Molecular Orbital Studies of Enzyme Catalysed Reactions. Rearrangement of Chorismate to Prephenate

1979 ◽  
Vol 32 (9) ◽  
pp. 1921 ◽  
Author(s):  
PR Andrews ◽  
RC Haddon
Keyword(s):  
Aqueous Solution ◽  
Transition State ◽  
Molecular Orbital ◽  
Active Site ◽  
Active Sites ◽  
Transition States ◽  
Reaction Pathways ◽  
Carboxyl Groups ◽  
Molecular Orbital Calculations ◽  
Charge Delocalization

Molecular orbital calculations are used to describe the reaction surface for the non-enzymic Claisen rearrangement of chorismate to prephenate, which may proceed through either a boat-like or a chair-like transition state. Detailed molecular geometries are obtained for the neutral and dianionic forms of chorismate, prephenate, and the alternative transition states. The transition states are asymmetric structures in which the breaking C-O bond (c. 1.45 A) is significantly shorter than the making C-C bond (c. 1.95 A). The alternative reaction pathways have almost identical enthalpies of activation (chair, 277.4 kJ/mol ; boat, 282.8 kJ/mol; dianionic forms) which result partly from a loss of internal bond strength and partly from repulsive interactions between the polar carboxyl groups. Protonation stabilizes the transition states (chair, 247.3 kJ/mol; boat, 248.5 kJ/mol ; diacid forms) by delocalization of charge in the carboxyl groups, and a similar mechanism is proposed for the greatly reduced enthalpy of activation in aqueous solution (86.6 kJ/mol). The enthalpy difference between the alternative reaction pathways is insufficient to define a preferred transition state structure, and either pathway may be favoured for the non-enzymic reaction in aqueous solution. For the enzyme-catalysed reaction the chair pathway is used, and the calculated transition state structures and enthalpy barriers provide information relevant to the catalytic mechanism. They indicate that an active site comprising only two essential binding groups is sufficient to account for catalysis; the orientation of these groups within the active site should allow simultaneous bond formation, accompanied by charge delocalization, to both carboxyl groups of the transition state, but not to those of substrate or product. The calculated structure for the chair transition state, taken in conjunction with those for chorismate and prephenate, thus provides a template for the active sites of chorismate mutases.

Ab initio molecular orbital study of simple 1,3-dipolar reactions

1976 ◽  
Vol 29 (3) ◽  
pp. 465 ◽  
Author(s):  
D Poppinger
Keyword(s):  
Transition State ◽  
Ab Initio ◽  
Molecular Orbital ◽  
Transition States ◽  
Basis Sets ◽  
Molecular Orbital Calculations ◽  
Molecular Orbital Study ◽  
Orbital Study ◽  
Extended Basis ◽  
Optimized Geometries

Ab initio molecular orbital calculations with minimal and extended basis sets have been carried out for the 1,3-dipolar addition of fulminic acid to acetylene, ethylene, ethynamine and propynenitrile. Optimized geometries are reported for the transition states HCNO+C2H2, HCNO+C2H4, HCNO+ C2HNH2, for the adducts isoxazole and 2-isoxazoline, and for nitrosocyclopropene as a possible intermediate. The calculations indicate that (a) these 1,3-dipolar reactions are synchronous processes, (b) the geometry of the transition state is insensitive to substitution and (c) of the isomeric substituted adducts, 5-aminoisoxazole and isoxazole-4-carbonitrile should be formed preferentially.

scholarly journals Computational Investigation of the Role of Active Site Heterogeneity for a Supported Organovanadium(III) Hydrogenation Catalyst

2021 ◽  
Author(s):  
Prajay Patel ◽  
Robert Wells ◽  
David Kaphan ◽  
Massimiliano Delferro ◽  
Rex T. Skodje ◽  
...  
Keyword(s):  
Active Site ◽  
Active Sites ◽  
Density Functional ◽  
Computational Models ◽  
Surface Heterogeneity ◽  
Reaction Pathways ◽  
Spectroscopic Techniques ◽  
Organometallic Catalysts ◽  
Heterolytic Cleavage ◽  
Styrene Hydrogenation

