Syntheses, π-stacking interactions and base-pairings of uracil pyridinium salts and uracilyl betaines with nucleobases

Abstract

Reaction of 6-chlorouracil with 4-(dimethylamino)pyridine, 4-methylpyridine, and pyridin-4-yl-morpholine yielded pyridinium-substituted uracils as chlorides which were converted into pyridinium uracilates by deprotonation. These heterocyclic mesomeric betaines are cross-conjugated and thus possess separate cationic (pyridinium) and anionic (uracilate) moieties. Calculations and X-ray single crystal analyses were performed in order to characterize these systems and to compare the salts with the betaines. (1)H NMR experiments in D(2)O proved pi-interactions between the uracilyl betaines and adenine, adenosine, as well as adeninium. No pi-stacking interactions were detected between the betaines and guanosine. The acidic N8-H group of the uracil pyridinium salts caused acid-base reactions which were observed in parallel to pi-stacking interactions. Self-complementarity of the modified uracils was detected by (1)H NMR experiments in DMSO-d(6) and electrospray ionisation mass spectrometry (ESIMS). Ab initio calculations predicted base-pairings of the modified uracils with adeninium, cytosine, and guanine. Several geometries of hydrogen-bonded associates were calculated. Hoogsteen pairings between the uracil-4-(dimethylamino)pyridinium salt and adeninium, as well as associates between the corresponding betaine plus cytosine, and the betaine plus guanine were calculated, and the most stable conformations were determined. In the ESI mass spectra, prominent peaks of associates between the modified uracils and adeninium, cytosine, cytidine, guanosine and d(CpGp) were detected.

Effects of Nucleobase Metalation on Frontier Molecular Orbitals: Potential Implications for π-Stacking Interactions with Tryptophan

“…This is because, if a π-complex is assumed to form via a donor−acceptor interaction, then the strength of the interaction may be estimated by comparison of the energies of the HOMO of the donor system and the LUMO of the acceptor . The approach of comparing frontier orbital energies has been used to explain π-stacking interactions between alkylated nucleobases with tryptophan. , Overlap with the HOMO of the electronic-rich indole moiety in tryptophan is enhanced by a decrease in LUMO energy in the nucleobase upon N7 alkylation. Several experimental studies regarding structural characterization of this binary system in the solid state, as well as in solution, have been performed. − Ishida et al’s discussion, using semiempirical methods (MNDO), of π-stacking of nucleobases with indole rings focused on the lowering of the nucleobase LUMO upon quaternization .…”

“…There is a formal analogy between protonation, alkylation, and metalation of nucleic acids and their biological effects. , Especially for the effects of alkylation and metalation, both involve an electrophilic interaction of the alkylating or metallating agent on an electron-rich purine or pyrimidine site. Given the previous applications of frontier orbital energies of isolated donor and acceptor molecules in the analysis of π-stacking interactions involving alkylated nucleobases, − we have estimated the strength of the HOMO/LUMO interactions between metallated nucleobases and tryptophan. We considered this approach valid to understanding the effect of nucleic acid base metalation on π-stacking interactions, given the stated analogy between alkylation and metalation.…”

“…30 The approach of comparing frontier orbital energies has been used to explain π-stacking interactions between alkylated nucleobases with tryptophan. 31,32 Overlap with the HOMO of the electronic-rich indole moiety in tryptophan is enhanced by a decrease in LUMO energy in the nucleobase upon N7 alkylation. Several experimental studies regarding structural characterization of this binary system in the solid state, as well as in solution, have been performed.…”

N‐Heterocyclic Carbenes of 5‐Haloindazoles Generated by Decarboxylation of 5‐Haloindazolium‐3‐carboxylates

“…In continuation of our interest in heterocyclic mesomeric betaines31 and their relationship to N‐heterocyclic carbenes,29 we describe here the syntheses of 5‐fluoro‐,chloro‐, bromo‐, and iodo‐substituted 1,2‐indazolium‐3‐carboxylates, their decarboxylations to NHC, and some trapping experiments. In addition, we present results of thermogravimetric analyses and differential scanning calorimetry.…”

Catalyst selective and regiodivergent O- to C- or N-carboxyl transfer of pyrazolyl carbonates: synthetic and computational studies

“…As yet, the exact origins of this p vs. s reactivity are unknown. Our working hypothesis is that the relatively sterically unencumbered conjugated DMAP promotes p-p electrostatic interactions, 42 allowing the p-system of the extended enolate to be an energetically more competent nucleophile compared with the s-N(1)-lone pair.…”