Chiral imprinting of palladium with cinchona alkaloids.

In the search for new materials and concepts in materials science, metallo-organic hybrids are attractive candidates; they can combine the rich diversity of organic molecules with the advantages of metals. Transition metals such as palladium are widely applied in catalysis, and small organic molecules such as those in the cinchona alkaloid family can control the stereochemistry of a number of organic reactions. Here, we show that reducing a metal salt in the presence of a cinchona alkaloid dopant gives a chirally imprinted metallo-organic hybrid material that is catalytically active and shows moderate enantioselectivity in hydrogenation. Furthermore, using photoelectron emission spectroscopy, we show that the metal retains some chiral character even after extraction of the dopant. This simple and effective methodology opens exciting opportunities for developing a variety of chiral composite materials.

Getting a library of activities from a single compound: tunability and very large shifts in acidity constants induced by sol--gel entrapped micelles.

Acidity constants (in terms of K(i) values) can be fine-tuned, their values can be pushed to extremes, and their location can be placed either at the basic or acidic range of the pH scale, by tailoring intra-cage properties of SiO(2) sol--gel materials with surfactants. With the entrapped "solid-state pseudomicelles", an 8-orders magnitude K(i) shift--from the high-basic pH region to the acidic one--was obtained for acid fuchsin (AF); and tunability of the pK(i) values of the solvatochromic dye E(T)(30) and of crystal violet over much of the pH scale was achieved. This tailoring of various activities from the same dopant was achieved either by utilizing surfactants of different nature or by utilizing mixtures of anionic/cationic surfactants. The extraction of a wide range of reactivities from a single compound and the ability to fine-tune it is a powerful concept with potential extensions beyond acid/base reactions.

Continuous symmetry analysis of tetrahedral/planar distortions. Copper chlorides and other AB4 species.

The symmetry of tetracoordinated copper complexes, especially of CuCl4(2-), is analyzed in terms of quantitative continuous symmetry. These complexes acquire structures that span from tetrahedral to planar, with all gradual variations in between, a property that is evaluated here in terms of their degrees of tetrahedricity (S(Td)) and square planarity (S(D4h)). It was found that out of the large arsenal of geometry-allowed tetrahedral structures, each of which is characterized by specific S(Td) and S(D4h) pair values, copper complexes concentrate on an extremely well-defined correlation line linking these two symmetry-content measures; that is, only very specific pairs of S(Td) and S(D4h) values that dictate each other are allowed. Furthermore, it was found that of the various routes that can lead from a tetrahedron to a planar square, the mode known as spread fits exactly in its symmetry S(Td)/S(D4h) characteristics the observed symmetry behavior of the copper complexes. Interestingly, the spread mode reflects also the (nearly) minimal possible values of S(Td)/S(D4h) pairs, namely, the minimal symmetry-distortive route. Hints that this symmetry correlation line reflects universal features that go beyond copper are provided by the symmetry-content analysis of Ni and Pt complexes, of various Zn complexes within a metalloprotein and even of CC4 fragments, all of which obey the same line. A new potential-energy surface is introduced, the axes of which are S(Td), S(D4h), and the energy. Calculating this surface for CuCl4(2-) reveals an important result: The minimal molecular symmetry distortive spread correlation line coincides with the (only) energy valley of the map. Symmetry and energy are intimately related in their drive to minimal values.

Quantitative chirality/enantioselectivity relations in large random supramolecular structures

We study the relationship between shape and enantioselectivity, employing quantitative geometric chirality measurements. The model we use comprises of the boundary surfaces of two-dimensional (2D) chiral, large, random selectors (diffusion limited aggregates), interacting with homologous series of small 2D-chiral S-shaped probes (the selectands). We show how the enantioselectivity of the selectors depends on the chirality of the selectands and report the following findings: I) The enantioselectivity of a chiral selector can switch preference from the "right" to the "left" enantiomer within a homologous series of selectands. II) At this switch point the chiral selector is functionally achiral. III) Within a homologous series of chiral selectands, there is a "resonance of recognition", namely, the classical key-lock concept is replaced by a picture of various degrees of recognition. IV) The degree of enantioselectivity and the switch in handedness preference are the outcome of a complex interplay between the details of the specific geometry of the selector and the selectand, and the global shape parameter of chirality measure. V) It is shown that isochiral selectands, namely selectands of the same chirality value, may be recognized differently by a chiral selector. VI) It is proposed that a more realistic way to treat the issue of minimal points needed for chiral interaction is resolution based. VII) It is shown how to attach handedness to purely random objects.

Pattern formation and a clustering transition in power-law sequential adsorption.

We present a model that describes adsorption and clustering of particles on a surface. A clustering transition is found that separates between a phase of weakly correlated particle distributions and a phase of strongly correlated distributions in which the particles form localized fractal clusters. The order parameter of the transition is identified and the fractal nature of both phases is examined. The model is relevant to a large class of clustering phenomena such as aggregation and growth on surfaces, population distribution in cities, and plant and bacterial colonies, as well as gravitational clustering.