<div> <div> <p></p><p><a>A crucial consideration for supported heterogeneous catalysts is the non-uniformity of the active sites, particularly for Supported Organometallic Catalysts (SOMCs). Standard spectroscopic techniques, such as X-ray absorption spectroscopy (XAS), reflect the nature of the most populated sites, which are often intrinsically structurally distinct from the most catalytically active sites. With computational models, often only a few representative structures are used to depict catalytic active sites on a surface, even though there are numerous observable factors of surface heterogeneity that contribute to the kinetically favorable active species. A previously reported study on the mechanism of a surface organovanadium(III) catalyst [(SiO)V<sup>III</sup>(Mes)(THF)] for styrene hydrogenation yielded two possible mechanisms: heterolytic cleavage and redox cycling. These two mechanistic scenarios are challenging to differentiate experimentally based on the kinetic readouts of the catalyst are identical. To showcase the importance of modeling surface heterogeneity and its effect on catalytic activity, density functional theory (DFT) computational models of a series of potential active sites of [(SiO)V<sup>III</sup>(Mes)(THF)] for the reaction pathways are applied in combination with kinetic Monte Carlo (kMC) simulations. Computed results were t then compared to the previously reported experimental kinetic study</a><a>.: 1) DFT free energy reaction pathways indicated the likely active site and pathway for styrene hydrogenation; a heterolytic cleavage pathway requiring a bare tripodal vanadium site. 2) From the kMC simulations, a mixture of the different bond lengths from the support oxygen to the metal center was required to qualitatively describe the experimentally observed kinetic aspects of a supported organovanadium(III) catalyst for olefin hydrogenation. </a>This work underscores the importance of modeling surface heterogeneity in computational catalysis.</p><p></p></div></div>

Catalytic routes to fuels from C1 and oxygenate molecules

2017 ◽  
Vol 197 ◽  
pp. 9-39 ◽  
Author(s):  
Shuai Wang ◽  
Iker Agirrezabal-Telleria ◽  
Aditya Bhan ◽  
Dante Simonetti ◽  
Kazuhiro Takanabe ◽  
...  
Keyword(s):  
Transition State ◽  
Active Sites ◽  
Aldol Condensation ◽  
Bond Formation ◽  
Transition States ◽  
Solid Acids ◽  
State Theory ◽  
Side Reactions ◽  
Oh Radicals ◽  
Acid Base

This account illustrates concepts in chemical kinetics underpinned by the formalism of transition state theory using catalytic processes that enable the synthesis of molecules suitable as fuels from C1 and oxygenate reactants. Such feedstocks provide an essential bridge towards a carbon-free energy future, but their volatility and low energy density require the formation of new C–C bonds and the removal of oxygen. These transformations are described here through recent advances in our understanding of the mechanisms and site requirements in catalysis by surfaces, with emphasis on enabling concepts that tackle ubiquitous reactivity and selectivity challenges. The hurdles in forming the first C–C bond from C1 molecules are illustrated by the oxidative coupling of methane, in which surface O-atoms form OH radicals from O2 and H2O molecules. These gaseous OH species act as strong H-abstractors and activate C–H bonds with earlier transition states than oxide surfaces, thus rendering activation rates less sensitive to the weaker C–H bonds in larger alkane products than in CH4 reactants. Anhydrous carbonylation of dimethyl ether forms a single C–C bond on protons residing within inorganic voids that preferentially stabilize the kinetically-relevant transition state through van der Waals interactions that compensate for the weak CO nucleophile. Similar solvation effects, but by intrapore liquids instead of inorganic hosts, also become evident as alkenes condense within MCM-41 channels containing isolated Ni2+ active sites during dimerization reactions. Intrapore liquids preferentially stabilize transition states for C–C bond formation and product desorption, leading to unprecedented reactivity and site stability at sub-ambient temperatures and to 1-alkene dimer selectivities previously achieved only on organometallic systems with co-catalysts or activators. C1 homologation selectively forms C4 and C7 chains with a specific backbone (isobutane, triptane) on solid acids, because of methylative growth and hydride transfer rates that reflect the stability of their carbenium ion transition states and are unperturbed by side reactions at low temperatures. Aldol condensation of carbonyl compounds and ketonization of carboxylic acids form new C–C bonds concurrently with O-removal. These reactions involve analogous elementary steps and occur on acid–base site pairs on TiO2 and ZrO2 catalysts. Condensations are limited by α-H abstraction to form enolates via concerted interactions with predominantly unoccupied acid–base pairs. Ketonization is mediated instead by C–C bond formation between hydroxy-enolates and monodentate carboxylates on site pairs nearly saturated by carboxylates. Both reactions are rendered practical through bifunctional strategies, in which H2 and a Cu catalyst function scavenge unreactive intermediates, prevent sequential reactions and concomitant deactivation, and remove thermodynamic bottlenecks. Alkanal–alkene Prins condensations on solid acids occur concurrently with alkene dimerization and form molecules with new C–C bonds as skeletal isomers unattainable by other routes. Their respective transition states are of similar size, leading to selectivities that cannot sense the presence of a confining host. Prins condensation reactions benefit from weaker acid sites because their transition states are less charged than those for oligomerization and consequently less sensitive to conjugate anions that become less stable as acids weaken.

