Gas-phase thermochemical properties of pyrimidine nucleobases

The gas-phase acidity and proton affinity of thymine, cytosine, and 1-methyl cytosine have been examined using both theoretical (B3LYP/6-31+G*) and experimental (bracketing, Cooks kinetic) methods. This paper represents a comprehensive examination of multiple acidic sites of thymine and cytosine and of the acidity and proton affinity of thymine, cytosine, and 1-methyl cytosine. Thymine exists as the most stable "canonical" tautomer in the gas phase, with a DeltaH(acid) of 335 +/- 4 kcal mol(-1) (DeltaG(acid) = 328 +/- 4 kcal mol(-1)) for the more acidic N1-H. The acidity of the less acidic N3-H site has not, heretofore, been measured; we bracket a DeltaH(acid) value of 346 +/- 3 kcal mol(-1) (DeltaG(acid) = 339 +/- 3 kcal mol(-1)). The proton affinity (PA = DeltaH) of thymine is measured to be 211 +/- 3 kcal mol(-1) (GB = DeltaG = 203 +/- 3 kcal mol(-1)). Cytosine is known to have several stable tautomers in the gas phase in contrast to in solution, where the canonical tautomer predominates. Using bracketing methods in an FTMS, we measure a DeltaH(acid) for the more acidic site of 342 +/- 3 kcal mol(-1) (DeltaG(acid) = 335 +/- 3 kcal mol(-1)). The DeltaH(acid) of the less acidic site, previously unknown, is 352 +/- 4 kcal mol(-1) (345 +/- 4 kcal mol(-1)). The proton affinity is 228 +/- 3 kcal mol(-1) (GB = 220 +/- 3 kcal mol(-1)). Comparison of these values to calculations indicates that we most likely have a mixture of the canonical tautomer and two enol tautomers and possibly an imine tautomer under our conditions in the gas phase. We also measure the acidity and proton affinity of cytosine using the extended Cooks kinetic method. We form the proton-bound dimers via electrospray of an aqueous solution, which favors cytosine in the canonical form. The acidity of cytosine using this method is DeltaH(acid) = 343 +/- 3 kcal mol(-1), PA = 227 +/- 3 kcal mol(-1). We also examined 1-methyl cytosine, which has fewer accessible tautomers than cytosine. We measure a DeltaH(acid) of 349 +/- 3 kcal mol(-1) (DeltaG(acid) = 342 +/- 3 kcal mol(-1)) and a PA of 230 +/- 3 kcal mol(-1) (GB = 223 +/- 3 kcal mol(-1)). Our ultimate goal is to understand the intrinsic reactivity of nucleobases; gas-phase acidic and basic properties are of interest for chemical reasons and also possibly for biological purposes because biological media can be quite nonpolar.     

Gas‐phase radical–radical recombination reactions of nitroxides with substituted phenyl radicals

Fourier‐transform ion cyclotron resonance mass spectrometry has been used to examine gas‐phase reactions of four different nitroxide free radicals with eight positively charged pyridyl and phenyl radicals (some containing a Cl, F, or CF₃ substituent). All the radicals reacted rapidly (near collision rate) with nitroxides by radical–radical recombination. However, some of the radicals were also able to abstract a hydrogen atom from the nitroxide. The results establish that the efficiency (k_reaction/k_collision) of hydrogen atom abstraction varies with the electrophilicity of the radical, and hence is attributable to polar effects (a lowering of the transition‐state energy by an increase in its polar character). The efficiency of the recombination reaction is not sensitive to substituents, presumably due to a very low reaction barrier. Even so, after radical–radical recombination has occurred, the nitroxide adduct was found to fragment in different ways depending on the structure of the radical. For example, a cationic fragment was eliminated from the adducts of the more electrophilic radicals via oxygen anion abstraction by the radical (i.e., the nitroxide adduct cleaves heterolytically), whereas adducts of the less electrophilic radicals predominantly fragmented via homolytic cleavage (oxygen atom abstraction). Therefore, differences in the product branching ratios were found to be attributable to polar factors. © 2004 Wiley Periodicals, Inc. Int J Chem Kinet 36: 216–229 2004     

Chemical properties of a para-benzyne

5,8-Didehydroisoquinolinium ion, a para benzyne analogue, was generated in a Fourier transform ion cyclotron resonance mass spectrometer, and its reactivity toward various neutral reagents was examined. A direct comparison of the reaction kinetics of the para benzyne, a meta isomer, and analogous monoradicals, indicates that the para benzyne is a poorer electrophile but a more reactive radical than its meta isomer.     

