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Biomedical subjects

K N Houk

Publications and source records attributed to K N Houk.

At least 127 records · Page 7Linked to original sources
PubMed2002

Potential surface for the quadruply degenerate rearrangement of bicyclo[3.1.0]hex-2-ene.

Previous experimental studies have shown that bicyclo[3.1.0]hex-2-ene and substituted derivatives undergo thermal rearrangements to form three products identical to the starting material save for the position of the labeling substituents. Despite the likely involvement of a symmetric diradical intermediate, cyclohexene-3,5-diyl, these products are formed at unequal rates. DFT (B3LYP), CASSCF, and CASPT2 calculations were performed to map out the details of the potential energy landscape for the reaction. A qualitative hypothesis, based on dynamical considerations, is offered to explain the observed nonstatistical product distribution.

Journal Article↗
PubMed2002

Theoretical study of factors controlling rates of cyclization of radical intermediates from diallylamine and diallylammonium monomers in radical polymerizations.

The radical cyclization reactions of models for the growing radical chains formed from N,N-diallylamine (1), N-methyl-N,N-diallylamine (2), N,N-diallylammonium (3), N-methyl-N,N-diallylammonium (4) and N,N-dimethyl-N,N-diallylammonium (5) have been investigated computationally by DFT theory, using the B3LYP functional. Models formed by hydrogen atom addition to dienes 1-5 undergo five-membered ring cyclization reactions with activation energies predicted to be 7.2, 5.0, 8.6, 6.4, and 6.2 kcal/mol, respectively. Methyl substitution on nitrogen decreases the barrier to cyclization. One methyl has a larger effect on the cyclization rate than the second methyl. This rate enhancement is attributed to a decrease in gauche interactions in the transition state as compared to the initial structure and to different destabilizing effects when an H is replaced by a methyl group. These predicted rate effects are in agreement with the experimental data on polymerization efficiencies.

Alkylation↗
PubMed2002

Diels-Alder and ene reactions of singlet oxygen, nitroso compounds and triazolinediones: transition states and mechanisms from contemporary theory.

Singlet oxygen, nitroso compounds and triazolinediones have similar electronic structures: they share a low lying LUMO, making them powerful electrophiles, and a high lying HOMO, orthogonal to the LUMO and consisting of an antibonding combination of lone paris. This bestows some nucleophilic character on these species. We describe a number of studies employing the best levels of theory currently available for systems of this size and demonstrate that the Diels-Alder and ene reactions of these three species are calculated to show subtle changes in mechanism. The calculations have been calibrated, wherever possible, by comparison to experimental observations including measured activation and reaction energies, regio- and stereo-selectivities, intermediates observed either spectroscopically or by trapping, and kinetic isotope effects.

Journal Article↗
PubMed2002

Magnitudes and chemical consequences of R(3)N(+)-C-H...O[double bond]C hydrogen bonding.

The magnitude of the stabilizing interaction between an aliphatic C[bond]H bond attached to an ammonium nitrogen and a carbonyl oxygen was evaluated by ab initio calculations at the MP2/6-311++G** level of theory. Attractive R(3)N(+)-C-H...O[double bond]C interactions play an important role in supramolecular recognition and various types of stereoselective catalysis. Our calculations show that R(3)N(+)-C-H...O[double bond]C is the strongest hydrogen bond of the C-H...O type known to date. Such hydrogen bonds remain as stabilizing interactions even in water for amide acceptors.

Acetates↗
PubMed2002

The origins of noncovalent catalysis of intermolecular Diels-Alder reactions by cyclodextrins, self-assembling capsules, antibodies, and RNAses.

