Probing Non-Covalent Interactions through Molecular Balances: A REG-IQA Study

Abstract

The interaction energies of two series of molecular balances (1-X with X = H, Me, OMe, NMe₂ and 2-Y with Y = H, CN, NO₂, OMe, NMe₂) designed to probe carbonyl…carbonyl interactions were analysed at the B3LYP/6-311++G(d,p)-D3 level of theory using the energy partitioning method of Interacting Quantum Atoms/Fragments (IQA/IQF). The partitioned energies are analysed by the Relative Energy Gradient (REG) method, which calculates the correlation between these energies and the total energy of a system, thereby explaining the role atoms have in the energetic behaviour of the total system. The traditional "back-of-the-envelope" open and closed conformations of molecular balances do not correspond to those of the lowest energy. Hence, more care needs to be taken when considering which geometries to use for comparison with the experiment. The REG-IQA method shows that the 1-H and 1-OMe balances behave differently to the 1-Me and 1-NMe₂ balances because the latter show more prominent electrostatics between carbonyl groups and undergoes a larger dihedral rotation due to the bulkiness of the functional groups. For the 2-Y balance, REG-IQA shows the same behaviour across the series as the 1-H and 1-OMe balances. From an atomistic point of view, the formation of the closed conformer is favoured by polarisation and charge-transfer effects on the amide bond across all balances and is counterbalanced by a de-pyramidalisation of the amide nitrogen. Moreover, focusing on the oxygen of the amide carbonyl and the α-carbon of the remaining carbonyl group, electrostatics have a major role in the formation of the closed conformer, which goes against the well-known n-π* interaction orbital overlap concept. However, REG-IQF shows that exchange-correlation energies overtake electrostatics for all the 2-Y balances when working with fragments around the carbonyl groups, while they act on par with electrostatics for the 1-OMe and 1-NMe₂. REG-IQF also shows that exchange-correlation energies in the 2-Y balance are correlated to the inductive electron-donating and -withdrawing trends on aromatic groups. We demonstrate that methods such as REG-IQA/IQF can help with the fine-tuning of molecular balances prior to the experiment and that the energies that govern the probed interactions are highly dependent on the atoms and functional groups involved.

Keywords: DFT; IQA; QTAIM; Relative Energy Gradient (REG); conformational analysis; molecular balances; quantum chemical topology (QCT).

Figure 1

Schematic representation of the conformational equilibrium of a typical molecular balance. On the left, the molecular balance is in its open conformer state, with functional groups F and G not interacting. On the right, the balance ends up in its closed conformation state where functional groups F and G are interacting after a series of rotations marked by the curved arrows. The timescale, indicated by the hourglass, of the conformational equilibrium is slow enough such that two separate peaks are observed in an NMR spectrum.

Figure 2

(top) Formamide balances by Cockroft et al. [19] and (bottom) N-formylproline balances by Raines et al. [50]. The open conformers for both balances are shown on the left-hand side of the equilibrium arrows, while the closed conformers are on the right-hand side.

Figure 3

Optimised geometries of closed conformers for the four 1-X balances. Gray carbon geometries correspond to the B3LYP/6-311++G(d,p) local energy minimum structures for the BOTECs, which also correspond to the LECC geometries. Yellow carbon geometries correspond to the X-ray structures (only for 1-H and 1-Me), as obtained from the Cambridge Crystallographic Database as in reference [19]. The red, blue, white and pale blue balls are respectively oxygens, nitrogens, hydrogens and fluorines. The optimised geometries and the energies for the 1-X balances are also shown in Figures S1–S4.

Figure 4

Optimised geometries of open conformers for the four 1-X balances. Gray carbon geometries correspond to the B3LYP/6-311++G(d,p) + D3 and Becke–Johnson damping local energy minima structures for the BOTECs. Magenta carbon geometries correspond to the B3LYP/6-311++G(d,p) + D3 and Becke–Johnson damping local energy minima structures for the LEOC. The red, blue, white and pale blue balls are respectively oxygens, nitrogens, hydrogens and fluorines. The optimised geometries and the energies for the 1-X balances are also shown in Figures S1–S4.

Figure 5

The carbonyl…carbonyl moiety in the closed conformer of the 1-X molecular balance series. Labels of atoms are shown to aid the REG-IQA analysis.

Figure 6

The atomic labelling of the whole 2-H molecular balance in the closed conformer. This labelling is common to all the balances of the 2-Y series except for the variation in any of the four remaining functional groups. Hence, only the changing functional groups are shown for the 2-NO₂, 2-CN, 2-OMe and 2-NMe₂ balances. Atomic labelling is shown to aid the REG-IQA analysis.

Figure 7

The 1-X and 2-Y balances in the closed conformer state. Groups of atoms for the REG-IQF analysis are highlighted with different colours.