Ligand Hydrogenation during Hydroformylation Catalysis Detected by In Situ High-Pressure Infra-Red Spectroscopic Analysis of a Rhodium/Phospholene-Phosphite Catalyst.

Phospholane-phosphites are known to show highly unusual selectivity towards branched aldehydes in the hydroformylation of terminal alkenes. This paper describes the synthesis of hitherto unknown unsaturated phospholene borane precursors and their conversion to the corresponding phospholene-phosphites. The relative stereochemistry of one of these ligands and its Pd complex was assigned with the aid of X-ray crystal structure determinations. These ligands were able to approach the level of selectivity observed for phospholane-phosphites in the rhodium-catalysed hydroformylation of propene. High-pressure infra-red (HPIR) spectroscopic monitoring of the catalyst formation revealed that whilst the catalysts showed good thermal stability with respect to fragmentation, the C=C bond in the phospholene moiety was slowly hydrogenated in the presence of rhodium and syngas. The ability of this spectroscopic tool to detect even subtle changes in structure, remotely from the carbonyl ligands, underlines the usefulness of HPIR spectroscopy in hydroformylation catalyst development.

Effects of the Morphology, Surface Modification and Application Methods of ZnO-NPs on the Growth and Biomass of Tomato Plants.

Benefits of nanotechnology in agriculture include reduced fertilizer loss, improved seed germination rate and increased crops quality and yield. The objective of this research was to evaluate the effects of zinc oxide nanoparticles (ZnO-NPs), at 1500 ppm, on tomato (Solanum lycopersicum L.) growth. ZnO-NPs were synthetized to produce either spherical or hexagonal morphologies. In this research, we also studied two application methods (foliar and drench) and nanoparticles' (NPs) surface modification with maltodextrin. The results obtained indicate that ZnO-NP-treated tomato plants significantly increased plant height, stem diameter and plant organs (leaves, stem and root) dry weight compared to plants without NP treatment.

High iso Aldehyde Selectivity in the Hydroformylation of Short-Chain Alkenes.

The hydroformylation of propene to give predominantly iso-butanal has been achieved; class-leading selectivity is possible even at higher temperatures that deliver fast conversion. Racemic rhodium complexes of bidentate phospholane phosphites derived from tropos-biphenols and unusual solvent systems are the key to the selectivity observed.

Understanding a Hydroformylation Catalyst that Produces Branched Aldehydes from Alkyl Alkenes.

This paper reports experimental and computational studies on the mechanism of a rhodium-catalyzed hydroformylation that is selective for branched aldehyde products from unbiased alkene substrates. This highly unusual selectivity relies on a phospholane-phosphite ligand prosaically called BOBPHOS. Kinetic studies using in situ high pressure IR (HPIR) and the reaction progress kinetic analysis methodology suggested two steps in the catalytic cycle were involved as turnover determining. Negative order in CO and positive orders in alkene and H2 were found and the effect of hydrogen and carbon monoxide partial pressures on selectivity were measured. Labeling studies found rhodium hydride addition to the alkene to be largely irreversible. Detailed spectroscopic HPIR and NMR characterization of activated rhodium-hydrido dicarbonyl species were carried out. In the absence of H2, reaction of the rhodium-hydrido dicarbonyl with allylbenzene allowed further detailed spectroscopic characterization of four- and five-coordinate rhodium-acyl species. Under single-turnover conditions, the ratios of branched to linear acyl species were preserved in the final ratios of aldehyde products. Theoretical investigations uncovered unexpected stabilizing CH-π interactions between the ligand and substrate which influenced the high branched selectivity by causing potentially low energy pathways to become unproductive. Energy span and degree of TOF control analysis strongly support experimental observations and mechanistic rationale. A three-dimensional quadrant model was built to represent the structural origins of regio- and enantioselectivity.

Rapid Asymmetric Transfer Hydroformylation (ATHF) of Disubstituted Alkenes Using Paraformaldehyde as a Syngas Surrogate.

