Transfer Catalysis Research Articles

Mass Transfer Performance of a Capillary Microreactor during Ultrasound-Assisted Phase Transfer Catalysis

In this study, the liquid–liquid catalytic phase transfer reaction between benzyl chloride and sodium sulfide was investigated in an ultrasound-based capillary microreactor. The mass transfer performance in the multiphase reaction was evaluated in terms of the mass transfer coefficient and was compared to the performance of other systems namely, a capillary microreactor under silent conditions, a batch reactor with different speeds of agitation, an ultrasound-assisted batch reactor, and an ultrasound-assisted batch reactor with mechanical agitation.In the batch reactor system, the mass transfer coefficient increased by a large factor when mechanical agitation was accompanied by ultrasound irradiation. However, the capillary microreactor was superior to the batch reactor system under different operation conditions.In the case of the capillary microreactor, it was found that the mass transfer performance was enhanced by a greater degree under sonication conditions than under silent conditions. Under sonication conditions, the mass transfer performance was further enhanced by increasing the aqueous-to-organic phase flow rate ratio.

A short, strong hydrogen bond in the active site of human carbonic anhydrase II.

The crystal structure of human carbonic anhydrase II (HCA II) obtained at 0.9 A resolution reveals that a water molecule, termed deep water, Dw, and bound in a hydrophobic pocket of the active site forms a short, strong hydrogen bond with the zinc-bound solvent molecule, a conclusion based on the observed oxygen-oxygen distance of 2.45 A. This water structure has similarities with hydrated hydroxide found in crystals of certain inorganic complexes. The energy required to displace Dw contributes in significant part to the weak binding of CO(2) in the enzyme-substrate complex, a weak binding that enhances k(cat) for the conversion of CO(2) into bicarbonate. In addition, this short, strong hydrogen bond is expected to contribute to the low pK(a) of the zinc-bound water and to promote proton transfer in catalysis.

Role of Hydrophilic Residues in Proton Transfer during Catalysis by Human Carbonic Anhydrase II

Catalysis by the zinc metalloenzyme human carbonic anhydrase II (HCA II) is limited in maximal velocity by proton transfer between His64 and the zinc-bound solvent molecule. Asn62 extends into the active site cavity of HCA II adjacent to His64 and has been shown to be one of several hydrophilic residues participating in a hydrogen-bonded solvent network within the active site. We compared several site-specific mutants of HCA II with replacements at position 62 (Ala, Val, Leu, Thr, and Asp). The efficiency of catalysis in the hydration of CO 2 for the resulting mutants has been characterized by (18)O exchange, and the structures of the mutants have been determined by X-ray crystallography to 1.5-1.7 A resolution. Each of these mutants maintained the ordered water structure observed by X-ray crystallography in the active site cavity of wild-type HCA II; hence, this water structure was not a variable in comparing with wild type the activities of mutants at residue 62. Crystal structures of wild-type and N62T HCA II showed both an inward and outward orientation of the side chain of His64; however, other mutants in this study showed predominantly inward (N62A, N62V, N62L) or predominantly outward (N62D) orientations of His64. A significant role of Asn62 in HCA II is to permit two conformations of the side chain of His64, the inward and outward, that contributes to maximal efficiency of proton transfer between the active site and solution. The site-specific mutant N62D had a mainly outward orientation of His64, yet the difference in p K a between the proton donor His64 and zinc-bound hydroxide was near zero, as in wild-type HCA II. The rate of proton transfer in catalysis by N62D HCA II was 5% that of wild type, showing that His64 mainly in the outward orientation is associated with inefficient proton transfer compared with His64 in wild type which shows both inward and outward orientations. These results emphasize the roles of the residues of the hydrophilic side of the active site cavity in maintaining efficient catalysis by carbonic anhydrase.

