New mechanistic insights regarding Pd/Cu catalysts for the Sonogashira reaction: HRMAS NMR studies of silica-immobilized systems

The title technique, high-resolution magic angle spinning NMR of suspensions, constitutes a powerful new tool for investigating the structures and mobilities of immobilized species and, thus, for optimizing heterobimetallic catalyst systems, such as the Sonogashira coupling of terminal alkynes and aryl halides.     

Multidimensional HRMAS NMR: a platform for in vivo studies using intact bacterial cells

In vivo analysis in whole cell bacteria, especially the native tertiary structures of the bacterial cell wall, remains an unconquered frontier. The current understanding of bacterial cell wall structures has been based on destructive analysis of individual components. These in vitro results may not faithfully reflect the native structural and conformational information. Multidimensional High Resolution Magic Angle Spinning NMR (HRMAS NMR) has evolved to be a powerful technique in a variety of in vivo studies, including live bacterial cells. Existing studies of HRMAS NMR in bacteria, technical consideration of its successful application, and current limitations in studying true human pathogens are briefly reviewed in this report.     

Layered structure of room-temperature ionic liquids in microemulsions by multinuclear NMR spectroscopic studies

Microemulsions form in mixtures of polar, nonpolar, and amphiphilic molecules. Typical microemulsions employ water as the polar phase. However, microemulsions can form with a polar phase other than water, which hold promise to diversify the range of properties, and hence utility, of microemulsions. Here microemulsions formed by using a room‐temperature ionic liquid (RTIL) as the polar phase were created and characterized by using multinuclear NMR spectroscopy. ¹H, ¹¹B, and ¹⁹F NMR spectroscopy was applied to explore differences between microemulsions formed by using 1‐butyl‐3‐methylimidazolium tetrafluoroborate ([bmim][BF₄]) as the polar phase with a cationic surfactant, benzylhexadecyldimethylammonium chloride (BHDC), and a nonionic surfactant, Triton X‐100 (TX‐100). NMR spectroscopy showed distinct differences in the behavior of the RTIL as the charge of the surfactant head group varies in the different microemulsion environments. Minor changes in the chemical shifts were observed for [bmim]⁺ and [BF₄]^? in the presence of TX‐100 suggesting that the surfactant and the ionic liquid are separated in the microemulsion. The large changes in spectroscopic parameters observed are consistent with microstructure formation with layering of [bmim]⁺ and [BF₄]^? and migration of Cl^? within the BHDC microemulsions. Comparisons with NMR results for related ionic compounds in organic and aqueous environments as well as literature studies assisted the development of a simple organizational model for these microstructures.     

Characterization of the 310-helix in model peptides by HRMAS NMR spectroscopy

A tetra- and a hepta-homopeptide from the C(alpha)-tetrasubstituted Aib (alpha-aminoisobutyric acid) residue were covalently linked to the POEPOP resin by the fragment-condensation approach. The conformational preferences of the two model peptides were determined for the first time on a solid support by means of high-resolution magic angle spinning NMR spectroscopy. The results obtained indicate that the Aib homopeptides adopt a regular 3(10)-helical structure even when they are covalently bound to a polymeric matrix, and thus confirm the remarkable conformational stability of the peptides rich in this amino acid. An ATR-FTIR spectroscopic investigation, performed in parallel, also confirmed that these polymer-bound peptides do indeed adopt a helical conformation. The results of this study open the possibility to exploit the peptide-resin conjugates based on C(alpha)-tetrasubstituted alpha-amino acids as helpful, structurally organized templates in molecular recognition studies or as catalysts in asymmetric synthesis.     

DEUSS: a perdeuterated poly(oxyethylene)-based resin for improving HRMAS NMR studies of solid-supported molecules

A novel resin called DEUSS (perdeuterated poly(oxyethylene)-based solid support) has been prepared by anionic polymerization of deuterated [D4]ethylene oxide, followed by cross-linking with deuterated epichlorohydrin. DEUSS can be suspended in a wide range of solvents including organic and aqueous solutions, in which it displays a high swelling capacity. As measured by proton HRMAS of the swollen polymer, the signal intensity of the oxyethylene protons is reduced by a factor of 110 relative to the corresponding nondeuterated poly(oxyethylene)poly(oxypropylene) (POEPOP) resin, thus facilitating detailed HRMAS NMR studies of covalently linked molecules. This 1H NMR invisible matrix was used for the solid-phase synthesis of peptides, oligoureas, and a series of amides as well as their characterization by HRMAS NMR spectroscopy. On-bead NMR spectra of high quality and with resolution comparable to that of liquid samples were obtained and readily interpreted. The complete absence of the parasite resin signals will be of great advantage, for example, for the optimization of multistep solid-phase stereoselective reactions, and for the conformational study of resin-bound molecules in a large variety of solvents.     

