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Product Inhibition (product + inhibition)
Selected AbstractsPartial Oxidation of 4- tert -Butyltoluene Catalyzed by Homogeneous Cobalt and Cerium Acetate Catalysts in the Br,/H2O2/Acetic Acid System: Insights into Selectivity and MechanismCHEMISTRY - A EUROPEAN JOURNAL, Issue 28 2007Abstract The partial oxidation of 4- tert -butyltoluene to 4- tert -butylbenzaldehyde by hydrogen peroxide in glacial acetic acid, catalyzed by bromide ions in combination with cobalt(II) acetate or cerium(III) acetate, has been studied in detail. Based on the observed differences in reaction rates and product distributions for the different catalysts, a reaction mechanism involving two independent pathways is proposed. After the initial formation of a benzylic radical species, either oxidation of this intermediate by the metal catalyst or reaction with bromine generated in situ occurs, depending on which catalyst is used. The first pathway leads to the exclusive formation of 4- tert -butylbenzaldehyde, whereas reaction of the radical intermediate with bromine leads to formation of the observed side products 4- tert -butylbenzyl bromide and its hydrolysis and solvolysis products 4- tert -butylbenzyl alcohol and 4- tert -butylbenzyl acetate, respectively. The cobalt(II) catalysts Co(OAc)2 and Co(acac)2 are able to quickly oxidize the radical intermediate, thereby largely preventing the bromination reaction (i.e., side-product formation) from occurring, and yield the aldehyde product with 75,80,% selectivity. In contrast, the cerium catalyst studied here exhibits an aldehyde selectivity of around 50,% due to the competing bromination reaction. Addition of extra hydrogen peroxide leads to an increased product yield of 72,% (cerium(III) acetate) or 58,% (cobalt(II) acetate). Product inhibition and the presence of increasing amounts of water in the reaction mixture do not play a role in the observed low incremental yields. [source] Comparative Study of Cyanobacteria as Biocatalysts for the Asymmetric Synthesis of Chiral Building BlocksENGINEERING IN LIFE SCIENCES (ELECTRONIC), Issue 2 2006J. Havel Abstract The three representative cyanobacteria, Synechococcus PCC7942, Anabaena variabilis, and Nostoc muscorum, were studied for their ability to asymmetrically reduce the prochiral ketones 2,-3,-4,-5,-6,-pentafluoroacetophenone, ethyl 4-chloroacetate, 4-chloroacetophenone, and ethylbenzoylacetate to the corresponding chiral alcohols. Photosynthesis as well as respiration was applied for intracellular regeneration of the NAD(P)H cofactor. It was shown for the first time that all cyanobacteria were able to reduce the prochiral ketones asymmetrically without light for cofactor regeneration. By comparison of the cell specific product formation capacities of cyanobacteria with typical heterotrophic whole cell biocatalysts in batch processes, it is shown that comparable or, in some cases, better performances at high enantiomeric excess (ee > 99.8,%) are obtained. As a consequence of a generally strong product inhibition, in situ product removal must be applied in order to restore process efficiency when using cyanobacteria as biocatalysts. [source] Asymmetric Ring Opening of Benzo-7-oxabicyclo[2.2.1]heptadienes with Cationic Rhodium ComplexesADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 11-12 2010Angelika Preetz Abstract The efficient design of stereochemically challenging ring systems by ring opening of heterobicyclic alkenes has become a very important reaction in the chemistry of CC and CX bond formation. By using the hitherto applied in situ technique for the generation of the ,2 -bridged, dimeric neutral rhodium complexes, however, the catalytically active species and its concentration remained unidentified. Furthermore, the reaction temperature is at least 80,°C. The application of cationic rhodium(I) solvate complexes (that no longer contain blocking diolefins) shows that a much greater activity and enantioselectivity for the synthesis of 1,2-dihydro-1-naphthols can be reached than was described so far, even at ambient temperature. NMR spectroscopy and X-ray analysis show that a product inhibition during the ring opening reaction takes place that is independent of the nucleophile. [source] Game theoretic approach to multiobjective designs: Focus on inherent safetyAICHE JOURNAL, Issue 1 2006Anjana Meel Abstract A method for designing processes that are inherently safer,with the primary focus on disturbances having the potential for unbounded hazardous responses,is introduced. In cases where safety is not threatened (as in