New Chiral Ligands for Catalytic Asymmetric Transfer Hydrogenation of Acetophenone

Two novel planar chiral diferrocenylphosphine-diimines I and II were prepared and characterized by IR and 1 HNMR spectroscopy. In addition, the application of their complexes with Ir formed complexes formed in situ as catalysts in asymmetric transfer hydrogenation and the discussion of the effects of the reaction conditions, as well as the structure of ligands and the configuration of products, are described.

Investigation of Catalytic Chain Transfer Copolymerization of Methacrylates

Batch experiments were carried out to investigate the kinetics of catalytic chain transfer copolymerization of methyl methacrylate and n-butyl methacrylate. The Predici® model developed to represent the system describes the numerous experimental data measured at high concentrations of Co(II) catalyst, taking into account the chain-length dependencies of termination, propagation and catalytic chain transfer. The constants for catalytic chain transfer are determined as 2.3 ×10 4 for both methyl methacrylate and n-butyl methacrylate from fitting the experimental data. Two inhibition mechanisms are shown to describe the decrease of the polymerization rate in the presence of catalyst equally well, with an unknown impurity dissolved in initiator introduced to explain experimental profiles measured at high initiator concentrations.

Tautomerism of histidine 64 associated with proton transfer in catalysis of Carbonic Anhydrase

The imidazole 15N signals of histidine 64 (His‐64), associated with the proton‐transfer function of human carbonic anhydrase II (hCAII), were observed [1]. Using the pH‐dependency of ring 15N signals and a comparison between experimental and simulated curves, we determined that the tautomeric equilibrium constant (KT) of His‐64 is 1.0. This unique value characterizes the nitrogen atoms of the His‐64 ring as both a general acid and base. Based on this feature, we suggest that the tautomerization of His‐64 can mediate the transfer of protons at a neutral pH with high efficiency. Comparing the KT of His‐64 with that of the histidine analog compounds shows that the imidazole group intrinsically tends to be the Nε2‐H tautomer in aqueous solution, unless hydrogen bond interacts with δ1‐nitrogen. This clarifies the structure ‐specifically, the hydrogen bonding pattern of His‐64. As a result, we propose that the formation and decay of hydrogen bonds should occur in the water bridge between His‐64 and zinc‐bound water during hydration and dehydration reactions in catalysis. This provides a new insight into the proton‐transfer mechanism in hCAII, i.e., a reorganization or flow of water molecules occurs in the water bridge when His‐64 is the Nε2‐H tautomer. During this conference, extensively low field shifts of 1H signals and theoretical consistency will be also discussed.

C-Glycosyl Amino-Substituted Hydro- and Benzoquinones: Synthesis and Preliminary Biological Evaluation

Reaction of C-β-D-glycopyranosyl-1,4-dimethoxybenzenes with acetyl nitrate afforded 2-(β-D-glycopyranosyl)-1,4-dimethoxy-5-nitrobenzenes in high yields. These were converted smoothly (reduction to amines, N-acylation, oxidation, and reduction) into the corresponding C-glycosyl-hydro(benzo)quinone derivatives, with different amide-based substituents at C-5. Reduction of the nitro compounds to amines proceeded smoothly by catalytic hydrogen transfer with HCO 2 NH 4 .

Solvent‐Mediated Proton Transfer in Catalysis by Carbonic Anhydrase

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Synthesis, structure, and properties of branched polymethacrylates

The methacrylate: branching agent: chain growth regulator optimal ratios that allow the synthesis of branched polymethacrylates via the crosslinking free-radical copolymerization under the regime of conventional or catalytic chain transfer have been estimated. Relationships between the molecular-mass characteristics of the copolymers, their content of intact C=C bonds, the composition of the starting monomer mixture, and the structure of the branching agent and polymer chain growth regulator have been established. The rheological properties of the branched MMA-based copolymers have been studied. It has been shown that the copolymers are characterized by a weaker dependence of reduced viscosity on the polymer concentration in solution than that for the linear PMMA. The diffusion-sorption behavior of the branched polymethacrylates is determined by the content of the branching agent in them.