Combinatorial multinuclear NMR and X-ray diffraction studies of uranium(VI)-nucleotide complexes

The complex formation of uranium(VI) with four nucleotides, adenosine- (AMP), guanosine- (GMP), uridine- (UMP), and cytidine-monophosphate (CMP), has been studied in the alkaline pH range (8.5-12) by (1)H, (31)P, (13)C, and (17)O NMR spectroscopy, providing spectral integral, chemical shift, homo- and heteronuclear coupling, and diffusion coefficient data. We find that two and only two complexes are formed with all ligands in the investigated pH region independently of the total uranium(VI) and ligand concentrations. Although the coordination of the 5'-phosphate group and the 2'- and 3'-hydroxyl groups of the sugar unit to the uranyl ions is similar to that proposed earlier ("Feldman complex"), the number and the structures of the complexes are different. The uranium-to-nucleotide ratio is 6:4 in one of the complexes and 3:3 in the other one, as unambiguously determined by a combinatorial approach using a systematic variation of the ratio of two ligands in ternary uranium(VI)-nucleotide systems. The structure of the 3:3 complex has been determined by single-crystal diffraction as well, and the results confirm the structure proposed by NMR in aqueous solution. The results have important implications on the synthesis of oligonucleotides.     

NMR self-diffusion studies in heterogeneous systems

The principles and main limitations of the application of the NMR field gradient technique to self-diffusion measurements are discussed. Due to their higher sensitivity for small diffusion coefficients and due to several advantages with the analytical treatment of the experimental data, the pulsed gradient methods are of special importance for the investigation of heterogeneous systems. Examples of the application of these techniques to diffusion studies in multicomponent systems and bounded media are given.     

Study of association of alcohols in aprotic solvents by multinuclear NMR

Binary mixtures of alcohols(ethyl,n-butyl and n-amyl)with several aprotic sol-vents,such as acetone,dioxane,THF,DMSO and DMF have been studied systematically by~1H,~(13)C,~(15)N and ~(17)O NMR measurements.The concentration dependence of chemical shift ofthe solvent was used to evaluate equilibrium constants of the complexation of alcohols withthe solvents.A relationship between the proton shift of alcohol uncombined with the solventand its concentration was found,and the fraction of unassociated hydroxyl groups was thusquantitatively described.The effect of solvent on self association and complexation of thealcohol is discussed on the basis of the electron donicity of the solvents.     

Synthesis and characterization of fluorophenylpalladium pincer complexes: electronic properties of some pincer ligands evaluated by multinuclear NMR spectroscopy and electrochemical studies

Palladium fluorophenyl complexes with different pincer ligands Pd(Ar)[2,6-(tBu(2)PCH(2))(2)C(6)H(3)] (13), Pd(Ar)[2,6-(tBu(2)PO)(2)C(6)H(3)] (14), Pd(Ar)[{2,5-(tBu(2)PCH(2))(2)C(5)H(2)}Fe(C(5)H(5))] (15), and Pd(Ar)[{2,5-(tBu(2)PCH(2))(2)C(5)H(2)}Ru(C(5)H(5))] (16) were synthesized by the reaction of LiAr (Ar = C(6)H(4)F-4) with the respective trifluoroacetate palladium pincer complexes 9-12. The molecular structures of 14 and 16 were determined by an X-ray crystallographic method. Complexes 13-16 and {Pd(Ar)[{2,5-(tBu(2)PCH(2))(2)C(5)H(2)}Fe(C(5)H(5))]}PF(6) (17) were studied by multinuclear NMR spectroscopy and cyclic voltammetry. On the basis of (19)F NMR chemical shifts and (1)J((13)C-(19)F) coupling constants, as well as Pd(II)/Pd(IV) oxidation potentials, electronic characteristics of the corresponding pincer ligands were elucidated.     

