Synthesis of new calixarene-based lubricant additives

The lubricants are normally composed by base oils and a number of additives which are added to improve the performances of the final product. In this work, which is due to the collaboration between ENI S.p.A. and Prof. Casnati’s group, significant results in the application of calixarene structures to two classes of lubricant additives (viscosity index improvers and detergents) were shown. In particular, several calix[8]arene derivatives were synthesized to use as core precursors in the “arm-first" synthetic processes of star polymers for viscosity index improver applications. The use of calixarene derivatives enable the production of star polymers with a high and well-defined number of branches and endowed with a very low dispersivity of molecular weight which can originate better performances than the current commercially available viscosity index improvers of the major competitor. Several functional groups were considered to prepare reactive p-tert-butylcalix[8]arene cores to be used in living anionic polymerization. n-butyllithium was used as model of the living anionic polymer to test the outcome of the reaction of polymer insertion on the calixarene core, facilitating the analyses of the products. The calixarene derivative, which easier reacts with n-BuLi, was selected for the preparation of star polymers by using a isoprene/styrene living anionic polymer. Finally, the lubricant formulations, which include the calixarene-based star polymers or commercially available products as viscosity index improvers, were prepared and comparatively tested. In the last part of Thesis, the use of calixarenes as polycarboxylic acids to synthetize new sulfur-free detergents as lubricant additives was carried out. In this way, these calcium-based detergents can be used for the formulation of new automotive lubricants with low content of ash, phosphorus and sulfur (low SAPS). To increase the low deprotonation degree of OH groups and their capacity to complex calcium ions, a complete functionalization of the calixarene mixtures with acetic acid groups was required. Futhermore, the “one-step” synthesis of new calixarenes with alkyl chains in para positions longer than the ones already known was necessary to improve the oil solubility and stability of reverse micelles formed by the detergents. Moreover, the separation and characterization of the calixarenes were carried out to optimize their synthetic process, also on pilot scale. For our purpose, the use of p-tert-octylcalixarenes for the preparation of detergents was carried out to compare the properties of the final detergents respect to the use of the p-dodecyl calixarenes. Once achieved the functionalization of both calixarene mixtures with carboxylic acid groups, the syntheses of new calixarene-based detergents were carried out to identify the best calixarene derivative for our research goals. The synthetic process for the preparation of calixarene-based detergent having very high basicity (TBN 400) was also investigated for applications in lubricants for marine engines. In addition, with the aim of testing the calixarene-based detergents in automotive lubricants, several additive packages (concentrated mixture of additives) containing our detergents were prepared. Using these packages the corresponding automotive lubricants can be formulated. Besides, a lubricant containing commercial calcium alkylbenzene-sulfonates detergents was prepared to compare its detergency properties with those of the calixarene-based oils.

Estudo da adição aldólica do éster terc-butílico da n-(difenilmetileno)glicina a alguns aldeídos aromáticos

As reações de adição aldólica entre a cetimina 1 e aldeídos aromáticos foram inicialmente efetuadas à temperatura ambiente, em sistema bifásico constituído por uma fase aquosa básica (KOH 10% ou NaOH 5% m/v) e por uma fase orgânica (aldeído), na ausência de solventes e de catalisadores, observando-se baixa conversão em produto. Porém, quando se utilizou o catalisador aliquat®-336, foi possível reduzir a concentração da base (NaOH 1%), com conversão total da imina em produto que, na maioria dos casos, era uma mistura de duas oxazolidinas isoméricas de estereoquímica cis e trans. Esses compostos puderam ser isolados e purificados por recristalização de etanol ou metanol. Em todas as reações efetuadas com benzaldeído, m-clorobenzaldeído e p-nitrobenzaldeído, não se observou excesso diastereomérico significativo. No entanto, as reações com p-clorobenzaldeído mostraram-se diastereosseletivas, conduzindo, à temperatura ambiente, quase que exclusivamente à oxazolidina de estereoquímica cis. A comparação entre o resultado de reações efetuadas a curto e longo tempo de reação, ou em diferentes temperaturas, permitiu concluir que o aldol de estereoquímica anti é o produto cinético, o qual se transforma lentamente na oxazolidina cis. O produto termodinâmico (aldol syn) cicliza rapidamente, não sendo observado nos espectros de RMN de H dos produtos brutos de reação, mas sim seu produto ciclizado, a oxazolidina trans. Tentativas de obter os produtos de reação com excesso enantiomérico, pelo emprego de catalisadores de transferência de fase assimétricos, não foram bem sucedidas.

