Rabindranath Lo

Efficacy of carbenes for CO2 chemical fixation and activation by their superbasicity/alcohol: a DFT study

DFT calculations predicted a highly efficient binary system consisting of acyclic or cyclic carbenes and alkylcarbonic acids for an efficient CO2 capture process. The driving force for such processes seems to be governed by the pKa of the base used. The calculated results suggest that the carbenes possess a much higher pKa compared to the superbases DBU and TBD used in earlier studies. The activation barriers computed for the formation of alkylcarbonate salt with the carbene superbases are also favourable compared to the nitrogen bases reported in the literature. The propylcarbonate salt formation is energetically more preferred with these carbenes than their direct CO2 zwitterionic adduct formation. The steric and electronic effects of such carbenes also play an important role towards the determination of the mode of CO2 capture.

Cation-induced fluorescent excimer emission in calix[4]arene-chemosensors bearing quinoline as a fluorogenic unit: experimental, molecular modeling and crystallographic studies

A number of calix[4]arene-based fluorescent chemosensors containing amide as a binding site and quinoline as a fluorogenic unit have been synthesised and characterized by a single crystal X-ray diffraction study. These compounds have been designed with variations in conformation and steric crowding in the calix moiety to investigate its effect on ion selectivity and thereby on excimer emission. The ion-binding property of these fluoroionophores has been investigated with a large number of cations and anions and the ion-recognition event was monitored by luminescence, UV-Vis and 1H NMR (for anions) spectral changes. Out of a large number of cations, Hg2+, Pb2+, Fe3+ and Cu2+ exhibited strong complexation with all of the ionophores, as evident from luminescence and UV-vis spectroscopy. In the case of anions, F− and HSO4− exhibited strong complexation with two of the ionophores, as shown by fluorescence and NMR spectroscopy. Interestingly, complexation with metal ions resulted in a new band at lower energy due to excimer emission, which was not observed for anions. The binding constants for all of the three fluoroionophores with strongly interacting ions have been determined from fluorescence, UV-vis and NMR titration data. The DFT calculations for all of the three compounds were performed and the results show that the modulation of frontier molecular orbital energies upon complexation of metal ions causes the fluorescent excimer emission.

First Principles Studies toward the Design of Silylene Superbases: A Density Functional Theory Study

In this paper we have reported for the first time some designed silylene superbases using DFT calculations. These divalent Si(II) compounds can act as powerful neutral organic superbases in the gas phase and in the solvent phase. The DFT calculations performed with the B3LYP/6-311+G**//B3LYP/6-31+G* level of theory showed that one of the designed silylene derivatives :Si(N═PY3)2 [Y = -N═C(NMe2)2] (8) can fall in the range of hyperbase with gas phase proton affinity ∼310 kcal/mol. In THF the calculated proton affinity of 8 was found to be 327.5 kcal/mol. The proton affinities computed at the B3LYP/6-311+G**//B3LYP/6-31+G* level for some simple silylenes have been found to be good agreement with the corresponding experimentally measured values. Phosphazene groups attached to the divalent silicon center of silylenes enhanced the basicity of the Si center significantly and further acted as a second protonation site. The calculated second proton affinity of the silylene derivative, 8 in THF was found to be 285.5 kcal/mol. We have shown that the dimerization and cyclization of such silyene superbases were less likely and the monomeric forms would be more stable than their corresponding dimers. The calculated proton affinities also showed a good correlation with the HOMO-LUMO energy gap and energy difference between the singlet and triplet states (ΔES-T) of the silylene systems. The isodesmic reactions have been employed to examine the stability of the silylene molecules by calculating the silylene stabilization energy (SiSE). The reactivity of silylene molecules has been presented in terms of the nucleophilicity, electronegativity, and hardness of such systems. The Lewis basic properties of these silylene systems have also been explored.