The evolution of chemical patterns in reactive liquids, driven by hydrodynamic instabilities.

We summarize our activity in unveiling a very wide phenomenon: When a chemical reaction takes place at a liquid interface, spectacular patterns of product form (see Plate 1). The pattern formation phenomenon is general, and is observed in reactions between liquids separated by a membrane, in liquids subjected to gaseous reactants, and in photoreactive liquids. We have demonstrated the phenomenon on over 100 different reactions of all types, thus discovering what we believe to be one of the widest macroscopic pattern formation processes known to chemistry. As can be seen in the accompanying pictures, the richness, beauty, and variations in types of patterns can be breathtaking. Two important aspects of these patterns are noted: First, the patterns are true far-from-equilibrium structures, which are maintained only as long as reactants are available, or only as long as light energy is supplied to the system; and second, the chemical products that form the patterns are not precipitates, but are entirely soluble in the liquid in which they form. Thus, if the containers in which the patterns form are shaken or stirred, a homogeneous solution results. Our research of this phenomenon concentrated on three main aspects. The first one was phenomenological. Here we explored the scope and generality of the phenomenon, motivated both by the aesthetic appeal of the phenomenon, and by the puzzle of how is it that such a wide-scope, experimentally simple phenomenon, has by and large, escaped the attention of the scientific community.The second aspect was devoted to the understanding of the underlying general mechanism. Of the many mechanisms we analyzed and tested, some very complex, others quite trivial, the one that fits the majority of the physical and chemical observations is the following: By performing a reaction through a liquid interface, a concentration gradient of the product forms near the interface. We have shown that in many cases, these gradients lead to hydrodynamic instabilities, which then break nonlinearly into a pattern which onsets slow convections. In other words, we found that these patterns mark the route along which a chemical instability relaxes. The third aspect of our research was theoretical. Here we concentrated in depth on one of the reactions (the Fe(+2)/Fe(+3) photoredox reaction), determined all its important physical parameters, and modeled its behavior theoretically. Our model, which was based on the instability buildup described above, was solved numerically, and its results compared with computerized image analysis of the evolving patterns; very good agreement between theory and experiment, was obtained. (c) 1995 American Institute of Physics.

Pharmacokinetic analysis of diethylcarbonate prodrugs of ibuprofen and naproxen.

The pharmacokinetics of ibuprofen diethylcarbonate (ibudice) and naproxen diethythylcarbonate (napdice), two new diethylcarbonate prodrugs of ibuprofen and naproxen, was investigated in dogs. The rationale for the development of ibudice and napdice was that esterification of the carboxylic moiety of the parent compounds would suppress gastrotoxicity without adversely affecting their anti-inflammatory activity. In addition the biotransformation of the prodrugs to the parent compounds may be utilized to achieve rate and time controlled drug delivery of the active entities. Following oral administration the diethylcarbonate esters were rapidly biotransformed to the parent compounds and no ibudice or napdice was detected in the plasma. The relative bioavailability of ibuprofen and naproxen, following oral administration of ibudice and napdice, was 96% and 74%, respectively, and the rate of absorption was not significantly different from that obtained following oral dosing of the parent compound. Stability studies in gastric and intestinal juice showed that, unlike napdice, ibudice was stable in gastric juice, with both prodrugs undergoing rapid biotransformation to their parent compounds in intestinal juice. This rapid conversion led to the lack of sustained release performance following oral administration of ibudice or napidice.

Properties of trypsin and of acid phosphatase immobilized in sol-gel glass matrices.

Trypsin and acid phosphatase-containing silica sol-gel glasses were obtained by mixing a solution of an enzyme with polyethylene glycol (PEG) 6000 and tetramethoxy orthosilicate at room temperature, followed by gelation and drying. Activity of the immobilized trypsin toward small substrates, such as N-benzoyl-L-arginine-4-nitroanilide at its Km, for the best preparations equaled that of the soluble enzyme. Polylysine (M(r) less than or equal to 13,000) and aprotinin (M(r) = 6,500) inhibited this activity. Larger polylysines as well as soybean trypsin inhibitor (M(r) = 20,100) were ineffective. The sol-gel-entrapped trypsin activity was stable when sol-gel glasses were incubated at ambient temperature (pH 7.5) for several months. In comparison, trypsin, immobilized in sol-gel glass by surface adsorption and incubated under the same conditions overnight, was completely autodigested. The firm interaction between the protein molecules and the silica matrix stabilized the enzymes. Thus, the half-life of sol-gel-entrapped acid phosphatase at 70 degrees C (pH 8.0) was two orders of magnitude larger than that of the enzyme in solution. Transparent, mechanically and chemically stable bioactive sol-gel glasses may be used for the development of robust on-line biochemical photodetection sensors and for the purposes of chemical catalysis.

Use of fractal geometry to determine effects of surface morphology on drug dissolution.