Solvent-Mediated Proton Transfer in Catalysis by Carbonic Anhydrase

Considerable attention has been focused on proton transfer through intervening water molecules in complex macromolecules of biological interest, such as bacteriorhodopsin, cytochrome c oxidase, and many others. Proton transfer in catalysis by carbonic anhydrase provides a useful model for the study of the properties of such proton translocations. High-resolution X-ray crystallography in combination with measurements of catalysis have revealed new details of this process. A prominent proton shuttle residue His64 shows evidence of structural mobility, which appears to enhance proton transfer between the active site and bulk solvent. Moreover, the properties of the imidazole side chain of His64, including its conformations and pK(a), are finely tuned by surrounding residues of the active-site cavity. The structure of a network of ordered solvent molecules located between His64 and the active site are also sensitive to surrounding residues. These features combine to provide efficient proton-transfer rates as great as 10(6) s(-1) necessary to sustain rapid catalysis.

Efficient synthesis of 1β- O-acyl glucuronides via selective acylation of allyl or benzyl d-glucuronate

Acyl glucuronides are key metabolites for many carboxylic acid-containing drugs, notably those of the non-steroidal anti-inflammatory class. In the processes of drug safety assessment and new drug development, it is essential that acyl glucuronides, if formed in vivo, should be made conveniently available for bioevaluation. We recently showed that selective acylation of allyl glucuronate is a promising method for the synthesis of these metabolites in good yield and with excellent β-anomeric selectivity. We now give fuller details of the allyl ester method and further report that benzyl glucuronate performs at least equally well in the acylation step, offering the advantage of very mild deprotection by catalytic transfer (or conventional) hydrogenation. Depending on the compatibility of other functional groups, as discussed below, this will be the method of choice for many acyl glucuronide syntheses. The value of the method is demonstrated in particular by the synthesis of several acyl glucuronides that are known metabolites of important drugs.

Structural and kinetic analysis of proton shuttle residues in the active site of human carbonic anhydrase III

We report the X-ray crystal structures and rate constants for proton transfer in site-specific mutants of human carbonic anhydrase III (HCA III) that place a histidine residue in the active-site cavity: K64H, R67H, and K64H-R67N HCA III. Prior evidence from the exchange of 18O between CO2 and water measured by mass spectrometry shows each mutant to have enhanced proton transfer in catalysis compared with wild-type HCA III. However, His64 in K64H and K64H-R67N HCA III have at most a capacity for proton transfer that is only 13% that of His64 in HCA II. This reduced rate in mutants of HCA III is associated with a constrained side-chain conformation of His64, which is oriented outward, away from the active-site zinc in the crystal structures. This conformation appears stabilized by a prominent pi stacking interaction of the imidazole ring of His64 with the indole ring of Trp5 in mutants of HCA III. This single orientation of His64 in K64H HCA III predominates also in a double mutant K64H-R67N HCA III, indicating that the positive charge of Arg67 does not influence the observed conformation of His64 in the crystal structure. Hence, the structures and catalytic activity of these mutants of HCA III containing His64 account only in small part for the lower activity of this isozyme compared with HCA II. His67 in R67H HCA III was also shown to be a proton shuttle residue, having a capacity for proton transfer that was approximately four times that of His64 in K64H HCA III. This is most likely due to its proximity and orientation inward towards the zinc-bound solvent. These results emphasize the significance of side chain orientation and range of available conformational states as characteristics of an efficient proton shuttle in carbonic anhydrase.

Paramagnetic (Alkene)Rh and (Alkene)Ir Complexes: Metal or Ligand Radicals?

