[Show abstract][Hide abstract] ABSTRACT: The gas-phase substitution reactions of methyl chloride and 1,3-dimethyluracil (at the N1-CH(3)) are examined computationally and experimentally. It is found that, although hydrochloric acid and 3-methyluracil are similar in acidity, the leaving group abilities of chloride and N1-deprotonated 3-methyluracil are not: chloride is a slightly better leaving group. The reason for this difference is most likely related to the electron delocalization in the N1-deprotonated 3-methyluracil anion, which we explore further herein. The leaving group ability of the N1-deprotonated 3-methyluracil anion relative to the N1-deprotonated 3-methylthymine anion is also examined in the context of an enzymatic reaction that cleaves uracil but not thymine from DNA.
Journal of the American Chemical Society 11/2009; 131(51):18376-85. DOI:10.1021/ja906814d · 12.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The gas phase acidity (DeltaH(acid) and DeltaG(acid)) and proton affinity (PA, and gas phase basicity (GB)) of adenine, guanine, and O(6)-methylguanine (OMG) have been examined using both theoretical (B3LYP/6-31+G*) and experimental (bracketing, Cooks kinetic) methods. We previously measured the acidity of adenine using bracketing methods; herein we measure the acidity of adenine by the Cooks kinetic method (DeltaH(acid) = 335 +/- 3 kcal mol(-1); DeltaG(acid) = 329 +/- 3 kcal mol(-1)). We also measured the PA/GB of adenine using both bracketing and Cooks methods (PA = 224 and 225 kcal mol(-1); GB = 216 and 217 kcal mol(-1)). Guanine is calculated to have several stable tautomers in the gas phase, in contrast to in solution, where the canonical tautomer predominates. Experimental measurements of gas phase guanine properties are difficult due to its nonvolatility; using electrospray and the Cooks kinetic method, we are able to measure a DeltaH(acid) of 335 +/- 3 kcal mol(-1) (DeltaG(acid) = 328 +/- 3 kcal mol(-1)). The proton affinity is 227 +/- 3 kcal mol(-1) (GB = 219 +/- 3 kcal mol(-1)). Comparison of these values to calculations indicates that we may have a mixture of the keto and enol tautomers under our conditions in the gas phase, although it is also possible that we only have the canonical form since in the Cooks method, we form the proton-bound dimers via electrospray of an aqueous solution, which should favor guanine in the canonical form. We also examined O(6)-methylguanine (OMG), a highly mutagenic damaged base that arises from the alkylation of guanine. Our calculations indicate that OMG may exist as both the "N9" (canonical) and "N7" (proton on N7 rather than N9) tautomers in the gas phase, as both are calculated to be within 3 kcal mol(-1) in energy. We have bracketed the acidity and proton affinity of OMG, which were previously unknown. The more acidic site of OMG has a DeltaH(acid) value of 338 +/- 3 kcal mol(-1) (DeltaG(acid) = 331 +/- 3 kcal mol(-1)). We have also bracketed the less acidic site (DeltaH(acid) = 362 +/- 3 kcal mol(-1), DeltaG(acid) = 355 +/- 3 kcal mol(-1)) and the PA (229 +/- 4 kcal mol(-1) (GB = 222 +/- 4 kcal mol(-1))). We confirmed these results through Cooks kinetic method measurements as well. 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, since biological media can be quite nonpolar. We find that OMG is considerably less acidic at N9 than adenine and guanine and less basic at O6 than guanine; the biological implications of these differences are discussed.
The Journal of Organic Chemistry 10/2009; 74(19):7429-40. DOI:10.1021/jo901479m · 4.72 Impact Factor