Probing the reactivation process of sarin-inhibited acetylcholinesterase with α-nucleophiles: Hydroxylamine anion is predicted to be a better antidote with DFT calculations

Inactivation of acetylcholinesterase (AChE) due to inhibition by organophosphorus (OP) compounds is a major threat to human since AChE is a key enzyme in neurotransmission process. Oximes are used as potential reactivators of OP-inhibited AChE due to their α-effect nucleophilic reactivity. In search of more effective reactivating agents, model studies have shown that α-effect is not so important for dephosphylation reactions. We report the importance of α-effect of nucleophilic reactivity towards the reactivation of OP-inhibited AChE with hydroxylamine anion. We have demonstrated with DFT [B3LYP/6-311G(d,p)] calculations that the reactivation process of sarin-serine adduct 2 with hydroxylamine anion is more efficient than the other nucleophiles reported. The superiority of hydroxylamine anion to reactivate the sarin-inhibited AChE with sarin-serine adducts 3 and 4 compared to formoximate anion was observed in the presence and absence of hydrogen bonding interactions of Gly121 and Gly122. The calculated results show that the rates of reactivation process of adduct 4 with hydroxylamine anion are 261 and 223 times faster than the formoximate anion in the absence and presence of such hydrogen bonding interactions. The DFT calculated results shed light on the importance of the adjacent carbonyl group of Glu202 for the reactivation of sarin-serine adduct, in particular with formoximate anion. The reverse reactivation reaction between hydroxylamine anion and sarin-serine adduct was found to be higher in energy compared to the other nucleophiles, which suggests that this α-nucleophile can be a good antidote agent for the reactivation process.

Exploiting propane-1,3-diimines as building blocks for superbases: a DFT study

The DFT calculations are employed to construct propane-1,3-diimine as an essential building block to design organic superbases in the gas and acetonitrile phases. This molecular framework is versatile in terms of anchoring different functional groups to achieve higher basicities. Some of these organic superbases showed very high pKa values of ∼40. The influence of iminophosphorane substituents on the propane-1,3-diimine scaffold 4 showed a remarkable enhancement in the basicity, which leads to an increase in the pKa by ∼20 units. The same molecular scaffold also leads to the design of a chiral organic superbase, which keeps a close resemblance to the known ligands for asymmetric synthesis. This newly designed chiral superbase exhibits the highest proton affinity and pKa compared to other reported chiral superbases. The topographical analysis of the molecular electrostatic potential (MESP) has been carried out for some selected compounds at the B3LYP/6-311+G** level of theory. The MESP analyses and steric strain calculations revealed the importance of intrinsic basicity of nitrogen centers and the cation strain effect. To the best of our knowledge, this is the first time that the combination of MESP and strain calculations is employed to segregate the intrinsic basicity of reactive centers and the structural factors responsible for determining the basicities of such organic superbases. The cation resonance effect also plays an important role in enhancing the basicities of the systems studied here. Intramolecular and intermolecular proton transfer barriers have been calculated to examine the kinetic activity of these diimines.

Quantum chemical and steered molecular dynamics studies for one pot solution to reactivate aged acetylcholinesterase with alkylator oxime

