Efficient pKa Determination in a Nonaqueous Solvent Using Chemical Shift Imaging.

pKa is an important property of a molecule which impacts many fields, such as drug design, catalysis, reactivity, and environmental toxicity. It is often necessary to measure pKa in nonaqueous media due to the poor solubility of an analyte in water, for example, many compounds of pharmaceutical interest. Although NMR methods to measure pKa in water are well established, determining pKa in organic solvents is laborious and problematic. We present an efficient one-shot method to determine the pKa of an analyte in an organic solvent in a single measurement. Diffusion of an acid into a basic solution of the analyte and a set of pH indicators establishes a pH gradient in the NMR tube. The chemical shift of a pH sensitive resonance of the analyte and the pH of the solution are then determined simultaneously as a function of position along the pH gradient by recording a chemical shift image of the NMR tube. The pKa of the analyte is then determined using the Henderson-Hasselbalch equation. The method can be implemented in any laboratory with a gradient equipped NMR high-field spectrometer and is demonstrated for a range of pharmaceutical compounds and inorganic phosphazene bases.

Polyanionic Ligand Platforms for Methyl- and Dimethylaluminum Arrays.

Trimethylaluminum finds widespread applications in chemical and materials synthesis, most prominently in its partially hydrolyzed form of methylalumoxane (MAO), which is used as a cocatalyst in the polymerization of olefins. This work investigates the sequential reactions of trimethylaluminum with hexaprotic phosphazenes (RNH)6P3N3 (=XH6) equipped with substituents R of varied steric bulk including tert-butyl (1H6), cyclohexyl (2H6), isopropyl (3H6), isobutyl (4H6), ethyl (5H6), propyl (6H6), methyl (7H6), and benzyl (8H6). Similar to MAO, the resulting complexes of polyanionic phosphazenates [XH n] n-6 accommodate multinuclear arrays of [AlMe2]+ and [AlMe]2+. Reactions were monitored by 31P NMR spectroscopy, and structures were determined by single-crystal X-ray diffraction. They included 1H4(AlMe2)2, 1H3(AlMe2)3, 2H3(AlMe2)3, 3(AlMe2)4AlMe, 4H(AlMe2)5, 4(AlMe2)6, {5H(AlMe2)4}2AlMe, 5(AlMe2)6, 6(AlMe2)6, {7(AlMe2)4AlMe}2, and 8(AlMe2)6. The study shows that subtle variations of the steric properties of the R groups influence the reaction pathways, levels of aggregation, and fluxional behavior. While [AlMe2]+ is the primary product of the metalation, [AlMe]2+ is utilized to alleviate overcrowding or to aid aggregation. At the later stages of metalation, [AlMe2]+ groups start to scramble around congested sites. The ligands proved to be very robust and extremely flexible, offering a unique platform to study complex multinuclear metal arrangements.

Titrations without the Additions: The Efficient Determination of p Ka Values Using NMR Imaging Techniques.

It can be very informative to acquire NMR spectra of a sample as a function of the solution pH. Examples can be found in the design of host-guest complexes or in the determination of the p Ka values of organic molecules. In the conventional procedure, a series of spectra must be recorded and the pH of the sample adjusted manually between successive NMR measurements. As an alternative to this laborious procedure, we demonstrate how controlled pH gradients may be established in 5 mm NMR tubes and analyzed using standard NMR equipment in a "single shot" experiment. Using 1H NMR imaging techniques and a set of NMR pH indicator compounds, we are able to measure the pH of a sample as a function of position along a pH gradient. We are thus able to obtain the necessary set of 1H NMR spectra as a function of pH from a single sample in a single NMR experiment. As proof of concept, we demonstrate how the technique may be employed for the determination of the p Ka values of small organic molecules. We are able to measure p Ka values from 1 to 11 to within 0.1 units of their literature values. The method is robust to variations in the setting of the pH gradients and can be readily implemented through an automated sample changer.

Probing the surface chemistry of self-assembled peptide hydrogels using solution-state NMR spectroscopy.

