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Mechanism of Hydroxyl Radical Addition to Imidazole and Subsequent Water Elimination
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Quantum Chemistry.
1999 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 103, no 26, 5598-5607 p.Article in journal (Refereed) Published
Abstract [en]

The addition reaction of the hydroxyl radical to imidazole and subsequent elimination of water to form the 1-dehydroimidazolyl radical is investigated using MP2 and B3LYP methods, including large basis sets and SCI-PCM modeling of solvent effects. It is found that the barrier to addition of the hydroxyl radical at the 5-position is energetically favored over addition to the 2- or 4-positions by 2−3 kcal/mol at the SCI-PCM/MP2/6-311G(2df,p)//MP2/6-31G(d,p) level, whereas the corresponding B3LYP calculations yield a barrier-free addition at the 5-position. The lower barrier and NBO analysis explain the experimentally observed specificity for the 5-hydroxylation of imidazole and histidine, albeit the 2-adduct is about 4 kcal/mol more stable than the 5-adduct. The NBO energetic analysis shows that the exoanomeric effect stabilizes the transition state at the 5-position about 0.3 kcal/mol more than that at the 2-position. Moreover, the π-interaction between the attacking nonbonding spin orbital of the hydroxyl radical and the π-cloud of imidazole is the least for the transition state at the 5-position, favoring the σC5-O bond formation. The 5-hydroxyimidazolyl radical undergoes a slow elimination of water (the added OH group and the hydrogen at the N1 position) to yield the 1-dehydroimidazolyl radical. The base-catalyzed dehydration profile was modeled in two steps at the B3LYP/6-311G(2df,p)//6-31G(d,p) level. The PES for the dehydration reaction seems rather flat. The first step is a barrier-free loss of the proton at N1 induced by the hydroxide ion to yield the 1-dehydro-5-hydroxyimidazolyl radical anion. In the second step, the hydroxide ion is regenerated from the intermediate to yield the final product with a barrier of 2.7 kcal/mol. The calculated hyperfine structures in the presence of the continuum solvent model for the 5-hydroxyimidazolyl and 1-dehydroimidazolyl radicals are in close agreement with the experimental ones recorded in aqueous solution.

Place, publisher, year, edition, pages
1999. Vol. 103, no 26, 5598-5607 p.
National Category
Natural Sciences
URN: urn:nbn:se:uu:diva-91639DOI: 10.1021/jp9902957OAI: oai:DiVA.org:uu-91639DiVA: diva2:164438
Available from: 2004-04-08 Created: 2004-04-08 Last updated: 2013-09-11Bibliographically approved
In thesis
1. Modern Computational Physical Chemistry: An Introduction to Biomolecular Radiation Damage and Phototoxicity
Open this publication in new window or tab >>Modern Computational Physical Chemistry: An Introduction to Biomolecular Radiation Damage and Phototoxicity
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Modern fysikalisk-kemisk beräkningsmetodik : En introduktion till biomolekylära strålningsskador och fototoxicitet
Abstract [en]

The realm of molecular physical chemistry ranges from the structure of matter and the fundamental atomic and molecular interactions to the macroscopic properties and processes arising from the average microscopic behaviour.

Herein, the conventional electrodic problem is recast into the simpler molecular problem of finding the electrochemical, real chemical, and chemical potentials of the species involved in redox half-reactions. This molecular approach is followed to define the three types of absolute chemical potentials of species in solution and to estimate their standard values. This is achieved by applying the scaling laws of statistical mechanics to the collective behaviour of atoms and molecules, whose motion, interactions, and properties are described by first principles quantum chemistry. For atomic and molecular species, calculation of these quantities is within the computational implementations of wave function, density functional, and self-consistent reaction field theories. Since electrons and nuclei are the elementary particles in the realm of chemistry, an internally consistent set of absolute standard values within chemical accuracy is supplied for all three chemical potentials of electrons and protons in aqueous solution. As a result, problems in referencing chemical data are circumvented, and a uniform thermochemical treatment of electron, proton, and proton-coupled electron transfer reactions in solution is enabled.

The formalism is applied to the primary and secondary radiation damage to DNA bases, e.g., absorption of UV light to yield electronically excited states, formation of radical ions, and transformation of nucleobases into mutagenic lesions as OH radical adducts and 8-oxoguanine. Based on serine phosphate as a model compound, some insight into the direct DNA strand break mechanism is given.

Psoralens, also called furocoumarins, are a family of sensitizers exhibiting cytostatic and photodynamic actions, and hence, they are used in photochemotherapy. Molecular design of more efficient photosensitizers can contribute to enhance the photophysical and photochemical properties of psoralens and to reduce the phototoxic reactions. The mechanisms of photosensitization of furocoumarins connected to their dark toxicity are examined quantum chemically.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 80 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 965
Biology, statistical mechanics, biophysical chemistry, interface, surface thermodynamics, bioelectrochemistry, ionizing radiation, radiation therapy, condensed matter, computational chemistry, nucleic acids, radiation damage, electrode potential, electronic transport, photochemistry, strand break, photodynamic action, cytostatic, solvation, solvated electron, absolute potential, chemical potential, Biologi
National Category
Biological Sciences
urn:nbn:se:uu:diva-4224 (URN)91-554-5940-4 (ISBN)
Public defence
2004-05-03, B42, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2004-04-08 Created: 2004-04-08Bibliographically approved

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