isothermal fermentation reactors), but product quality can rapidly degrade, this method provides designs that ensure high product quality (as in pharmaceutical processes). Using game theory, the method accounts for the trade-offs in profitability, controllability, safety and/or product quality, and flexibility. For nonlinear processes that are hard to control; that is, have an unstable and/or nonminimum-phase steady state, over a wide range of operating conditions, extended bifurcation diagrams are introduced. When a steady state is nonminimum phase, the process may exhibit inverse response. The steady states of processes are classified on the basis of instability and nonminimum-phase behavior to segregate the operating regimes into distinct zones. Locally optimal designs, one corresponding to each zone, are obtained first. These are compared with other locally optimal designs at alternate operating conditions, and/or process reconfigurations, to obtain the globally optimal design using game theory. Four indices,profitability, controllability, safety and/or product quality, and flexibility,characterize the optimality of a design. A novel index for safe operation and/or product quality at a steady state is formulated as a function of the eigenvalues of the Jacobian of the process model and the Jacobian of the process zero dynamics, providing a quantitative measure of instability and nonminimum-phase behavior. The application of the proposed method to an isothermal, continuous stirred-tank reactor (CSTR) with van der Vusse reactions, an exothermic CSTR, and an anaerobic fermentor with substrate and product inhibition is presented. © 2005 American Institute of Chemical Engineers AIChE J, 2006 [source] Contribution of NADH Increases to Ethanol's Inhibition of Retinol Oxidation by Human ADH IsoformsALCOHOLISM, Issue 4 2009Jennifer R. Chase Background:, A decrease in retinoic acid levels due to alcohol consumption has been proposed as a contributor to such conditions as fetal alcohol spectrum diseases and ethanol-induced cancers. One molecular mechanism, competitive inhibition by ethanol of the catalytic activity of human alcohol dehydrogenase (EC 1.1.1.1) (ADH) on all-trans-retinol oxidation has been shown for the ADH7 isoform. Ethanol metabolism also causes an increase in the free reduced nicotinamide adenine dinucleotide (NADH) in cells, which might reasonably be expected to decrease the retinol oxidation rate by product inhibition of ADH isoforms. Methods:, To understand the relative importance of these two mechanisms by which ethanol decreases the retinol oxidation in vivo we need to assess them quantitatively. We have built a model system of 4 reactions: (1) ADH oxidation of ethanol and NAD+, (2) ADH oxidation of retinol and NAD+, (3) oxidation of ethanol by a generalized Ethanoloxidase that uses NAD+, (4) NADHoxidase which carries out NADH turnover. Results:, Using the metabolic modeling package ScrumPy, we have shown that the ethanol-induced increase in NADH contributes from 0% to 90% of the inhibition by ethanol, depending on (ethanol) and ADH isoform. Furthermore, while the majority of flux control of retinaldehyde production is exerted by ADH, Ethanoloxidase and the NADHoxidase contribute as well. Conclusions:, Our results show that the ethanol-induced increase in NADH makes a contribution of comparable importance to the ethanol competitive inhibition throughout the range of conditions likely to occur in vivo, and must be considered in the assessment of the in vivo mechanism of ethanol interference with fetal development and other diseases. [source] A fundamental analysis of continuous flow bioreactor and membrane reactor models with noncompetitive product inhibitionASIA-PACIFIC JOURNAL OF CHEMICAL ENGINEERING, Issue 1 2009Mark Ian Nelson Abstract We analyze the steady-state production of a product produced through the growth of microorganisms in both a continuous flow bioreactor and in an idealized continuous flow membrane reactor. The reaction is assumed to be governed by Monod growth kinetics subject to noncompetitive product inhibition. Although this reaction scheme is often mentioned in textbooks, a stability analysis does not appear in the literature. The steady-state solutions of the model are found and their stability determined as a function of the residence time. The performance of the reactor at large residence times is obtained. Knowledge of the steady-state solutions and their asymptotic limits may be useful to estimate parameter values from experimental data. The key dimensionless parameter that controls the degree of noncompetitive product