-).19H2O (Ln=La, Nd, Ho or Lu; L=L2 or L3) were characterized by theoretical calculations at the HF level. Our calculations provide two minimum energy geometries where the ligand adopts different conformations: twist-wrap (tw), in which the ligand wraps around the metal ion by twisting the pyridyl units relative to each other, and twist-fold (tf), where the slight twisting of the pyridyl units is accompanied by an overall folding of the two pyridine units towards one of the phosphonate groups. The relative free energies of the tw and tf conformations of [Ln(L)(H2O)]3- (L=L2, L3) complexes calculated in aqueous solution (C-PCM) by using the B3LYP model indicate that the tw form is the most stable one along the whole lanthanide series for the complexes of L3, while for those of L2 only the Gd(III) complex is more stable in the tf conformation by ca. 0.5 kcal mol-1. 1H NMR studies of the Eu(III) complex of L3 show the initial formation of the tf complex in aqueous solution, which slowly converts to the thermodynamically stable tw form. The structures calculated for the Nd(III) complexes are in reasonably good agreement with the experimental solution structures, as demonstrated by Nd(III)-induced relaxation rate enhancement effects in the 1H NMR spectra.

Theoretical investigation of paramagnetic group 13 diazabutadiene radicals: insights into the prediction and interpretation of EPR spectroscopy parameters

The electronic structures and the spin density distributions of the group 13 1,4-diaza(1,3)butadiene (DAB) radicals [(R-DAB)2M]*, [(R-DAB)MX2] and {[(R-DAB)MX]2}** (M = Al, Ga, In; X = F, Cl, Br, I; R = H, Me, tBu, Ph) are studied using density functional theory at both non-relativistic and relativistic levels of theory. The calculations demonstrate that all systems share a qualitatively similar electronic structure and are primarily ligand centred pi-radicals. The calculated metal, nitrogen and hydrogen hyperfine couplings are found to be independent of the identity of the R-group and the halogen atom. They are, however, dependent on the geometry and oxidation state of the metal centre. Both observed trends contrast what has previously been deduced from the interpretation of experimental EPR and ENDOR spectra. Good agreement between the calculated and experimentally determined hyperfine coupling constants is found only for some of the studied systems. Instances where significant discrepancies between the calculated and experimental values exist can be attributed to the tendency of these systems toward complex solution behaviour, which results in differences between the solid state and solution structures of certain complexes. A careful re-evaluation of the experimental data as well as calculated reaction energies lends strong support to this hypothesis. However, further studies are needed before the identity of some of the studied radical species in solution can be unambiguously determined.

Coordination chemistry of phosphanyl amino acids: solid state and solution structures of neutral and cationic rhodium complexes

Copper phosphide or arsenide complexes, [Cu(EPh(2))(neo)] (E = P, As, neo = 2,9-dimethyl-1,10-phenanthroline; trivial name: neocuprine) react selectively with the N-protected brominated serine derivatives, 2-(S)-(alkoxycarbonylamino)-3-bromomethylpropionates ((ROCO)SerBr, : R = PhCH(2), : tBu, : Me) to give the corresponding phosphanylated or arsanylated amino acids, (ROCO)SerPhos (: Phos = PPh(2)) and (Z)SerArs (Ars = AsPh(2), Z = PhCH(2)OCO). The dipeptide (Z)AlaSerPhos was likewise prepared. The phosphanes , and the arsane reacted cleanly with [Rh(2)(micro-Cl)(2)(cod)(2)] to give the rhodium(I) complexes [RhCl(cod)((Z)SerPhos)] , [RhCl(cod)((Boc)SerPhos)] (Boc = tBuOCO), [RhCl(cod)((Z)AlaSerPhos)] , and [RhCl(cod)((Z)SerArs)] which were characterized by X-ray diffraction studies. A common structural feature is an intramolecular (N)H[dot dot dot]Cl(Rh)-hydrogen bridge which according to NMR investigations remains intact in solution. The abstraction of chloride from the coordination sphere of Rh(I) in or has a profound structural impact. While in and , the ligands bind in a monodentate fashion, via the phosphorus atom only, they serve as bidentate ligands via the phosphorus centre and the peptidic C=O group in [Rh(cod)(kappa(2)-(Z)SerPhos)]PF(6) and [Rh(cod)(kappa(2)-(Z)AlaSerPhos)]PF(6). This causes also the amino acid residue structures to change from alpha-helix type in and to a beta-sheet type in both. Addition of chloride to and fully re-establishes the structures of both. The complexes [RhCl(cod)((Z)SerPhos)] and [RhCl(cod)((Boc)SerPhos)] show good activities in homogeneously catalyzed hydrogenations of olefins while the dipeptide complex is less active. Phosphane addition to greatly diminishes the catalytic activity. The cationic complex [Rh(cod)(kappa(2)-(Z)AlaSerPhos)]PF(6) shows low activity which, however, is greatly increased by addition of one equivalent of phosphane.