Borotungstate polyoxometalates: multinuclear NMR structural characterization and conversions in solutions

The unique heteropolyanion [H(3)BW(13)O(46)](8-) (BW(13)), previously suggested on the basis of indirect evidence, and protonated lacunary heteropolyanion [HBW(11)O(39)](8-) (BW(11)) have been identified in aqueous solutions at pH 5-7.5 from NMR spectra. The pattern of tungsten-tungsten connectivities based on the analysis of the (2)J(W-O-W) coupling satellites in the (183)W NMR spectrum of BW(11), containing six peaks of relative intensities ～2:2:2:1:2:2, indicates that the latter is the α isomer. The (17)O NMR spectrum confirms the protonated state of the polyanion with the proton delocalized on two out of four terminal O atoms surrounding the tungsten vacancy. The (183)W NMR spectrum of BW(13) contains seven peaks of relative intensities ～2:1:2:2:2:2:2 with additional large couplings due to the connectivity between BW(11) and [W(2)O(7)](2-) fragments. According to the (17)O NMR spectrum, two protons of [BW(13)O(46)H(3)](8-) are delocalized on the two terminal trans O atoms of the dimeric fragment while the third one is linked to its bridging O atom. The conversions of BW(11) and BW(13) in solution were followed by using (183)W NMR spectra at a "fingerprint" level. In the pH range from ～7.5 to 6, BW(11) transforms to BW(13), transforming further to [BW(12)O(40)](5-) (BW(12)) and [B(3)W(39)O(132)H(n)](n-21) (B(3)W(39)) in different ratios. Conversion of BW(13) to BW(12) proceeds through an intermediate complex of suggested composition [BW(11)O(39)·WO(2)](7-). At high acidity (pH ～ 0), B(3)W(39) gradually decomposes into tungstic acid, BW(12) and H(3)BO(3). Polyanion BW(12) persists in the pH range ～0-7.5.     

Copper and amine free Sonogashira cross-coupling reaction catalyzed by efficient diphosphane-palladium catalyst

The commercially available diphosphane ligand MeO-BIPHEP was first investigated in the palladium-catalyzed Sonogashira reaction in the absence of copper and amine.The coupling of various aryl bromides and aryl chlorides with phenylacetylene gave moderate to excellent yields.     

Sonogashira reactions catalyzed by a new and efficient copper(I) catalyst incorporating N-benzyl DABCO chloride

A new and effective catalytic system using [N-benzyl DABCO]⁺[Cu₄Cl₅]⁻ was developed for the palladium-free Sonogashira cross-coupling reactions of phenylacetylene with a variety of aryl halides. In this homogeneous catalytic system, 1-benzyl-4-aza-1-azoniabicyclo[2.2.2]octane chloride, a quaternary ammonium salt containing a coordinating center, plays an important role and increases the efficiency of Cu(I) species during the reaction. A number of internal alkynes were produced in moderate to excellent yields, in short reaction times in DMF at 135 °C.     

A new platinum vapor-derived highly efficient hydrosilylation catalyst: NMR structural investigation

The structural features of a highly efficient hydrosilylation catalyst generated by reaction of Pt vapor and a mixture of mesitylene and 1,3-divinyltetramethyldisiloxane (DVS) were investigated by mono- and bidimensional NMR analyses. The structure around the Pt atoms was highlighted and compared with a commercial sample (Karstedt catalyst) and previously reported Pt vapor-derived system.     

Ruthenium agostic (phosphinoaryl)borane complexes: multinuclear solid-state and solution NMR, X-ray, and DFT studies

The reactivity of the (o-phosphinophenyl)(amino)borane compound HB(N(i)Pr(2))C(6)H(4)(o-PPh(2)) prepared from Li(C(6)H(4))PPh(2) and HBCl(N(i)Pr(2)) toward the bis(dihydrogen) complex RuH(2)(H(2))(2)(PCy(3))(2) (1) was studied by a combination of DFT, X-ray, and multinuclear NMR techniques including solid-state NMR, a technique rarely employed in organometallic chemistry. The study showed that the complex RuH(2){HB(N(i)Pr(2))C(6)H(4)(o-PPh(2))}(PCy(3))(2) (3), isolated in excellent yield as yellow crystals and characterized by X-ray diffraction, led in solution to PCy(3) dissociation and formation of an unsaturated 16-electron complex RuH(2){HB(N(i)Pr(2))C(6)H(4)(o-PPh(2))}(PCy(3)) (4), with a hydride trans to a vacant site. In both cases, the (phosphinoaryl)(amino)borane acts as a bifunctional ligand through the phosphine moiety and a Ru-H-B interaction, thus featuring an agostic interaction.     

