B. De Sterck

Metalated 3-halo-1-azaallylic anions are important building blocks for the preparation of a wide variety of heterocyclic and highly functionalized compounds. A theoretical description of the structural properties of halogenated 1-azaallylic anions in vacuo and in tetrahydrofuran (THF) solution is presented to gain insight into their reactivity behavior. The configurational flexibility of fluorinated and chlorinated 1-azaallylic anions is examined, and it is shown that these anions have far less configurational flexibility as compared with nonhalogenated analogues, with a strong preference to occur as Z/anti isomers. In addition, the driving force for transmetalation, that is, the replacement of the lithium cations with K+, Cu+, ZnCl+, CuCl+, or MgBr+ is studied. To obtain reliable results, the structures were modeled in THF using the combined implicit/explicit solvent approach resulting in different coordination numbers for lithium in the Z/anti and E/anti isomers. Calculations on dimerization energies show that coordination with THF is energetically preferred over aggregation.

The polymerization of acrylamide (AA) and methacrylamide (MAA) was studied by an extensive set of computational methods with a particular focus on the possible influence of water molecules on the propagation reaction. An extensive set of electronic structure methods was tested, consisting of B3LYP, BMK, MPWB1K, MP2, and B2-PLYP of which some include dispersion effects. The effect of water on the transition state is modeled in two different ways. Explicit water molecules are added to the system, showing that replacing the hydrogen bond that dominates the transition state structure by a water-mediated hydrogen bond, results in more stable, more feasible transition states. This effect is the largest for AA polymerization, a monomer that is known to experience a larger solvent effect than MAA. Additionally, a conductor-like polarizable continuum model (C-PCM) is applied on both the transition states in gas phase and the ones bearing explicit water molecules. This model has a dramatic effect on all the propagation rates, raising them by about 3 orders of magnitude. The inclusion of explicit water molecules gives insight into the role of water molecules and the formation of prereactive complexes. The relative rate of polymerization of AA with regard to MAA is well reproduced for a trimeric propagating radical with inclusion of explicit water molecules or by using an implicit solvation model at the BMK and MPWB1K level of theory.

The neutral and anionic semiquinone radicals of the flavin adenine dinucleotide (FAD) cofactor noncovalently bound in glucose oxidase from A. niger are examined with the aid of QM/MM molecular modeling methods, enabling complete inclusion of the protein environment. Recently, the electron paramagnetic resonance (EPR) characteristics, the anisotropic g tensor and all the significant hyperfine couplings, of these flavoprotein radicals were determined at high resolution (J. Phys. Chem. B 2008, 112, 3568). A striking difference between the neutral and anionic radical forms was found to be a shift in the gy principal value. Within the QM/MM framework, geometry optimization and molecular dynamics simulations are combined with EPR property calculations, employing a recent implementation by some of the authors in the CP2K software package. In this way, spectroscopic characteristics are computed on the fly during the MD simulations of the solvated protein structure, mimicking as best as possible the experimental conditions. The general agreement between calculated and experimental EPR properties is satisfactory and on par with those calculated with other codes (Gaussian 03, ORCA). The protonation state of two histidines (His559 and His516) at the catalytic site of this flavoprotein is found to have a remarkable influence on the isotropic hyperfine coupling of one of the methyl groups on the neutral FAD radical, which is consistent with experimental findings in other flavoproteins (J. Biol. Chem. 2007, 282, 4738). Furthermore, the shift in the gy principal values between the neutral and anionic radicals is well reproduced by QM/MM simulations. Incorporation of at least the nearest protein environment of the cofactor radicals proves to be vital for a correct reproduction, indicating that this shift is a global feature of the protein rather than a local one. In addition, QM/MM techniques are used to make a prediction of relative angles between important spectroscopic principal directions, which are not readily determined by conventional EPR experiments. Significantly, the directions of the gx and the gy components of the g-tensor that lie in the plane of the isoalloxazine moiety are rotated by approximately 59° between the neutral and the anionic radicals.

In this study, the effect of alcohols as solvents on the kinetics and the tacticity of poly(N-Isopropylacrylamide) (PNIPAM) is investigated with a combined static and molecular dynamics set of computational tools. Classical molecular dynamics calculations have been carried out to determine the location of the solvent molecules in the proximity of the monomer and the dimer. A combined implicit/explicit solvent model was used for the evaluation of the kinetics of the dimeric polymer chains. Rate constants are calculated with the B3LYP/6-311 + G(d,p)//B3LYP/6-31 + G(d), BMK/6-311 + G(d,p)//B3LYP/6-31 + G(d), and MPWB1K/6-311 + G(d,p)//B3LYP/6-31 + G(d) methodologies via the standard transition state theory. We show that due to the proximity of the –NH and carbonyl groups on the syndiotactic propagating dimeric and trimeric chains, the alcohol can stabilize the corresponding transition states by forming a bridge between these functionalities and accelerate this path more than its isotactic counterpart. In agreement with experiment, the increase in the syndiotactic PNIPAM and the acceleration of the reaction in the presence of t-BuOH is predicted with all the DFT functionals utilized in this study.