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.
