A New Motif in Halogen Bonding: Cooperative Intermolecular S-Br⋠⋠⋠O, O⋠⋠⋠F, and F⋠⋠⋠F Associations in the Crystal Packing of α,ω-Di(sulfonyl bromide) Perfluoroalkanes.

We recently reported the first examples of S-Cl⋅⋅⋅O halogen bonding complemented by short F⋅⋅⋅F contacts between neighboring chains that resulted in stabilized crystals of ClSO2 (CF2 )4 SO2 Cl and ClSO2 (CF2 )6 SO2 Cl. More recently, other researchers studied our crystallographic data further using an Independent Gradient Model (IGM), and they suggested if one goes beyond IUPAC's proposed 'less than the sum of the van der Waals radii' criterion that even more noncovalent interactions between fluorine atoms on neighboring chains as well as Cl⋅⋅⋅Cl, Cl⋅⋅⋅S, O⋅⋅⋅F, and O⋅⋅⋅S attractive interactions can be found. With that said, we have prepared samples of the related BrSO2 (CF2 )n SO2 Br derivatives (where n=4, 6, 8, and others), which give rise to even stronger S-Br⋅⋅⋅O halogen bonding interactions complemented minimally by O⋅⋅⋅F and F⋅⋅⋅F intermolecular interactions as shown by X-ray crystallography and computational chemistry using IGM isosurface plots. Additional spectroscopic characterization (multinuclear NMR, FT-IR, and MS) of the disulfonyl bromide derivatives BrSO2 (CF2 )4 SO2 Br, BrSO2 (CF2 )6 SO2 Br, and BrSO2 (CF2 )8 SO2 Br has also been obtained as well as some preliminary spectroscopic evidence for BrSO2 (CF2 )2 SO2 Br and BrSO2 CF2 O(CF2 )2 OCF2 SO2 Br. The implication of these results toward the preparation of the corresponding disulfonyl iodides is discussed.

Binding Between Antibiotics and Polystyrene Nanoparticles Examined by NMR.

Elucidating the interactions between plastic nanoparticles and small molecules is important to understanding these interactions as they occur in polluted waterways. For example, plastic that breaks down into micro- and nanoscale particles will interact with small molecule pollutants that are also present in contaminated waters. Other components of natural water, such as dissolved organic matter, will also influence these interactions. Here we use a collection of complementary NMR techniques to examine the binding between polystyrene nanoparticles and three common antibiotics, belonging to a class of molecules that are expected to be common in polluted water. Through examination of proton NMR signal intensity, relaxation times, saturation-transfer difference (STD) NMR, and competition STD-NMR, we find that the antibiotics have binding strengths in the order amoxicillin < metronidazole ≪ levofloxacin. Levofloxacin is able to compete for binding sites, preventing the other two antibiotics from binding. The presence of tannic acid disrupts the binding between levofloxacin and the polystyrene nanoparticles, but does not influence the binding between metronidazole and these nanoparticles.

Quantum mechanical study of interactions between sunscreen ingredients and nucleotide bases.

Interactions between the popular sunscreen ingredients oxybenzone and homosalate and DNA bases have been studied using density functional theory and ab initio methods. Low-energy structures for each sunscreen ingredient interacting with each nucleotide base in either a pi-stacked or hydrogen-bonded fashion were found. The binding energies are comparable to those for the Watson-Crick-Franklin Ade-Thy and Cyt-Gua pairs. Pi-stacked and hydrogen-bonded structures are comparable in energy, with hydrogen-bonded structures having a more negative counterpoise-corrected binding energy, while the final pi-stacked structures are lower in energy. This is due to a geometrical rearrangement required to form the hydrogen bonds that raise the total energy of the complex. It was also found that when using the M06-2X density functional, the STO-3G basis set favors hydrogen bonding, but 6-31G(d) and 6-31 + G(s) basis sets predict similar binding geometries.

Probing driving forces for binding between nanoparticles and amino acids by saturation-transfer difference NMR.

As nanotechnology becomes increasingly used in biomedicine, it is important to have techniques by which to examine the structure and dynamics of biologically-relevant molecules on the surface of engineered nanoparticles. Previous work has shown that Saturation-Transfer Difference (STD)-NMR can be used to explore the interaction between small molecules, including amino acids, and the surface of polystyrene nanoparticles. Here we use STD-NMR to further explore the different driving forces that are responsible for these interactions. Electrostatic effects are probed by using zwitterionic polystyrene beads and performing STD-NMR experiments at high, low, and neutral pH, as well as by varying the salt concentration and observing the effect on the STD buildup curve. The influence of dispersion interactions on ligand-nanoparticle binding is also explored, by establishing a structure-activity relationship for binding using a series of unnatural amino acids with different lengths of hydrophobic side chains. These results will be useful for predicting which residues in a peptide are responsible for binding and for understanding the driving forces for binding between peptides and nanoparticles in future studies.

