Increasing Complexity in a Conformer Space Step-by-Step: Weighing London Dispersion against Cation−π Interactions

Abstract

We report an evaluation of the importance of London dispersion in moderately large (up to 36 heavy atoms) organic molecules by means of a molecular torsion balance whose conformations "weigh" one interaction against another in the absence of solvents. The experimental study, with gas-phase cryogenic ion vibrational predissociation (CIVP) spectroscopy, solid-state Fourier transfer infrared (FT-IR), and single-crystal Xray crystallography, is accompanied by density functional theory calculations, including an extensive search and analysis of accessible conformations. We begin with the unsubstituted molecular torsion balance, and then step up the complexity systematically by adding alkyl groups incrementally as dispersion energy donors (DEDs) to achieve a degree of chemical complexity comparable to what is typically found in transition states for many regio-and stereoselective reactions in organic and organometallic chemistry. We find clear evidence for the small attractive contribution by DEDs, as had been reported in other studies, but we also find that small individual contributions by London dispersion, when they operate in opposition to other weak noncovalent interactions, produce composite effects on the structure that are difficult to predict intuitively, or by modern quantum chemical calculations. The experimentally observed structures, together with a reasonable value for a reference cation−π interaction, indicate that the pairwise interaction between two tert-butyl groups, in the best case, is modest. Moreover, the visualization of the conformational space, and comparison to spectroscopic indicators of the structure, as one steps up the complexity of the manifold of noncovalent interactions, makes clear that in silico predictive ability for the structure of moderately large, flexible, organic molecules falters sooner than one might have expected.

Atomistic simulations of the E. coli ribosome provide selection criteria for translationally active substrates

“…Conformational dynamics alone remains an enormous challenge for computational analyses, with increasing challenges as the complexity of the system increases 23 . While others have used 3D puzzles for RNA structural predictions 24 , physics-based methods such as molecular dynamics (MD) simulations provide a more accurate description of atomistic dynamics of biological systems [25][26][27] .…”

“…RNA contains more degrees of freedom than protein, and the polyanionic composition demands accurate, long-range electrostatic and solvation models that include explicit metal ions and water, especially within the PTC 22 . Conformational dynamics alone remains an enormous challenge for computational analyses, with increasing challenges as the complexity of the system increases 23 . While others have used 3D puzzles for RNA structural predictions 24 , physics-based methods such as molecular dynamics (MD) simulations provide a more accurate description of atomistic dynamics of biological systems 25–27 .…”

Silyl Groups Are Strong Dispersion Energy Donors

“…The computational error due to conformational complexity was shown by Lledós et al to surmount up to 10 kcal mol –1 for bulky and flexible ligands. To account for a larger conformational space, , multiple conformers must be included in thermochemical investigations as well as spectral predictions. , Recently, the necessity of a conformational analysis has been demonstrated by Chen et al to rationalize the interplay of bulky DEDs with cation−π interactions. We utilized the conformer-rotamer ensemble sampling tool (CREST) to identify the conformers lowest in energy.…”

Influence of Metal Identity in Bipyridine-Based Metal-4N Complexes With Formate

“…In addition, cryogenic preparation of the target ions allows suppression of thermal broadening. Cryogenic ion vibrational spectroscopy (CIVS) has been used to great success by many groups − and today represents a powerful part of the toolbox of cold chemistry.…”