5-Fluorouracil-Complete Insight into Its Neutral and Ionised Forms.

5-Fluorouracil (5FU), a common anti-cancer drug, occurs in four tautomeric forms and possesses two potential sites of both protonation and deprotonation. Tautomeric and resonance structures of the ionized forms of 5FU create the systems of connected equilibriums. Since there are contradictory reports on the ionized forms of 5FU in the literature, complex theoretical studies on neutral, protonated and deprotonated forms of 5FU, based on the broad spectrum of DFT methods, are presented. These indicate that the O4 oxygen is more willingly protonated than the O2 oxygen and the N1 nitrogen is more willingly deprotonated than the N3 nitrogen in a gas phase. Such preferences are due to advantageous charge delocalization of the respective ions, which is demonstrated by the NBO and ESP analyses. In an aqueous phase, stability differences between respective protonated and deprotonated forms of 5FU are significantly diminished due to the competition between the mesomeric effect and solvation. The calculated pKa values of the protonated, neutral and singly deprotonated 5FU indicate that 5FU does not exist in the protonated and double-deprotonated forms in the pH range of 0-14. The neutral form dominates below pH 8 and the N1 deprotonated form dominates above pH 8.

Cyclophosphamide and isophosphamide - DFT conformational studies in the gas phase and solution.

Cyclophosphamide and isophosphamide have been subjected to comprehensive conformational studies in the vacuum and solution using the SMD solvation model. Vacuum calculations were conducted using the B3LYP, M05-2X, M06-2X and ωB97XD functionals. Natural bond orbital (NBO) analysis has been performed for selected geometries. A preference for a chair conformation with the axial P=O bond is shown (1C4). The 5S0 conformation is 1.25-2.31 kcal/mol and 1.72-2.92 kcal/mol higher in energy than the global minimum conformations of cyclophosphamide and isophosphamide, respectively. In the gas phase, the chair conformation with the equatorial P=O bond (4C1) is of comparable stability or less stable than the skew form, depending on the method used, while it is slightly more favored than the 5S0 conformation in solution. The stereoelectronic effects do not differentiate the ring conformer stability. The steric strains between N(EtCl)1-2 and the C4 and C6 carbon atoms mainly influence the stability of cyclophosphamide and isophosphamide conformers.

Threocytidines: Insight into the Conformational Preferences of Artificial Threose Nucleic Acid (TNA) Building Blocks in B3LYP Studies.

A systematic DFT conformational studies of four building blocks of TNA with cytosine attached to the C1' atom of the α-L-threofuranose moiety are presented. Structures bearing 2'-OR and 3'-OR substituents, where R represents H, CH3 and phosphate groups, were used in the studies using a B3LYP functional in the gas phase. The χ angle (C2-N1-C1'-O4'), the ν0-ν4 endocyclic torsion angles and the exocyclic torsion angles ε (X-O2'-C2'-C1') and γ (X-O3'-C3'-C2') geometry parameter variations were taken into consideration. Three energy minima, high-anti, anti and syn, were found for the rotation about the C1'-N1 bond. The high-anti orientation of the base with respect to the sugar moiety, turned out to be preferred, regardless of the substituents at the C2' and C3' positions. Other orientations are at least 1.65 kcal/mol higher in Gibbs free energy than the high-anti one. It has been shown that intramolecular H-bonds and the anomeric effect of phosphate groups strongly affect the conformational preferences of the studied compounds. Further, the structure of substituents attached to the sugar moiety influence the pucker of the furanoid ring. The furanoid ring in the global minima of the compound with two OH groups (TC1) in the 2' and 3' positions, and the compound having a 3'-phosphate group (TC2), adopt roughly the same conformation located at the southern range of the pseudorotation wheel, and thus are close to those found in the B type DNA helix. The low-energy high-anti rotamers of the geometry with the phosphate group attached to the sugar ring in the 2' position (TC3) and the geometry with two methoxyl groups (TC4) have their furanoid rings in conformations resembling those found in A DNA and RNA helices (the northern range of the pseudorotation wheel).

Theoretical studies on the reaction of mono- and ditriflate derivatives of 1,4:3,6-dianhydro-D-mannitol with trimethylamine--Can a quaternary ammonium salt be a source of the methyl group?

DFT studies on the mechanism of the formation of "gemini" quaternary ammonium salts in the reaction of 1,4:3,6-dianhydro-D-mannitol ditriflate derivative with trimethylamine and its subsequent conversion to tertiary amine through the methyl-transfer reaction are discussed. Two alternative reaction pathways are presented in the gas phase and in ethanol. Additionally, the transformation of the monotriflate derivative of 1,4:3,6-dianhydro-D-mannitol into the single quaternary ammonium salt is presented. Two functionals (B3LYP, M062X) and two basis sets (6-31+G** and 6-311++G**) were used for the calculations. The effect of the substituent attached to the five-membered rings at the C2 (and/or C5) carbon atom on the activation barrier is described. The trimethylammonium group bond to the five-membered ring greatly reduces the activation barrier height. The preferred reaction pathway for the conversions was established. Including the London dispersion in the calculations increases the stabilization of all the points on the potential energy surface in relation to individual reactants.

DFT studies of the formation of furanoid derivatives of ammonium chlorides.

B3LYP/6-31+G** level computations were performed on the formation of ammonium salts during the reaction of (S)-1,4-anhydro-5-chloro-2,3,5-trideoxypentitol (1) (2S,5S)-2,5-anhydro-6-chloro-1,3,4,6-tetradeoxyhexitol (2) and methyl 5-chloro-2,3,5-trideoxy-ß-D-pentofuranoside (3) with ammonia in order to describe the reaction pathway in detail. All the structures were fully optimized in the gas phase, in chloroform and water. In addition, the gas phase activation barrier heights were estimated at B3LYP/6-311++G**, MPWIK/6-31+G**, MPWIK/6-311++G** and MP2/6-311++G(2d,2p)//MPWIK/6-31+G** levels of theory. All the calculations in solvents were performed the using polarizable continuum model (PCM) and the B3LYP functional with the 6-31+G** basis set. A detailed description of all the stationary points is presented, and the conformational behavior of the five-membered ring is discussed in the gas phase and in the solvents. The conversion of the reactant complexes into ion pairs is accompanied by a strong energy decrease in the gas phase and in all the solvents. The overall process is strongly unfavorable in the gas phase, but takes place readily in high-polarity solvents.

The conformational behavior, geometry and energy parameters of Menshutkin-like reaction of O-isopropylidene-protected glycofuranoid mesylates in view of DFT calculations.

The formation of pyridinium salts in the transformation of three O-isopropylidene-protected mesylates of furanoid sugar derivatives under pyridine action is considered at the B3LYP/6-31+G** computation level. All the structures were optimized in the gas phase, in chloroform and water. Activation barrier heights in the gas phase were also estimated at the B3LYP/6-311++G**, MPW1K/6-31+G** and MPW1K/6-311++G** levels. The conducted calculations, both in the gas phase (regardless of the computation level) and in solvents, revealed the barrier height increasing order as follows: 1>2>3 for the three reactions studied. The conformational behavior of the five-membered ring is discussed in the gas phase and in solvents. The fused dioxolane ring makes the furanoid ring less likely to undergo conformational changes. In the case of reaction 3, the furanoid ring shape does not change either in the gas phase or in solvents. All conformers are close to E0 or (0)E.