Abstract
In search for the cause leading to low reaction yields, each step along the reaction energy profile computed for the assumed oxidative nucleophilic substitution of hydrogen (ONSH) reaction between 2-phenylquinoxaline and lithium phenylacetylide was modelled computationally. Intermolecular and intramolecular interaction energies and their changes between consecutive steps of ONSH were quantified for molecular fragments playing leading roles in driving the reaction to completion. This revealed that the two reactants have a strong affinity for each other, driven by the strong attractive interactions between Li and two N-atoms, leading to four possible reaction pathways (RP-C2, RP-C3, RP-C5, and RP-C10). 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 intermediates (5a–d), very high energy barriers were observed for RP-C5 and RP-C10. The data obtained at the nucleophilic addition stage indicated that RP-C3 was both kinetically and thermodynamically favored over RP-C2. However, the energy barriers observed at this stage were very comparable for both RPs, indicating that they both can progress to form intermediates 5a and 5b. Interestingly, the phenyl substituent (Ph1) on the quinoxaline guided the nucleophile towards both RP-C2 and RP-C3, indicating that the preferred RP cannot be attributed to the steric hindrance caused by Ph1. Upon the introduction of H2O to the system, both RPs were nearly spontaneous towards their respective hydrolysis products (8a and 8b), although only 8b can proceed to the final oxidation stage of the ONSH reaction mechanism. The results suggest that RP-C2 competes with RP-C3, which may lead to a possible mixture of their respective products. Furthermore, an alternative, viable, and irreversible reaction path was discovered for the RP-C2 that might lead to substantial waste. Finally, the modified experimental protocol is suggested to increase the yield of the desired product.
Highlights
Quinoxaline is a chemical compound that is made up of benzene and pyrazine rings fused together
The results suggest that reaction pathway (RP)‐C2 competes with RP‐C3, which may lead to a possible mixture of their respective products
An alternative, viable, and irreversible reaction path was discovered for the RP‐C2 that might lead to substantial waste
Summary
Quinoxaline is a chemical compound that is made up of benzene and pyrazine rings fused together. It is characterized as a bioisostere of naphthalene, quinoline, and benzoth‐. In recent year, these heterocyclic compounds have attracted a lot of atten‐. Tion in medicinal chemistry as they have been identified as pharmacologically important compounds due to their distinct biological properties. Logical activities, etc., [2]. These compounds are of great interest due to their potential in fighting pathophysiological conditions such as Alzheimer’s diseases and epilepsy [3]. Quinoxaline derivatives are regarded as an important class of N‐heterocyclic compounds in organic synthesis and drug discovery.
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