The surface chemistry of self-assembled hydrogel fibres - their charge, hydrophobicity and ion-binding dynamics - is recognised to play an important role in determining how the gels develop as well as their suitability for different applications. However, to date there are no established methodologies for the study of this surface chemistry. Here, we demonstrate how solution-state NMR spectroscopy can be employed to measure the surface chemical properties of the fibres in a range of hydrogels formed from N-functionalised dipeptides, an effective and versatile class of gelator that has attracted much attention. By studying the interactions with the gel fibres of a diverse range of probe molecules and ions, we can simultaneously study a number of surface chemical properties of the NMR invisible fibres in an essentially non-invasive manner. Our results yield fresh insights into the materials. Most notably, gel fibres assembled using different tiggering methods bear differing amounts of negative charge as a result of a partial deprotonation of the carboxylic acid groups of the gelators. We also demonstrate how chemical shift imaging (CSI) techniques can be applied to follow the formation of hydrogels along chemical gradients. We apply CSI to study the binding of Ca2+ and subsequent gelation of peptide assemblies at alkaline pH. Using metal ion-binding molecules as probes, we are able to detect the presence of bound Ca2+ ions on the surface of the gel fibres. We briefly explore how knowledge of the surface chemical properties of hydrogels could be used to inform their practical application in fields such as drug delivery and environmental remediation.

Using solution state NMR spectroscopy to probe NMR invisible gelators.

Supramolecular hydrogels are formed via the self-assembly of gelator molecules upon application of a suitable trigger. The exact nature of this self-assembly process has been widely investigated as a practical understanding is vital for the informed design of these materials. Solution-state NMR spectroscopy is an excellent non-invasive tool to follow the self-assembly of supramolecular hydrogels. However, in most cases the self-assembled aggregates are silent by conventional (1)H NMR spectroscopy due to the low mobility of the constituent molecules, limiting NMR spectroscopy to following only the initial assembly step(s). Here, we present a new solution-state NMR spectroscopic method which allows the entire self-assembly process of a dipeptide gelator to be followed. This gelator forms transparent hydrogels by a multi-stage assembly process when the pH of an initially alkaline solution is lowered via the hydrolysis of glucono-δ-lactone (GdL). Changes in the charge, hydrophobicity and relative arrangement of the supramolecular aggregates can be followed throughout the assembly process by measuring the residual quadrupolar couplings (RQCs) of various molecular probes (here, (14)NH4(+) and isopropanol-d8), along with the NMR relaxation rates of (23)Na(+). The initially-formed aggregates comprise negatively charged fibrils which gradually lose their charge and become increasingly hydrophobic as the pH falls, eventually resulting in a macroscopic contraction of the hydrogel. We also demonstrate that the in situ measurement of pH by NMR spectroscopy is both convenient and accurate, representing a useful tool for the characterisation of self-assembly processes by NMR.

Magnetically aligned supramolecular hydrogels.

The magnetic-field-induced alignment of the fibrillar structures present in an aqueous solution of a dipeptide gelator, and the subsequent retention of this alignment upon transformation to a hydrogel upon the addition of CaCl2 or upon a reduction in solution pH is reported. Utilising the switchable nature of the magnetic field coupled with the slow diffusion of CaCl2 , it is possible to precisely control the extent of anisotropy across a hydrogel, something that is generally very difficult to do using alternative methods. The approach is readily extended to other compounds that form viscous solutions at high pH. It is expected that this work will greatly expand the utility of such low-molecular-weight gelators (LMWG) in areas where alignment is key.

Cooperative catalysis: combining an achiral metal catalyst with a chiral Brønsted acid enables highly enantioselective hydrogenation of imines.