Chiral gold(I) vs chiral silver complexes as catalysts for the enantioselective synthesis of the second generation GSK-hepatitis C virus inhibitor

The synthesis of a GSK 2nd generation inhibitor of the hepatitis C virus, by enantioselective 1,3-dipolar cycloaddition between a leucine derived iminoester and tert-butyl acrylate, was studied. The comparison between silver(I) and gold(I) catalysts in this reaction was established by working with chiral phosphoramidites or with chiral BINAP. The best reaction conditions were used for the total synthesis of the hepatitis C virus inhibitor by a four step procedure affording this product in 99% ee and in 63% overall yield. The origin of the enantioselectivity of the chiral gold(I) catalyst was justified according to DFT calculations, the stabilizing coulombic interaction between the nitrogen atom of the thiazole moiety and one of the gold atoms being crucial.

Enantioselective 1,3-dipolar cycloadditions of azlactones and electrophilic alkenes catalyzed by dimeric BinapAuTFA complexes

Glycine-derived azlactones react with maleimides using (S)- or (R)-dimeric BinapAuTFA complexes affording the corresponding cycloadducts in good yields and high enantioselections (up to 99% ee). The intermediate carboxylic acids are treated with trimethylsilyldiazomethane and isolated as Δ¹-pyrroline methyl esters. These cycloadducts are transformed into exo-proline derivatives by reduction with NaBH3CN in acidic media. On the other hand, N-benzoylalanine-derived oxazolone reacts with tert-butyl acrylate providing the cycloadduct with the ester group at the 3-position with a trans-relative configuration with respect to the methyl ester group.

Synthetic scope and DFT analysis of the chiral binap-gold (I) complex-catalyzed 1,3-dipolar cycloaddition of azlactones with alkenes

The 1,3-dipolar cycloaddition between glycine-derived azlactones with maleimides is efficiently catalyzed by the dimeric chiral complex [(Sa)-Binap·AuTFA]2. The alanine-derived oxazolone only reacts with tert-butyl acrylate giving anomalous regiochemistry, which is explained and supported by Natural Resonance Theory and Nucleus Independent Chemical Shifts calculations. The origin of the high enantiodiscrimination observed with maleimides and tert-butyl acrylate is analyzed using DFT computed at M06/Lanl2dz//ONIOM(b3lyp/Lanl2dz:UFF) level. Several applications of these cycloadducts in the synthesis of new proline derivatives with a 2,5-trans-arrangement and in the preparation of complex fused polycyclic molecules are described.

The influence of the sample introduction system on signals of different tin compounds in inductively coupled plasma-based techniques

The influence of the sample introduction system on the signals obtained with different tin compounds in inductively coupled plasma (ICP) based techniques, i.e., ICP atomic emission spectrometry (ICP–AES) and ICP mass spectrometry (ICP–MS) has been studied. Signals for test solutions prepared from four different tin compounds (i.e., tin tetrachloride, monobutyltin, dibutyltin and di-tert-butyltin) in different solvents (methanol 0.8% (w/w), i-propanol 0.8% (w/w) and various acid matrices) have been measured by ICP–AES and ICP–MS. The results demonstrate a noticeable influence of the volatility of the tin compounds on their signals measured with both techniques. Thus, in agreement with the compound volatility, the highest signals are obtained for tin tetrachloride followed by di-tert-butyltin/monobutyltin and dibutyltin. The sample introduction system exerts an important effect on the amount of solution loading the plasma and, hence, on the relative signals afforded by the tin compounds in ICP–based techniques. Thus, when working with a pneumatic concentric nebulizer, the use of spray chambers affording high solvent transport efficiency to the plasma (such as cyclonic and single pass) or high spray chamber temperatures is recommended to minimize the influence of the tin chemical compound. Nevertheless, even when using the conventional pneumatic nebulizer coupled to the best spray chamber design (i.e., a single pass spray chamber), signals obtained for di-tert-butyltin/monobutyltin and dibutyltin are still around 10% and 30% lower than the corresponding signal for tin tetrachloride, respectively. When operating with a pneumatic microconcentric nebulizer coupled to a 50 °C-thermostated cinnabar spray chamber, all studied organotin compounds provided similar emission signals although about 60% lower than those obtained for tin tetrachloride. The use of an ultrasonic nebulizer coupled to a desolvation device provides the largest differences in the emission signals, among all tested systems.

