Kinetic Control (kinetic + control)

Distribution by Scientific Domains

Selected Abstracts

Face-Selective [2]- and [3]Rotaxanes: Kinetic Control of the Threading Direction of Cyclodextrins

Tomoya Oshikiri
Abstract New [2]- and [3]pseudorotaxanes containing ,-cyclodextrin (,-CDs) molecules as rotors and alkyl pyridinium derivatives as axles were prepared by a slipping process. The inclusion behavior of these rotaxanes was investigated by using one- and two-dimensional NMR spectroscopy. The methyl group at the 2-position of the pyridinium moiety at the end of each axle molecule was found to control the rates of threading of the ,-CD onto the axle molecules. ,-CD can approach axle molecules from a particular direction to form inclusion complexes. Axle molecules that contain a 2-methylpyridinium moiety at one end and a bulky stopper at the other end can regulate the direction of approach to give a [2]pseudorotaxane such as 2,b,,-CD. A [3]pseudorotaxane in which two ,-CD molecules are arranged facing in the same direction at two stations of the tetracationic axle molecule was also obtained. These face-selective behaviors are dominated by kinetic processes rather than thermodynamic processes. [source]

Thermodynamic/Kinetic Control in the Isomerization of the [{tBuNP(,-NtBu)}2]2, Ion

Andrew D. Bond Dr.
Abstract The unique structure of [(tBuN)2PK], (2) (containing [(tBuN)2P], monoanions) is in stark contrast to the previously reported Li+ analogue [{[tBuNP(,-NtBu)]2}2]Li4 (1) (containing the dimeric [{tBuNP(,-NtBu)}2]2, ion). DFT and 31P NMR spectroscopic studies reveal that the formation of the monoanion arrangements are most thermodyamically favored for Li, Na, and K, 1 being the product of kinetic control and 2 being the product of thermodynamic control. [source]

Lewis Acid Induced [2+2] Cycloadditions of Silyl Enol Ethers with ,,,-Unsaturated Esters: A DFT Analysis

Manuel Arnó
Abstract The Lewis acid (LA) induced cycloaddition of trimethysilyl vinyl ether with methyl acrylate has been studied by DFT methods at the B3LYP/6-31G* level. In the absence of an LA, a [4+2] cycloaddition between the silyl enol ether and methyl acrylate in the s-cis conformation takes place through an asynchronous, concerted bond-formation process. This cycloaddition presents a large activation enthalpy of 21.1 kcal,mol,1. Coordination of the LA AlCl3 to the carbonyl oxygen atom of methyl acrylate yields a change of molecular mechanism from a concerted to a two-step mechanism and produces a drastic reduction of the activation energy. This stepwise mechanism is initialized by the nucleophilic attack of the enol ether at the ,-position of methyl acrylate in a Michael-type addition. The very low activation energy (7.1 kcal,mol,1)associated with this nucleophilic attack can be related to the increase of the electrophilicity of the LA-coordinated ,,,-unsaturated ester, which favors the cycloaddition through a polar process. The subsequent ring-closure allows the formation of the corresponding [2+2] and [4+2] cycloadducts. While the [4+2] cycloadduct is formed by kinetic control, the [2+2] cycloadducts are formed by thermodynamic control. The energetic results provide an explanation for the conversion of [4+2] cycloadducts into the thermodynamically more stable [2+2] ones. The cis/trans ratio found for the catalytic [2+2] process is in agreement with the experimental outcome. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005) [source]

Asymmetric Synthesis of ,-Fluorinated ,-Amino Acid Derivatives

Deepak M. Shendage
Abstract Asymmetric alkylation of (S)-Boc-BMI (1a, BMI = 2- tert -butyl-3-methylimidazolidin-4-one) and its ,-methyl derivative 1b with 2-fluoroallyl tosylate, subsequent mild acidic deprotection of the products 2a and 2b, and basic hydrolysis of the thus formed N -methylamides 4a and 4b gave (S)-2-amino-4-fluoropent-4-enoic acid (5a) and (S)-2-amino-4-fluoro-2-methylpent-4-enoic acid (5b). Basic hydrolysis of compound 4a was accompanied by partial racemization, which was overcome by applying a new stereoconservative deamidation procedure. The alkylated cis -configured product 2a formed under kinetic control epimerized on refluxing with 2 n NaOH to give the thermodynamically more stable trans isomer 9. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005) [source]