Dimethyl(pyridin-2-yl)sulfonium based oxime has been designed to reverse the aging process of organophosphorus inhibited AChE and to reactivate the aged-AChE adduct. We have employed DFT M05-2X/6-31G(∗) level of theory in aqueous phase with polarizable continuum solvation model (PCM) for the methylation of phosphonate ester monoanion of the soman-aged adduct. The calculated free energy of activation for the methyl transfer process from designed dimethyl(phenyl)sulfonium (1) to aged AChE-OP adduct occurs with a barrier of 31.4kcal/mol at M05-2X/6-31G(∗) level of theory, which is 6.4kcal/mol lower compared to the aging process signifies the preferential reversal process to recover the aged AChE-OP adduct. The pyridine ring containing alkylated sulfonium species, dimethyl(pyridin-2-yl)sulfonium (2), reduced the free energy of activation by 4.4kcal/mol compared to the previously reported alkylating agent N-methyl-2-methoxypyridinium species (A) for the alkylation of aged AChE-OP adduct. The free enzyme can be liberated from the inhibited acetylcholinesterase with the sulfonium compound decorated with an oxime group to avoid the administration of oxime drugs separately. The calculated potential energy surfaces show that the oxime based sulfonium compound (3) can effectively methylate the aged phosphonate ester monoanion of soman aged-adduct. The calculated global reactivity descriptors of the oxime 3 also shed light on this observation. To gain better understanding for protein drug interaction as well as the unbinding and conformational changes of the drug candidate in the active site of cholinesterase, steered molecular dynamics (SMD) simulation with 3 has been performed. Through a protein-drug interaction parameters (rupture force profiles, hydrogen bonds, hydrophobic interactions), geometrical and the orientation of drug-like candidate, the oxime 3 suggests to orchestrate the better reactivation process. The docking studies have been performed with 3 in the aged AChE and BChE to obtain the initial geometry of the SMD studies. The docking methods adopted in this study have been verified with the available crystal geometry of 1-methyl-2-(pentafluorobenzyloxyimino)pyridinium compound in aged soman inhibited human BChE (PDB code: 4B0P). The computational study suggests that the newly designed oxime is a potential candidate to reactivate the aged-AChE adduct.

Probing the O/Br-Br halogen bonding in X-ray crystal structures with ab initio calculations†

Halogen bonding is a class of non-covalent interaction in which a halogen atom interacts with an electronegative atom such as oxygen or nitrogen in an attractive fashion. In this work, we investigate the X-ray crystallographically observed non-bonded C–O⋯Br–Br interactions with methanol, 1,4-dioxane and acetone by quantum chemical calculations. The C–O⋯Br–Br interaction was further extended with dimethyl ether, 1,3-dioxane and formaldehyde. The CBS-QB3 calculated results show that the oxygen and bromine non-bonded interactions are in the order of 3–5 kcal mol−1, which are comparable to the typical O–H⋯O and N–H⋯O type hydrogen bond strengths [S. J. Grabowski, Chem. Rev., 2011, 111, 2597]. The AIM calculations show good correlation between the density at the intermolecular critical point and the interaction energy. This study has also explored the directionality of bromine molecule addition to the lone pairs at the sp2 and sp3oxygen atoms of methanol, 1,4-dioxane, acetone, dimethyl ether, 1,3-dioxane and formaldehyde. The calculated results show that the directionality of bromine molecules towards interacting with the oxygen atoms of 1,4-dioxane and acetone is in accord with the observed X-ray crystal structure analysis. However, in the case of methanol, the approach of the bromine molecule seems to be influenced by the crystal forces. The influence of stereoelectronic effects towards the approach of the bromine molecule to 1,3-dioxane is more prominent than that of the 1,4-dioxane system. The existence and magnitude of the positive regions (σ-hole) on the other side of the bromine molecule complexed with the donor molecule seem to facilitate the bridge formation as observed in the X-ray crystal structures.

Revealing halogen bonding interactions with anomeric systems: An ab initio quantum chemical studies

A computational study has been performed using MP2 and CCSD(T) methods on a series of O⋯X (X=Br, Cl and I) halogen bonds to evaluate the strength and characteristic of such highly directional noncovalent interactions. The study has been carried out on a series of dimeric complexes formed between interhalogen compounds (such as BrF, BrCl and BrI) and oxygen containing electron donor molecule. The existence and consequences of the anomeric effect of the electron donor molecule has also been investigated through an exploration of halogen bonding interactions in this halogen bonded complexes. The ab initio quantum chemical calculations have been employed to study both the nature and directionality of the halogen molecules toward the sp(3) oxygen atom in anomeric systems. The presence of anomeric nO→σ*CN interaction involves a dominant role for the availability of the axial and equatorial lone pairs of donor O atom to participate with interhalogen compounds in the halogen-bonded complexes. The energy difference between the axial and equatorial conformers with interhalogen compounds reaches up to 4.60 kJ/mol, which however depends upon the interacting halogen atoms and its attaching atoms. The energy decomposition analysis further suggests that the total halogen bond interaction energies are mainly contributed by the attractive electrostatic and dispersion components. The role of substituents attached with the halogen atoms has also been evaluated in this study. With the increase of halogen atom size and the positive nature of σ-hole, the halogen atom interacted more with the electron donor atom and the electrostatic contribution to the total interaction energy enhances appreciably. Further, noncovalent interaction (NCI) studies have been carried out to locate the noncovalent halogen bonding interactions in real space.