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Speeding Up Proton Transfer in a Fast Enzyme: Kinetic and Crystallographic Studies on the Effect of Hydrophobic Amino Acid Substitutions in the Active Site of Human Carbonic Anhydrase II

Catalysis of the hydration of CO2 by human carbonic anhydrase isozyme II (HCA II) is sustained at a maximal catalytic turnover of 1 mus-1 by proton transfer between a zinc-bound solvent and bulk solution. This mechanism of proton transfer is facilitated via the side chain of His64, which is located 7.5 A from the zinc, and mediated via intervening water molecules in the active-site cavity. Three hydrophilic residues that have previously been shown to contribute to the stabilization of these intervening waters were replaced with hydrophobic residues (Y7F, N62L, and N67L) to determine their effects on proton transfer. The structures of all three mutants were determined by X-ray crystallography, with crystals equilibrated from pH 6.0 to 10.0. A range of changes were observed in the ordered solvent and the conformation of the side chain of His64. Correlating these structural variants with kinetic studies suggests that the very efficient proton transfer (approximately 7 micros-1) observed for Y7F HCA II in the dehydration direction, compared with the wild type and other mutants of this study, is due to a combination of three features. First, in this mutant, the side chain of His64 showed an appreciable inward orientation pointing toward the active-site zinc. Second, in the structure of Y7F HCA II, there is an unbranched chain of hydrogen-bonded waters linking the proton donor His64 and acceptor zinc-bound hydroxide. Finally, the difference in pKa of the donor and acceptor appears favorable for proton transfer. The data suggest roles for residues 7, 62, and 67 in fine-tuning the properties of His64 for optimal proton transfer in catalysis.

Tautomerism of Histidine 64 Associated with Proton Transfer in Catalysis of Carbonic Anhydrase

The imidazole (15)N signals of histidine 64 (His(64)), involved in the catalytic function of human carbonic anhydrase II (hCAII), were assigned unambiguously. This was accomplished by incorporating the labeled histidine as probes for solution NMR analysis, with (15)N at ring-N(delta1) and N(epsilon2), (13)Cat ring-Cepsilon1, (13)C and (15)N at all carbon and nitrogen, or (15)N at the amide nitrogen and the labeled glycine with (13)C at the carbonyl carbon. Using the pH dependence of ring-(15)N signals and a comparison between experimental and simulated curves, we determined that the tautomeric equilibrium constant (K(T)) of His(64) is 1.0, which differs from that of other histidine residues. This unique value characterizes the imidazole nitrogen atoms of His(64) as both a general acid (a) and base (b): its epsilon2-nitrogen as (a) releases one proton into the bulk, whereas its delta1-nitrogen as (b) extracts another proton from a water molecule within the water bridge coupling to the zinc-bound water inside the cave. This accelerates the generation of zinc-bound hydroxide to react with the carbon dioxide. Releasing the productive bicarbonate ion from the inside separates the water bridge pathway, in which the next water molecules move into beside zinc ion. A new water molecule is supplied from the bulk to near the delta1-nitrogen of His(64). These reconstitute the water bridge. Based on these features, we suggest here a catalytic mechanism for hCAII: the tautomerization of His(64) can mediate the transfers of both protons and water molecules at a neutral pH with high efficiency, requiring no time- or energy-consuming processes.

Mechanisms of Electron Transfer in Catalysis by Copper Zinc Superoxide Dismutase

Activated oxygen intermediates during copper zinc superoxide dismutase (SOD) catalysis were investigated using an isotope fractionation technique and natural abundance reagents. Competitive oxygen kinetic isotope effects (KIEs) are reported for the enzyme-catalyzed disproportionation of superoxide as well as the stoichiometric reaction of reduced SOD with molecular oxygen. Analysis within the context of quantum mechanical electron transfer theory provides evidence against an outer-sphere mechanism for O2*- oxidation. A CuII-O2-I intermediate is, therefore, proposed. The SOD-catalyzed oxidation of O2*- is characterized by an inverse (<1) KIE which is similar to those determined for the analogous reactions of synthetic copper compounds. An inverse kinetic isotope effect upon the enzymatic reduction of O2*- is also observed and proposed to arise from rate-determining proton transfer which leads to the formation of HO2* in the SOD active site.

