Liquid-phase combinatorial synthesis.

A concept termed liquid-phase combinatorial synthesis (LPCS) is described. The central feature of this methodology is that it combines the advantages that classic organic synthesis in solution offers with those that solid-phase synthesis can provide, through the application of a linear homogeneous polymer. To validate this concept two libraries were prepared, one of peptide and the second of nonpeptide origin. The peptide-based library was synthesized by a recursive deconvolution strategy [Erb, E., Janda, K. D. & Brenner, S. (1994) Proc. Natl. Acad. Sci. USA 91, 11422-11426] and several ligands were found within this library to bind a monoclonal antibody elicited against beta-endorphin. The non-peptide molecules synthesized were arylsulfonamides, a class of compounds of known clinical bactericidal efficacy. The results indicate that the reaction scope of LPCS should be general, and its value to multiple, high-throughput screening assays could be of particular merit, since multimilligram quantities of each library member can readily be attained.

Double-level “orthogonal” dynamic combinatorial libraries on transition metal template

Dynamic combinatorial libraries are mixtures of compounds that exist in a dynamic equilibrium and can be driven to compositional self adaptation via selective binding of a specific assembly of certain components to a molecular target. We present here an extension of this initial concept to dynamic libraries that consists of two levels, the first formed by the coordination of terpyridine-based ligands to the transition metal template, and the second, by the imine formation with the aldehyde substituents on the terpyridine moieties. Dialdehyde 7 has been synthesized, converted into a variety of ligands, oxime ethers L11–L33 and acyl hydrazones L44–L77, and subsequently into corresponding cobalt complexes. A typical complex, Co(L22)22+ is shown to engage in rapid exchange with a competing ligand L11 and with another complex, Co(L22)22+ in 30% acetonitrile/water at pH 7.0 and 25°C. The exchange in the corresponding Co(III) complexes is shown to be much slower. Imine exchange in the acyl hydrazone complexes (L44–L77) is strongly controlled by pH and temperature. The two types of exchange, ligand and imine, can thus be used as independent equilibrium processes controlled by different types of external intervention, i.e., via oxidation/reduction of the metal template and/or change in the pH/temperature of the medium. The resulting double-level dynamic libraries are therefore named orthogonal, in similarity with the orthogonal protecting groups in organic synthesis. Sample libraries of this type have been synthesized and showed the complete expected set of components in electrospray ionization MS.

Surface geochemistry of the clay minerals

Clay minerals are layer type aluminosilicates that figure in terrestrial biogeochemical cycles, in the buffering capacity of the oceans, and in the containment of toxic waste materials. They are also used as lubricants in petroleum extraction and as industrial catalysts for the synthesis of many organic compounds. These applications derive fundamentally from the colloidal size and permanent structural charge of clay mineral particles, which endow them with significant surface reactivity. Unraveling the surface geochemistry of hydrated clay minerals is an abiding, if difficult, topic in earth sciences research. Recent experimental and computational studies that take advantage of new methodologies and basic insights derived from the study of concentrated ionic solutions have begun to clarify the structure of electrical double layers formed on hydrated clay mineral surfaces, particularly those in the interlayer region of swelling 2:1 layer type clay minerals. One emerging trend is that the coordination of interlayer cations with water molecules and clay mineral surface oxygens is governed largely by cation size and charge, similarly to a concentrated ionic solution, but the location of structural charge within a clay layer and the existence of hydrophobic patches on its surface provide important modulations. The larger the interlayer cation, the greater the influence of clay mineral structure and hydrophobicity on the configurations of adsorbed water molecules. This picture extends readily to hydrophobic molecules adsorbed within an interlayer region, with important implications for clay–hydrocarbon interactions and the design of catalysts for organic synthesis.