The oxidative nucleophilic substitution of Hydrogen (ONSH): A theoretical modelling of 2-phenylquinoxaline reacting with organolithium nucleophiles

Abstract

The recently implemented REP-FAMSEC method was used to explain each step along the reaction energy profile computed for the assumed Oxidative Nucleophilic Substitution of Hydrogen (ONSH) reaction between 2-phenylquinoxaline (1) and two organolithium reagents, namely lithium phenylacetylide (2) and 1-octynyllithium (10). Intermolecular and intramolecular interaction energies and their changes between consecutive steps of ONSH were quantified for selected molecular fragments. This revealed that the two reactants have a strong affinity for each other, driven by the strong attractive interactions between the Li- and two N-atoms, leading to four possible reaction pathways (RP-C2, RP-C3, RP-C5 and RP-C10). Therefore, a theoretical study for the preferred electrophilic site when 1 reacts with 2 is presented in Chapter 3. From this study, four comparable in energy and stabilizing molecular system adducts were formed, each well prepared for the subsequent formation of a C–C bond at either one of the four identified sites. However, as the reaction proceeded through the TS to form the so called σH-adducts, very high energy barriers were observed for RP-C5 and RP-C10. Supported by REP-FAMSEC data, these RPs were eliminated. Although RP-C3 appeared more favourable than RP-C2, their energy barriers were very comparable, indicating that they can both proceed to the formation of the respective σH-adducts. A similar study but with 10 is presented in Chapter 4. From these studies, it was observed that the phenyl substituent at C2 of 1 guides the incoming nucleophile towards C2 and C3, suggesting that the preferred RP and relatively low yields cannot be attributed to steric hinderance caused by this substituent. Upon the introduction of H2O to the system, both RP-C2 and RP-C3 were nearly spontaneous towards their respective hydrolysis products. The results suggest that RP-C2 competes with RP-C3 which may lead to a possible mixture of their respective products. A secondary RP along RP-C2 was investigated and found a much more stable hydrolysis product, indicating yet another possible waste that may influence the yield of the desired product. Of the three reported hydrolysis products, only that of RP-C3 can proceed to the final oxidation stage of the ONSH reaction mechanism to give the desired product. Moreover, it was observed that since hydrolysis and oxidation occur once the reaction is exposed to the atmosphere, they can be seen as concurrent reactions. Modified experimental protocol is suggested to increase the yield of the desired product. In Chapter 5, we present a theoretical study of the oxidation of the σH-adducts with halogens, namely bromine and chlorine. The computed data shows that this reaction should proceed smoothly to the desired aromatic compound. Because the use of halogens to oxidize the σH-adducts requires no moisture which is important for RP-C2, this route can be seen as a way to eliminate RP-C2 and to maximize yields.