Crystal structure of nitrated human manganese superoxide dismutase: Mechanism of inactivation

A cellular consequence of the reaction of superoxide and nitric oxide is enhanced peroxynitrite levels. Reaction of peroxynitrite with manganese superoxide dismutase (MnSOD) causes nitration of the active-site residue Tyr34 and nearly complete inhibition of catalysis. We report the crystal structures at 2.4 Å resolution of human MnSOD nitrated by peroxynitrite and the unmodified MnSOD. A comparison of these structures showed no significant conformational changes of active-site residues or solvent displacement. The side chain of 3-nitrotyrosine 34 had a single conformation that extended toward the manganese with O1 of the nitro group within hydrogen-bonding distance (3.1 Å) of Nε2 of the second-shell ligand Gln143. Also, nitration of Tyr34 caused a weakening, as evidenced by the lengthening, of a hydrogen bond between its phenolic OH and Gln143, part of an extensive hydrogen-bond network in the active site. Inhibition of catalysis can be attributed to a steric effect of 3-nitrotyrosine 34 that impedes substrate access and binding, and alteration of the hydrogen-bond network that supports proton transfer in catalysis. It is also possible that an electrostatic effect of the nitro group has altered the finely tuned redox potential necessary for efficient catalysis, although the redox potential of nitrated MnSOD has not been measured.

Control of Branching Vs. Cross‐Linking in Conventional Free Radical Copolymerization of MMA and EGDMA Using CoBF as a Catalytic Chain Transfer Agent

Solution copolymerization of methyl methacrylate (MMA) and ethylene glycol dimethacrylate (EGDMA) by conventional free radical methodology using a cobalt oxime (CoBF) as a catalytic chain transfer agent allows synthesis at high conversion of fully soluble branched poly (methyl methacrylate)s. Using CoBF levels of 8–32 ppm, mole ratios of MMA/EGDMA up to ∼100/10 can be employed in producing branched products without any macrogelation or microgel formation. Higher levels of EGDMA require higher levels of CoBF to inhibit cross‐linking, but the reactions are difficult to control and have poor reproducibility. An 1H NMR analysis confirms the incorporation of EGDMA at a level comparable to that of the comonomer feed and typically 50–70% of these residues are present as branching segments rather than as pendent partially reacted residues. Double detection (DD) and triple detection (TD) size exclusion chromatographs (SEC) have been used to evaluate the molar mass and branching character of the products. Molar mass data from both instruments show good agreement, and products with molar mass distribution curves very similar to those of previous products prepared using dodecanethiol (DDT) as a stoichiometric chain transfer agent can be produced. The maximum level of EGDMA that can be incorporated using CoBF is, however, lower than is the case when DDT is used. The analytical data from the TDSEC instrument allows the slice‐by‐slice generation of intrinsic viscosity (IV) data and corresponding data for the Zimm branching factor, g′, across the molar mass distribution. At a given molar mass of 130,000 g/mol, g′ correlates well with the level of EGDMA used in the polymerization feed, and is consistent with the 1H NMR data showing efficient incorporation of this branching comonomer. Dedicated to Professor John L. Stanford on the occasion of his 60th birthday.

Counter‐Phase Transfer Catalysis

AbstractFor Abstract see ChemInform Abstract in Full Text.

Macromolecular design of the network structure of copolymers of ethylene glycol dimethacrylate with methyl methacrylate using the catalytic chain transfer reaction

Abstract It has been shown that catalytic chain transfer reaction is an effective instrument for the macromolecular design of the network structure of copolymers of ethylene glycol dimethacrylate with methyl methacrylate. Copolymers of various macromolecular architectures - from networks to soluble branched low-molecularweight oligomers - have been produced using cobalt porphyrin as catalytic chain transfer agent. The influence of cobalt porphyrin on the kinetics of copolymerization, structure and properties of final copolymers has been studied.