Thermally induced conformational changes in horseradish peroxidase

FEBS JOURNAL, Issue 1 2001
David G. Pina
Detailed differential scanning calorimetry (DSC), steady-state tryptophan fluorescence and far-UV and visible CD studies, together with enzymatic assays, were carried out to monitor the thermal denaturation of horseradish peroxidase isoenzyme c (HRPc) at pH 3.0. The spectral parameters were complementary to the highly sensitive but integral method of DSC. Thus, changes in far-UV CD corresponded to changes in the overall secondary structure of the enzyme, while that in the Soret region, as well as changes in intrinsic tryptophan fluorescence emission, corresponded to changes in the tertiary structure of the enzyme. The results, supported by data about changes in enzymatic activity with temperature, show that thermally induced transitions for peroxidase are irreversible and strongly dependent upon the scan rate, suggesting that denaturation is under kinetic control. It is shown that the process of HRPc denaturation can be interpreted with sufficient accuracy in terms of the simple kinetic scheme where k is a first-order kinetic constant that changes with temperature, as given by the Arrhenius equation; N is the native state, and D is the denatured state. On the basis of this model, the parameters of the Arrhenius equation were calculated. [source]

Carbothermal synthesis of vanadium nitride: Kinetics and mechanism

A. Ortega
Constant rate thermal analysis (CRTA) has been used for the first time to study the kinetics of the carbothermal reduction of V2O5 in nitrogen to obtain vanadium nitride. It is noteworthy to point out that CRTA method allows both a good control of pressure in the sample surroundings and the use of reaction rates low enough to keep temperatures gradients at a negligible level to avoid any heat or mass transfer phenomena. This method allows one to control the texture and the structure of many materials through kinetic control of the thermal treatment of the precursors. The precise control of the external parameters of the reaction shows that CRTA is an attractive method for kinetic studies and leads to more reliable kinetic data. It has been shown that the carbothermal synthesis of vanadium nitride is best described by a three-dimensional diffusion kinetic model (the Jander equation) with an activation energy which falls in the range of 520,540 kJ/mol. © 2006 Wiley Periodicals, Inc. Int J Chem Kinet 38: 369,375, 2006 [source]

Kinetic Analysis of L -Carnosine Formation by ,-Aminopeptidases

Tobias Heck
Abstract The ,,,-dipeptide L -carnosine occurs in high concentrations in long-lived innervated mammalian tissues and is widely sold as a food additive. On a large scale L -carnosine is produced by chemical synthesis procedures. We have established two aqueous enzymatic reaction systems for the preparation of L -carnosine using the dissolved bacterial ,-aminopeptidases DmpA from Ochrobactrum anthropi and BapA from Sphingosinicella xenopeptidilytica as catalysts and investigated the kinetics of the enzyme-catalyzed peptide couplings. DmpA catalyzed the formation of L -carnosine from C-terminally activated ,-alanine derivatives (acyl donor) and L -histidine (acyl acceptor) in an aqueous reaction mixture at pH,10 with high catalytic rates (Vmax=19.2,,mol,min,1 per mg of protein, kcat=12.9,s,1), whereas Vmax in the BapA-catalyzed coupling reaction remained below 1.4,,mol,min,1 per mg of protein (kcat=0.87,s,1). Although the equilibrium of this reaction lies on the side of the hydrolysis products, the reaction is under kinetic control and L -carnosine temporarily accumulated to concentrations that correspond to yields of more than 50% with respect to the employed acyl donor. However, competing nucleophiles caused unwanted hydrolysis and coupling reactions that led to decreased product yield and to formation of various peptidic by-products. The substitution of L -histidine for L -histidine methyl ester as acyl acceptor shifted the pKa of the amino functionality from 9.25 to 6.97, which caused a drastic reduction in the amount of coupling by-products in an aqueous reaction system at pH,8. [source]

Side chain contributions to the interconversion of the topological isomers of guanylin-like peptides

Dr Axel Schulz
Abstract The peptide hormones guanylin and uroguanylin are ligands of the intestinal guanylyl cyclase-C (GC-C) that is involved in the regulation of epithelial water and electrolyte transport. The small peptides contain 15 and 16 amino acids, respectively, and two disulfide bonds with a 1,3/2,4 connectivity. This structural feature causes the unique existence of two topological isoforms for each peptide in an approximate 3:2 ratio, with only one of the isoforms exhibiting GC-C-activating potential. The two uroguanylin isomers can be separated by HPLC and are of sufficient stability to be studied separately at ambient temperatures while the two guanylin isomers are rapidly interconverting even at low temperatures. Both isomers show clearly distinguishable 1H chemical shifts. To investigate the influence of certain amino acid side chains on this isomerism and interconversion kinetics, derivatives of guanylin and uroguanylin (L -alanine scan and chimeric peptides) were designed and synthesized by Fmoc solid-phase chemistry and compared by HPLC and 2D 1H NMR spectroscopy. Amino acid residues with the most significant effects on the interconversion kinetics were predominantly identified in the COOH-terminal part of both peptides, whereas amino acids in the central part of the peptides only moderately affected the interconversion. Thus, the conformational conversion among the isomers of both peptides is under the control of a COOH-terminal sterical hindrance, providing a detailed model for this dynamic isomerism. Our results demonstrate that kinetic control of the interconversion process can be achieved by the introduction of side chains with a defined sterical profile at suitable sequence positions. This is of potential impact for the future development of GC-C peptide agonists and antagonists. Copyright © 2004 European Peptide Society and John Wiley & Sons, Ltd. [source]