inhibition is identified and we quantify the effect that this has on the reactor performance in the limit when product inhibition is 'small' and 'large'. Copyright © 2009 Curtin University of Technology and John Wiley & Sons, Ltd. [source] Measurement of key metabolic enzyme activities in mammalian cells using rapid and sensitive microplate-based assaysBIOTECHNOLOGY & BIOENGINEERING, Issue 3 2010R. Janke Abstract Sensitive microplate-based assays to determine low levels of key enzyme activities in mammalian cells are presented. The enzyme platform consists of four cycling assays to measure the activity of 28 enzymes involved in central carbon and glutamine metabolism. The sensitivity limit of all cycling assays was between 0.025 and 0.4,nmol product. For the detection of glutaminase activity, a new glutamate cycle system involving the enzymes glutamate dehydrogenase and aspartate transaminase was established. The relative standard deviation of the method was found to be 1.7% with a limit of detection of 8.2,pmol and a limit of quantitation of 24.8,pmol. Hence, cell extracts could be highly diluted to reduce interferences caused by other components in the extract, which in addition minimized underestimates or overestimates of actual enzyme activities. Since substrate concentrations could be maintained at a nearly constant level throughout the assay product accumulation during the reaction was low, which minimized product inhibition. As an example, the enzyme platform was used to investigate maximum enzyme activities of stationary-phase MDCK cells grown in serum-containing GMEM medium as typically used in influenza vaccine production. Biotechnol. Bioeng. 2010;107: 566,581. © 2010 Wiley Periodicals, Inc. [source] A mechanistic model of the enzymatic hydrolysis of celluloseBIOTECHNOLOGY & BIOENGINEERING, Issue 1 2010Seth E. Levine Abstract A detailed mechanistic model of enzymatic cellulose hydrolysis has been developed. The behavior of individual cellulase enzymes and parameters describing the cellulose surface properties are included. Results obtained for individual enzymes (T. reesei endoglucanase 2 and cellobiohydrolase I) and systems with both enzymes present are compared with experimental literature data. The model was sensitive to cellulase-accessible surface area; the EG2,CBHI synergy observed experimentally was only predicted at a sufficiently high cellulose surface area. Enzyme crowding, which is more apparent at low surface areas, resulted in differences between predicted and experimental rates of hydrolysis. Model predictions also indicated that the observed decrease in hydrolysis rates following the initial rate of rapid hydrolysis is not solely caused by product inhibition and/or thermal deactivation. Surface heterogeneities, which are not accounted for in this work, may play a role in decreasing the hydrolysis rate. The importance of separating the enzyme adsorption and complexation steps is illustrated by the model's sensitivity to the rate of formation of enzyme,substrate complexes on the cellulose surface. Biotechnol. Bioeng. 2010;107: 37,51. © 2010 Wiley Periodicals, Inc. [source] Bioproduction of the aroma compound 2-Phenylethanol in a solid,liquid two-phase partitioning bioreactor system by Kluyveromyces marxianusBIOTECHNOLOGY & BIOENGINEERING, Issue 2 2009Fang Gao Abstract The rose-like aroma compound 2-phenylethanol (2-PE) is an important fragrance and flavor ingredient. Several yeast strains are able to convert l -phenylalanine (l -phe) to 2-PE among which Kluyveromyces marxianus has shown promising results. The limitation of this process is the low product concentration and productivity primarily due to end product inhibition. This study explored the possibility and benefits of using a solid,liquid Two-Phase Partition Bioreactor (TPPB) system as an in situ product removal technique. The system applies polymer beads as the sequestering immiscible phase to partition 2-PE and reduce the aqueous 2-PE concentration to non-inhibitory levels. Among six polymers screened for extracting 2-PE, Hytrel® 8206 performed best with a partition coefficient of 79. The desired product stored in the polymer was ultimately extracted using methanol. A 3,L working volume solid,liquid batch mode TPPB using 500,g Hytrel® as the sequestering phase generated a final overall 2-PE concentration of 13.7,g/L, the highest reported in the current literature. This was based on a polymer phase concentration of 88.74,g/L and aqueous phase concentration of 1.2,g/L. Even better results were achieved via contact with more polymers (approximately 900,g) with the aqueous phase applying a semi-continuous reactor configuration. In this system, a final 2-PE concentration (overall) of 20.4,g/L was achieved with 1.4,g/L in the aqueous and 97,g/L in the polymer phase. The overall productivities of these two reactor systems were 0.38 and 0.43,g/L,h, respectively. This is the first report in the literature of the use of a polymer sequestering phase to enhance the bioproduction of 2-PE, and exceeds the performance of two-liquid phase systems in terms of productivity as well as ease of operation (no emulsions) and ultimate product recovery. Biotechnol. Bioeng. 