Exploring Free Energy Profiles of Uracil and Cytosine Reactions with Formaldehyde

Abstract

Simple polymers can be potentially formed by the cooligomerization of pyrimidine nucleobases, uracil and cytosine, with the small molecule formaldehyde. Using density functional calculations, we have constructed a free energy map outlining the thermodynamics and kinetics for (1) the addition of formaldehyde to uracil and cytosine to form hydroxymethylated uracil (HMU) and hydroxymethylated cytosine (HMC), (2) the deamination of cytosine and HMC to uracil and HMU, respectively, and (3) the initial oligomerization of 5-HMU. For the initial formation of monomeric HMU, addition of formaldehyde to the C5 and C6 positions is thermodynamically favored over N1 and N3, but faces higher kinetic barriers, and explains why 5-HMU is the main product observed experimentally. Oligomerization of 5-HMU is thermodynamically favorable although decreasingly so at the tetramer stage. In addition, decreasing concentrations of initial monomer shifts the equilibrium disfavoring oligomer formation.

Early Steps of Glycolonitrile Oligomerization: A Free-Energy Map

“…36 In our previous work requiring such daisy-chain S N 2 transition states, our calculated barriers were in the ∼35 kcal/mol range, likely overestimated by 10 or more kcal/mol given that the reactions studied were somewhat facile at room temperature experimentally. 11,12,32 Thus, in the present work, although our calculated barrier for 39 → 46 is ∼40 kcal/mol, the experimental barrier for this S N 2 reaction is likely 30 kcal/ mol (or possibly lower). There is a route to glycine, but it would require higher temperatures to be kinetically accessible.…”

“…Although water may be reactant or product in hydration/dehydration reactions, concentration corrections are not included in this map, the advantages and disadvantages of which are discussed in detail in previous work. 9,12,22 Our protocol was previously put to the test with a detailed comparison of our computational results with NMR measurements for the self-oligomerization of a 1 M solution of glycolaldehyde; 9 our calculated equilibrium concentrations of the dominant species in solution (monomers and dimers) agreed very well with experiment. In addition, our calculations allowed us to successfully predict the concentrations of trimers in solution, 2 orders of magnitude lower than the monomers.…”

“…Our group has developed a fast protocol to construct free-energy profiles involving oligomerization of small molecules, and it performs relatively well when explicitly compared to available experimental results. − The protocol outlined below is similar to that of our previous work, and therefore, much of the text in this section is reproduced from earlier work for clarity and reading ease. All calculations in the present work were carried out using Jaguar 10.0 at the B3LYP − flavor of density functional theory with the 6-311G** basis set.…”

Factors Governing the Chemical Stability and NMR Parameters of Uracil Tautomers and Its 5-Halogen Derivatives

“…The six-membered heteroatom ring of uracil is planar, resembling aromatic molecules of benzene or pyridine. Due to its importance in nature and interesting biological activities, there have been many theoretical and experimental studies on uracil and its derivatives, for example, as reported in references [18,[22][23][24][25][27][28][29][30][31][32][33]. The main scientific problems analyzed were structure [26,34,35], energetics [34,36,37], vibrational [27][28][29][30][31]38] and NMR spectra [33,[39][40][41].…”

“…Pyrimidine nitrogen bases, including uracil and its 5-halogeno derivatives, can potentially exist in several tautomeric forms ( Figure 2 ) as free molecules [ 22 , 23 , 24 , 25 ] and in solution [ 26 ]. The six-membered heteroatom ring of uracil is planar, resembling aromatic molecules of benzene or pyridine.…”