Low-temperature NMR studies on the geometry of base pairs involving 5-substituted uracil derivatives.

Uridine (U) imino proton chemical shifts, measured in the slow hydrogen-bond exchange regime at low temperatures in a freonic solution, show that electron-withdrawing 5-bromo and 5-fluoro substituents on the uracil base strengthen NHN hydrogen bonds in (X)U·A base pairs formed by the free nucleosides. Whereas the halogens do not alter the preferential formation of Watson-Crick geometries, self-associates of the halouracils point to a more favorable engagement of the 2-carbonyl as proton acceptor in the cyclic hydrogen bonds, suggesting increased formation of reverse geometries and wobble base pairs with guanine when compared to the thymine base. Employing (15)N-labeled 5-bromouridine, no noticeable population of minor enol tautomers is found in the freonic mixture at 113 K.

Predicting the tautomeric equilibrium of acetylacetone in solution. I. The right answer for the wrong reason?

This study investigates how the various components (method, basis set, and treatment of solvent effects) of a theoretical approach influence the relative energies between keto and enol forms of acetylacetone, which is an important model system to study the solvent effects on chemical equilibria from experiment and theory. The computations show that the most popular density functional theory (DFT) approaches, such as B3LYP overestimate the stability of the enol form with respect to the keto form by approximately 10 kJ mol(-1), whereas the very promising SCS-MP2 approach is underestimating it. MP2 calculations indicate that in particular the basis set size is crucial. The Dunning Huzinaga double zeta basis (D95z(d,p)) used in previous studies overestimates the stability of the keto form considerably as does the popular split-valence plus polarization (SVP) basis. Bulk properties of the solvent included by continuum approaches strongly stabilize the keto form, but they are not sufficient to reproduce the reversal in stabilities measured by low-temperature nuclear magnetic resonance experiments in freonic solvents. Enthalpic and entropic effects further stabilize the keto form, however, the reversal is only obtained if also molecular effects are taken into account. Such molecular effects seem to influence only the energy difference between the keto and the enol forms. Trends arising due to variation in the dielectric constant of the solvent result from bulk properties of the solvent, i.e., are already nicely described by continuum approaches. As such this study delivers a deep insight into the abilities of various approaches to describe solvent effects on chemical equilibria.

Tautomeric equilibria of 3-formylacetylacetone: low-temperature NMR spectroscopy and ab initio calculations.

Keto-enol tautomerization of 3-formylacetylacetone has been studied by NMR spectroscopy, ab initio, and DFT calculations in the gas phase and continuum solvation. By employing very low temperatures in a freonic solvent, tautomeric and conformational equilibria in the slow exchange regime were analyzed in detail. The beta-tricarbonyl compound always adopts a structure with an enolized keto group irrespective of an increasing dielectric constant of the solvent when lowering the temperature of the Freon mixture. This experimentally observed tautomeric distribution of 3-formylacetylacetone is correctly reproduced by continuum solvated DFT calculations.

Geometry and cooperativity effects in adenosine-carboxylic acid complexes.

NMR experiments and theoretical investigations were performed on hydrogen bonded complexes of specifically 1- and 7-15N-labeled adenine nucleosides with carboxylic acids. By employing a freonic solvent of CDClF2 and CDF3, NMR spectra were acquired at temperatures as low as 123 K, where the regime of slow hydrogen bond exchange is reached and several higher-order complexes were found to coexist in solution. Unlike acetic acid, chloroacetic acid forms Watson-Crick complexes with the proton largely displaced from oxygen to the nitrogen acceptor in an ion pairing structure. Calculated geometries and chemical shifts of the proton in the hydrogen bridge favorably agree with experimentally determined values if vibrational averaging and solvent effects are taken into account. The results indicate that binding a second acidic ligand at the adenine Hoogsteen site in a ternary complex weakens the hydrogen bond to the Watson-Crick bound carboxylic acid. However, substituting a second adenine nucleobase for a carboxylic acid in the trimolecular complex leads to cooperative binding at Watson-Crick and Hoogsteen faces of adenosine.

A combined computational and experimental study of the hydrogen-bonded dimers of xanthine and hypoxanthine.