Asymmetric hydrogenation of imines leads directly to chiral amines, one of the most important structural units in chemical products, from pharmaceuticals to materials. However, highly effective catalysts are rare. This article reveals that combining an achiral pentamethylcyclopentadienyl (Cp*)-iridium complex with a chiral phosphoric acid affords a catalyst that allows for highly enantioselective hydrogenation of imines derived from aryl ketones, as well as those derived from aliphatic ones, with ee values varying from 81 to 98 %. A range of achiral iridium complexes containing diamine ligands were examined, for which the ligands were shown to have a profound effect on the reaction rate, enantioselectivity and catalyst deactivation. The chiral phosphoric acid is no less important, inducing enantioselection in the hydrogenation. The induction occurs, however, at the expense of the reaction rate.

Modular synthesis of bicyclic twisted amides and anilines.

Bridged amides and anilines display interesting properties owing to perturbation of conjugation of the nitrogen lone-pair with the adjacent π-system. A convergent approach to diazabicyclic scaffolds which contain either twisted amides or anilines is described, based on the photocatalysed hydroamination of cyclic enecarbamates and subsequent cyclisation. The modular nature of the synthesis allows for variation of the degree of 'twist' and hence the properties of the amides and anilines.

Thiazolide Prodrug Esters and Derived Peptides: Synthesis and Activity.

Amino acid ester prodrugs of the thiazolides, introduced to improve the pharmacokinetic parameters of the parent drugs, proved to be stable as their salts but were unstable at pH > 5. Although some of the instability was due to simple hydrolysis, we have found that the main end products of the degradation were peptides formed by rearrangement. These peptides were stable solids: they maintained significant antiviral activity, and in general, they showed improved pharmacokinetics (better solubility and reduced clearance) compared to the parent thiazolides. We describe the preparation and evaluation of these peptides.

Hydrogen-bonding-promoted oxidative addition and regioselective arylation of olefins with aryl chlorides.

The first, general, and highly efficient catalytic system that allows a wide range of activated and unactivated aryl chlorides to couple regioselectively with olefins has been developed. The Heck arylation reaction is likely to be controlled by the oxidative addition of ArCl to Pd(0). Hence, an electron-rich diphosphine, 4-MeO-dppp, was introduced to facilitate the catalysis. Solvent choice is critical, however; only sluggish arylation is observed in DMF or DMSO, whereas the reaction proceeds well in ethylene glycol at 0.1-1 mol % catalyst loadings, displaying excellent regioselectivity. Mechanistic evidence supports that the arylation is turnover-limited by the oxidative addition step and, most importantly, that the oxidative addition is accelerated by ethylene glycol, most likely via hydrogen bonding to the chloride at the transition state as shown by DFT calculations. Ethylene glycol thus plays a double role in the arylation, facilitating oxidative addition and promoting the subsequent dissociation of chloride from Pd(II) to give a cationic Pd(II)-olefin species, which is key to the regioselectivity observed.

Phosphine ligands in the palladium-catalysed methoxycarbonylation of ethene: insights into the catalytic cycle through an HP NMR spectroscopic study.

Novel cis-1,2-bis(di-tert-butyl-phosphinomethyl) carbocyclic ligands 6-9 have been prepared and the corresponding palladium complexes [Pd(O(3)SCH(3))(L-L)][O(3)SCH(3)] (L-L=diphosphine) 32-35 synthesised and characterised by NMR spectroscopy and X-ray diffraction. These diphosphine ligands give very active catalysts for the palladium-catalysed methoxycarbonylation of ethene. The activity varies with the size of the carbocyclic backbone, ligands 7 and 9, containing four- and six-membered ring backbones giving more active systems. The acid used as co-catalyst has a strong influence on the activity, with excess trifluoroacetic acid affording the highest conversion, whereas excess methyl sulfonic acid inhibits the catalytic system. An in operando NMR spectroscopic mechanistic study has established the catalytic cycle and resting state of the catalyst under operating reaction conditions. Although the catalysis follows the hydride pathway, the resting state is shown to be the hydride precursor complex [Pd(O(3)SCH(3))(L-L)][O(3)SCH(3)], which demonstrates that an isolable/detectable hydride complex is not a prerequisite for this mechanism.

The acyl nitroso Diels-Alder (ANDA) reaction of sorbate derivatives: an X-ray and 15N NMR study with an application to amino-acid synthesis.