Copper-Catalyzed Asymmetric Alkylation of β-Keto Esters with Xanthydrols

The copper(II) triflate-tert-butyl-bisoxazoline [Cu(OTf)2-t-Bu-BOX]-catalyzed asymmetric alkylation of β-keto esters using free benzylic alcohols such as xanthydrols, as alkylating agents, is herein described for the first time. This green protocol renders in general the corresponding products with good results in terms of both yields and enantioselectivities using different keto esters, even when quaternary stereocenters were created. The scope, limitations and mechanistic aspects of the process are also discussed.

Biodiesel wastes: An abundant and promising source for the preparation of acidic catalysts for utilization in etherification reaction

Environmentally friendly sulfonated black carbon (BC) catalysts were prepared from biodiesel waste, glycerol. These black carbons (BCs) contain a high amount of acidic groups, mainly sulfonated and oxygenated groups. Furthermore, these catalysts show a high catalytic activity in the glycerol etherification reaction with tert-butyl alcohol, the activity being larger for the sample prepared with a higher glycerol:sulfuric acid ratio (1:3). The yield for mono-tert-butyl glycerol (MTBG), di-tert-butyl glycerol (DTBG) and tri-tert-butyl-glycerol (TTBG) were very similar to those obtained using a commercial resin, Amberlyst-15. Furthermore, experimental results show that the carbon with the lowest acidic surface group content, BC prepared in minor glycerol:sulfuric acid ratio (10:1), can be chemically treated after carbonization to achieve an improved catalytic activity. The activity of all BCs is high and very similar, about 50% and 20% for the MTBG and DTBG + TTBG, respectively.

Regulation of lipocalin prostaglandin-D synthase expression by interleukin-1β in human chondrocytes

L'arthrose est une maladie multifactorielle complexe. Parmi les facteurs impliqués dans sa pathogénie, les certains prostaglandines exercent un rôle inflammatoire et d’autres un rôle protecteur. La prostaglandine D2 (PGD2) est bien connue comme une PG anti-inflammatoire, qui est régulée par l’enzyme «Lipocalin prostaglandine D-synthase». Avec l’inflammation de l'arthrose, les chondrocytes essaient de protéger le cartilage en activant certaines voies de récupération dont l'induction du gène L-PGDS. Dans cette étude, nous étudions la voie de signalisation impliquée dans la régulation de l'expression du (L-PGDS) sur les chondrocytes traités avec différents médiateurs inflammatoires. Le but de projet: Nous souhaitons étudier la régulation de la L-PGDS dans le but de concevoir des approches thérapeutiques qui peuvent activer la voie intrinsèque anti-inflammatoire. Méthode et conclusions: In vivo, l'arthrose a été suivie en fonction de l’âge chez la souris ou chirurgicalement suivant une intervention au niveau des genoux de souris. Nous avons confirmé les niveaux d’expression de L-PGDS histologiquement et par immunohistochimie. In vitro, dans les chondrocytes humains qui ont été traités avec différents médiateurs de l'inflammation, nous avons observé une augmentation de l’expression de la L-PGDS dose et temps dépendante. Nous avons montré, in vivo et in vitro que l’inflammation induit une sécrétion chondrocytaire de la L-PGDS dans le milieu extracellulaire. Enfin, nous avons observé la production de différentes isoformes de la L-PGDS en réponse à l'inflammation.

1H-1,3-Diazepines, 5H-1,3-diazepines, 1,3-diazepinones, and 2,4-diazabicyclo[3.2.0]heptenes