2009; 104: 332,339 © 2009 Wiley Periodicals, Inc. [source] In situ magnetic separation for extracellular protein productionBIOTECHNOLOGY & BIOENGINEERING, Issue 2 2009Tobias Käppler Abstract A new approach for in situ product removal from bioreactors is presented in which high-gradient magnetic separation is used. This separation process was used for the adsorptive removal of proteases secreted by Bacillus licheniformis. Small, non-porous bacitracin linked magnetic adsorbents were employed directly in the broth during the fermentation, followed by in situ magnetic separation. Proof of the concept was first demonstrated in shake flask culture, then scaled up and applied during a fed batch cultivation in a 3.7 L bioreactor. It could be demonstrated that growth of B. licheniformis was not influenced by the in situ product removal step. Protease production also remained the same after the separation step. Furthermore, degradation of the protease, which followed first order kinetics, was reduced by using the method. Using a theoretical modeling approach, we could show that protease yield in total was enhanced by using in situ magnetic separation. The process described here is a promising technique to improve overall yield in bio production processes which are often limited due to weak downstream operations. Potential limitations encountered during a bioprocess can be overcome such as product inhibition or degradation. We also discuss the key points where research is needed to implement in situ magnetic separation in industrial production. Biotechnol. Bioeng. 2009;102: 535,545. © 2008 Wiley Periodicals, Inc. [source] Carbon metabolism and product inhibition determine the epoxidation efficiency of solvent-tolerant Pseudomonas sp. strain VLB120,CBIOTECHNOLOGY & BIOENGINEERING, Issue 6 2007Jin-Byung Park Abstract Utilization of solvent tolerant bacteria as biocatalysts has been suggested to enable or improve bioprocesses for the production of toxic compounds. Here, we studied the relevance of solvent (product) tolerance and inhibition, carbon metabolism, and the stability of biocatalytic activity in such a bioprocess. Styrene degrading Pseudomonas sp. strain VLB120 is shown to be solvent tolerant and was engineered to produce enantiopure (S)-styrene oxide from styrene. Whereas glucose as sole source for carbon and energy allowed efficient styrene epoxidation at rates up to 97 µmol/min/(g cell dry weight), citrate was found to repress epoxidation by the engineered Pseudomonas sp. strain VLB120,C emphasizing that carbon source selection and control is critical. In comparison to recombinant Escherichia coli, the VLB120,C-strain tolerated higher toxic product levels but showed less stable activities during fed-batch cultivation in a two-liquid phase system. Epoxidation activities of the VLB120,C-strain decreased at product concentrations above 130 mM in the organic phase. During continuous two-liquid phase cultivations at organic-phase product concentrations of up to 85 mM, the VLB120,C-strain showed stable activities and, as compared to recombinant E. coli, a more efficient glucose metabolism resulting in a 22% higher volumetric productivity. Kinetic analyses indicated that activities were limited by the styrene concentration and not by other factors such as NADH availability or catabolite repression. In conclusion, the stability of activity of the solvent tolerant VLB120,C-strain can be considered critical at elevated toxic product levels, whereas the efficient carbon and energy metabolism of this Pseudomonas strain augurs well for productive continuous processing. Biotechnol. Bioeng. 