Conformation-dependent side reactions in interstrand-disulfide bridging of trimeric collagenous peptides by regioselective cysteine chemistry

Barbara Saccá
Abstract Conversion of single-chain or disulfide-bridged dimeric collagenous peptides into Cys(Npys) derivatives as activated species for subsequent regioselective thiol/disulfide exchange reactions leads to side products whose origin and nature was determined by HPLC and ESI-MS. In both cases the high tendency of the educts to self-associate into triple-helical homotrimers, as assessed by their dichroic properties in the reaction media, is responsible for the failure of this well established cysteine chemistry. Only by optimizing the synthetic strategy or by exploiting a kinetic control of the reaction, could these conformation-dependent limitations be more or less efficiently bypassed for the regioselective assembly of heterotrimeric collagen model peptides crosslinked with artificial cystine knots. Copyright © 2002 European Peptide Society and John Wiley & Sons, Ltd. [source]

Aggregation kinetics of recombinant human FVIII (rFVIII)

Karthik Ramani
Abstract The physical phenomenon of aggregation can have profound impact on the stability of therapeutic proteins. This study focuses on the aggregation behavior of recombinant human FVIII (rFVIII), a multi-domain protein used as the first line of therapy for hemophilia A, a bleeding disorder caused by the deficiency or dysfunction of factor VIII (FVIII). Thermal denaturation of rFVIII was investigated using circular dichroism (CD) spectroscopy and size exclusion chromatography (SEC). The dependence of unfolding on heating rate indicated that the thermal denaturation of the protein was at least partly under kinetic control. The data was interpreted in terms of a simple two-state kinetic model, , where k is a first-order kinetic constant that changes with temperature, as given by the Arrhenius equation. Analysis of the data in terms of the above scheme suggested that under the experimental conditions used in this study, the rate-controlling step in the aggregation of rFVIII may be a unimolecular reaction involving conformational changes. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:2023,2029, 2005 [source]

Efficient synthesis of a long carbohydrate chain alkyl glycoside catalyzed by cyclodextrin glycosyltransferase (CGTase)

David Svensson
Abstract Alkyl glycosides with long carbohydrate groups are surfactants with attractive properties but they are very difficult to synthesize. Here, a method for extension of the carbohydrate group of commercially available dodecyl-,- d -maltoside (DDM) is presented. DDM was converted to dodecyl-,- d -maltooctaoside (DDMO) in a single step by using a CGTase as catalyst and ,-cyclodextrin (,-CD) as glycosyl donor. The coupling reaction is under kinetic control and the maximum yield depends on the selectivity of the enzyme. The Bacillus macerans CGTase favored the coupling reaction while the Thermoanaerobacter enzyme also catalyzed disproportionation reactions leading to a broader product range. A high ratio ,-CD/DDM favored a high yield of DDMO and yields up to 80% were obtained using the B. macerans enzyme as catalyst. Biotechnol. Bioeng. 2009; 104: 854,861. © 2009 Wiley Periodicals, Inc. [source]

Cobalt Coordination and Clustering in ,-Co(OH)2 Revealed by Synchrotron X-ray Total Scattering

