Density Functional Theory Investigation of the Binding of ThioTEPA to Purine Bases: Thermodynamics and Bond Evolution Theory Analysis.

Density functional theory with the ωB97X-D exchange-correlation functional together with implicit as well as explicit solvation is used to describe the reactions of the adenine and guanine purine bases on N,N',N″-triethylenethiophosphoramide (thioTEPA), an alkylating agent used as an anticancer drug. This reaction is decomposed into (i) a nucleophilic addition and (ii) a proton "migration" that is mediated by the solvent molecules. The calculations reveal that the first step is rate determining and that the presence of an explicit water molecule to mediate the proton migration has a negligible role on the kinetics of the first step, so that the focus is set on the first step of the reaction. ωB97X-D calculations highlight (i) the activation energy (Gibbs free enthalpy) is smaller for imine nitrogens than amine nitrogens, (ii) for the imine functions, the activation energy is slightly smaller for adenine than for guanine together with a larger exergonicity for the alkylation by adenine, and (iii) among the amine nitrogens, the presence of stabilizing H-bonds in the case of exocyclic amines leads to smaller activation energy than for the endocyclic ones. The reaction mechanisms are unraveled by employing the bond evolution theory, combining the use of electronic localization functions, and their evolution along the intrinsic reaction coordinate, with Thom's catastrophe theory. These analyses, suitable for highlighting the populations of the major monosynaptic and disynaptic basins, show (i) the reaction with imine nitrogens begins by the cleavage of the C-N aziridine bond and is followed by the simultaneous formation of the new C-N bond and the disappearance of the nitrogen lone pair, (ii) the reaction with the nitrogen atom of an endocyclic or exocyclic amine proceeds first by the formation of the cross-linking C-N bond and then by the cleavage of the C-N aziridine bond and the disappearance of the nitrogen lone pair, and (iii) in case ii, this bond breaking and forming occur before the transition state, which has been correlated to the increased Gibbs enthalpy of activation with respect to the reaction with the nitrogen atom of imine functions.

Magnetically-induced current density investigation in carbohelicenes and azahelicenes.

A computational study of the magnetically-induced current (MIC) density has been carried out for a variety of ortho fused polycyclic aromatic molecules at the density functional theory level with the gauge including magnetically induced current (GIMIC) method. With this method, the aromatic character of each ring in a homologous series of carbohelicenes with an increasing number of fused benzene rings is assessed and compared with other aromaticity criteria such as the Nucleus Independent Chemical Shift [NICS(0), NICSzz(0)] and Bond Length Alternation (BLA) parameters. All criteria indicate that the two outer rings are the most aromatic ones [i.e. higher induced current, more negative NICS(0) and NICSzz(0) values, and smaller BLA values]. For the large helicenes (n > 10), the current drops along the following four rings and then rises again. Additionally, we have proven that this behavior is not due to a difference of the local magnetic field coming from a difference of orientation of the ring with respect to the external magnetic field (oriented along the helical axis). Upon fusing additional benzene rings to form hexa-peri-hexabenzo[7]helicene, some rings (B, D, and F) are a lot less aromatic (even non-aromatic) than the others. The NICS(0) and NICSzz(0) values exaggerate this behavior because they are all positive values, which is a signature of antiaromaticity. Then, when substituting one, three, or four benzene rings with pyrrole ones to form mono-aza-[7]-helicene, tri-aza-[7]-helicene, and tetra-aza-[7]-helicene, remarkable changes in the electronic structures of the helicenes are observed. Indeed, the induced currents are always smaller in the pyrrole rings than in the benzene ones. This has been further investigated using the streamline and the color map representations, which indicate that the diatropic current density passing through the plane cutting the C-N bonds in the pyrrole rings is stronger but is more localized than the current density passing through the plane cutting the C-C bonds in the benzene rings. This gives a positive but smaller total induced current for the pyrrole rings than for the benzene ones. For these systems, the NICS(0) and even more the NICSzz(0) values are not fully reliable to probe the local aromaticity, contrary to the induced current. Indeed, the NICSzz(0) values for the tri-aza-[7]-helicene molecule range from -14.23 to 1.14 ppm, which cannot lead to the same conclusion as the induced current values (10.03 to 12.87 nA T-1).

Theoretical investigation of the regioselective ring opening of 2-methylaziridine. Lewis acid effect.

The formation of substituted 1,2-diamines via the regiospecific nucleophilic ring opening of 2-methylaziridine with methylamine was performed by nucleophilic attack at aziridine carbon atoms. A detailed theoretical study was investigated by density functional theory (DFT) at the B3LYP level and second order Moller Plesset perturbation theory (MP2) by using the 6-311G(d,p) basis set. The third Grimme correction term (D3) was used to take into account weak interactions. Solvent effects were computed in methanol and dimethylsulfoxide using the polarizable continuum model (PCM). Emphasis was placed on the ring opening mechanisms of neutral aziridines and aziridinium ions obtained through N-complexation with the BF3 Lewis acid. Moreover, the effect of substituent groups on the regioselectivity of the ring opening was investigated. The nucleophilic attack was carried out via two pathways (frontside attack M1 and backside attack M2) where activation barriers proved the preference for ring opening through the backside attack at the C3 aziridine carbon atom. The obtained results showed that the frontside attack with methylamine takes place along a concerted mechanism that leads to formation of products through one transition state. However, the backside attack is carried via a stepwise process in which the methylamine attack takes place in an SN2 fashion where the leaving group is the ring nitrogen. It first conduces a ring opening considered as the rate-determining step followed by formation of a zwitterionic intermediate. This latter undergoes a rotation to allow the proton transfer step and finally leads to formation of the thermodynamic products.