Conformational analysis by HRMAS NMR spectroscopy of resin-bound homo-peptides from C(alpha)-methyl-leucine

A series of [L-(alphaMe)Leu]n (n = 1-5) homo-peptides have been covalently linked to Tentagel and POEPOP resins and submitted to a conformational study using HRMAS NMR spectroscopy. Whereas the mono- and dipeptide are mainly fully-extended, stable 3(10)-helical structures are formed beginning from the trimer.     

Regio- and stereoselective lithiation of 2,3-diphenylaziridines: a multinuclear NMR investigation

The alpha-lithiation-trapping sequence of trans-N-alkyl-2,3-diphenylaziridines (s-BuLi or s-BuLi/TMEDA), taking place with a stereochemistry which dramatically depends on the solvent coordinating ability (inversion of configuration in THF and retention in toluene), has been carefully investigated. 1H,13C, and 7Li multinuclear NMR investigations at low temperature suggest that two differently configured lithiated aziridines (monomeric cis-1-Li in THF and dimeric trans-1-Li in toluene) are involved.     

Potentiometric and multinuclear NMR studies on the interaction of aluminum with ascorbic acid in acidic aqueous solution

The complex-formation equilibria between aluminum(III) ion and L-(+)-ascorbic acid (AA) in 0.1 M KCl ionic medium at 25 degrees C and 0.15 M NaCl ionic medium at 37 degrees C were studied by glass electrode pH-metric measurements. The obtained experimental results were explained by the formation of the following complexation species: a weak mononuclear 1:1 species AlL(2+) together with two trinuclear mixed-hydroxo species Al(3)H(-5)L(4) and Al(3)H(-5)L(3+) in acidic aqueous solutions. Meanwhile, the formation of the complexes and structures of Al with AA were proved by multinuclear (1H, 13C, 27Al) NMR spectra in the pH range 2.0-5.0. It is supposed that Al directly coordinates with AA at O-3 moiety; also, Al can coordinate with the O-1 and O-2 moieties of ascorbate ion through the weakly binding and the intramolecular hydrogen bonding in acidic aqueous solutions.     

Sonogashira cross-coupling reactions of aryl chlorides with alkynes catalysed by a tetraphosphine-palladium catalyst

A range of aryl chlorides undergoes cross-couplings with alkynes in good yields in the presence of [PdCl(C₃H₅)]₂/cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane as catalyst. A variety of aryl chlorides such as chloroacetophenone, chlorobenzonitrile, chloronitrobenzene, chloroanisole or chlorotoluene have been used successfully. The reaction also tolerates several alkynes such as phenylacetylene, dec-1-yne, ethynylcyclohexene or alk-1-ynols. Furthermore, this catalyst can be used at low loading with some substrates.     

NMR and MRI studies of drug delivery systems

Nuclear magnetic resonance imaging and spectroscopy are now commonplace in most academic and industrial research environments. The ability of magnetic resonance techniques to provide the researcher with non-invasive, quantitative, physicochemical information in the disciplines of chemistry, biology, materials science, chemical engineering and medicine is widely known. In the last 10–15 years a variety of magnetic resonance methods have provided the pharmaceutical research community with valuable information, especially in the important area of drug delivery using solid dosage forms. This review will highlight recent advances in magnetic resonance techniques and its specific applications to further our understanding of pharmaceutical drug delivery systems. The review is aimed at non-clinical research and development, and will focus on the behaviour and characterisation of drug release from pellets, tablets and capsules, which are the most commonly used drug delivery systems. In addition to magnetic resonance techniques a number of complementary analytical techniques are mentioned to illustrate the importance of adopting a multi-modal analytical approach to gain a better scientific understanding of the behaviour of drug delivery devices.