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Leo Radom

Publications and source records attributed to Leo Radom.

29 records · Page 2Linked to original sources
PubMed2004

Suicide inactivation of dioldehydratase by glycolaldehyde and chloroacetaldehyde: an examination of the reaction mechanism.

High-level ab initio calculations have been used to study the mechanism for the inactivation of diol dehydratase (DDH) by glycolaldehyde or 2-chloroacetaldehyde. As in the case of the catalytic substrates of DDH, e.g., ethane-1,2-diol, the 5'-deoxyadenosyl radical (Ado*) is able to abstract a hydrogen atom from both substrate analogues in the initial step on the reaction pathway, as evidenced by comparable energy barriers. However, in subsequent step(s), each substrate analogue produces the highly stable glycolaldehyde radical. The barrier for hydrogen atom reabstraction by the glycolaldehyde radical is calculated to be too high ( approximately 110 kJ mol-1) to allow Ado* to be regenerated and recombine with the cob(II)alamin radical, the latter therefore remaining tightly bound to DDH. As a consequence, the catalytic pathway is disrupted, and DDH becomes an impotent enzyme. Interconversion of equivalent structures of the glycolaldehyde radical via the symmetrical cis-ethanesemidione radical is calculated to require 38 kJ mol-1. EPR indications of a symmetrical cis-ethanesemidione structure are likely to be the result of formation of an equilibrium mixture of glycolaldehyde radical structures, this equilibration being facilitated by partial deprotonation of the glycolaldehyde radical by the carboxylate of an amino acid residue within the active site of DDH.

Acetaldehyde↗
PubMed2004

The unusual bifunctional catalysis of epimerization and desaturation by carbapenem synthase.

High-level ab initio calculations have been used to study the mechanism for the conversion of (3S,5S)-carbapenam to the biologically active beta-lactam antibiotic, (5R)-carbapenem, catalyzed by carbapenem synthase. This process involves epimerization at C5 and desaturation at C2/C3. Our calculations suggest that the reaction proceeds via initial abstraction of the C5 hydrogen atom, followed by epimerization. In addition, we have identified an attractive mechanism for coupling the epimerization and desaturation in thermodynamically favorable steps with the aid of an external reductant. Other mechanisms that have been examined have significantly higher energy requirements or do not appear to be consistent with available experimental evidence.

Carbapenems↗
PubMed2004

Comparison of the kinetics and thermodynamics for methyl radical addition to C=C, C=O, and C=S double bonds.

The barriers, enthalpies, and rate constants for the addition of methyl radical to the double bonds of a selection of alkene, carbonyl, and thiocarbonyl species (CH(2)=Z, CH(3)CH=Z, and (CH(3))(2)C=Z, where Z = CH(2), O, or S) and for the reverse beta-scission reactions have been investigated using high-level ab inito calculations. The results are rationalized with the aid of the curve-crossing model. The addition reactions proceed via early transition structures in all cases. The barriers for addition of methyl radical to C=C bonds are largely determined by the reaction exothermicities. Addition to the unsubstituted carbon center of C=C double bonds is favored over addition to the substituted carbon center, both kinetically (lower barriers) and thermodynamically (greater exothermicities). The barriers for addition to C=O bonds are influenced by both the reaction exothermicity and the singlet-triplet gap of the substrate. Addition to the carbon center is favored over addition to the oxygen, also both thermodynamically and kinetically. For the thiocarbonyl systems, addition to the carbon center is thermodynamically favored over addition to sulfur. However, in this case, the reaction is contrathermodynamic, addition to the sulfur center having a lower barrier due to spin density considerations. Entropic differences among corresponding addition and beta-scission reactions are relatively minor, and the differences in reaction rates are thus dominated by differences in the respective reaction barriers.

Journal Article↗
PubMed2003

Variable trends in R-X bond dissociation energies (R = Me, Et, i-Pr, t-Bu).

[structure: see text] High level ab initio molecular orbital calculations confirm experimental indications that the effect of alkyl substituents (R = Me, Et, i-Pr, t-Bu) on R-X bond dissociation energies varies considerably according to the nature of X. A simple qualitative explanation in terms of valence-bond theory is presented, highlighting the increasing importance of the stabilization of R-X by the ionic R(+)X(-) configuration for electronegative X substituents (such as F, OH, and OCH(3)).

Journal Article↗
PubMed2003

Design of radical-resistant amino acid residues: a combined theoretical and experimental investigation.

Ab initio calculations have been used to design radical-resistant amino acid residues. Optimized structures of free and protected amino acids and their corresponding alpha-carbon-centered radicals were determined with B3-LYP/6-31G(d). Single-point RMP2/6-31G(d) calculations on these structures were then used to obtain radical stabilization energies, to examine the effect of steric repulsion between the side chains and amide carbonyl groups on the stability of alpha-carbon-centered peptide radicals. Relative to glycine, the destabilization for alanine and valine residues was found to be approximately 9 and 18 kJ mol(-1), respectively, which correlates with the reactivity of analogous amino acid residues in peptides toward hydrogen atom abstraction in conventional free radical reactions. To design amino acid residues that would resist radical reactions, strategies by which the steric effects could be magnified were considered. This resulted in the identification of tert-leucine and 3,3,3-trifluoroalanine as suitable molecules. With these amino acid residues, the destabilization of the alpha-carbon-centered radicals relative to that of glycine is increased substantially to approximately 36 and 41 kJ mol(-1), respectively. The theoretical predictions have been supported by experimental observations: a tert-leucine derivative was shown to be very slow to react with N-bromosuccinimide, while the corresponding trifluoroalanine derivative was found to be inert.

Amino Acids↗
PubMed2003

Ab initio evidence for slow fragmentation in RAFT polymerization.