2007;98: 1219,1229. © 2007 Wiley Periodicals, Inc. [source] Optimization of enzyme complexes for lignocellulose hydrolysisBIOTECHNOLOGY & BIOENGINEERING, Issue 2 2007Alex Berlin Abstract The ability of a commercial Trichoderma reesei cellulase preparation (Celluclast 1.5L), to hydrolyze the cellulose and xylan components of pretreated corn stover (PCS) was significantly improved by supplementation with three types of crude commercial enzyme preparations nominally enriched in xylanase, pectinase, and ,-glucosidase activity. Although the well-documented relief of product inhibition by ,-glucosidase contributed to the observed improvement in cellulase performance, significant benefits could also be attributed to enzymes components that hydrolyze non-cellulosic polysaccharides. It is suggested that so-called "accessory" enzymes such as xylanase and pectinase stimulate cellulose hydrolysis by removing non-cellulosic polysaccharides that coat cellulose fibers. A high-throughput microassay, in combination with response surface methodology, enabled production of an optimally supplemented enzyme mixture. This mixture allowed for a ,twofold reduction in the total protein required to reach glucan to glucose and xylan to xylose hydrolysis targets (99% and 88% conversion, respectively), thereby validating this approach towards enzyme improvement and process cost reduction for lignocellulose hydrolysis. Biotechnol. Bioeng. 2007;97: 287,296. © 2006 Wiley Periodicals, Inc. [source] Use of a plant-derived enzyme template for the production of the green-note volatile hexanalBIOTECHNOLOGY & BIOENGINEERING, Issue 3 2003Frank Schade Abstract Hexanal is a key organoleptic element of green-note that is found in both fragrances and flavors. We report a novel process for the production of hexanal using immobilized enzyme templates extracted from different plant sources in combination with hollow-fiber ultrafiltration for in situ separation. Enzyme templates, known to be responsible for the synthesis of hexanal from linoleic acid (18:2), were isolated from naturally enriched tissues including carnation petals, strawberry and tomato leaves. These templates were immobilized in an alginate matrix and used as a biocatalyst in a packed-bed bioreactor. Continuous product recovery was achieved using a hollow-fiber ultrafiltration unit. The effects of pH, reaction temperature, and substrate and enzyme concentrations were studied and their effects on hexanal generation identified and optimized. Utilizing optimized conditions, hexanal production 112-fold higher than endogenous steady-state levels in a corresponding amount of plant tissue could be achieved over a 30-minute period. Based on the reactor studies, product inhibition also appears to be an important factor for bioreactor-based hexanal production. © 2003 Wiley Periodicals, Inc. Biotechnol Bioeng 84: 265,273, 2003. [source] Kinetics of lactose hydrolysis by ,-galactosidase of Kluyveromyces lactis immobilized on cotton fabricBIOTECHNOLOGY & BIOENGINEERING, Issue 2 2003Quinn Zhengkun Zhou Abstract A mathematic model for describing the Michaelis-Menten-type reaction kinetics with product competitive inhibition and side-reaction is proposed. A multiresponse nonlinear simulation program was employed to determine the coefficients of a four-parameter rate expression. The rate expression was compared with the conventional Michaelis-Menten reaction rate models with and without product inhibition. Experimental data were obtained using ,-galactosidase of Kluyveromyces lactis immobilized on cotton fabric in a batch system at a temperature of 37°C and at various initial concentrations of dissolved lactose ranging from 3,12.5% (w/v). The reaction is followed by concentration changes with time in the tank. Samples were obtained after the outlet stream of the packed bed reactor is mixed in a well-stirred tank. High-performance liquid chromatography (HPLC) was applied to monitor the concentrations of all the sugars (reactants as well as products). The four-parameter rate model is featured with a term to describe the formation of trisaccharides, a side-reaction of the enzymatic hydrolysis. The proposed model simulates the process of lactose hydrolysis and the formation of glucose and galactose, giving better accuracy compared with the previous models. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 81: 127,133, 2003. [source] Continuous screening system for inhibited enzyme catalysis: A membrane reactor approachBIOTECHNOLOGY JOURNAL, Issue 8 2010Evgenij Lyagin Abstract The screening of catalysts, substrates or conditions in the early stages of bioprocess development requires an enormous number of experiments and is a tedious, expensive and time-consuming task. Currently available screening systems can only be operated in batch or fed-batch mode, which can lead to severe misinterpretations of screening results. For example, catalysts that are inhibited by substrates or accumulating products will be excluded from further investigations in the early stages of