Solvolysis process of organophosphorus compound P-[2-(dimethylamino)ethyl]-N,N-dimethylphosphonamidic fluoride with simple and α-nucleophiles: a DFT study

Density functional theory (DFT) has been used to study the solvolysis process of the organophosphorus compound P-[2-(dimethylamino)ethyl]-N,N-dimethylphosphonamidic fluoride (GV) with simple nucleophile [hydroxide (HO^?)] and α-nucleophiles [hydroperoxide (HOO^?) and hydroxylamine anion (NH₂O^?)]. The lowest energy conformer of GV used for the solvolysis process was identified with Monte Carlo conformational search (MCMM) algorithm employing MMFFs force field followed by DFT calculations. The profound effect was found for α-nucleophiles toward the solvolysis of GV compared to normal alkaline hydrolysis. Incorporation of solvent (water) employing SCRF (PCM) model at B3LYP/6-31+G* showed that solvolysis of GV with hydroperoxide (activation energy = 7.6 kcal/mol) is kinetically more favored compared to hydroxide and hydroxylamine anion (activation energy = 11.0 and 9.2 kcal/mol, respectively). The faster solvolysis of GV with hydroperoxide is achieved due to strong intermolecular hydrogen bonding in the transition state geometry compared to similar α-nucleophile hydroxylamine anion. Assistance of a water molecule in solvolysis of GV affects the activation barriers; however, the hydroperoxidolysis remains the preferential process. The topological properties of electron density distributions for (–X–H···O, X = O, N) intermolecular hydrogen bonding bridges have been analyzed in terms of Bader theory of atoms in molecules (AIM). Further, the analysis was extended by natural bond orbital (NBO) methods for the strength of intermolecular hydrogen bonding in the transition state geometries. This study showed that the reactivity of these α-nucleophiles toward the solvolysis of GV is a delicate balance between the nucleophilicity and hydrogen-bond strength. Solvation governs the overall thermodynamics for the destruction of GV, which otherwise is unfavored in the gas phase studies.     

Heats of formation of the amino acids re-examined by means of W1-F12 and W2-F12 theories

We have obtained accurate heats of formation for the twenty natural amino acids by means of explicitly correlated high-level thermochemical procedures. Our best theoretical heats of formation, obtained by means of the ab initio W1-F12 and W2-F12 thermochemical protocols, differ significantly (RMSD = 2.3 kcal/mol, maximum deviation 4.6 kcal/mol) from recently reported values using the lower-cost G3(MP2) method. With the more recent G4(MP2) procedure, RMSD drops slightly to 1.8 kcal/mol, while full G4 theory offers a more significant improvement to 0.72 kcal/mol (max. dev. 1.4 kcal/mol for glutamine). The economical G4(MP2)-6X protocol performs equivalently at RMSD = 0.71 kcal/mol (max. dev. 1.6 kcal/mol for arginine and glutamine). Our calculations are in excellent agreement with experiment for glycine, alanine and are in excellent agreement with the recent revised value for methionine, but suggest revisions by several kcal/mol for valine, proline, phenylalanine, and cysteine, in the latter case confirming a recent proposed revision. Our best heats of formation at 298 K ( $\Delta H_{f,298}^{\circ }$ ) are as follows: at the W2-F12 level: glycine ?94.1, alanine $-$ 101.5, serine $-$ 139.2, cysteine $-$ 94.5, and methionine $-$ 102.4  kcal/mol, and at the W1-F12 level: arginine $-$ 98.8, asparagine $-$ 146.5, aspartic acid $-$ 189.6, glutamine $-$ 151.0, glutamic acid $-$ 195.5, histidine $-$ 69.8, isoleucine $-$ 118.3, leucine $-$ 118.8, lysine $-$ 110.0, phenylalanine $-$ 76.9, proline $-$ 92.8, threonine $-$ 149.0, and valine $-$ 113.6 kcal/mol. For the two largest amino acids, an average over G4, G4(MP2)-6X, and CBS-QB3 yields best estimates of $-$ 58.4 kcal/mol for tryptophan, and of $-$ 117.5 kcal/mol for tyrosine. For glycine, we were able to obtain a “quasi-W4” result corresponding to $\hbox {TAE}_e$  = 968.1, $\hbox {TAE}_0$  = 918.6, $\Delta H_{f,298}^{\circ }=-90.0$ , and $\Delta H_{f,298}^{\circ }=-94.0$  kcal/mol.     

Probing O-dealkylation and deamination aging processes in tabun-conjugated AChE: a computational study

The mechanisms of the aging process of tabun-conjugated acetylcholinesterase were explored using density functional theory calculations. The free energy surfaces were calculated for O-dealkylation (C–O bond breaking) and deamination (P–N bond breaking) pathways for the aging process of tabun-conjugated acetylcholinesterase as suggested by mass and crystallographic studies. Initially, the calculations were performed using tabun-conjugated serine (SUN) molecule. O-dealkylation mechanism proceeds via one-step S_N2 type process, whereas the deamination process proceeds via two steps addition–elimination reaction at the phosphorus center of SUN molecule. The recent proposal of another deamination mechanism using human butyrylcholinesterase (hBChE) conjugated with N-mono methyl analogue of tabun (TA4) has also been explored (Nachon et al. in Chem Biol Interact 187:44–48, 2010). The rate-determining activation barrier calculated for this deamination mechanism (26.3 kcal/mol) was comparable with O-dealkylation process (26.9 kcal/mol) with B3LYP/6-31+G* level of theory. To examine the influence of catalytic residue His447, additional calculations were performed with imidazole group of His447 residue. The incorporation of imidazole group of catalytic residue His447 showed marked decrease in the free energies of activation for all the studied aging processes of tabun-inhibited serine. The aging mechanisms have been explored with TA4-inhibited serine, and calculated results showed that the deamination with the rearrangement process is markedly preferred in this case, which supports the Nachon et al. proposal based on the crystallographic studies.     

An alternative approach: a highly selective dual responding fluoride sensor having active methylene group as binding site

A newly designed phosphonium derivative (L) having active methylene functionality, shows unusual preference towards F(-) over all other anions. The binding process through C-H···F(-) hydrogen bond formation was probed by monitoring the changes in either electronic or luminescence spectra. Changes in both cases are significant enough to allow visual detection. The loss of molecular flexibility of L on forming L·F(-) effectively interrupts the non-radiative deactivation pathway and accounts for the observed switch on fluorescence response. The results of the time-resolved emission studies for L and L·F(-) using a time-correlated single photon counting technique further corroborate this presumption. The excellent preference of L towards F(-) is attributed to an efficient hydrogen bonding interaction between the strongly polarized methylene protons and F(-), which delineates the subtle difference in the affinity among other competing anionic analytes like CN(-), H(2)PO(4)(-), CH(3)CO(2)(-), etc. The relative affinities of various anions and the preferential binding of F(-) to reagent L are also rationalized using computational studies.