The catalysis of Diels-Alder reactions by noncovalent binding by synthetic, protein, and nucleic acid hosts has been surveyed and compared. These catalysts consist of binding cavities that form complexes containing both the diene and the dienophile; the cycloaddition reaction occurs in the cavity. The binding requires no formation of covalent bonds and is driven principally by the hydrophobic (or solvophobic) effect. A molecular mechanics and dynamics study of the cyclodextrin catalysis of a Diels-Alder reaction is used to exemplify and probe this form of catalysis. Detailed kinetic data is available for catalysis by antibodies, RNA, cyclodextrins, and Rebek's tennis ball capsules. Some of these catalysts stabilize the reactants more than the transition state and consequently will only have catalytic effect under conditions of low substrate-to-catalyst ratios. None of the hosts achieve significant specific binding of transition states that is the hallmark of enzyme catalysis.

Antibodies, Catalytic↗
PubMed2002

Mechanism of the forbidden [3s,5s]-sigmatropic shift: orbital symmetry influences stepwise mechanisms involving diradical intermediates.

The mechanisms of [3s,5s]-sigmatropic shifts of octa-1,3,7-triene and 7-methylenenona-1,3,8-triene have been elaborated using B3LYP and BPW91 density functional theory and CASPT2 methods. These orbital symmetry forbidden rearrangements are stepwise, involving diradical intermediates. A comparison with several [3,3]-sigmatropic shifts of substituted hexadienes and of [5,5]-sigmatropic shifts that are allowed, but nevertheless follow stepwise paths, shows that the activation barrier for the disallowed [3,5] shift is significantly larger than that for the stepwise reactions that are orbital symmetry allowed. Cyclic diradicals that have an aromatic circuit of electrons including the two radical centers and conjugated pi or sigma bonds are stabilized as compared to cyclic diradicals with an antiaromatic circuit of electrons. This applies to the transition states leading to and from the diradicals and influences the activation energies of stepwise sigmatropic shifts. The magnitudes of these effects are small but will have a significant influence on the rates of competing processes. This series of calculations has been used to assess the relative capabilities of the two functionals. We find that BPW91 underestimates the endothermicity of diradical formation and the barrier to diradical formation whereas B3LYP overestimates these quantities.

Journal Article↗
PubMed2002

Transition state docking: a probe for noncovalent catalysis in biological systems. Application to antibody-catalyzed ester hydrolysis.

A strategy for pinpointing favorable noncovalent interactions between transition states and active sites of biological catalysts is described. This strategy combines high-level quantum mechanical calculations of transition state geometries with an automated docking procedure using AutoDock. By applying this methodology to antibody-catalyzed hydrolyses of aryl esters (by the 48G7, CNJ206, and 17E8 families of antibodies), varying levels of catalysis are explained in terms of specific hydrogen bonding interactions between combining site residues and transition states. Although these families of antibodies were produced in separate experiments by different researchers using related but different haptens, the mechanism of transition state stabilization appears to be highly conserved. Despite being elicited in response to anionic phosphonate haptens, the best catalysts often utilize hydrogen bond acceptors to stabilize transition states. A mutant of antibody CNJ206, designed based on this observation and predicted to be a better catalyst, is proposed. In the case of antibody 48G7, affinity maturation is shown to produce a catalyst that is highly selective for one of two enantiomeric transition states from a nonselective germline precursor.

Amino Acids↗
PubMed2002

H-vinyl conical intersections for dienes: a mechanism for the photochemical hula twists.

The potential role of "H-vinyl" conical intersections in a photochemical process known as the hula twist has been evaluated. The H-vinyl conical intersections of butadiene are explored with complete active space self-consistent field calculations, and proposals about the geometries involved in the hula-twist mechanism are discussed and contrasted with the conventional one-bond flip mechanism of cis-trans isomerization.

Journal Article↗
PubMed2001

Transition states of amine-catalyzed aldol reactions involving enamine intermediates: theoretical studies of mechanism, reactivity, and stereoselectivity.