Solid-state nuclear magnetic resonance studies of nanoparticles.

In this trends article, we review seminal and recent studies using static and magic-angle spinning solid-state NMR to study the structure of nanoparticles and ligands attached to nanoparticles. Solid-state NMR techniques including one-dimensional multinuclear NMR, cross-polarization, techniques for measuring dipolar coupling and internuclear distances, and multidimensional NMR have provided insight into the core-shell structure of nanoparticles as well as the structure of ligands on the nanoparticle surface. Hyperpolarization techniques, in particular solid-state dynamic nuclear polarization (DNP), have enabled detailed studies of nanoparticle core-shell structure and surface chemistry, by allowing unprecedented levels of sensitivity to be achieved. The high signal-to-noise afforded by DNP has allowed homonuclear and heteronuclear correlation experiments involving nuclei with low natural abundance to be performed in reasonable experimental times, which previously would not have been possible. The use of DNP to study nanoparticles and their applications will be a fruitful area of study in the coming years as well.

Calculating nuclear magnetic resonance chemical shifts in solvated systems.

The nuclear magnetic resonance (NMR) chemical shift is extremely sensitive to molecular geometry, hydrogen bonding, solvent, temperature, pH, and concentration. Calculated magnetic shielding constants, converted to chemical shifts, can be valuable aids in NMR peak assignment and can also give detailed information about molecular geometry and intermolecular effects. Calculating chemical shifts in solution is complicated by the need to include solvent effects and conformational averaging. Here, we review the current state of NMR chemical shift calculations in solution, beginning with an introduction to the theory of calculating magnetic shielding in general, then covering methods for inclusion of solvent effects and conformational averaging, and finally discussing examples of applications using calculated chemical shifts to gain detailed structural information.

Dehydration of fructose over thiol- and sulfonic- modified alumina in a continuous reactor for 5-HMF production: Study of catalyst stability by NMR.

In the present study, the synthesis of an organic group-modified alumina by the sol-gel method is proposed. This material has shown to have an enhanced catalytic performance with grafted organic groups and showed an improved stability. The prepared material has shown to have several O - H groups and an enhanced surface acidity. The alumina acidity was improved by incorporating thiol groups by grafting method, which promotes the tautomerization of fructose to its furanose form. Furthermore, the grafting of sulfonic groups catalyzes its dehydration. The modified alumina was thermally treated up to 200 °C to improve the functional groups stability. After, this modified material was packed into a continuous reactor system, designed and built by this group, to obtain 5-hydroxymethylfurfural (5-HMF) from fructose dissolved in a single-phase solution of tetrahydrofuran (THF) and H2O (4:1 w/w). The catalytic activity of this material was evaluated by the reaction of fructose dehydration at different reaction temperatures (60, 70, 80 and 90 °C). Fructose conversion and selectivity toward 5-HMF were determined by high performance liquid chromatography (HPLC), obtaining 95% and 73% respectively for the highest temperature. The catalyst showed an efficient stability after 24 hours in continuous flow at 70 °C. The loss of sulfur content was 15%, but the fructose conversion yield and the selectivity to 5-HMF after 24 hours of continuous reaction did not undergo significant changes (less than 5%). The nuclear magnetic resonance (NMR) tests confirmed the presence of the thiol and sulfonic groups before and after 24 hours of reaction, as well as the conservation of the same structure, demonstrating the efficient catalytic performance of the material. The catalysts were characterized by nitrogen adsorption/desorption, X-ray diffraction and infrared (IR) spectroscopy. Also, before and after use by utilizing elemental analysis and   1 H - 13 C cross-polarization magic-angle spinning (CPMAS) and dynamic-nuclear polarization (DNP)-enhanced   1 H - 13 C and   1 H - 29 Si CPMAS as well as directly excited   29 Si magic-angle spinning (MAS) NMR methods in solid-state.

Probing Amino Acid Interaction with a Polystyrene Nanoparticle Surface Using Saturation-Transfer Difference (STD)-NMR.

