Optimization of the Synthesis of Glycerol Derived Monoethers from Glycidol by Means of Heterogeneous Acid Catalysis.

We present an efficient and green methodology for the synthesis of glycerol monoethers, starting from glycidol and different alcohols, by means of heterogeneous acid catalysis. A scope of Brønsted and Lewis acid catalysts were applied to the benchmark reaction of glycidol and methanol. The selected catalysts were cationic exchangers, such as Nafion NR50, Dowex 50WX2, Amberlyst 15 and K10-Montmorillonite, both in their protonic form and exchanged with Al(III), Zn(II) and Fe(III). Thus, total conversions were reached in short times by using 1 and 5% mol catalyst loading and room temperature, without the need for excess glycidol or the presence of a solvent. Finally, these conditions and the best catalysts were successfully applied to the reaction of glycidol with several alcohols such as butanol or isopropanol.

Theoretical study on the BF3-catalyzed Meinwald rearrangement reaction.

The mechanisms of the BF3-catalyzed Meinwald rearrangement reactions of five epoxides in dichloromethane solution have been studied at the M062X/6-311++G(2df,2pd) level. Accordingly, the Lewis acid-epoxide complex can react through several alternative pathways, though three phases (ring opening, C-C bond rotation, and hydrogen or alkyl group migration) are required in any path. In some cases, a concerted pathway (involving all three successive phases) is found. Otherwise, the reaction takes place through a reaction mechanism involving a zwitterion or a BF3 addition compound (formed by fluoride transfer from the BF3 moiety to the incipient carbocationic center generated by C-O bond rupture) or both as reaction intermediate(s). The BF2-bound fluorohydrin yields the reaction product through a concerted process involving fluoride transfer from the C-F bond to the OBF2 group and hydrogen or alkyl group migration, as first demonstrated in this work. Effects of a number of features (solvent effects, concurrent hydrogen/alkyl group migration, carbocation substitution, benzylic conjugation) are also discussed.

Theoretical insight on the treatment of ß-hexachlorocyclohexane waste through alkaline dehydrochlorination.

The occurrence of 4.8-7.2 million tons of hexachlorocyclohexane (HCH) isomers stocked in dumpsites around the world constitutes a huge environmental and economical challenge because of their toxicity and persistence. Alkaline treatment of an HCH mixture in a dehydrochlorination reaction is hampered by the low reactivity of the ß-HCH isomer (HCl elimination unavoidably occurring through syn H-C-C-Cl arrangements). More intriguingly, the preferential formation of 1,2,4-trichlorobenzene in the ß-HCH dehydrochlorination reaction (despite the larger thermodynamical stability of the 1,3,5-isomer) has remained unexplained up to now, though several kinetic studies had been reported. In this paper, we firstly show a detailed Density Functional study on all paths for the hydroxide anion-induced elimination of ß-HCH through a three-stage reaction mechanism (involving two types of reaction intermediates). We have now demonstrated that the first reaction intermediate can follow several alternative paths, the preferred route involving abstraction of the most acidic allylic hydrogen which leads to a second reaction intermediate yielding only 1,2,4-trichlorobenzene as the final reaction product. Our theoretical results allow explaining the available experimental data on the ß-HCH dehydrochlorination reaction (rate-determining step, regioselectivity, instability of some reaction intermediates).

Monitoring New Long-Lasting Intravitreal Formulation for Glaucoma with Vitreous Images Using Optical Coherence Tomography.

Intravitreal injection is the gold standard therapeutic option for posterior segment pathologies, and long-lasting release is necessary to avoid reinjections. There is no effective intravitreal treatment for glaucoma or other optic neuropathies in daily practice, nor is there a non-invasive method to monitor drug levels in the vitreous. Here we show that a glaucoma treatment combining a hypotensive and neuroprotective intravitreal formulation (IF) of brimonidine-Laponite (BRI/LAP) can be monitored non-invasively using vitreoretinal interface imaging captured with optical coherence tomography (OCT) over 24 weeks of follow-up. Qualitative and quantitative characterisation was achieved by analysing the changes in vitreous (VIT) signal intensity, expressed as a ratio of retinal pigment epithelium (RPE) intensity. Vitreous hyperreflective aggregates mixed in the vitreous and tended to settle on the retinal surface. Relative intensity and aggregate size progressively decreased over 24 weeks in treated rat eyes as the BRI/LAP IF degraded. VIT/RPE relative intensity and total aggregate area correlated with brimonidine levels measured in the eye. The OCT-derived VIT/RPE relative intensity may be a useful and objective marker for non-invasive monitoring of BRI/LAP IF.