scholarly journals Interactive design and synthesis of a novel antibacterial agent

1994 ◽  
Vol 72 (4) ◽  
pp. 1051-1065 ◽  
Author(s):  
Saul Wolfe ◽  
Haolun Jin ◽  
Kiyull Yang ◽  
Chan-Kyung Kim ◽  
Ernest McEachern
Keyword(s):  
Molecular Orbital ◽  
Active Site ◽  
Antibacterial Agent ◽  
De Novo ◽  
Three Dimensional ◽  
Hydroxyl Group ◽  
Molecular Orbital Calculations ◽  
Binding Studies ◽  
Molecular Mechanics Calculations ◽  
Substrate Complex

β-Lactam compounds act on penicillin-recognizing enzymes via acylation of the hydroxyl group of an active site serine. When the resulting acyl enzyme is kinetically stable, as in the case of a penicillin-binding protein (PBP), the biosynthesis of a bacterial cell wall is inhibited, and death of the organism results. The de novo design of an antibacterial agent targeted to a PBP might be possible if the three-dimensional structural requirements of the equilibrium (i.e, fit) and catalytic (i.e. reactivity) steps of the aforementioned enzymatic process could be determined. For a model of the active site of a PBP from Streptomyces R61, the use of molecular mechanics calculations to treat "fit," and ab initio molecular orbital calculations to treat "reactivity," leads to the idea that the carboxyl group (G1) and the amide N-H (G2) of the antibiotic are hydrogen bonded to a lysine amino group and a valine carbonyl group in the enzyme–substrate complex. These two hydrogen bonds place the serine hydroxyl group on the convex face of the antibiotic, in position for attack on the β-lactam ring by a neutral reaction, catalyzed by water, that involves a direct proton transfer to the β-lactam nitrogen. Molecular orbital calculations of structure–reactivity relations associated with this mechanism suggest that C=N is bioisosteric to the β-lactam N-C(=O), comparable to a β-lactam in its reactivity with an alcohol, and that the product RO(C-N)H is formed essentially irreversibly (−ΔE > 10 kcal/mol). Accordingly, structures containing a G1 and a G2 separated by a C=N, and positioned in different ways with respect to this functional group, have been synthesized computationally and examined for their ability to fit to the PBP model. This strategy identified a 2H-5,6-dihydro-1,4-thiazine substituted by hydroxyl and carboxyl groups as a target for chemical synthesis. However, exploratory experiments suggested that the C=N of this compound equilibrates with endocyclic and exocyclic enamine tautomers. This required that the C2 position be substituted, and that the hydroxyl group not be attached to the carbon atom adjacent to the C=N. These conditions are met in a 2,2-dimethyl-3-(2-hydroxypropyl)-1,4-thiazine, which also exhibits the necessary fit to the PBP model. Two epimers of this compound have been synthesized, from D- and L-serine. The compound derived from L-serine is not active. The compound derived from D-serine exhibits antibacterial activity, but is unstable, and binding studies with PBP's have not been performed. It is hoped that these studies can be carried out if modification of the lead structure leads to compounds with improved chemical stability.