High-level ab initio molecular orbital calculations on model reversible addition-fragmentation transfer (RAFT) polymerization reactions indicate that the retardation effect that is widely observed for methyl acrylate polymerization in the presence of cumyl dithiobenzoate may be attributed to the slow fragmentation of the RAFT adduct radical.

Journal Article↗
PubMed2002

Understanding the mechanism of action of B12-dependent ethanolamine ammonia-lyase: synergistic interactions at play.

Ab initio molecular orbital calculations are used to examine the mechanism of action of B(12)-dependent ethanolamine ammonia-lyase involving the conversion of 2-aminoethanol to acetaldehyde plus ammonia. We attempt to elucidate the mechanism by which the enzyme facilitates this reaction through interactions between active-site residues and the substrate. Our calculations suggest a preferred pathway involving a 1,2-shift in the associated radical and also suggest that interactions between the enzyme and the migrating group of the substrate that afford an almost fully protonated migrating group will lead to the most efficient catalysis. However, this criterion on its own is insufficient to fully understand the rearrangement. Additional synergistic interactions between the spectator hydroxyl group in the substrate and active-site residues on the enzyme are required to lower the barrier height to a value consistent with experimental observations.

Cobamides↗
PubMed2001

Factors Controlling the Addition of Carbon-Centered Radicals to Alkenes-An Experimental and Theoretical Perspective.

The successful exploitation of syntheses involving the generation of new carbon-carbon bonds by radical reactions rests on some prior knowledge of the rate constants for the addition of carbon-centered radicals to alkenes and other unsaturated molecules, and of the factors controlling them. Two former classical reviews in Angewandte Chemie by Tedder (1982) and by Giese (1983) provided mechanistic insight and led to various qualitative rules on the complex interplay of enthalpic, polar, and steric effects. In the meantime, the field has experienced very rapid progress: many more experimental absolute rate constants have become available, and there have been major advances in the efficiency and reliability of quantum-chemical methods for the accurate calculation of transition structures, reaction barriers, and reaction enthalpies. Herein we review this progress, recommend suitable experimental and theoretical procedures, and display representative data series for radical additions to alkenes. On this basis, and guided by the pictorial tool of the state-correlation diagram for radical additions, we then offer a new and more stringent quantification of the controlling factors. Our analysis leads to a partial revision of the previous qualitative rules, and it more clearly exhibits the interplay of the reaction enthalpy effects, polar charge-transfer contributions, and steric substituent effects on the reaction energy barrier. The various contributions are cast into the form of new, simple, and physically meaningful but non-linear, predictive equations for the preestimation of rate constants. These equations prove successful in several tests but call for additional theoretical and experimental foundation. The kinetics of related reactions such as polymer propagation, copolymerization, and the addition of radicals to alkynes and aromatic compounds is shown to follow the same principles.

Journal Article↗
PubMed1999

A G2 Ab Initio Investigation of Ligand-Exchange Reactions Involving Mono- and Bis-Adducts of the Phosphenium Ion.

Ab initio calculations at the G2 level have been employed to investigate the ligand-exchange reactions between mono-adducts of the phosphenium ion (e.g., [H(3)N-PH(2)](+)) and simple first- or second-row Lewis bases (e.g., NH(3)). We have found virtually all the reactions to proceed without an intermediate barrier via a bis-adduct of the phosphenium ion with two Lewis bases (e.g., [H(3)N-PH(2)-NH(3)](+)). The ligand-exchange reactions are predicted to be experimentally feasible and the bis-adducts of the phosphenium ion to be experimentally observable in appropriate cases. The energetics of the ligand-exchange reactions may be rationalized using qualitative orbital interaction arguments in terms of the electronegativity of the ligand in the mono-adducts and the donor ability of the reacting Lewis base. Comparisons with previous investigations of corresponding ligand-exchange reactions involving pi-ligands reveal that the electronic characteristics of the bis-adduct resemble those of the transition structures for pi-ligand exchange.

Journal Article↗
PubMed1997

Fulvalenes, Fulvenes, and Related Molecules: An ab Initio Study.

Ab initio calculations using conventional (HF/6-31G and MP2/6-31G) and density functional theory (B-LYP/6-31G) methods have been used to determine the structures of the [n]fulvene and [n,m]fulvalene (n, m = 3, 5, 7) series of molecules, with particular emphasis on heptafulvalene (n = m = 7: 12). Calculations have also been performed on the parent cycloalkenes: cyclopropene, cyclopentadiene, and cycloheptatriene (1-3, respectively). All the fulvenes (n = 3, 5, 7: 4-6, respectively) and the smaller fulvalenes (n = 3, m= 3, 5, 7: 7-9, respectively, and n = m = 5: 10) are found to be planar. Pentaheptafulvalene (n = 5, m = 7: 11) adopts a very slightly nonplanar C(s)() arrangement of the five- and seven-membered rings. Heptafulvalene (12) is predicted to have an anti-folded C(2)(h)() structure, in accord with the X-ray crystal structure. We propose that the underlying reason for 11 and 12 adopting nonplanar conformations is the proximity of the H(2) and H(2)(') hydrogen atoms which promotes a distortion of the rings away from planarity at the central fulvalenic C=C double bond. In the process, pi-overlap is lost but this is partially regained by pyramidalization of the carbon centers in the seven-membered ring(s). The degree of folding is substantially more pronounced in 12 than in 11. Our calculated dipole moments, pi-electron distributions, bond alternation parameters, and energy comparisons indicate that the unknown smallest fulvalene, triafulvalene (7), is highly destabilized with localized bonding while triapentafulvalene (8), which is also unknown, is predicted to be stabilized and quite delocalized, consistent with Hückel 4n + 2 considerations.

Journal Article↗