Urine transferrin as an early endothelial dysfunction marker in type 2 diabetic patients without nephropathy: a case control study.

BACKGROUND: Albumin, along with other proteins, is abnormally eliminated via the urine during early stages of diabetic nephropathy. Moreover, endothelial dysfunction (ED) accompanying early diabetic nephropathy may develop even before microalbuminuria is detectable. Transferrin has a molecular weight comparable to albumin, whereas transferrinuria and microalbuminuria in a 24-h urine sample may comparably reflect early diabetic nephropathy. Whereas transferrin metabolism is related with ED during very early diabetic nephropathy has not been elucidated yet. This case-control study aimed to evaluate the relation between ED and urine transferrin, even before early diabetic nephropathy is present. METHODS: Patients were enrolled from two study sites in Mexico City: Ticomán General Hospital (healthy controls); and a Specialized Clinic for the Management of the Diabetic Patient (cases). All patients provided written informed consent. The primary endpoint was the correlation between urinary transferrin concentration and ED measured in type 2 diabetic patients without albuminuria. ED was evaluated by ultrasonographic validated measurements, which included carotid intima-media thickness (CIMT) and flow mediated dilation (FMD). Plasma biomarkers included glycated hemoglobin, creatinine, cholesterol and triglycerides, as well as urine albumin, transferrin and evidence of urinary tract infection. RESULTS: Sixty patients with type 2 Diabetes Mellitus (t2DM; n = 30) or without t2DM (n = 30), both negative for microalbuminuria, were recruited. The group with t2DM were older, with higher values of HbA1c and higher ED. This group also showed significant differences in urine transferrin and urine/plasma transferrin ratio, as compared with healthy controls (14.4 vs. 18.7 mg/mL, p = 0.04, and 74.2 vs. 49.5; p = 0.01; respectively). Moreover, urine transferrin correlated with higher CIMT values (r = 0.37, p = 0.04), being particularly significant for t2DM population. CIMT also correlated with time from t2DM diagnosis (r = 0.48, p < 0.001) and HbA1c (r = 0.48; p < 0.001). CONCLUSION: Urine transferrin correlated with subclinical atherogenesis in patients with t2DM without renal failure, suggesting its potential to identify cardiovascular risk in patients at very early nephropathy stage without microalbuminuria.

Dexamethasone delivery to the ocular posterior segment by sustained-release Laponite formulation.

This paper presents a novel nanoformulation for sustained-release delivery of dexamethasone (DEX) to the ocular posterior segment using a Laponite (LAP) carrier-DEX/LAP 1:10 w w-1 formulation; 10 mg ml-1. In vivo ocular feasibility and pharmacokinetics after intravitreal (IV) and suprachoroidal (SC) administration in rabbit eyes are compared against IV administration of a DEX solution (1 mg ml-1). Thirty rabbit eyes were injected with the DEX/LAP formulation (15 suprachoroid/15 intravitreous). Ophthalmological signs were monitored at day 1 and at weeks 1-4-12-24 post-administration. Three eyes per sample time point were used to quantify DEX concentration using high-performance liquid chromatography-mass spectrometry. The ocular tissues' pharmacokinetic parameters (lens, vitreous humour, choroid-retina unit and sclera) were studied. DEX/LAP was well tolerated under both administration methods. Peak intraocular DEX levels from the DEX/LAP were detected in the vitreous humour after both deliveries soon after administration. The vitreous area under the curve was significantly greater after both DEX/LAP deliveries (IV: 205 968.47; SC: 11 442.22 ng g-1 d-1) than after IV administration of the DEX solution (317.17 ng g-1 d-1). Intravitreal DEX/LAP delivery extended higher vitreous DEX levels up to week 24 (466.32 ± 311.15 ng g-1). With SC delivery, DEX levels were detectable in the choroid-retina unit (12.04 ± 20.85 ng g-1) and sclera (25.46 ± 44.09 ng g-1) up to week 24. This study demonstrated the intraocular feasibility of both SC and IV administration of the DEX/LAP formulation. The LAP increased the intraocular retention time of DEX when compared with conventional solutions. DEX/LAP could be considered a biocompatible and useful sustained-release formulation for treating posterior-pole eye diseases.