The interaction between individual amino acids and the surface of carboxylate-modified polystyrene nanoparticles in solution was studied using Saturation-Transfer Difference (STD)-Nuclear Magnetic Resonance (NMR). Individual amino acids were screened for nanoparticle binding using an STD-NMR experiment at a fixed saturation time, and STD buildup curves were measured for those amino acids that exhibited significant STD difference signals in the initial screening. The strongest STD effects were measured for protons of aromatic side chains, with relatively weaker effects observed for protons in long-chain aliphatic and positively charged side chains. This indicates that there are several modes of binding to these polystyrene nanoparticles: electrostatic attraction between the negatively charged surface of the carboxylate-modified polystyrene nanoparticle and positively charged amino acids, hydrophobic effects between long aliphatic side chains and the nanoparticle surface, and π-π interactions between aromatic amino acids and aromatic groups in styrene. This information can be used in future studies to predict and understand interactions between nanoparticle surfaces and specific amino acid residues in small peptides and proteins.

Interaction between cyanine dye IR-783 and polystyrene nanoparticles in solution.

The interactions between small molecule drugs or dyes and nanoparticles are important to the use of nanoparticles in medicine. Noncovalent adsorption of dyes on nanoparticle surfaces is also important to the development of nanoparticle dual-use imaging contrast agents. In this work, solution-state NMR is used to examine the noncovalent interaction between a near-infrared cyanine dye and the surface of polystyrene nanoparticles in solution. Using 1D proton NMR, we can approximate the number of dye molecules that associate with each nanoparticle for different sized nanoparticles. Saturation-Transfer Difference NMR was also used to show that protons near the positively charged nitrogen in the dye are more strongly associated with the negatively charged nanoparticle surface than protons near the negatively charged sulfate groups of the dye. The methods described here can be used to study similar drug or dye molecules interacting with the surface of organic nanoparticles.

Interplay Between π-Stacking and Hydrogen Bonding in the Self-Association of Different Isomers of Naphthalenedicarboxylic Acid.

Using proton and carbon chemical shifts, we investigated the self-association of three isomers of naphthalenedicarboxylic acid, a model for the aggregation of asphaltenes. Experimental proton chemical shifts of each isomer were measured as a function of concentration in an aprotic solvent. Several potential structures of the monomer and dimer of each naphthalenedicarboxylic acid were considered, and calculated proton chemical shifts for the potential monomer and dimer structures were compared to the experimental chemical shifts to find the weighted average structure that best fit the experimental shifts. Calculated carbon chemical shifts were also compared to experimental values. The chemical shift comparison and calculated energies indicate that π-stacked dimers are not likely to contribute significantly to the dimer structure of any of the three naphthalenedicarboxylic acid isomers studied.

Effect of Curvature on Carbon Chemical Shielding in Extended Carbon Systems.

The effect of curvature on the chemical shielding of carbons in curved polycyclic aromatic hydrocarbons has been systematically studied by examining structures analogous to the circumcoronene molecule with different degrees of curvature. We attempt to eliminate effects from Knight shifts in carbon nanotubes, differing ring currents from five-membered rings, and edge effects in finite nanotube models in order to separate out the change in shielding that is due to curvature alone. Using curved structures derived from geometry-optimized structures of carbon nanotubes, we calculate the carbon chemical shielding tensor for carbons in the central aromatic ring as well as the Nucleus Independent Chemical Shift (NICS) on the convex and concave side of each structure. All three tensor components become less shielded with increasing curvature of the system, with the σ33 component radial to the curve experiencing the greatest change. The NICS values are influenced by both the decrease in aromaticity as the structure is curved as well as geometric effects that bring the outside rings closer to the central aromatic ring.

BDPA-Doped Polystyrene Beads as Polarization Agents for DNP-NMR.

The aromatic free radical BDPA (α,γ-bisdiphenylene-ß-phenylallyl), which has been widely used as a polarizing agent for Dynamic Nuclear Polarization (DNP) of hydrophobic analytes, has been incorporated into nanometer-scale polystyrene latex beads. We have shown that the resulting BDPA-doped beads can be used to hyperpolarize (13)C and (7)Li nuclei in aqueous environments, without the need for a glassing cosolvent. DNP enhancement factors of between 20 and 100 were achieved with overall BDPA concentrations of 2 mM or less. These Highly-Effective Polymer/Radical Beads (HYPR-beads) have potential use as an inexpensive polarizing agent for water-soluble analytes, and also have applications as model nanoparticles in DNP studies.

Chirped CPMG for well-logging NMR applications.