We present a study of the acyl nitroso Diels-Alder (ANDA) reaction of sorbate esters and sorbic alcohol derivatives, using alkoxycarbonyl nitroso dienophiles. An optimisation of the reaction conditions for ethyl sorbate is first presented, and the product is used in an efficient synthesis of 5-methylornithine. Structure-reactivity trends in sorbic alcohol (E,E-2,4-hexadien-1-ol) and its acylated analogues are then discussed. We present single-crystal X-ray structural proof for key adducts in both series and present in detail a novel HMBC/HSQC ((1)H-(15)N) criterion for ready distinction of regioisomers arising from such ANDA reactions.

Direct acylation of aryl bromides with aldehydes by palladium catalysis.

A new protocol for the direct acylation of aryl bromides with aldehydes is established. It appears to involve palladium-amine cooperative catalysis, affording synthetically important alkyl aryl ketones in moderate to excellent yields in a straightforward manner, and broadening the scope of metal-catalyzed coupling reactions.

The reaction of mixtures of [Rh4(CO)12] and triphenylphosphite with carbon monoxide or syngas as studied by high-resolution, high-pressure NMR spectroscopy.

The fragmentation and redistribution reactions of [Rh4(CO)12-x{P(OPh)3}x] (x = 1-4) with carbon monoxide have been studied using high-resolution, high-pressure NMR spectroscopy. Under the conditions of efficient gas mixing in a high-pressure NMR bubble column, [Rh4(CO)9{P(OPh)3}3] fragments to give mainly [Rh2(CO)6{P(OPh)3}2]; [Rh4(CO)11{P(OPh)3}] is also observed,implying redistribution of the phosphite ligand and/or recombination of the dimers to tetrameric clusters. Fragmentation of[Rh4(CO)10{P(OPh)3}2] is found to be pressure-dependent giving predominantly [Rh2(CO)6{P(OPh)3}2] at low CO pressure (1-40 bar), and increasing amounts of [Rh2(CO)7{P(OPh)3}] at higher (40-80 bar) pressure. Using Syngas (CO : H2 (1 : 1)) instead of CO in the above fragmentations, homolytic addition of H2 to the dimer [Rh2(CO)6{P(OPh)3}2] to give [RhH(CO)3{P(OPh3}] and [RhH(CO)2{P(OPh)3}2] is observed. The distribution of tetrameric species obtained is similar to that obtained under the same partial pressure of CO. On depressurisation/out-gassing of the sample, the original mixture of tetrameric clusters is obtained.

Methanol as hydrogen source: transfer hydrogenation of aromatic aldehydes with a rhodacycle.

A cyclometalated rhodium complex has been shown to perform highly selective and efficient reduction of aldehydes, deriving the hydrogen from methanol. With methanol as both the solvent and hydrogen donor under mild conditions and an open atmosphere, a wide range of aromatic aldehydes were reduced to the corresponding alcohols, without affecting other functional groups.

The effect of mechanistic pathway on activity in the Pd and Pt catalysed methoxycarbonylation of ethene.

All the intermediates involved in the platinum catalysed methoxycarbonylation of ethene have been characterised by in situ NMR; the low activity of platinum catalysts in this reaction is shown to be due to trapping of the active intermediates by carbon monoxide at every step in the catalytic cycle and to the ready reversibility of the product forming reactions.

Direct synthesis of 1-indanones via Pd-catalyzed olefination and ethylene glycol-promoted aldol-type annulation cascade.

A wide range of multisubstituted 1-indanones of potential pharmaceutical use were synthesized in a one-pot fashion in moderate to excellent yields via palladium catalysis in ethylene glycol. The Heck reaction first installs an enol functionality on the aromatic ring; this is followed by an ethylene glycol promoted aldol-type annulation with a neighboring carbonyl group, resulting in the formation of various 1-indanones.

The synthesis of, and characterization of the dynamic processes occurring in Pd(II) chelate complexes of 2-pyridyldiphenylphosphine.