Tetrazolo[1,5-a] pyridines/ 2-azidopyridines 1 undergo photochemical nitrogen elimination and ring expansion to 1,3-diazacyclohepta-1,2,4,6-tetraenes 3, which react with alcohols to afford 2-alkoxy-1H-1,3-diazepines 4 (5), with secondary amines to 2-dialkylamino-5H-1,3-diazepines 16, sometimes via isolable 2-dialkylamino-1H-1,3-diazepines 15, and with water to 1,3-diazepin-2-ones 19. The latter are also obtained by elimination of isobutene or propene from 2-tert-butoxy- or 2-isopropoxy-1H-1,3-diazepines 4 or 5. 1,3-Diazepin-2-one 22B and 1,3-diazepin-4-one 24 were obtained from hydrolysis of the corresponding 4-chlorodiazepines. Diazepinones 19 undergo photochemical ring closure to diazabicycloheptenones 25 in high yields. The 2-alkoxy-1H-1,3-diazepines 4 and 5 interconvert by rapid proton exchange between positions N1 and N3. The free energies of activation for the proton exchange were measured by the Forsen - Hoffman method as DeltaGdouble dagger(298) = 16.2 +/- 0.6 kcal mol(-1) as an average for 4a - c in CD2Cl2, acetone-d(6), and methanol-d(4), and 14.1 +/- 0.6 kcal mol(-1) for 4c in acetone/D2O. The structures of 2-methoxy-5,6-bis( trifluoromethyl)-1H-1,3-diazepine 4k, 1,2-dihydro-4-diethylamino-5H-1,3-diazepin-2-one 22bB, and diazabicycloheptanone 26 were determined by X-ray crystallography. The former represents the first reported X-ray crystal structure of any monocyclic N-unsubstituted 1H-azepine.

Imidoylketene dimerization and rearrangement

FVT of pyrroledione 10 affords the NH-imidoylketene 11, which is characterized by its matrix isolation IR spectrum ( 2117 cm 1). On warming above 170 K, 11 dimerizes to the oxazinone 13, the X-ray crystal structure of which is reported. Imidoylketene 11 also undergoes a (reversible) 1,3-phenyl shift to afford the detectable alpha-oxoketenimine 16 (2062 cm(-1)) which at FVT temperatures above 400degreesC, isomerizes to 2-cyano-2-phenylacetophenone 18 (optimally at 700degreesC). Moreover, imidoylketene 11 can cyclize to azetinone 19, detectable at FVT temperatures up to 570degreesC, which undergoes cycloreversion to diphenylacetylene 20 and isocyanic acid (HNCO) 21. Energy profiles calculated at the B3LYP/6-31G** level for the unsubstituted imidoylketene, the diphenylimidoylketene 11 and the N-tert-butylimidoylketene are also reported.

A safety catch linker for Fmoc-based assembly of constrained cyclic peptides

A new safety-catch linker for Fmoc solid-phase peptide synthesis of cyclic peptides is reported. The linear precursors were assembled on a tert-butyl protected catechol derivative using optimized conditions for Fmoc-removal. After activation of the linker using TFA, neutralization of the N-terminal amine induced cyclization with concomitant cleavage from the resin yielding the cyclic peptides in DMF solution. Several constrained cyclic peptides were synthesized in excellent yields and purities. Copyright (c) 2005 European Peptide Society and John Wiley & Sons, Ltd.

NMR studies of exchange between intra- and extracellular glutathione in human erythrocytes

Glutathione is the main source of intracellular antioxidant protection in the human erythrocyte and its redox status has frequently been used as a measure of oxidative stress. Extracellular glutathione has been shown to enhance intracellular reduced glutathione levels in some cell types. However, there are conflicting reports in the literature and it remains unclear as to whether erythrocytes can utilise extracellular glutathione to enhance the intracellular free glutathione pool. We have resolved this issue using a C-13-NMR approach. The novel use of L-gamma-glutamyl-L-cysteinyl-[2-C-13] glycine allowed the intra- and extracellular glutathione pools to be distinguished unequivocally, enabling the direct and non-invasive observation over time of the glutathione redox status in both compartments. The intracellular glutathione redox status was measured using H-1 spin-echo NMR, while C-13[H-1-decoupled] NMR experiments were used to measure the extracellular status. Extracellular glutathione was not oxidised in the incubations, and did not affect the intracellular glutathione redox status. Extracellular glutathione also did not affect erythrocyte glucose metabolism, as measured from the lactate-to-pyruvate ratio. The results reported here refute the previously attractive hypothesis that, in glucose-starved erythrocytes, extracellular GSH can increase intracellular GSH concentrations by releasing bound glutathione from mixed disulfides with membrane proteins.

