Introduction
N -heterocyclic carbenes (NHCs) are well known species with many unique properties. High nucleophilicity is one of the distinctive properties of these species, which help them in coordinating with transition metals as well as main group elements [1-5]. Especially, compounds with ()→C bond are quite intriguing and lots of research is in progress to understand the unique properties of these species [6,7]. For example, carbones (A and B , Figure 1) are species which were shown to carry the ()→C coordination interaction [8-10]. Recent work reports the importance of ligand exchange reactions due to carbones [11]. There are many reports which do not specifically mention about the bonding characteristics but consider the unit as a well-defined functional unit in the organic molecules, either in the cationic state, radical or in neutral state. For example, the recently reported radical species (C , D and E ) [12-15] were considered to carry the unit in its cationic state, whereas in N -heterocyclic olefins (NHOs) (F ,G) , the unit is considered to carry ()-C umpolung character [16-18]. Exploring the characteristic features of ()-C bond has been of current interest. In this context, it was realized that species with the imidazolium-2-aldoximes (H , Figure 2) and related species offer a unique opportunity to explore the chemical bond between the ring and the oximic carbon center.
Fig. 1 Examples of carbones (A , B ),N -heterocyclic carbene radical cations (B , C, D ), N -heterocyclic Olefin (F ) and Breslow intermediate (G ).
Imidazolium-2-aldoxime (H ) and pyridinium oxime (I ) are cationic species, which exhibit organophosphate detoxification property [19-24]. The pralidoxime (I ), obidoxime (L ), HI-6 (M ), etc. are drugs/leads, being used as antidotes in the poisoning due to nerve agents (tabun, sarin, soman, etc.) [25-29]. TAB2OH (N ), a cationic nonpyridinium aldoxime is a lead molecule and considered as an efficient acetylcholineesterase reactivator [30]. The drug action of these species is expected to involve the participation of the zwitterionic nitroso compound (O ) [31], which may be considered as the nitroso-N -heterocyclic olefins (NNHOs), the chemistry of which has not been explored in detail. The crystal structure of pralidoxime (I ) has been reported, the (ring) C-C (oxime) bond length has been found to be 1.46 Å [32,33]. Grosev et al . reported the vibrational analysis of I and its isomer K . They concluded that the N-O stretching frequencies for I andK are 1082 cm-1 and 1074 cm-1, respectively and C=N stretching frequencies are 1649 cm-1 and 1611 cm-1, respectively for I and K . These wavenumbers indicateI can behave as a strong acid when compared to K[34].
Fig. 2 Representative examples of cationic oximes reported in medicinal chemistry literature.
The chemistry of I involves the reaction as shown in Scheme 1, in which the drug pralidoxime (I ) is the starting material and the phosphorylated pralidoxime (J ) is the product. Castro and Figueroa-Villar reported quantum chemical studies on the molecular structure and the conformations of I using B3LYP/6-31G(d) level. The NHC-C rotational barrier was estimated to be 6 kcal/mol and the corresponding NNHO has been shown to carry largely increased rotational barrier (~30 kcal/mol) [35]. Quantum chemical studies on the chemistry of the reaction shown in Scheme 1 confirmed the participation of NNHO as the causative agent in the reactivation of OP-inhibited human acetylcholinesterase [31,36]. Quantum chemical studies have also been performed on the reactivity profiles of phosphyloximes (J ) [37]. Wong et al . studied the oxime reactivation reaction by exploring the influence of chirality and mutagenesis (experimental and theoretical analysis) [38]. Delfino and Figueroa-Villar proposed that the oximates participate in the reaction in a three-step mechanistic path, in comparison to other nucleophiles, which may require four-step processes [39], in an extended work, this group concluded that the neutral oximes have greater potential to act as antidotes [40]. Franca and co-workers performed molecular modelling studies, estimated the free energy change values using molecular dynamics simulations and suggested that the blood brain barrier (BBB) related limitations of the cationic oximes can be overcome [41]. Further, similar study using QM/MM analysis was reported to explore the reactivation by pralidoxime [42].
Scheme 1 Representation of reactivation mechanism of VX‐Inhibited Human Acetylcholineesterase triggered by zwitterionic nitroso compounds.
In this work, quantum chemical analysis has been carried out to explore the electronic structure of a series of cationic oximes (O-1 toO-15 ) and the corresponding NNHOs (O′-1 toO′-15 ) using density functional methods. This work is in continuation of our efforts in exploring the L→N coordination bond in nitreone class of compounds [43-52]. The chemical bond between the ring systems and the carbon center was explored; the bond dissociation energy of the NHC in these species has been estimated.