Atropisomerism in Diarylamines: Structural Requirements and Mechanisms of Conformational Interconversion

Abstract In common with other hindered structures containing two aromatic rings linked by a short tether, diarylamines may exhibit atropisomerism (chirality due to restricted rotation). Previous examples have principally been tertiary amines, especially those with cyclic scaffolds. Little is known of the structural requirement for atropisomerism in structurally simpler secondary and acyclic diarylamines. In this paper we describe a systematic study of a series of acyclic secondary diarylamines, and we quantify the degree of steric hindrance in the ortho positions that is required for atropisomerism to result. Through a detailed experimental and computational analysis, the role of each ortho‐substituent on the mechanism and rate of conformational interconversion is rationalised. We also present a simple predictive model for the design of configurationally stable secondary diarylamines.

The oil was then purified by distillation (4.9 mbar, 120°C) to yield the title compound as a colourless oil (1.5 g, 5.3 mmol, 43%).  Data consistent with that reported in the literature. 3
The reaction mixture was poured on ice, filtered and recrystallized in ethanol, yielding the title compound as a pale-yellow solid (3.1 g, 12.2 mmol, 49%) together with 2.2 g of crude product.  Data consistent with that reported in the literature. 4
After filtration, the mixture was extracted with diethyl ether and concentrated in vacuo. The   Data consistent with that reported in the literature. 4

Calculation of barriers to enantiomerisation
VT 1 H NMR experiments 1 H NMR spectra of a solution of 6d-g in various deuterated solvent were recorded at different temperatures until coalescence was reached and line sharpening was observed. Their slow exchange spectra were simulated using the software Spinworks 4 (available at ftp://davinci.chem.umanitoba.ca/pub/marat/SpinWorks/ (accessed on 09/05/2020)), and for each temperature recorded, the corresponding rate of enantiomerisation kenant was estimated using the dynamic NMR simulation module MEXICO.
From an Eyring plot, their enthalpy ΔH ≠ and entropy ΔS ≠ were calculated, and their corresponding Gibbs free energy ΔG ≠ were found at 25 °C. Using the following equations, their rate of exchange and half-life to enantiomerisation at 25 °C were calculated:        Exploration of the conformational free energy surface (FES) was performed using Metadynamics. 17 Here, biases were deposited along two sets of collective variables (CVs) using the torsional angles Ψ and Φ involved in axial chirality. They are defined as the dihedral angles between atoms 1, 2, 3 and 5, and 2, 3, 5 and 14, respectively ( Figure S15). N-aryl substituents rings are distinguished by roman numerals I and II.). The initial Gaussian height was 1.2 kcal mol -1 , the width was 0.35 rad, and the deposition stride was 10 ps. The total simulation time was 20 ns. Each calculation was run in quadruplicate. Thus, leading to 80 ns of cumulative simulation time per system.  grids Grid6 and GridX6 were employed. Tight PNO cut-offs were found to be necessary to obtain chemical accuracy.

LFER Analysis
Given the effect of steric repulsion on the geometry of both the ground state and transition state, we hypothesised that a relationship between the steric bulk of each substituent and the barrier to isomerisation could be generated. Among the steric descriptors considered, we employed Charton values 22,23 which were found to work best for the small dataset considered here. Charton values are derived from Taft steric parameters, which provide information about substituent-effects on the rate of the hydrolysis of methyl esters. 24 The parameters for the substituents considered here were obtained from the literature and are tabulated in Table S1.
No parameter has been defined for the 'benzo' substituent, so this value was estimated from the calculated structure using 6R1 = rVX -rVH. With these data, the following model was The standard error is 6.7 kJ mol -1 , and the adjusted R 2 = 0.93 (N = 13). This model allows the prediction of the missing data values (Table S1).  For the systems studied in this work, a coplanar transition state with equal delocalisation can only occur when R 2 and R 4 are small (i, green dot at (180°, 180°)). When R 2 is large, the lowest energy transition state becomes bent, with the N lone pair delocalised unequally into both rings (blue dots).
Rotation within each valley occurs through transition states where the N lone pair is delocalised only into one aryl group (red dots).

S65
The direct path from 6d_A to 6d_A' can no longer pass through a coplanar transition state, as this will result in a steric clash between an ortho-substituent on the disubstituted aryl group and the ortho-C-H on the monosubstituted aryl group. A bent transition state similar to 6a_TS2 with face-to-face aryl groups minimises this repulsion. The CAr-Et, N-H and CAr-iPr bond vectors are approximately parallel, leaving the smallest substituents (Me and H) to clash in 6d_TS1. Increase in pyramidalization at nitrogen minimises the loss of delocalisation of the lone pair. A higher-energy pathway that instead has the CAr-Me, N-H and CAr-iPr bond vectors approximately parallel leaves Et and H to clash in 6d_TS2. Given the similar size of Me and Et, these two transition states are similar in energy (∆∆G ‡ = 5.2 kJ mol -1 ). However, while 6d_TS1 leads directly to 6d_A', 6d_TS2 leads to metastable 6d_B, which must subsequently undergo a concerted rotation to return to the lowest energy conformer.

S67
The direct path from 6j_A to 6j_A' goes via 6j_TS1. This path involves disrotation of the two aryl groups that facilitates the formation of a bent transition state similar to that in 6d that minimises steric repulsion between the methyl group and the ortho-C-H on the monosubstituted aryl group. This comes at the expense of delocalisation of the nitrogen lone pair into the monosubstituted aryl group. A second pathway that places the bulkier isopropyl group near to the ortho-CAr-H on the monosubstituted aryl group is only marginally higher in energy, suggesting that steric clashing between methyl and tert-butyl is also significant and comparable to the clash between isopropyl and tert-butyl.

S69
In the ground state 6t_A, the two aryl groups are perpendicular to each other, with the nitrogen lone pair almost entirely delocalised into the naphthyl arene. To undergo isomerisation, the naphthyl group twists out of conjugation to avoid steric clashing between the two pairs of orthosubstituents. As a result of this geometric constraint, the planes of the two aryl rings become perpendicular to the N-H bond vector at 6t_TS1 and 6t_TS2, and nitrogen lone pair delocalisation decreases significantly. The two pathways (via 6t_TS1 or 6t_TS2) differ only in the initial direction of the naphthyl group rotation; the lower energy path places the methyl substituent of the trisubstituted arene close to the second ring of the naphthyl group. Table S6. Dihedral angles (! and "), absolute electronic energies (Eel), zero point energy (ZPE), enthalpy (H), entropies (T.S), quasi-harmonic entropies (T.qh-S), free energies (G), quasi-harmonic Gibbs energy (qh-G), and changes in quasi-harmonic Gibbs free energies (∆Grel) for stationary points on the FES of 6a. Geometry and thermochemistry was calculated at the SMD(toluene)-M06-2X/6-31+G* level of theory at 298. 15