Abstract Structures of layered metal hydroxides are not well described by traditional crystallography. Total scattering from a synthesis-controlled subset of these materials, as described here, reveals that different cobalt coordination polyhedra cluster within each layer on short length scales, offering new insights and approaches for understanding the properties of these and related layered materials. Structures related to that of brucite [Mg(OH)2] are ubiquitous in the mineral world and offer a variety of useful functions ranging from catalysis and ion-exchange to sequestration and energy transduction, including applications in batteries. However, it has been difficult to resolve the atomic structure of these layered compounds because interlayer disorder disrupts the long-range periodicity necessary for diffraction-based structure determination. For this reason, traditional unit-cell-based descriptions have remained inaccurate. Here we apply, for the first time to such layered hydroxides, synchrotron X-ray total scattering methods,analyzing both the Bragg and diffuse components,to resolve the intralayer structure of three different ,-cobalt hydroxides, revealing the nature and distribution of metal site coordination. The different compounds with incorporated chloride ions have been prepared with kinetic control of hydrolysis to yield different ratios of octahedrally and tetrahedrally coordinated cobalt ions within the layers, as confirmed by total scattering. Real-space analyses indicate local clustering of polyhedra within the layers, manifested in the weighted average of different ordered phases with fixed fractions of tetrahedrally coordinated cobalt sites. These results, hidden from an averaged unit-cell description, reveal new structural characteristics that are essential to understanding the origin of fundamental material properties such as color, anion exchange capacity, and magnetic behavior. Our results also provide further insights into the detailed mechanisms of aqueous hydrolysis chemistry of hydrated metal salts. We emphasize the power of the methods used here for establishing structure,property correlations in functional materials with related layered structures. [source]

Theoretical Calculations on the Tetramethyldisilene Rearrangement: A New Approach to an Old Mechanistic Problem

Mrinmoy Nag Dr.
Abstract Roark and Peddle first observed that, when not trapped, Me2SiSiMe2 underwent a series of rearrangements to give two major isomeric products: 1,1-dimethyl-1,3-disilacyclobutane and 1,3-dimethyl-1,3-disilacyclobutane. The widely accepted mechanism for this rearrangement was proposed by Barton and co-workers. However, little is known about the thermodynamic or kinetic properties of this reaction, because the relevant data are limited to the product ratios of the two isomers. Our calculations predict that the product ratio is driven by kinetic control rather than thermodynamic control. We also show that new DFT functionals, such as MPW1K and M052X, produce thermochemical results comparable with CCSD(T) calculations. [source]

A Formal Total Synthesis of Eleutherobin Using the Ring-Closing Metathesis (RCM) Reaction of a Densely Functionalized Diene as the Key Step: Investigation of the Unusual Kinetically Controlled RCM Stereochemistry

Damiano Castoldi Dr.
Abstract Asymmetric oxyallylation reactions and ring-closing metathesis have been used to synthesize compound 3, a key advanced intermediate used in the total synthesis of eleutherobin reported by Danishefsky and co-workers. The aldehyde 6, which is readily prepared from commercially available R -(,)-carvone in six steps in 30,% overall yield on multigram quantities, was converted into the diene 5 utilizing two stereoselective titanium-mediated Hafner,Duthaler oxyallylation reactions. The reactions gave the desired products (8 and 12) in high yields (73 and 83,%, respectively) as single diastereoisomers, with the allylic alcohol already protected as the p -methoxyphenyl (PMP) ether, which previous work has demonstrated actually aids ring-closing metathesis compared to other protective groups and the corresponding free alcohol. Cyclization under forcing conditions, using Grubbs' second-generation catalyst 13, gave the ten-membered carbocycle (E)- 14 in 64,% yield. This result is in sharp contrast to similar, but less functionalized, dienes, which have all undergone cyclization to give the Z stereoisomers exclusively. A detailed investigation of this unusual cyclization stereochemistry by computational methods has shown that the E isomer of the ten-membered carbocycle is indeed less thermodynamically stable than the corresponding Z isomer. In fact, the selectivity is believed to be due to the dense functionality around the ruthenacyclobutane intermediate that favors the trans -ruthenacycle, which ultimately leads to the less stable E isomer of the ten-membered carbocycle under kinetic control. During the final synthetic manipulations the double bond of enedione (E)- 16 isomerized to the more thermodynamically stable enedione (Z)- 4, giving access to the advanced key-intermediate 3, which was spectroscopically and analytically identical to the data reported by Danishefsky and co-workers, and thereby completing the formal synthesis of eleutherobin. [source]

Thermodynamic/Kinetic Control in the Isomerization of the [{tBuNP(,-NtBu)}2]2, Ion

Andrew D. Bond Dr.
Abstract The unique structure of [(tBuN)2PK], (2) (containing [(tBuN)2P], monoanions) is in stark contrast to the previously reported Li+ analogue [{[tBuNP(,-NtBu)]2}2]Li4 (1) (containing the dimeric [{tBuNP(,-NtBu)}2]2, ion). DFT and 31P NMR spectroscopic studies reveal that the formation of the monoanion arrangements are most thermodyamically favored for Li, Na, and K, 1 being the product of kinetic control and 2 being the product of thermodynamic control. [source]