In silico studies in probing the role of kinetic and structural effects of different drugs for the reactivation of tabun-inhibited AChE.

We have examined the reactivation mechanism of the tabun-conjugated AChE with various drugs using density functional theory (DFT) and post-Hartree-Fock methods. The electronic environments and structural features of neutral oximes (deazapralidoxime and 3-hydroxy-2-pyridinealdoxime) and charged monopyridinium oxime (2-PAM) and bispyridinium oxime (Ortho-7) are different, hence their efficacy varies towards the reactivation process of tabun-conjugated AChE. The calculated potential energy surfaces suggest that a monopyridinium reactivator is less favorable for the reactivation of tabun-inhibited AChE compared to a bis-quaternary reactivator, which substantiates the experimental study. The rate determining barrier with neutral oximes was found to be ∼2.5 kcal/mol, which was ∼5.0 kcal/mol lower than charged oxime drugs such as Ortho-7. The structural analysis of the calculated geometries suggest that the charged oximes form strong O…H and N…H hydrogen bonding and C-H…π non-bonding interaction with the tabun-inhibited enzyme to stabilize the reactant complex compared to separated reactants, which influences the activation barrier. The ability of neutral drugs to cross the blood-brain barrier was also found to be superior to charged antidotes, which corroborates the available experimental observations. The calculated activation barriers support the superiority of neutral oximes for the activation of tabun-inhibited AChE compared to charged oximes. However, they lack effective interactions with their peripheral sites. Docking studies revealed that the poor binding affinity of simple neutral oxime drugs such as 3-hydroxy-2-pyridinealdoxime inside the active-site gorge of AChE was significantly augmented with the addition of neutral peripheral units compared to conventional charged peripheral sites. The newly designed oxime drug 2 appears to be an attractive candidate as efficient antidote to kinetically and structurally reactivate the tabun-inhibited enzyme.

In silico study on aging and reactivation processes of tabun conjugated AChE

We have examined the aging and reactivation mechanisms of the tabun-conjugated AChE using MP2/6-31 + G*//M05-2X/6-31G* level of theory. The activation barriers have been calculated for the aging process considering both O-dealkylation and deamination (P–N anti deamination and rearrangement–deamination) pathways. The aging process is reported as a competing reaction with the reactivation process as the deamination/dealkylation process occurs rapidly with a half-life (<1–30 min) depending on the enzyme. To avoid the aging process, suitable reactivators are in demand to restore the function of AChE. 3-Hydroxy-2-pyridylamide oxime (amidoxime (I)) has been chosen as the reactivator to examine the competing aging process of tabun-conjugated AChE. The energy of activation predicted for the reactivation of tabun-conjugated AChE by 3-hydroxy-2-pyridylamide oxime (amidoxime (I)) is 2.3 kcal mol−1, which is lower than the activation energies calculated for studied aging processes. The structural analysis from the docking studies of the model oxime (I) and the oximes used for the reactivation of tabun-inhibited AChE reveals that the peripheral sites play an important role for the efficacy of drugs. The reactivator is stabilized by π–π interaction with Tyr337, edge to face (C–H⋯π) interaction with Trp86 residues and hydrogen bonding interactions with His447 and alkoxy oxygen of tabun in the active site of tabun-inhibited AChE. Such stabilization from surrounding aromatic residues is helpful for the favourable orientation of the oxime group towards the phosphorus centre of tabun. The calculated Log P value indicates that the neutral reactivator can effectively penetrate through the blood brain barrier. The calculated results show that the neutral antidotes can effectively reactivate the tabun-inhibited AChE prior to its aging process.