As an alternative to conventional asymmetric hydroformylation (AHF), asymmetric transfer hydroformylation (ATHF) by using formaldehyde as a surrogate for syngas is reported. A catalyst derived from commercially available [Rh(acac)(CO)2 ] (acac=acetylacetonate) and 1,2-bis[(2S,5S)-2,5-diphenylphospholano]ethane(1,5-cyclooctadiene) (Ph-BPE) stands out in terms of both activity and enantioselectivity. Remarkably, not only are high selectivities achievable, the reactions are very simple to perform, and higher enantioselectivity (up to 96 % ee) and/or turnover frequencies than those achievable by using the same catalyst (or other leading catalysts) can be obtained by using typical conditions for AHF.

On the Functional Group Tolerance of Ester Hydrogenation and Polyester Depolymerisation Catalysed by Ruthenium Complexes of Tridentate Aminophosphine Ligands.

The synthesis of a range of phosphine-diamine, phosphine-amino-alcohol, and phosphine-amino-amide ligands and their ruthenium(II) complexes are reported. Five of these were characterised by X-ray crystallography. The activities of this collection of catalysts were initially compared for the hydrogenation of two model ester hydrogenations. Catalyst turnover frequencies up to 2400 h(-1) were observed at 85 °C. However, turnover is slow at near ambient temperatures. By using a phosphine-diamine Ru(II) complex, identified as the most active catalyst, a range of aromatic esters were reduced in high yield. The hydrogenation of alkene-, diene-, and alkyne-functionalised esters was also studied. Substrates with a remote, but reactive terminal alkene substituent could be reduced chemoselectively in the presence of 4-dimethylaminopyridine (DMAP) co-catalyst. The chemoselective reduction of the ester function in conjugated dienoate ethyl sorbate could deliver (2E,4E)-hexa-2,4-dien-1-ol, a precursor to leaf alcohol. The monounsaturated alcohol (E)-hex-4-en-1-ol was produced with reasonable selectivity, but complete chemoselectivity of C=O over the diene is elusive. High chemoselectivity for the reduction of an ester over an alkyne group was observed in the hydrogenation of an alkynoate for the first time. The catalysts were also active in the depolymerisation reduction of samples of waste poly(ethylene terephthalate) (PET) to produce benzene dimethanol. These depolymerisations were found to be poisoned by the ethylene glycol side product, although good yields could still be achieved.

CuO-NPs Improve Biosynthesis of Bioactive Compounds in Lettuce.

The application of metallic nanoparticles improves the yield and content of bioactive compounds in plants. The aim of the present study was to determine the effects of the foliar application of copper nanoparticles (CuO-NPs) in the yield and content of bioactive compounds in lettuce. Different concentrations of CuO-NPs (0, 0.5, 1, 2, 4, and 6 mg mL-1) were applied in lettuce. The yield, nutraceutical quality, and enzymatic activity were determined. Foliar spraying of CuO-NPs induced an increase in the biosynthesis of bioactive compounds. In addition to an increase in the activity of the enzymes superoxide dismutase (SOD) and catalase (CAT) in lettuce plants, there were no negative effects on yield. Therefore, with the application of CuO-NPs, better quality lettuces are produced for the human diet due to the higher production of bioactive compounds.

Palladium-catalysed synthesis of aryl-alkyl ethers using alkoxysilanes as nucleophiles.

Changing the activator from tetrabutyl ammonium fluoride (TBAF) to sodium hydroxide unexpectedly switches the catalytic pathway of the Hiyama coupling reaction of vinyl trialkoxysilanes with aryl bromides into a Pd catalysed C-O bond forming reaction; if the correct conditions are used, high yields of aryl-alkyl ethers are observed. In addition, coupling between readily available tetraalkoxysilanes and aryl bromides can also be realised with NaOH or TBAF activation. The reactions take place in only 20 minutes if microwave heating is employed.

A convenient catalyst system for microwave accelerated cross-coupling of a range of aryl boronic acids with aryl chlorides.

A convenient microwave accelerated cross-coupling procedure between aryl chlorides with a range of boronic acids has been developed. An explanation for the low reactivity of highly fluorinated boronic acids in Suzuki coupling is provided.

