Exploration of Chemical Compound, Conformer, and Reaction Space with Meta-Dynamics Simulations Based on Tight-Binding Quantum Chemical Calculations

S. Grimme (2019)

Highlighted by Jan Jensen

The paper describes a new way to search for conformers, chemical reactions, and estimate barriers using the semiempirical GFNn-XTB method using meta-dynamics. A force term is included that scales exponentially with the Cartesian RMSD from previously found structures, thereby forcing the MD explore new areas of phase space. For simulations with more than one molecule it is necessary to add a constraining potential so that the RMSD cannot be increased simply by increasing the distance between molecules. Each individual MD can be relatively short and most of the CPU time is actually spend on energy minimising the snapshots that are saved.

The results depend on a few hyperparameters, so several MD simulations with different values are run in parallel. Because of the extra force the temperature is also a hyperparameters so the method doesn't necessarily tell you what reactions are most likely to occur at, say, 300K.

The conformational search is tested on 22 (mostly) organic molecules and includes the GFN2-xTB energies of the lowest energy conformer for each molecules. This is a valuable benchmark set for other conformational search algorithms designed to find the global minimum.

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Ambimodal Trispericyclic Transition State and Dynamic Control of Periselectivity

Xue, X.-S.; Jamieson, C. S.; Garcia-Borràs, M.; Dong, X.; Yang, Z.; Houk, K. N., J. Am. Chem. Soc. 2019, 141, 1217
Contributed by Steven Bachrach
Reposted from Computational Organic Chemistry with permission

A major topic of this blog has been the growing body of studies that demonstrate that dynamic effects can control reaction products (see these posts). Often these examples crop up with valley ridge inflection points. Another cause can be bispericyclic transition states, first discovered by Caramello et al for the dimerization of cyclopentadiene.¹ The Houk group now reports on the first trispericyclic transition state.²

Using ωB97X-D/6-31G(d), they examined the reaction of the tropone derivative 1 with dimethylfulvene 2. Three possible products can arrive from different pericyclic reactions: 3, the [4+6] product; 4, the [6+4] product; and 5, the [8+2] product. The thermodynamic product is predicted to be 5, but it is only 1.2 kcal mol^-1 lower in energy than 4 and 6.2 kcal mol^-1 lower than 3.

They identified one transition state originating from the reactants TS1. Hypothesizing that it would be trispericyclic, they performed a molecular dynamics study with trajectories starting from TS1. They ran a total of 142 trajectories, and 87% led to 3, 3% led to 4, and 3% led to 5. This demonstrates the unusual nature of TS1 and the dynamic effects on this reaction surface.

TS1
TS2	TS3

Figure 1. ωB97X-D/6-31G(d) optimized geometries of TS1-TS3.

Additionally, there are two different Cope rearrangements (through TS2 and TS3) that convert 3 into 4 and 5. Some trajectories can pass from TS1 and then directly through either TS2 or TS3 and these give rise to products 4 and 5. In other words, some trajectories will pass from a trispericyclic transition state and then through a bispericyclic transition state before ending in product.

References

1. Caramella, P.; Quadrelli, P.; Toma, L., “An Unexpected Bispericyclic Transition Structure Leading to 4+2 and 2+4 Cycloadducts in the Endo Dimerization of Cyclopentadiene.” J. Am. Chem. Soc. 2002, 124, 1130-1131, DOI: 10.1021/ja016622h

2. Xue, X.-S.; Jamieson, C. S.; Garcia-Borràs, M.; Dong, X.; Yang, Z.; Houk, K. N., “Ambimodal Trispericyclic Transition State and Dynamic Control of Periselectivity.” J. Am. Chem. Soc. 2019, 141, 1217-1221, DOI: 10.1021/jacs.8b12674.

InChIs

1: InChI=1S/C10H6N2/c11-7-10(8-12)9-5-3-1-2-4-6-9/h1-6H
InChIKey=KAWLLELUFONBGI-UHFFFAOYSA-N

2: InChI=1S/C8H10/c1-7(2)8-5-3-4-6-8/h3-6H,1-2H3
InChIKey=WXACXMWYHXOSIX-UHFFFAOYSA-N

3: InChI=1S/C18H16N2/c1-11(2)17-15-7-8-16(17)14-6-4-3-5-13(15)18(14)12(9-19)10-20/h3-8,13-16H,1-2H3
InChIKey=DRPXVBLNTKGMTB-UHFFFAOYSA-N

4: InChI=1S/C18H16N2/c1-18(2)13-6-8-14(12(10-19)11-20)15(9-7-13)16-4-3-5-17(16)18/h3-9,13,15-16H,1-2H3
InChIKey=FSIPGNLAWKVXDD-UHFFFAOYSA-N

5: InChI=1S/C18H16N2/c1-12(2)13-8-9-16-17(13)14-6-4-3-5-7-15(14)18(16,10-19)11-20/h3-9,14,16-17H,1-2H3/t14?,16-,17-/m1/s1
InChIKey=SYLWEGLODFLARZ-VNCLPFQGSA-N

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