In NMR well-logging, the measurement apparatus typically consists of a permanent magnet which is inserted into a bore, and the sample is the rock surrounding the borehole. When compared to the conditions of standard NMR experiments, this application is thus challenged by relatively weak and invariably inhomogeneous B0 and B1 fields. Chemical shift information is not generally obtained in these measurements. Instead, diffusivity, porosity and permeability information is collected from multi-echo decay measurements - most often using a Carr-Purcell Meiboom-Gill (CPMG) pulse sequence to enhance the experiment's limited sensitivity. In this work, we explore the consequences of replacing the hard square pulses used in a typical CPMG sequence with chirped pulses sweeping a range of frequencies. The greater bandwidths that for a maximum B1 level can be excited by chirped pulses translates into marked expansion of the detection volume, and thus significant signal-to-noise improvements when compared to standard CPMG acquisitions using hard pulses. This improvement, usually amounting to signal enhancements ⩾3, can be used to reduce the experimental time of NMR well-logging measurements, for measuring T2 even when B0 and B1 inhomogenieties complicate the measurements, and opening new opportunities in the determination of diffusional properties.

Chemical structures of hydrazine-treated graphene oxide and generation of aromatic nitrogen doping.

Chemically modified graphene platelets, produced via graphene oxide, show great promise in a variety of applications due to their electrical, thermal, barrier and mechanical properties. Understanding the chemical structures of chemically modified graphene platelets will aid in the understanding of their physical properties and facilitate development of chemically modified graphene platelet chemistry. Here we use (13)C and (15)N solid-state nuclear magnetic resonance spectroscopy and X-ray photoelectron spectroscopy to study the chemical structure of (15)N-labelled hydrazine-treated (13)C-labelled graphite oxide and unlabelled hydrazine-treated graphene oxide, respectively. These experiments suggest that hydrazine treatment of graphene oxide causes insertion of an aromatic N(2) moiety in a five-membered ring at the platelet edges and also restores graphitic networks on the basal planes. Furthermore, density-functional theory calculations support the formation of such N(2) structures at the edges and help to elucidate the influence of the aromatic N(2) moieties on the electronic structure of chemically modified graphene platelets.

The hydroxyl functionality and a rigid proximal N are required for forming a novel non-covalent quinine-heme complex.

Quinoline antimalarial drugs bind both monomeric and dimeric forms of free heme, with distinct preferences depending on the chemical environment. Under biological conditions, chloroquine (CQ) appears to prefer to bind to µ-oxo dimeric heme, while quinine (QN) preferentially binds monomer. To further explore this important distinction, we study three newly synthesized and several commercially available QN analogues lacking various functional groups. We find that removal of the QN hydroxyl lowers heme affinity, hemozoin (Hz) inhibition efficiency, and antiplasmodial activity. Elimination of the rigid quinuclidyl ring has similar effects, but elimination of either the vinyl or methoxy group does not. Replacing the quinuclidyl N with a less rigid tertiary aliphatic N only partially restores activity. To further study these trends, we probe drug-heme interactions via NMR studies with both Fe and Zn protoporphyrin IX (FPIX, ZnPIX) for QN, dehydroxyQN (DHQN), dequinuclidylQN (DQQN), and deamino-dequinuclidylQN (DADQQN). Magnetic susceptibility measurements in the presence of FPIX demonstrate that these compounds differentially perturb FPIX monomer-dimer equilibrium. We also isolate the QN-FPIX complex formed under mild aqueous conditions and analyze it by mass spectrometry, as well as fluorescence, vibrational, and solid-state NMR spectroscopies. The data elucidate key features of QN pharmacology and allow us to propose a refined model for the preferred binding of QN to monomeric FPIX under biologically relevant conditions. With this model in hand, we also propose how QN, CQ, and amodiaquine (AQ) differ in their ability to inhibit Hz formation.

NMR-based structural modeling of graphite oxide using multidimensional 13C solid-state NMR and ab initio chemical shift calculations.