Synthesis and iron binding studies of myo-inositol 1,2,3-trisphosphate and (+/-)-myo-inositol 1,2-bisphosphate, and iron binding studies of all myo-inositol tetrakisphosphates

The first syntheses of the natural products myo-inositol 1,2,3-trisphosphate and (+/-)-myo-inositol 1,2-bisphosphate are described. The protected key intermediates 4,5,6-tri-O-benzoyl-myo-inositol and (+/-)-3,4,5,6-tetra-O-benzyl-myo-inositol were phosphorylated with dibenzyl N,N-di-isopropylphosphoramidite in the presence of 1H-tetrazole and subsequent oxidation of the phosphite. The crystal structures of the synthetic intermediates (+/-)-1-O-(tert-butyldiphenylsilyl)-2,3,O-cyclohexylidene-myo-inos itol and (+/-)-4,5,6-tri-O-benzoyl-1-O-(tert-butyldiphenylsilyl)-2,3-O-cycl ohexylidene- myo-inositol are reported. myo-Inositol 1,2,3-trisphosphate (+/-)-myo-inositol 1,2-bisphosphate, and all isomeric myo-inositol tetrakisphosphates were evaluated for their ability to alter HO. production in the iron-catalysed Haber-Weiss reaction. The results demonstrated that a 1,2,3-grouping of phosphates in myo-inositol was necessary for inhibition also that (+/-)-myo-inositol 1,2-bisphosphate potentiated HO. production. myo-Inositol 1,2,3-trisphosphate resembled myo-inositol hexakisphosphate (phytic acid) in its ability to act as a siderophore by promoting iron-uptake into Pseudomonas aeruginosa.

Living cationic polymerization of styrene monomers

This thesis describes an experimental investigation of synthesis of polystyrene under various polymerization conditions such as solvent polarity, temperature, initial concentrations of initiator, catalyst, monomer and added salts or co-catalyst, which was achieved using the living cationic polymerization technology in conjunction with gel permeation chromatography (GPC) and NMR spectroscopy. Polymerizations of styrene were conducted using 1-phenyl ethylchloride (1-PEC) as an initiator and tin tetrachloride (SnCI4) as a catalyst in the presence of tetra-n-Butylammonium chloride (nBu4NCI). Effects of solvent polarity varied by mixing dichloromethane (DCM) and less polar cyclohexane (C.hex), temperature, initial concentrations of SnC14, 1-PEC and nBu4NCI on the polymerizations were examined, and the conditions under which a living polymerization can be obtained were optimised as: [styrene]o ~ 0.75 - 2 M; [1-PEC]o ~ 0.005 - 0.05 M; [SnCI4Jo ~ 0.05 - 0.4 M; [nBu4NCIJo ~ 0.001 - 0.1 M; DCM/C.hex ~ 50/0 - 20/30 v/v; T ~ 0 to -45°C. Kinetic studies of styrene polymerization using the Omnifit sampling method showed that the number average molecular weight (Mn) of the polymers obtained increased in direct proportion to monomer conversion and agreed well with the theoretical Mn expected from the concentration ratios of monomer to initiator. The linearities of both the 1n([MJoI[M]) vs. time plot and the Mn vs. monomer conversion plot, and the narrow molecular weight distribution (MWD) measured using GPC demonstrated the livingness of the polymerizations, indicating the absence of irreversible termination and transfer within the lifetimes of the polymerizations. The proposed 'two species' propagation mechanism was found to apply for the styrene polymerization with 1-PEC/SnCI4 in the presence of nBu4NCl. The further kinetic experiments showed that living styrene polymerizations were achieved using the 1-PEC/SnCI4 initiating system in mixtures of DCM/C.hex 30/20 v/v at -15°C in the presence of various bromide salts, tetra-n-butylammonium bromide, tetra-n-pentylammonium bromide, tetra-n-heptylammonium bromide, and tetra-n-octylammonium bromide, respectively. The types of the bromide salts were found to have no significant effect on monomer conversion, Mn, polydispersity and initiation efficiency. Living polymerizations of styrene were also achieved using titanium tetrachloride (TiCI4) as a catalyst and 1-PEC as an initiator in the presence of a small amount of 2,6-di-tert-butylpyridine or pyridine instead of nBu4NCl. GPC analysis showed that the polymers obtained had narrow polydispersities (P.D. < 1.3), and the linearities of both the In([MJo/[MJ) vs. time plot and the Mn vs. monomer conversion plot demonstrated that the polymerizations are living, when the ratio of DCM and C.hex was less than 40 : 10 and the reaction temperature was not lower than -15°C. The reaction orders relative to TiCl4 and 1-PEC were estimated from the investigations into the rate of polymerization to be 2.56 and 1.0 respectively. lH and 13C NMR analysis of the resultant polystyrene would suggest the end-functionality of the product polymers is chlorine for all living polymerizations.