Diastereoselective and Branched-Aldehyde-Selective Tandem Hydroformylation-Hemiaminal Formation: Synthesis of Functionalized Piperidines and Amino Alcohols.

Starting from readily available allylglycine, a tandem hydroformylation-hemiaminal formation reaction has been developed for the synthesis of chiral functionalized piperidines, with very good diastereoselectivity and branched regioselectivity using Rh/(S,S,S)-BOBPHOS catalysts. Tandem hydroformylation-hemiacetal formation also proceeds with good diastereoselectivity (88:12), with the hemiacetal product being hydrogenated with retention of stereochemistry to give a chiral intermediate used in the synthesis of the new antibiotic nemonoxacin.

Synthesis and structure-activity relationships of a new model of arylpiperazines. 8. Computational simulation of ligand-receptor interaction of 5-HT(1A)R agonists with selectivity over alpha1-adrenoceptors.

We have designed and synthesized a new series of arylpiperazines V exhibiting high 5-HT(1A)R affinity and selectivity over alpha(1)-adrenoceptors. The new selective 5-HT(1A)R ligands contain a hydantoin (m = 0) or diketopiperazine (m = 1) moiety and an arylpiperazine moiety separated by one methylene unit (n = 1). The aryl substituent of the piperazine moiety (Ar) consists of different benzofused rings mimicking the favorable voluminous substituents at ortho and meta positions predicted by 3D-QSAR analysis in the previously reported series I. In particular, (S)-2-[[4-(naphth-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-a]pyrazine [(S)-9, CSP-2503] (5-HT(1A), K(i) = 4.1 nM; alpha(1), K(i) > 1000 nM) has been pharmacologically characterized as a 5-HT(1A)R agonist at somatodendritic and postsynaptic sites, endowed with anxiolytic properties. Ligand (S)-9 is predicted, in computer simulations, to bind Asp(3.32) in TMH 3, Thr(5.39) and Ser(5.42) in TMH 5, and Trp(6.48) in TMH 6. We propose that agonists modify, by means of an explicit hydrogen bond, the conformation of Trp(6.48) from pointing toward TMH 7, in the inactive gauche+ conformation, to pointing toward the ligand binding site, in the active trans conformation.

Anxiolytic-like effect of a serotonergic ligand with high affinity for 5-HT1A, 5-HT2A and 5-HT3 receptors.

S-(-)-2-[[4-(napht-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-alpha]-pyrazine (CSP-2503) is a serotonin (5-HT) receptor ligand with selectivity and high affinity for 5-HT1A, 5-HT2A and 5-HT3 receptors. CSP-2503 reduced rectal temperature and 5-HT neuronal hypothalamic activity in mice, decreased electrical activity of raphe nuclei cells in rats and blocked the enhancement of adenylate cyclase activity induced by forskolin in HeLa cells transfected with the human 5-HT1A receptor. This compound also blocked head-twitches induced by the 5-HT(2A/2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Contractions of guinea pig ileum induced by the 5-HT3 receptor agonist 2-methyl-5-HT were prevented by CSP-2503. Moreover, it reduced the bradycardia reflex induced by 2-methyl-5-HT in anaesthetized rats. In the light/dark box and social interaction tests, CSP-2503 presented anxiolytic activity, an action shared by 5-HT1 agonists and 5-HT3 antagonists. Taken together, these results suggest that CSP-2503 is a new 5-HT1 receptor agonist with 5-HT2A and 5-HT3)receptor antagonist activities that might be useful in a number of conditions associated with anxiety.

Cannabinoid/opioid crosstalk in the central nervous system.