Pd(II) complexes in which 2-pyridyldiphenylphosphine (Ph(2)Ppy) chelates the Pd(II) centre have been prepared and characterized by multinuclear NMR spectroscopy and by X-ray crystallographic analysis. trans-[Pd(kappa(1)-Ph(2)Ppy)(2)Cl(2)] is transformed into [Pd(kappa(2)-Ph(2)Ppy)(kappa(1)-Ph(2)Ppy)Cl]Cl by the addition of a few drops of methanol to dichloromethane solutions, and into [Pd(kappa(2)-Ph(2)Ppy)(kappa(1)-Ph(2)Ppy)Cl]X by addition of AgX or TlX, (X = BF(4)(-), CF(3)SO(3)(-) or MeSO(3)(-)). [Pd(kappa(1)-Ph(2)Ppy)(2)(p-benzoquinone)] can be transformed into [Pd(kappa(2)-Ph(2)Ppy)(kappa(1)-Ph(2)Ppy)(MeSO(3))][MeSO(3)] by the addition of two equivalents of MeSO(3)H. Addition of further MeSO(3)H affords [Pd(kappa(2)-Ph(2)Ppy)(kappa(1)-Ph(2)PpyH)(MeSO(3))][MeSO(3)](2). Addition of two equivalents of CF(3)SO(3)H, MeSO(3)H or CF(3)CO(2)H and two equivalents of Ph(2)Ppy to [Pd(OAc)(2)] in CH(2)Cl(2) or CH(2)Cl(2)-MeOH affords [Pd(kappa(2)-Ph(2)Ppy)(kappa(1)-Ph(2)Ppy)X]X, (X = CF(3)SO(3)(-), MeSO(3)(-) or CF(3)CO(2)(-)), however addition of two equivalents of HBF(4).Et(2)O affords a different complex, tentatively formulated as [Pd(kappa(2)-Ph(2)Ppy)(2)]X(2). Addition of excess acid results in the clean formation of [Pd(kappa(2)-Ph(2)Ppy)(kappa(1)-Ph(2)PpyH)(X)]X(2). In methanol, addition of MeSO(3)H and three equivalents of Ph(2)Ppy to [Pd(OAc)(2)] affords [Pd(kappa(2)-Ph(2)Ppy)(kappa(1)-Ph(2)Ppy)(2)][MeSO(3)](2) as the principal Pd-phosphine complex. The fluxional processes occuring in these complexes and in [Pd (kappa(1)-Ph(2)Ppy)(3)Cl]X, (X = Cl, OTf) and the potential for hemilability of the Ph(2)Ppy ligand has been investigated by variable-temperature NMR. The activation entropy and enthalpy for the regiospecific fluxional processes occuring in [Pd(kappa(2)-Ph(2)Ppy)(kappa(1)-Ph(2)Ppy)(2)][MeSO(3)](2) have been determined and are in the range -10 to -30 J mol(-1) K(-1) and ca. 30 kJ mol(-1) respectively, consistent with associative pathways being followed. The observed regioselectivities of the exchanges are attributed to the constraints imposed by microscopic reversibility and the small bite angle of the Ph(2)Ppy ligand. X-Ray crystal structure determinations of trans-[Pd(kappa(1)-Ph(2)Ppy)(2)Cl(2)], [Pd(kappa(2)-Ph(2)Ppy)(kappa(1)-Ph(2)Ppy)Cl][BF(4)], [Pd(kappa(1)-Ph(2)Ppy)(2)(p-benzoquinone)], trans-[Pd(kappa(1)-Ph(2)PpyH)(2)Cl(2)][MeSO(3)](2), and [Pd(kappa(1)-Ph(2)Ppy)(3)Cl](Cl) are reported. In [Pd(kappa(2)-Ph(2)Ppy)(kappa(1)-Ph(2)Ppy)Cl][BF(4)] a donor-acceptor interaction is seen between the pyridyl-N of the monodentate Ph(2)Ppy ligand and the phosphorus of the chelating Ph(2)Ppy resulting in a trigonal bipyramidal geometry at this phosphorus.