Cyclohexanyl Peptide Nucleic Acids (chPNAs) for Preferential RNA Binding: Effective Tuning of Dihedral Angle β in PNAs for DNA/RNA Discrimination

[structures: see text] A serious drawback of peptide nucleic acids (PNAs) from an application perspective that has not been adequately dealt with is nondiscrimination of identical DNA and RNA sequences. An analysis of the available X-ray and NMR solution structures of PNA complexes with DNA and RNA suggested that it might be possible to rationally impart DNA/RNA duplex binding selectivity by tuning the dihedral angle beta of the flexible ethylenediamine part of the PNA backbone (II) via suitable chemical modifications. Cyclohexanyl PNAs (chPNAs) with beta approximately = 65 degrees were designed on the basis of this rationale. The chPNAs introduced remarkable differences in duplex stabilities among their DNA and RNA complexes, with melting temperatures (deltaTm(RNA-DNA) = +16-50 degrees C) depending on the number of modifications and the stereochemistry. This is a highly significant, exceptional binding selectivity of a mix sequence of PNA to RNA over the same DNA sequence as that seen to date. In contrast, cyclopentanyl PNAs (cpPNAs) with beta approximately = 25 degrees hybridize to DNA/RNA strongly without discrimination because of the ring puckering of the cyclopentane ring. The high affinity of chPNAs to bind to RNA without losing base specificity will have immediate implications in designing improved PNAs for therapeutic and diagnostic applications.

Structure—Chemical Analysis of Multiple Complexations by Cyclodextrins

AbstractFor Abstract see ChemInform Abstract in Full Text.

Metal Ion Binding by a Bicyclic Diamide: Deep UV Raman Spectroscopic Characterization

Deep UV resonance Raman spectroscopy was used for characterizing ligand-metal ion complexes. The obtained results demonstrated a strong intrinsic sensitivity and selectivity of a Raman spectroscopic signature of a bicyclic diamide, a novel chelating agent for lanthanides and actinides (Lumetta, G. J.; Rapko, B. M.; Garza, P. A.; Hay, B. P.; Gilbertson, R. D.; Weakley, T. J. R.; Hutchison, J. E. J. Am. Chem. Soc. 2002, 124, 5644). Molecular modeling, which included structure optimization and calculation of Raman frequencies and resonance intensities, allowed for assigning all strong Raman bands of the bicyclic diamide as well as predicting the band shifts observed because of complex formation with metal ions. A comparative analysis of Raman spectra and the results of the molecular modeling could be used for elucidating the structure of complexes in solution.

Solid state and solution structures of 2-halophenolate complexes of lithium

Solvent-free 2-halophenolate complexes of lithium, [LiOC 6H 4-2-X)] n (X = F, Cl, Br), were synthesized by treating the corresponding 2-halophenols with n-butyllithium. ortho-Lithiation was avoided by cooling the reaction mixture to −78 °C and using n-hexane as solvent. Recrystallization from THF/ n-hexane lead to tetrameric [Li(THF)(μ 3-OC 6H 4-2-X)] 4 (X = F, 1; X = Cl, 2; X = Br, 3), which was verified by X-ray crystallography for 1 and 2 and derived for 3 by the strong similarities in the 1H, 13C and 7Li NMR data for 1, 2 and 3. Cubane structures were revealed for the Li 4O 4 core of 1 and 2. While complex salt 2 possesses only slight distortions within its cubane core, complex salt 1 has an unusual C 2 v distortion towards a butterfly shape. Additionally, dimeric [Li(H 2O) 2(μ-OC 6H 4-2-Br)] 2 was obtained containing an extensive network of hydrogen bonding between water molecules. Upfield shifts in the 1H NMR spectra for the coordinated THF molecules as well as 13C and 7Li NMR spectra are interpreted as indicating the tetrameric form observed in the X-ray crystal structure is preserved in solution.

The phase behavior of n-alkane systems

Normal alkanes show very complicated phase transition kinetics and macroscopic phase equilibrium behavior. This paper focuses on the phase stability and equilibrium of complicated mixtures like n-alkanes and on the enabling global optimization technologies needed to gather problem knowledge. The new ideas contained in this paper include: (1) novel level set methods for gathering encoded knowledge; (2) the differential geometry for uncovering pathways to more subtle knowledge; (3) all supporting non-linearly constrained optimization techniques; (4) all data handling needed to unravel complex solution structure. These new ideas are incorporated within the integral path methodology or terrain methods recently developed by Lucia, A., & Yang, F. (2003) [Lucia, A., & Yang F. (2003). Multivariable terrain methods. AIChE Journal 49, 2553] and Lucia, DiMaggio, and Depa (2004) [Lucia, A., DiMaggio, P.A., & Depa, P. (2004). A geometric terrain methodology for global optimization. Journal of Global Optimization 29, 297]. This framework provides global knowledge for understanding solution structure, like the complex solution structure of n-alkanes. In particular, it is shown that knowledge of the Newton and tangent vector fields, Gauss curvature, integral path bifurcation points, and non-differentiable manifolds provides a deterministic way of finding additional solutions, saddle points, and other information that might otherwise go undetected. It is shown that the optimization tools developed in this work provide all knowledge of interest on the appropriate hypothetical single-phase or composite surface (i.e., minima, saddle points, singular points, and integral paths) in phase stability applications. This knowledge can be obtained by solving the phase stability problem exactly once, in a pre-processing step, and used to reliably initialize any multi-phase equilibrium calculation for any feed. This removes the need to repeatedly solve the phase stability problem as the feed composition changes and greatly increases computational efficiency. Numerical examples and geometric illustrations are used to elucidate key ideas and to show how the proposed approach can be used to unravel the complicated phase behavior of n-alkane mixtures.