We extend and modify the Noyes-Whitney equation and the Hixon-Crowell cube root law to include surface roughness effects on the dissolution rate of drugs. The problem is treated theoretically in terms of the fractal reaction dimension, DR, of the effective surface which undergoes dissolution. Effects of changes in DR on the dissolution rate are identified and explained.

Fractal analysis of size effects and surface morphology effects in catalysis and electrocatalysis.

Fractal geometry tools are used in order to analyze several related problems in surface science, catalysis, and electrocatalysis. The effects of complex morphologies of adsorbents, catalysts, and electrodes on various molecular processes with these materials are determined both theoretically and experimentally. It is shown that fractal geometry provides a convenient and natural tool for the elucidation of geometry-performance relations in heterogeneous chemistry. Issues covered are particle size effects in physisorption and chemisorption; morphology effects on a variety of catalytic processes with unsupported catalysts (including coal liquefaction, alkene polymerizations, oxidations, dehydrogenations, and esterifications); surface accessibility effects on molecular interactions in an Eley-Rideal mechanism; surface patterning effects on concentration profiles near the surface; and electrode-morphology effects on a variety of electrochemical and electrocatalytic processes. The domains of applicability of the fractal approach to these problems is discussed.

Spatial dissipative structures formed by spontaneous molecular aggregation at interfaces.

Interfacial processes as well as formation of dissipative structures have been suggested to play a key role in early pre-biotic evolutionary stages, mainly due to the ability of such processes to induce aggregation and spatial structuring. In this context we would like to draw attention to our recent findings regarding a remarkably wide collection of interfacial chemical reactions which form dissipative spatial structures. Three types of interfacial processes were found to yield this phenomenon: photochemical oxidations at liquid/air and liquid/liquid interfaces; gas/solution reactions; and reactions at membrane surfaces. The phenomenon we describe is the first major example of a network of chemical reactions that develop into macroscopic far-from-equilibrium concentration patterns.

Multiple resolution texture analysis and classification.

Textures are classified based on the change in their properties with changing resolution. The area of the gray level surface is measured at serveral resolutions. This area decreases at coarser resolutions since fine details that contribute to the area disappear. Fractal properties of the picture are computed from the rate of this decrease in area, and are used for texture comparison and classification. The relation of a texture picture to its negative, and directional properties, are also discussed.

Mutagenicity of phenanthrene and phenanthrene K-region derivatives.

Phenanthrene and 9 K-region derivatives, most of them potential metabolites of phenanthrene, were tested for mutagenicity by the reversion of histidine-dependent Salmonella typhimurium TA1535, TA1537, TA1538, TA98 and TA100 and the rec assay with Bacillus subtilis H17 and M45. The strongest mutagenic effects in the reversion assay were observed with phenanthrene 9,10-oxide, 9-hydroxyphenanthrene and N-benzyl-phenanthrene-9,10-imine. Interestingly, the mutagenic potency of the arene imine was similar to that of the corresponding arene oxide. This is the first report on the mutagenicity of arene imine. The mutagenic effects of all these phenanthrene derivatives were much weaker than that of the positive control benzo[a]pyrene 4,5-oxide. Even weaker mutagenicty was found with cis-9,10-dihydroxy-9,10-dihydrophenanthrene and with trans-9,10-dihydroxy-9-10-dihydrophenanthrene. The other derivatives were inactive in this test. However, 9-10-dihydroxyphenanthrene and 9,10-phenanthrenequinone were more toxic to the rec- B. subtilis M45 strain than to the rec+ H17 strain. This was also true for phenanthrene 9,10-oxide and 9-hydroxyphenanthrene, but not with the other test compounds that reverted (9,10-dihydroxy-9,10-dihydrophenanthrenes; N-benzyl-phenanthrene 9,10-imine; benzo[a]pyrene 4,5-oxide) or did not revert (phenanthrene, 9,10-bis-(p-chlorophenyl)-phenanthrene 9,10-oxide, 9-10-diacetoxyphenanthrene) the Salmonella tester strains. Although the K region is a main site of metabolism and although all potential K-region metabolites were mutagenic, phenanthrene did not show a mutagenic effect in the presence of mouse-liver microsomes and an NADPH-generating system under standard conditions. However, uhen epoxide hydratase was inhibited, phenanthrene was activated to a mutagen that reverted his- S. typhimurium. This shows that demonstration of the mutagenic activity of metabolites together with the knowledge that a major metabolic route proceeds via these metabolites dose not automatically imply a mutagenic hazard of the mother compound, because the metabolites in question may not accumulate in sufficient quantities and therefore the presence and relative activities of enzymes that control the mutagenically active metabolites are crucial. N-Benzyl-phenanthrene 9.10-imine was mutagenic for the episome-containing S. typhimurium TA98 and TA100 but not for the precursor strains TA1538 and TA1535. This arene imine would therefore be useful as a positive control during routine testing to monitor in the former strains the presence of the episome which is rather easily lost.