The mechanisms, transition states, relative rates, and stereochemistries of amine-catalyzed aldol reactions involving enamine intermediates have been explored with density functional theory (B3LYP/6-31G*) and CPCM solvation models. Primary enamine-mediated aldol reactions involve half-chair transition states with hydrogen bonding leading to proton transfer. This leads to charge stabilization and low activation energies as compared to secondary enamine-mediated aldol reactions. Oxetane intermediates can be formed when C-C bond formation occurs without H-transfer in the transition state. The stereoselectivities of reactions of ketone enamines with aldehydes, including the facial stereoselectivity involving chiral aldehydes, were modeled and compared with experimental results. Transition states for the intramolecular aldol reactions leading to the formation of hydrindanone-beta-ketol and decalone-beta-ketol aldol products showed a preference for the formation of the cis-fused rings, in agreement with experimental results.

Acetaldehyde↗
PubMed2001

Torquoselectivity induced by lone-pair conjugation in the electrocyclic reactions of 1-azapolyenes.

Torquoselectivity in the electrocyclic interconversions of 1-azapolyenes and their heterocyclic isomers was investigated theoretically. The ring openings of 1,2-dihydroazete, 1,2-dihydropyridine, and 1,2-dihydroazocine were examined using HF, MP2, and B3LYP calculations. A large preference for inward rotation of the nitrogen lone pair and outward rotation of the N-H group was found for the four- and six-electron systems. No strong preference was observed for the eight-electron system.

Aza Compounds↗
PubMed2001

Donor and acceptor properties of the chromium tricarbonyl substituent in benzylic and homobenzylic anions, cations, and radicals.

Both benzylic cations and anions are strongly stabilized by chromium tricarbonyl complexation, while benzylic radicals are largely unaffected. Density functional theory calculations were performed on primary, secondary, and tertiary benzylic species to explore the effect of substitution on the stabilizing ability of the chromium tricarbonyl moiety. Complexed 1-indanyl species were also examined to elucidate the effect of conformational restraint. It was found that the strong stabilization of benzylic anions and the slight destabilization of benzylic radicals by chromium tricarbonyl are insensitive to skeletal changes. Chromium-complexed benzylic cations, however, are highly sensitive to changes in the organic framework, with increased substitution or constriction of conformational mobility eroding the effect of the metal. 2-Indanyl species were also examined to study the effect of the chromium tricarbonyl fragment on homobenzylic species. It was found that the metal fragment stabilizes distant anions by field and inductive effects and cations by a direct interaction of the metal with the cationic carbon. Homobenzylic radicals, however, do not interact with the chromium tricarbonyl moiety and suffer a slight inductive destabilization.

Journal Article↗
PubMed2001

The magnitude of [C-H...O] hydrogen bonding in molecular and supramolecular assemblies.

Ab initio calculations at the MP2/6-311++G** level on model systems (N-methylpyridinium complexes of dimethyl ether and dimethyl phosphate anion) provide quantitative measures of the large stabilization energies that arise from [C-H...O] contacts in charged systems. These attractive interactions control (i) the self-assembly of bipyridinium-based catenanes and rotaxanes in solution, (ii) the self-organization of left-handed Z-DNA with alternating [dC-dG] sequences in the solid state, and (iii) the binding of pyridinium derivatives with single- and double-stranded DNA. Slightly attractive interactions occur between the donor ether and phosphate moieties and a neutral pyridine molecule in the gas phase. Electrostatic potential and solvation calculations demonstrate that [C-H...O] interactions which involve a cationic [C-H] donor are dominated by electrostatic terms.

DNA↗
PubMed2001

Polyacene and cyclacene geometries and electronic structures: bond equalization, vanishing band gaps, and triplet ground states contrast with polyacetylene.

