Study on the regioselectivity of the N-ethylation reaction of N-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide

4-Oxoquinolines are a class of organic substances of great importance in medicinal chemistry, due to their biological and synthetic versatility. N-1-Alkylated-4-oxoquinoline derivatives have been associated with different pharmacological activities such as antibacterial and antiviral. The presence of a carboxamide unit connected to carbon C-3 of the 4-oxoquinoline core has been associated with various biological activities. Experimentally, the N-ethylation reaction of N-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide occurs at the nitrogen of the oxoquinoline group, in a regiosselective way. In this work, we employed DFT methods to investigate the regiosselective ethylation reaction of N-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide, evaluating its acid/base behavior and possible reaction paths.


Single crystal description
A single crystal from substance 7 was obtain and analyzed by XRD for structure determination.
The designed compound 7 crystalized in the monoclinic system with a centrosymmetric space group, P21/c. Crystallographic data, as cell parameters, and refinement statistical indicators within some molecular information are present in Table S1 for the refined model.

S2
The asymmetric unit corresponds to 7 and is shown in Figure S1. There are four molecules per unit cell. Figure S1: Asymmetric unit of product 7.
As can be seen in Figure S1, attached to the N1 of the central oxoquinoline ring is the ethyl group, and in C3 the carboxamide group. The solid-state structure confirms the regioselectivity of the reaction.
The central ring, as expected, displays a planar geometry with r.m.s. deviation equal to 0.0153. The C-C average distance are equal to 1.400 Å. (Table S2), in the range of double and single C-C bonds. Both geometrical parameters are in accordance to an aromatic system. Those geometrical parameters are in agreement with the NMR analysis, in which the chemical shifts for the hydrogens attached to the oxoquinoline core are assigned in the aromatic chemical shift region.
The second plane is defined by the carboxamide group and the phenyl ring. This last one is almost perpendicular to the oxoquinoline, forming an angle equal to 84.49(8)°.
The first observation that could lead to the phenyl orientation is the presence of a medium intramolecular H-bond, formed between H6b and N2. This causes the phenyl orientation in space. This H-bond could cause chemical shift differentiation for this H atom. However as expected in solution the molecular conformation is not restricted to the one observed in the solid packing, and as consequence the NMR analysis could not differentiate H2b and H6b, being them chemically equivalent in this condition.
Another feature that could cause the phenyl orientation is the supramolecular array.
C-H/π intermolecular interaction formed by the ethyl group and the phenyl ring are present, combined with a weak nonconventional H-bond formed by adjacent oxoquinoline C1-H1 and the O2 of the carboxamide group, which pulls over the phenyl moiety off the oxoquinoline ring plane. The third plane contains the ethyl group and the angle within the oxoquinoline plane is equal to 78.0(0.2)°.