scholarly journals Computational Investigation of the Role of Active Site Heterogeneity for a Supported Organovanadium(III) Hydrogenation Catalyst

2021 ◽  
Author(s):  
Prajay Patel ◽  
Robert Wells ◽  
David Kaphan ◽  
Massimiliano Delferro ◽  
Rex T. Skodje ◽  
...  
Keyword(s):  
Active Site ◽  
Active Sites ◽  
Density Functional ◽  
Computational Models ◽  
Surface Heterogeneity ◽  
Reaction Pathways ◽  
Spectroscopic Techniques ◽  
Organometallic Catalysts ◽  
Heterolytic Cleavage ◽  
Styrene Hydrogenation

<div> <div> <p></p><p><a>A crucial consideration for supported heterogeneous catalysts is the non-uniformity of the active sites, particularly for Supported Organometallic Catalysts (SOMCs). Standard spectroscopic techniques, such as X-ray absorption spectroscopy (XAS), reflect the nature of the most populated sites, which are often intrinsically structurally distinct from the most catalytically active sites. With computational models, often only a few representative structures are used to depict catalytic active sites on a surface, even though there are numerous observable factors of surface heterogeneity that contribute to the kinetically favorable active species. A previously reported study on the mechanism of a surface organovanadium(III) catalyst [(SiO)V<sup>III</sup>(Mes)(THF)] for styrene hydrogenation yielded two possible mechanisms: heterolytic cleavage and redox cycling. These two mechanistic scenarios are challenging to differentiate experimentally based on the kinetic readouts of the catalyst are identical. To showcase the importance of modeling surface heterogeneity and its effect on catalytic activity, density functional theory (DFT) computational models of a series of potential active sites of [(SiO)V<sup>III</sup>(Mes)(THF)] for the reaction pathways are applied in combination with kinetic Monte Carlo (kMC) simulations. Computed results were t then compared to the previously reported experimental kinetic study</a><a>.: 1) DFT free energy reaction pathways indicated the likely active site and pathway for styrene hydrogenation; a heterolytic cleavage pathway requiring a bare tripodal vanadium site. 2) From the kMC simulations, a mixture of the different bond lengths from the support oxygen to the metal center was required to qualitatively describe the experimentally observed kinetic aspects of a supported organovanadium(III) catalyst for olefin hydrogenation. </a>This work underscores the importance of modeling surface heterogeneity in computational catalysis.</p><p></p></div></div>

scholarly journals Substituent Effects on Carbon Acidity in Aqueous Solution and at Enzyme Active Sites

Synlett ◽  
2017 ◽  
Vol 28 (12) ◽  
pp. 1407-1421 ◽  
Author(s):  
John Richard ◽  
Tina Amyes
Keyword(s):  
Aqueous Solution ◽  
Amino Acids ◽  
Active Site ◽  
Active Sites ◽  
Substituent Effects ◽  
Imidazolium Cations ◽  
Enzyme Active Sites ◽  
Iminium Cations ◽  
Carbon Acids

Methods are described for the determination of pK as for weak carbon acids in water. The application of these methods to the determination of the pK as for a variety of carbon acids including nitriles, imidazolium cations, amino acids, peptides and their derivatives and, α-iminium cations is presented. The substituent effects on the acidity of these different classes of carbon acids are discussed, and the relevance of these results to catalysis of the deprotonation of amino acids by enzymes and by pyridoxal 5′-phosphate is reviewed. The procedure for estimating the pK a of uridine 5′-phosphate for C-6 deprotonation at the active site of orotidine 5′-phosphate decarboxylase is described, and the effect of a 5-F substituent on carbon acidity of the enzyme-bound substrate is discussed.1 Introduction2 The Carbon Acidity of Ethyl Thioacetate3 The Carbon Acidity of Carboxylic Acid Derivatives4 The Carbon Acidity of Imidazolium Cations5 The α-Carbon Acidity of Amino Acids, Peptides and Their Derivatives6 Electrophilic Catalysis of Deprotonation of Amino Acids: The α-Carbon Acidity of Iminium Cations7 pK as for Carbon Acids at Enzyme Active Sites8 Concluding Remarks

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