Copper-catalyzed cyclopropanation reaction of but-2-ene.

The mechanism of the copper(I)-catalyzed cyclopropanation reaction for methyl diazoacetate with both (Z)- and (E)-but-2-ene stereoisomers has been studied using the 6-311++G(d,p) basis set by means of M06-2X and O3LYP functionals. According to both methods, the rate-limiting step is the formation of a copper-carbene intermediate, formed by association between methyl diazoacetate and bis(acetonitrile)-copper(I) ion with the concomitant extrusion of dinitrogen. Cis/trans diastereoselectivity for the cyclopropanation reaction of a 1,2-disubstituted alkene ((Z)-but-2-ene) has been theoretically studied for the first time through the proper location of transition states on the potential-energy surface with the O3LYP method, since no transition structures could be found with the M06-2X functional due to the extreme flatness of the potential-energy surface. The calculated stereoselectivities involving two acetonitrile ligands or one dichloromethane molecule show qualitative agreement with experimental data. This study allows attributing the origin of the selectivity to steric interactions between the ligands of the catalyst system and the olefin substituents. The comparison between the corresponding activation barriers for the direct insertion step shows a higher reactivity for the Z stereoisomer of but-2-ene, consistently with the larger reactant destabilization through steric interactions.

Theoretical insights into enantioselective catalysis: the mechanism of the Kharasch-Sosnovsky reaction.

The mechanism of the Kharasch-Sosnovsky reaction has been investigated using B3 LYP/6-31G* calculations on a chiral reaction model [cyclohexene+tert-butyl perbenzoate-->cyclohex-2-enyl benzoate+tert-butyl alcohol, catalyzed by a chiral bisoxazoline-copper(I) complex]. Although two previous reaction mechanisms have been considered, the results are consistent with a new mechanistic pathway. This path involves ligand exchange between the catalyst-cyclohexene complex with tert-butyl perbenzoate to give a catalyst-perester complex, which undergoes an (either one- or two-step) oxidative addition reaction to yield a copper(III) complex. The limiting step of the Kharasch-Sosnovsky reaction consists of an intramolecular step involving the abstraction of an allylic hydrogen from cyclohexene [which is pi-bound to the copper(III) complex]. The resulting allyl-copper(III) complex (subsequent to the loss of tert-butanol) can undergo a haptotropic rearrangement by means of an eta1-allyl/eta3-allyl equilibrium, leading to scrambling between vinylic and allylic positions when an isotopically labeled substrate is used. The allyl-copper(III) ion undergoes a stereospecific reductive elimination involving the pi-bond migration to yield a reaction product-catalyst complex, which can regenerate the alkene-copper(I) complex by ligand exchange. The proposed reaction mechanism is consistent with all known experimental results (including enantioselectivity data).

Conformational preferences of methacrolein in Diels-Alder and 1,3-dipolar cycloaddition reactions.

A B3LYP/6-31G* study has been carried out for the reactions of methacrolein with cyclopentadiene, parent nitrone, 1-pyrroline-1-oxide, and (Z)-C,N-diphenylnitrone, in which the coordination of a Lewis acid (borane) and the solvent polarity (dichloromethane) have been taken into account. Calculated activation parameters, regioselectivities (for 1,3-dipolar cycloaddition reactions), and endo/exo stereoselectivities show good agreement with available experimental data. Gas-phase calculations show a varied behavior of the s-cis/s-trans TS stability for noncatalyzed reactions (from the systematic s-cis preference for the cyclopentadiene reaction to the systematic s-trans predilection encountered in the diphenylnitrone cycloaddition). BH3 coordination leads to a preferential stabilization of s-trans TSs in the reactions of cyclopentadiene (exo approach) and diphenylnitrone but a larger stabilization of s-cis structures in the processes involving the parent nitrone or 1-pyrroline-1-oxide. Additionally, a rather systematic preferential stabilization of s-trans structures is induced by solvent polarity in most reactions. As a consequence, an s-trans preference is predicted in solution for both thermal and catalyzed types of reactions in most approaches. Such a conclusion is consistent with some experimental results suggesting a preference for a particular conformation of the methacrolein-Lewis acid complexes.