In addition to uracil, the noncanonical nucleobases xanthine and hypoxanthine are important lesions that are formed from the canonical bases when a cell is under oxidative stress. It is known that they lead to point mutations; however, more detailed information about their ability to form hydrogen-bonded complexes is not available. In the present paper such information is obtained by a combined experimental and theoretical approach. Accurate association constants of xanthosine and inosine dimers are determined by concentration dependent 1H NMR experiments, and a structural characterization of individual complexes formed in solution is performed through measurements under slow exchange conditions at very low temperatures. An interpretation of the experimental data concerning complex geometries becomes possible through a comparison of measured and computed NMR chemical shifts. Further qualitative insights into the hydrogen bonding abilities of xanthine and hypoxanthine are obtained by a theoretical characterization of all possible pairing modes of xanthine and hypoxanthine dimers and by a comparison with simplified model systems. The influence of a polar medium on the bonding properties is also estimated and the importance of the various effects is discussed. Our analysis shows to what extent secondary electronic and electrostatic effects influence the hydrogen bonding properties of xanthine and hypoxanthine in the gas phase and in polar solvents.

Binding of an acetic acid ligand to adenosine: a low-temperature NMR study.

Binding of an acetic acid (HAc) ligand to adenosine (A) was studied by (1)H NMR spectroscopic techniques. Using a low-melting deuterated Freon mixture as solvent, liquid-state measurements could be performed in the slow exchange regime and allowed a detailed characterization of the formed associates. Thus, at 128 K, trimolecular complexes A.HAc(2) and A(2).HAc with both Watson-Crick and Hoogsteen sites of the central adenine base occupied coexist in various amounts depending on the adenosine:acetic acid molar ratio. Whereas the carboxylic acid OH proton is located closer to the acid for all hydrogen bonds formed, a more deshielded proton at the Watson-Crick site is evidence for a stronger hydrogen bond as compared to the Hoogsteen interaction. For the binding of acetic acid to an adenosine-thymidine base pair in either a Watson-Crick or a Hoogsteen configuration, hydrogen bonds to the available adenine binding site are strengthened as compared to the corresponding hydrogen bonds in the A.HAc(2) complex.

Loss of Hoogsteen pairing ability upon N1 adenine platinum binding.

Chloroform- and Freon-soluble mixed thymine, adenine complexes trans-[Pt(MeNH(2))(2)(ChmT-N3)(ChmA-N1)]NO(3) (2) and trans-[Pt(MeNH(2))(2)(ChmT-N3)(TBDMS-ado-N1)]BF(4) (3) (ChmT = anion of 1-cyclohexylmethylthymine ChmTH, ChmA = 9-cyclohexylmethyladenine, TBDMS-ado = 2',3',5'-tri-tert-butyldimethylsilyladenosine) have been prepared and characterized to study their propensity to undergo Hoogsteen and/or reversed Hoogsteen pairing in solution with free ChmTH and free 3',5'-diacetyl-2'-deoxyuridine, respectively. No Hoogsteen or reversed Hoogsteen pairing between 2 and ChmT takes place in CDCl(3). In Freon, partial H bonding between N1 platinated TBDMS-ado and 3',5'-diacetyl-2'-deoxyuridine as well as its [3-(15)N] labeled analogue is unambiguously observed only below 150 K. Comparison of (1)J ((15)N-(1)H) coupling constants of 3',5'-diacetyl-2'-deoxyuridine involved in Hoogsteen pairing with free and N1 platinated adenine suggests that the interaction is inherently weaker in the case of platinated adenine. To better understand the complete absence of hydrogen bonding between the ChmA ligand in 2 and free ChmTH, ab initio calculations (gas phase, 0 K) have been carried out for Hoogsteen pairs involving adenine (A) and thymine (T), as well as simplified analogues of 2 and T, both in the presence and absence of counteranions. The data strongly suggest that reduction of the effective positive charge of the heavy metal ion Pt(2+) by counterions diminishes interaction energies. With regard to mixtures of 2 and ChmTH in chloroform, this implies that ion pair formation between the cation of 2 and NO(3)(-) may be responsible for the lack of any measurable Hoogsteen pairing in this solvent.