Chemically modified graphenes and other graphite-based materials have attracted growing interest for their unique potential as lightweight electronic and structural nanomaterials. It is an important challenge to construct structural models of noncrystalline graphite-based materials on the basis of NMR or other spectroscopic data. To address this challenge, a solid-state NMR (SSNMR)-based structural modeling approach is presented on graphite oxide (GO), which is a prominent precursor and interesting benchmark system of modified graphene. An experimental 2D (13)C double-quantum/single-quantum correlation SSNMR spectrum of (13)C-labeled GO was compared with spectra simulated for different structural models using ab initio geometry optimization and chemical shift calculations. The results show that the spectral features of the GO sample are best reproduced by a geometry-optimized structural model that is based on the Lerf-Klinowski model (Lerf, A. et al. Phys. Chem. B 1998, 102, 4477); this model is composed of interconnected sp(2), 1,2-epoxide, and COH carbons. This study also convincingly excludes the possibility of other previously proposed models, including the highly oxidized structures involving 1,3-epoxide carbons (Szabo, I. et al. Chem. Mater. 2006, 18, 2740). (13)C chemical shift anisotropy (CSA) patterns measured by a 2D (13)C CSA/isotropic shift correlation SSNMR were well reproduced by the chemical shift tensor obtained by the ab initio calculation for the former model. The approach presented here is likely to be applicable to other chemically modified graphenes and graphite-based systems.

Distinguishing polymorphs of the semiconducting pigment copper phthalocyanine by solid-state NMR and Raman spectroscopy.

Cu(II)(phthalocyanine) (CuPc) is broadly utilized as an archetypal molecular semiconductor and is the most widely used blue printing pigment. CuPc crystallizes in six different forms; the chemical and physical properties are substantially modulated by its molecular packing among these polymorphs. Despite the growing importance of this system, spectroscopic identification of different polymorphs for CuPc has posed difficulties. This study presents the first example of spectroscopic distinction of alpha- and beta-forms of CuPc, the most widely used polymorphs, by solid-state NMR (SSNMR) and Raman spectroscopy. (13)C high-resolution SSNMR spectra of alpha- and beta-CuPc using very-fast magic angle spinning (VFMAS) at 20 kHz show that hyperfine shifts sensitively reflect polymorphs of CuPc. The experimental results were confirmed by ab initio chemical shift calculations. (13)C and (1)H SSNMR relaxation times of alpha- and beta-CuPc under VFMAS also showed marked differences, presumably because of the difference in electronic spin correlation times in the two forms. Raman spectroscopy also provided another reliable method of differentiation between the two polymorphs.

Antimalarial drugs and heme in detergent micelles: An NMR study.

Proton nuclear magnetic resonance relaxation times were measured for the protons of micelles formed by the detergents sodium dodecyl sulfate, dodecyltrimethyl ammonium bromide, and polyethylene glycol sorbitan monolaureate in the presence of ferriprotoporphyrin IX and the antimalarial drugs chloroquine, 7-chloro-4-quinolyl 4-N,N-diethylaminobutyl sulfide, and primaquine. Diffusion coefficients were extracted from pulsed gradient NMR experiments to evaluate the degree of association of these drugs with the detergent micelles. Results indicate that at low or neutral pH when the quinolyl N is protonated, chloroquine does not associate with neutral or cationic detergent micelles. For this reason, chloroquine's interaction with heme perturbs the partitioning of heme between the aqueous medium and detergent micelles.

4-N-, 4-S-, and 4-O-chloroquine analogues: influence of side chain length and quinolyl nitrogen pKa on activity vs chloroquine resistant malaria.

Using predictions from heme-quinoline antimalarial complex structures, previous modifications of chloroquine (CQ), and hypotheses for chloroquine resistance (CQR), we synthesize and assay CQ analogues that test structure-function principles. We vary side chain length for both monoethyl and diethyl 4-N CQ derivatives. We alter the pKa of the quinolyl N by introducing alkylthio or alkoxy substituents into the 4 position and vary side chain length for these analogues. We introduce an additional titratable amino group to the side chain of 4-O analogues with promising CQR strain selectivity and increase activity while retaining selectivity. We solve atomic resolution structures for complexes formed between representative 4-N, 4-S, and 4-O derivatives vs mu-oxo dimeric heme, measure binding constants for monomeric vs dimeric heme, and quantify hemozoin (Hz) formation inhibition in vitro. The data provide additional insight for the design of CQ analogues with improved activity vs CQR malaria.

Quinine and chloroquine differentially perturb heme monomer-dimer equilibrium.

Nuclear magnetic resonance (NMR) measurements of magnetic susceptibility have been utilized to study the equilibrium between two forms (high-spin monomer vs the antiferromagnetically coupled mu-oxo dimer) of ferriprotoporphyrin(IX) as a function of pH. The pH dependence of this equilibrium is significantly altered by the addition of either chloroquine or quinine. Chloroquine promotes the mu-oxo dimer whereas quinine promotes the monomer.