Communication pubs.acs.org/crystal
Correlation between Solid-State and Solution Conformational Ratios in a Series of N‑(o‑Tolyl)Succinimide Molecular Rotors Ping Li, Jungwun Hwang, Josef M. Maier, Chen Zhao, Darya V. Kaborda, Mark D. Smith, Perry J. Pellechia, and Ken D. Shimizu* Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208, United States S Supporting Information *
ABSTRACT: The syn-anti conformational equilibrium of a library of 30 N-(o-tolyl)succinimide molecular rotors was measured in solution via 1H 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 (χsyn). 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.
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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 framework18,20,23 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 nonpolar and does not form strong intermolecular interactions such as hydrogen bonds or dipole−dipole interactions.26,27 Second, the methyl group is relatively small, which minimizes the differences in the packing forces between the syn- and anti-conformers. This study was enabled by the ability to rapidly assemble a large library of o-tolyl rotors containing different shelves, bicyclic frameworks, and rotor substituents. The modular rotors were typically synthesized in one to two steps via previously described synthetic routes.18,20 The library included 20 new rotors (1−6, 8−11, 15−21, 24, 25, 29, and 30), 7 previously described rotors from our group (7, 17, 22, 23, and 26− 28),18,23 and 3 from the literature (12−14).14,15 First, the mole fraction of the syn-conformers (χsyn) were measured in solution via 1H NMR (Table S1). Due to restricted rotation around the Ctolyl−Nimide bond, the syn- and
-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 interactions5−7 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).
Figure 1. Schematic representation of the anti-syn conformational equilibrium of a bicyclic N-(o-tolyl)succinimide molecular rotor.
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 © 2015 American Chemical Society
Received: June 30, 2015 Published: July 13, 2015 3561
DOI: 10.1021/acs.cgd.5b00906 Cryst. Growth Des. 2015, 15, 3561−3564
Crystal Growth & Design
Communication
based on the following observations. First, there were almost an equal number of crystals favoring each conformer. Strong packing forces would have most likely favored one conformer over the other. Second, the two conformers had similar shapes and volumes (Figure 3).30−32 Although the anti-conformer with
Figure 3. (a) Schematic representation for the anti- and synconformers of o-tolyl rotor 7 occupying the same crystallographic site in crystal. (b) Partial side-view of crystal structures 7 highlighting the partial disorder at the o-tolyl rotor motif; the syn-conformer is highlighted in red and the anti-conformer is highlighted in blue.
its protruding ortho-methyl group appears to be the larger conformer, the imide nitrogen can readily pyramidalize33,34 reducing the size of the anti-conformer and allowing it to fit in the same space as the syn-conformer. For example, the syn- and anti-conformers occupied the same crystallographic space in the majority of the mixed conformer crystals. Third, no strong intermolecular interactions were observed such as hydrogen bonding or dipole−dipole interactions in the extended structures.35 The only exceptions were the hydrogen bonds formed by the carboxylic acid groups of 16 and 24. However, these carboxylic groups were positioned on the rotating axis of the o-tolyl rotors, and thus these hydrogen bonding interactions act equally on the syn- and anti-conformers. Next, a comparison of the solution and crystal χsyn values was performed (Figure 4). This analysis revealed a strong
Figure 2. Structures of molecular rotors 1−30 used in the solid-state versus solution correlation study. The o-tolyl rotor is highlighted in red, and the shelf surface is highlighted in blue.
anti-conformers were in slow exchange at room temperature leading to distinct sets of peaks for each conformer. Integration of the syn- and anti-methyl singlets yielded the equilibrium χsyn values with an accuracy from ±1.4% (χsyn = 0.41) to ±5.2% (χsyn = 0.97) (see SI for details). The solution χsyn values for the rotors spanned the entire range from 0.13 to 0.97. These variations were attributed to (1) the absence or presence of an intramolecular CH−π interaction between the o-tolyl methyl group and the aromatic shelves,18,20 (2) repulsive steric interactions between the o-tolyl methyl group and the aromatic shelf,28 and (3) differences in the “bite-angle” of the bicyclic framework due to the different steric and geometric constraints of the bicyclic bridge (X-groups in Figure 1).29 The χsyn values were also measured in the solid-state via X-ray crystallographic analysis. Single crystals for 27 rotors were obtained through slow evaporation from organic solutions, yielding 28 structures (two crystal forms for rotor 7; see SI for details). The structures of the three rotors (12, 13, and 14) in the literature were obtained from the CSD (refcodes: RIZCOS; UJULUG; IHUBOC). As in the solution studies, the crystal structures displayed a range of χsyn values from 0 to 1. More interestingly, approximately a third of the structures (13 out of 31) contained a mixture of syn- and anti-conformers, introducing the possibility that we might observe quantitative correlations between the crystal and solution χsyn values. Closer examination of these structures confirmed that the crystallization process did not appear to impose a strong bias toward one conformer, as the two conformers appeared to have very similar packing energies. This conclusion was reached
Figure 4. Correlation plot of the measured solution and crystal χsyn values for a library of 30 o-tolyl molecular rotors.
qualitative correlation between the solution and crystal χsyn values. For every rotor, the favored conformer in solution was also the favored conformer in the crystal. For example, there are no “mismatched” data points in the upper left or lower right quadrants of the plot in Figure 4 where the solution χsyn was >0.5 and crystal χsyn was 0.15 kcal/mol) would place the conformers in the more predictable Group 1.
broken line in Figure 4. The correlation was better described as a step-function (Figure 4, solid line) or steep sigmoidal function. Thus, the rotors fell into two distinct groups based on their solution χsyn values. Group 1 were rotors (1−8 and 23− 30) that displayed a conformational preference in solution (solution χsyn >0.56 or 0.5 or