Reactivity of aromatic σ,σ-biradicals toward riboses

The gas-phase reactions of sugars with aromatic, carbon-centered sigma,sigma-biradicals with varying polarities [as reflected by their calculated electron affinities (EA)] and extent of spin-spin coupling [as reflected by their calculated singlet-triplet (S-T) gaps] have been studied. The biradicals are positively charged, which allows them to be manipulated and their reactions to be studied in a Fourier-transform ion cyclotron resonance mass spectrometer. Hydrogen atom abstraction from sugars was found to be the dominant reaction for the biradicals with large EA values, while the biradicals with large S-T gaps tend to form addition/elimination products instead. Hence, not all sigma, sigma-biradicals may be able to damage DNA by hydrogen atom abstraction. The overall reaction efficiencies of the biradicals towards a given substrate were found to be directly related to the magnitude of their EA values, and inversely related to their S-T gaps. The EA of a biradical appears to be a very important rate-controlling factor, and it may even counterbalance the reduced radical reactivity characteristic of singlet biradicals that have large S-T gaps.     

Radical reactions of didehydroarenes with a 1,4-relationship

A gas-phase study of the radical reactivities of didehydroarenes with a 1,4-relationship reveals that electronic effects (due to singlet-triplet state splittings) can be offset by polar effects.     

Reactivity of the N-methylene-5,8-didehydroisoquinolinium triradical ion

The reactivity of a sigma,sigma,pi-triradical, N-methylene-5,8-didehydroisoquinolinium ion, has been compared to that of four related mono- and biradicals in a Fourier transform ion cyclotron resonance mass spectrometer. The triradical contains two weakly interacting orthogonal radical systems-the sigma,sigma-biradical moiety and the pi-monoradical moiety. The sigma,sigma-biradical moiety is found to be substantially more reactive than the pi-radical moiety. The pi-radical site reacts only after reactions have quenched the sigma-radical sites.     

Gas-phase reactivity of charged pi-type biradicals

Four pi,pi-biradicals, 2,6-dimethylenepyridinium and the novel isomers N-(3-methylenephenyl)-3-methylenepyridinium, N-phenyl-3,5-dimethylenepyridinium, and N-(3,5-dimethylenephenyl)pyridinium ions, were generated and structurally characterized in a Fourier transform ion cyclotron resonance mass spectrometer. Their gas-phase reactivity toward various reagents was compared to that of the corresponding monoradicals, 2-methylenepyridinium, N-phenyl-3-methylenepyridinium, and N-(3-methylenephenyl)pyridinium ions. The biradicals reactivity was found to reflect their predicted multiplicity. The 2,6-dimethylenepyridinium ion, the only biradical in this study predicted to have a closed-shell singlet ground state, reacts significantly faster than the other biradicals, which are predicted to have triplet ground states. In fact, this biradical reacts at a higher rate than the analogous monoradical, which suggests that to avoid the costly uncoupling of its unpaired electrons, the biradical favors ionic mechanisms over barriered radical pathways. In contrast, the second-order reaction rate constants of the isomeric biradicals with triplet ground states are well approximated by those of the analogous monoradicals, although the final reaction products are sometimes different. This difference arises from rapid radical-radical recombination of the initial monoradical reaction products. The overall reactivity toward the hydrogen-atom donors benzeneselenol and tributylgermanium hydride is significantly greater for the radicals with the charged site in the same ring system as the radical site. This finding indicates that polar effects play an important role in controlling the reactivity of pi,pi-biradicals, just as has been demonstrated for sigma,sigma-biradicals.