process development despite the fact that they might be superior to other candidates in a different operational mode. Important and advantageous properties such as turnover stability can also be overshadowed by product inhibition. The aim of this study was to develop a novel screening system that enables continuous feeding of substrates and continuous removal of products. A prototype based on the membrane reactor concept was designed and operated for a model reaction, the hydrolysis of cellulose. [source] Development of a Transient Segregated Mathematical Model of the Semicontinuous Microbial Production Process of DihydroxyacetoneBIOTECHNOLOGY PROGRESS, Issue 1 2006Rüdiger Bauer For the mathematical description of the semicontinuous two-stage repeated-fed-batch fermentation of dihydroxyacetone (DHA), a novel segregated model incorporating transient growth rates was developed. The fermentation process was carried out in two stages. A viable, not irreversibly product-inhibited culture was maintained in the first reactor stage until a predetermined DHA threshold value was reached. In the second reactor stage, high final product concentrations of up to 220 g L,1 were reached while the culture was irreversibly product-inhibited. The experimentally observed changes of the physiological state of the culture due to product inhibition were taken into account by introducing a segregation into the mathematical model. It was shown that the state of the cells was dependent on the current environment and on the previous history. This phenomenon was considered in the model by utilizing delay time equations for the specific rates of growth on the primary and the secondary substrate. A comparison with reproducible measurements gave a good correlation between computation and experiment. The mathematical model was validated using independent own experimental data. A comparison with a stationary and nonsegregated model demonstrated the essential improvements of the novel model. It was deduced from the model calculations that high product formation rates of 3.3,3.5 g L,1 h,1 as well as high final DHA concentrations of 196,215 g L,1 can be obtained with a residual broth volume in the first reactor stage of 2% and a DHA threshold value in the range of 100,110g L,1. [source] RhIII - and IrIII -Catalyzed Asymmetric Transfer Hydrogenation of Ketones in WaterCHEMISTRY - A EUROPEAN JOURNAL, Issue 7 2008Xiaofeng Wu Dr. Abstract Asymmetric transfer hydrogenation (ATH) of ketones by formate in neat water is shown to be viable with Rh-TsDPEN and Ir-TsDPEN catalysts, derived in situ from [Cp*MCl2]2 (M=Rh, Ir) and TsDPEN. A variety of ketones were reduced, including nonfunctionalized aryl ketones, heteroaryl ketones, ketoesters, and unsaturated ketones. In comparison with Ir-TsDPEN and the related RuII catalyst, the RhIII catalyst is most efficient in water, affording enantioselectivities of up to 99,% ee at substrate/catalyst (S/C) ratios of 100,1000 even without working under an inert atmosphere. The aqueous phase reduction is shown to be highly pH-dependent; the optimum pH windows for TOF greater than 50,mol,mol,1,h,1 for Rh- and Ir-TsDPEN are 5.5,10.0 and 6.5,8.5, respectively. Outside the pH window, the reduction becomes slow or stagnant depending on the pH. However, the enantioselectivities erode only under acidic conditions. At a higher S/C ratio, the aqueous ATH by Rh-TsDPEN is shown to be product- as well as byproduct-inhibited; the product inhibition appears to stem at least partly from the reaction being reversible. The aqueous phase reduction is simple, efficient and environmentally benign, thus presenting a viable alternative for asymmetric reduction. [source] Polyamide Synthesis from 6-Aminocapronitrile, Part 1: N -Alkyl Amide Formation by Amine Amidation of a Hydrolyzed NitrileCHEMISTRY - A EUROPEAN JOURNAL, Issue 27 2007Adrianus Abstract The synthesis of N -hexylpentanamide from a stoichiometric amount of pentanenitrile and hexylamine has been studied as a model reaction for the synthesis of nylon-6 from 6-aminocapronitrile. The reaction was carried out under mild hydrothermal conditions and in the presence of a homogeneous ruthenium catalyst. For the mild hydrothermal conditions the presence of hexylamine distinctively increases the nitrile hydrolysis compared to the nitrile hydrolysis in the absence of hexylamine. Amine-catalyzed nitrile hydrolysis mainly produces the N-substituted amide. A clear product development is observed, consisting of first the terminal amide formation and second the accumulation of N -hexylpentanamide. With a maximum conversion of only 80,% after 