The ground-state geometries and excited singlet and lowest triplet energies of polyacenes from benzene through nonacene are predicted with B3LYP/6-31G* calculations and compared to experimental data where available. The results are compared to these data for cyclacenes and polyenes. The polyacenes and cyclacenes have geometries consisting of two fully delocalized nonalternating ribbons joined by relatively long bonds. Polyacenes are predicted to have smaller band gaps than the corresponding polyenes and triplet ground states for nine or more benzene rings. The fully delocalized nonalternating nature of polyacenes differs from the bond alternation resulting from Peierls distortion in polyenes. The differences are rationalized in terms of a simple MO model, and the results are compared to extensive prior theoretical work in the literature. Predictions about the electronic structure of analogues containing polyacene units are made.

Journal Article↗
PubMed2001

Transition states and mechanisms of the hetero-Diels-Alder reactions of hyponitrous acid, nitrosoalkanes, nitrosoarenes, and nitrosocarbonyl compounds.

The transition states and energetics of Diels-Alder reactions for a variety of nitroso compounds with dienes were explored with density functional theory using the B3LYP functional and 6-31G basis set. The reactions involve HNO, various nitrosoalkanes and arenes (RNO and ArNO), and nitrosoformaldehyde (CHONO) as dienophiles with butadiene and a series of 1- and 2-substituted dienes. The mechanisms, activation energies, energies of reaction, stereoselectivities, and regioselectivities are predicted for these reactions. These predictions are compared to available experimental data. The mechanism is found to be concerted but involves highly asynchronous transition states. Although it is not evident in the products, we find that the endo path is very strongly favored over the exo alternative due to repulsion between the diene and nitrogen's lone pair. A range of experimental regioselectivities are reproduced by calculations and are found to hinge on a very sensitive balance between FMO interactions, electrostatics, and steric effects. A series of generalizations for predicting regioselectivity for untried diene-dienophile pairs are made.

Chemical Phenomena↗
PubMed2001

Reactivity of (eta(6)-arene)tricarbonylchromium complexes toward additions of anions, cations, and radicals.

A computational and experimental study of additions of electrophiles, nucleophiles, and radicals to tricarbonylchromium-complexed arenes is reported. Competition between addition to a complexed arene and addition to a noncomplexed arene was tested using 1,1-dideuterio-1-iodo-2-((phenyl)tricarbonylchromium)-2-phenylethane. Reactions under anionic and cationic conditions give exclusive formation of 1,1-dideuterio-1-((phenyl)tricarbonylchromium)-2-phenylethane arising from addition to the complexed arene. Radical conditions (SmI(2)) afford two isomeric products, reflecting a 2:1 preference for radical addition to the noncomplexed arene. In contrast, intermolecular radical addition competition experiments employing ketyl radical addition to benzene and (benzene)tricarbonylchromium show that addition to the complexed aromatic ring is faster than attack on the noncomplexed species by a factor of at least 100,000. Density functional theory calculations using the B3LYP method, employing a LANL2DZ basis set for geometry optimizations and a DZVP2+ basis set for energy calculations, for all three reactive intermediates showed that tricarbonylchromium stabilizes all three types of intermediates. The computational results for anionic addition agree well with established chemistry and provide structural and energetic details as reference points for comparison with the other reactive intermediates. Intermolecular radical addition leads to exclusive reaction on the complexed arene ring as predicted by the computations. The intramolecular radical reaction involves initial addition to the complexed arene ring followed by an equilibrium leading to the observed product distribution due to a high-energy barrier for homolytic cleavage of an exo bond in the intermediate cyclohexadienyl radical complex. Mechanisms are explored for electrophilic addition to complexed arenes. The calculations strongly favor a pathway in which the cation initially adds to the metal center rather than to the arene ring.

Anions↗
PubMed2001

Quantitative calculations of antibody--antigen binding: steroid--DB3 binding energies by the linear interaction energy method.

Linear interaction energy/molecular dynamics calculations have been used to compute steroid/antibody binding energies. The absolute binding affinities of 10 steroids to antibody DB3 and of a hapten to catalytic antibody 1E9 are computed and compared to experiment. A detailed analysis of the molecular origins of the observed binding patterns is provided. The binding energy of an untested steroid is predicted.

Algorithms↗