Correlation between Solid-State and Solution Conformational Ratios in a Series of N-(o-Tolyl)Succinimide Molecular Rotors

Abstract

The syn-anti conformational equilibrium of a library of 30 N-(o-tolyl)succinimide molecular rotors was measured in solution via 1 H NMR and in the solid-state via Xray crystallography. A strong correlation was observed between the solution and solid-state mole fractions of syn-conformers (χ syn ). All rotors, even those with a small conformational preference in solution (±0.15 kcal/mol), displayed the same conformation in their crystal structures. The conformational preferences in the crystals tended to be more pronounced with a predominance of all syn-or anti-structures. However, when the rotors had no conformational preference in solution, the conformational preferences in the crystal structures varied widely. X -ray crystallography is a powerful tool in modern chemistry and biochemistry for the determination of the three-dimensional structure of natural products, 1,2 rational drug design, 3,4 and the study of noncovalent interactions 5−7 and solid-form pharmaceuticals. 8,9 An important question in these studies is whether an X-ray crystal structure accurately reflects the conformation in solution. 10−12 Conversely, can the conformation in solution be used to predict the conformation in a crystal structure? To address these questions, the X-ray crystal structure and solution conformational ratios for a series of 30 molecular rotors based on an atropisomeric bicyclic N-(otolyl)succinimide framework were measured and compared ( Figure 1).The suitability of atropisomeric N-arylsuccinimides for studying the correlation between solid-state and solution structures was previously recognized by Verma, 13 Kishikawa, 14 and Grossmann. 15 The rigid bicyclic framework fixes the position of most of the atoms, which greatly simplifies its conformational analysis. The only major degree of rotational freedom is the C−N single bond connecting the o-tolyl rotor to the succinimide ring. Due to steric repulsion between the orthomethyl group of the rotor and the imide carbonyls, the N-tolyl and succinimide rings avoid the coplanar geometry. This leads to anti-and syn-atropisomers that are conformationally distinct due to the asymmetry of the succinimide ring arising from the fused bicyclic framework.In the course of our studies using molecular balances to measure weak noncovalent interactions, 16−23 we realized that we had access to a library of 30 N-(o-tolyl)succinimide rotors that displayed a wide range of anti-/syn-conformational ratios (Figure 2). This provided a unique opportunity to examine the correlation or lack of correlation between their solid-state and solution structures. By comparison, the scope of previous studies utilizing this framework 18,20,23 was based on a small number of structures (12−14) limiting the certainty and generality of the observed trends.We specifically focused on bicyclic N-(o-tolyl)succinimides with ortho-methyl groups because their atropisomers are generally bereft of the common factors that lead to differences in solid-state and solution structures. 24,25 First, the ortho-methyl group is nonpol...

Stabilizing Fluorine–π Interactions

“…The electrostatic nature of the F–π interaction was evident from comparison with the molecular balances 2 a – 2 d , which formed intramolecular CH–π interactions,, that have only a minor electrostatic component (Figure ). In contrast to the F–π molecular balances 1 a – 1 d , compounds 2 a – 2 d showed little variation across the same set of isomeric aromatic surfaces, providing support for the dominant electrostatic component of the F–π interactions in 1 .…”

Electrostatically Driven CO−π Aromatic Interactions

“…Thus, variations in the intramolecular interaction energies can be accurately measured via the folded–unfolded equilibrium. Our N -aryl­imide molecular balances have been successfully applied to a wide range of non-covalent interactions, including aromatic stacking, − heterocycle−π, CH−π, − halogen−π, , chalcogen−π, metal−π, substituent−π, and solvent effects. − For balances 1­(CO) – 6­(CO) , the carbonyl group of the N -pyridin-2­(1 H )-onyl rotor is held in close proximity in the folded conformer over the face of an aromatic shelf. The size of the shelf increased from ethylene ( 1­(CO) ) to benzene ( 2­(CO) ) to naphthalene ( 6­(CO) ).…”

“…The oxygen of the carbonyl group was positioned over the six-membered aromatic shelf (Figure ) within van der Waals contact (<3.22 Å) . The O-to-centroid distance (3.13 Å) and the dihedral angle (82.5°) between the arm carbonyl group and shelf six-membered ring were consistent with the previous crystal structure database surveys of CO−π interactions (2.91–3.32 Å and 60–90°). , Balances 1­(CO) , 2­(CO) , 3­(CO) , 4­(CO) , and 6­(CO) crystallized exclusively in the unfolded conformers (Supporting Information, Figure S1), which was consistent with their weaker or repulsive CO−π interactions ( vide infra ) …”

Some Recent Advances in the Design and Use of Molecular Balances for the Experimental Quantification of Intramolecular Noncovalent Interactions of π Systems

“…concluded that in their case the lone‐pair (LP)⋅⋅⋅π interaction was repulsive in nature. Further X‐ray and NMR studies of CH 3 ⋅⋅⋅π interactions using many different N ‐( o ‐tolyl)succinimides revealed that the preferred conformational state in solution was also retained in the solid state . The dependence of the strength of a face‐to‐face aryl⋅⋅⋅aryl alignment on the alkyl substituent (CH 3 , C 2 H 5 , CH(CH 3 ) 2 , and C(CH 3 ) 3 ), as well as its position in a phenyl ring ( meta and para ), was also evaluated .…”