18,h, the nitrile hydrolysis rate at 230,°C is still much too low for nylon-6 synthesis. Ruthenium dihydride phosphine was therefore used as a homogeneous catalyst, which significantly increases the nitrile hydrolysis rate. At a temperature of 140,°C and with only 0.5,mol,% [RuH2(PPh3)4] a 60,% nitrile conversion is already reached within 2,h. Initially the terminal amide is the sole product, which is gradually converted into N -hexylpentanamide. The reaction has a high initial rate, however, for higher conversions a strong decrease in hydrolysis rate is observed. This is ascribed to product inhibition, which results from the equilibrium nature of the reaction. [source] Palladium-Catalyzed Cross-Coupling Reactions of Amines with Alkenyl Bromides: A New Method for the Synthesis of Enamines and IminesCHEMISTRY - A EUROPEAN JOURNAL, Issue 2 2004José Barluenga Prof. Dr. Abstract The palladium-catalyzed cross-coupling reaction of alkenyl bromides with secondary and primary amines gives rise to enamines and imines, respectively. This new transformation expands the applicability of palladium-catalyzed CN bond forming reactions (the Buchwald,Hartwig amination), which have mostly been applied to aryl halides. After screening of different ligands, bases, and solvents, the catalytic combination [Pd2(dba)3]/BINAP in the presence of NaOtBu in toluene gave the best results in the cross-coupling of secondary amines with 1-bromostyrene (dba=dibenzylideneacetone, BINAP=2,2,-bis(diphenylphosphino)-1,1,-binaphthyl). The corresponding enamines are obtained cleanly and in nearly quantitative yields. However, steric hindrance seems to be a limitation of the reaction, as amines carrying large substituents are not well converted. The same methodology can be applied to the coupling of secondary amines with 2-bromostyrene. Moreover, the reaction with substituted 2-bromopropenes allows regioselective synthesis of isomerizable terminal enamines without isomerization of the double bond. The best catalytic conditions for the cross-coupling of 1-bromostyrene with primary amines include again the use of the Pd0/BINAP/NaOtBu system. The reaction gives rise to the expected imines in very short times and with low catalyst loadings. A set of structurally diverse imines can be prepared by this methodology through variations in the structure of both coupling partners. However, 2-bromostyrene failed to give good results in this coupling reaction, probably due to product inhibition of the catalytic cycle. Competition experiments of vinyl versus aryl amination reveal that the reaction occurs preferentially on vinyl bromides. La reacción de acoplamiento cruzado de bromuros de alquenilo con aminas secundarias y primarias da lugar a enaminas e iminas respectivamente. Esta nueva transformación expande las aplicaciones de la reacción de formación de enlaces CN catalizada por paladio (aminación Buchwald,Hartwig), que se había limitado fundamentalmente a haluros de arilo. Después de un estudio de diferentes ligandos. bases y disolventes, los mejores resultados en la reacción de acoplamiento cruzado de aminas secundarias con 1-bromoestireno, se obtuvieron para el catalizador constituido por la combinación Pd/BINAP en presencia de NaOtBu en tolueno. Las correspondientes enaminas se obtienen limpiamente y con rendimientos prácticamente cuantitativos. Sin embargo, los impedimentos estéricos en la amina parecen ser una limitación de la reacción, puesto que aminas con sustituyentes voluminosos proporcionan conversiones bajas. La misma metodología puede aplicarse al acoplamiento de aminas secundarias con 2-bromoestireno. Además, la reacción con 2-bromopropenos sustituidos permite obtener de forma regioselectiva enaminas terminales isomerizables, sin que la isomerización del doble enlace tenga lugar. Las mejores condiciones catalíticas para el acoplamiento de aminas primarias con 1-bromoestireno incluyen de nuevo la utilización del sistema Pd(0)/BINAP/NaOtBu. La reacción proporciona las iminas esperadas en tiempos de reacción muy cortos y con baja carga del catalizador. Mediante esta metodología pueden prepararse un conjunto de iminas de gran diversidad estructural, permitiendo variaciones en ambos reactivos de acoplamiento. Sin embargo, la reacción con 2-bromoestireno no produce buenos resultados en este acoplamiento, probablemente debido a inhibición del ciclo catalítico por parte del producto de reacción. Finalmente, experimentos de competencia de aminación vinílica frente a aminación arílica, ponen de manifiesto que esta reacción se produce de forma preferente sobre los bromuros de vinilo. [source] | |||||||||||||