Promising therapeutic uses and a great variety of pharmacological effects are the leading forces that focus actual cannabinoid research. Cannabinoid and opioid systems share neuroanatomical, neurochemical, and paharmacological features. This fact supports the notion that actions induced by each one of these types of drugs involved an interaction between the endogenous opioid and endocannabinoid neuronal systems. Over the last decade our group and others have investigated cannabinoid/opioid crosstalk in the central nervous system by studying the mechanisms underlying pharmacological and biochemical interactions between the two systems in experimental paradigms of antinociception, drug reinforcement, and anxiety. The goal of this review is to revise the latest work done on this subject, with special emphasis on the research done with genetically modified animals. Whereas clinical progress is going ahead slowly, basic research in this area is progressing rapidly. Clinical applications derived from the cannabinoid/opioid crosstalk and based tightly on medical evidence are yet to come, but it is hoped that knowledge of this central messenger interaction will help to develop new alternatives for the treatment of some pathological states.

Gastrin-releasing peptide mediated regulation of 5-HT neuronal activity in the hypothalamic paraventricular nucleus under basal and restraint stress conditions.

The purpose of this study was to examine the gastrin-releasing peptide (GRP) mediated regulation of 5-HT neuronal activity in the paraventricular nucleus of the hypothalamus under basal and restraint stress conditions. Intracerebroventricular (icv) administration of GRP (1, 10, 100 ng/rat) increased 5-HIAA concentrations in the paraventricular nucleus (PVN) of the hypothalamus, but was without effect in the accumbens, suprachiasmatic and arcuate nuclei. Administration of (Leu(13)-psi-CH(2)NH-Leu(14)) Bombesin (10, 100 and 1000 ng/rat; icv), a GRP antagonist, had no effect by itself on PVN serotonergic activity; however, a dose of 1 microg/rat of this compound, completely blocked the increase of 5-HIAA concentrations induced by GRP (10 ng). Restraint stress increased serotonergic activity -as shown by an elevation of 5-HIAA in the PVN- as well as plasma ACTH and corticosterone. This stress-induced activation of both the serotonergic neurons and the hypothalamus-pituitary-adrenal axis was blocked by CRF and GRP antagonists. Interestingly, when the activation of hypothalamic 5-HT neurons was induced by GRP administration, alpha-helical (9-41) CRF was ineffective. These data suggest that GRP, by acting on GRP receptors but not via CRF receptors, increases 5-HT neuronal activity in the PVN. In turn, it appears that endogenous GRP and CRF receptor ligands are both simultaneously involved in the regulation of the increase in 5-HT neuronal activity, ACTH and corticosterone secretion, under stress conditions.

Gender differences in proenkephalin gene expression response to delta9-tetrahydrocannabinol in the hypothalamus of the rat.

Chronic exposure to delta9-tetrahydrocannabinol (delta9-THC) produces an activation of preproenkephalin (PENK) gene expression in the rat hypothalamus. The levels of circulating gonadal steroids concurrently modulate this neuropeptide in male and female rats. However, whether gonadal steroids regulate delta9-THC effects on PENK gene expression in the hypothalamus of male and female rats remains unknown. To test this hypothesis, experiments were carried out on intact, 2-week-gonadectomized, 1-week-gonadectomized, 1-week-dihydrotestosterone (DHT) replaced male rats, and 2-week-gonadectomized, 1-week-gonadectomized, 1-week-oestradiol replaced female rats. One week after hormonal replacement, animals were treated with vehicle or delta9-THC (5 mg/kg/day, i.p. 7 days). In males, delta9-THC administration to intact animals induced PENK mRNA in the paraventricular nucleus (PVN) and ventromedial nucleus (VMN) of the hypothalamus. Orchidectomy did not affect basal PENK mRNA levels in the PVN, but reduced PENK mRNA levels in the VMN. However, delta9-THC treatment induced PENK gene expression to the same extent in both hypothalamic nuclei of intact, castrated and DHT-replaced males. In females, ovariectomy decreased PENK gene expression in PVN and VMN. delta9-THC administration increased PENK gene expression in castrated females, but had no effect in the oestradiol-replaced group. Taken together, these results suggest gender differences in the response of chronic exposure to cannabinoids on PENK gene expression in the hypothalamus. Furthermore, it appears that alterations in opioid gene expression induced by cannabinoids in female rats depend upon the presence or absence of circulating oestradiol.