Reliable and Performant Identification of Low-Energy Conformers in the Gas Phase and Water

Anna Theresa Cavasin, Alexander Hillisch, Felix Uellendahl, Sebastian Schneckener, and Andreas H. Göller (2018)
Highlighted by Jan Jensen

Copyright 2018 American Chemical Society

In my opinion the most important conclusion from this article is that PBEh-3c/GFN-xTB is an excellent approximation to PBE0-D3(BJ)/def2-TZVP/GFN-xTB when finding low energy conformations in both the gas phase and water. 

The authors chose 93 drug-like molecules and generated up to 100 conformation low-energy (< 20 kcal/mol) structures for each and computed the relative PBE0 energy of the conformer ranked lowest according to, e.g. PBEh-3c/GFN-xTB for each molecule. As you can see from the box-plots above the lowest energy structure found by PBEh-3c/GFN-xTB is virtually always within 0.5 kcal/mol of that predicted by PBE0-D3(BJ)/def2-TZVP/GFN-xTB. This is remarkable given the fact that PBEh-3c is 100-1000 times faster than PBE0-D3(BJ)/def2-TZVP according to the authors.

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An Exceptionally Close, Non-Bonded Hydrogen–Hydrogen Contact with Strong Through-Space Spin–Spin Coupling

Xiao, Y.; Mague, J. T.; Pascal, R. A., Angew. Chem. Int. Ed. 2018, 57, 2244-2247
Contributed by Steven Bacharach

Reposted from Computational Organic Chemistry with permission

The competition for finding molecules with ever-closer non-bonding H^…H interactions is heating up. I have previously blogged about 1, a in,in-Bis(hydrosilane) designed by Pascal,¹ with an H^…H distance of 1.57 Å, and also blogged about 2, the dimer of tri(di-t-butylphenyl)methane,² where the distance between methine hydrogens on adjacent molecules is 1.566 Å.

Now Pascal reports on 3, which shows an even closer H^…H approach.³

The x-ray structure of 3 shows the in,in relationship of the two critical hydrogens, H_A and H_B. Though the positions of these hydrogens were refined, the C-H distance are artificially foreshortened. A variety of computed structures are reported, and these all support a very short H^…H non-bonding distance of about 1.52 Å. The B3PW91-D3/cc-pVTZ optimized structure is shown in Figure 1.

Figure 1. B3PW91-D3/cc-pVTZ optimized structure of 3.

The authors also note an unusual feature of the ¹H NMR spectrum of 3: the H_B signal appears as a double with J_AB= 2.0 Hz. B3LYP/6–311++G(2df,2pd) NMR computations indicated a coupling of 3.1 Hz. This is the largest through-space coupling recorded.

References

1. Zong, J.; Mague, J. T.; Pascal, R. A., "Exceptional Steric Congestion in an in,in-Bis(hydrosilane)." J. Am. Chem. Soc. 2013, 135, 13235-13237, DOI: 10.1021/ja407398w.

2. Rösel, S.; Quanz, H.; Logemann, C.; Becker, J.; Mossou, E.; Cañadillas-Delgado, L.; Caldeweyher, E.; Grimme, S.; Schreiner, P. R., "London Dispersion Enables the Shortest Intermolecular Hydrocarbon H···H Contact." J. Am. Chem. Soc. 2017, 139, 7428–7431, DOI: 10.1021/jacs.7b01879.

3. Xiao, Y.; Mague, J. T.; Pascal, R. A., "An Exceptionally Close, Non-Bonded Hydrogen–Hydrogen Contact with Strong Through-Space Spin–Spin Coupling." Angew. Chem. Int. Ed. 2018, 57, 2244-2247, DOI: 10.1002/anie.201712304.

InChI

3: InChI=1S/C27H24S3/c1-4-17-13-28-10-16-11-29-14-18-5-2-8-21-24(18)27-23(17)20(7-1)26(21)22-9-3-6-19(25(22)27)15-30-12-16/h1-9,16,26-27H,10-15H2
InChIKey=NJBHGDPNFALCTL-UHFFFAOYSA-N

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MD studies of simple pericyclic reactions

Mackey, J. L.; Yang, Z.; Houk, K. N., "Dynamically concerted and stepwise trajectories of the Cope rearrangement of 1,5-hexadiene." Chem. Phys. Lett. 2017, 683, 253-257
Yang, Z.; Zou, L.; Yu, Y.; Liu, F.; Dong, X.; Houk, K. N., "Molecular dynamics of the two-stage mechanism of cyclopentadiene dimerization: concerted or stepwise?" Chem. Phys. 2018, in press
Yang, Z.; Dong, X.; Yu, Y.; Yu, P.; Li, Y.; Jamieson, C.; Houk, K. N., "Relationships between Product Ratios in Ambimodal Pericyclic Reactions and Bond Lengths in Transition Structures." J. Am. Chem. Soc. 2018, 140, 3061-3067
Contributed by Steven Bacharach
Reposted from Computational Organic Chemistry with permission

At the recent ACS meeting in New Orleans, Ken Houk spoke at the Dreyfus award session in honor of Michele Parrinello. Ken’s talk included discussion of some recent molecular dynamics studies of pericyclic reactions. Because of their similarities in approaches and observations, I will discuss three recent papers from his group (which Ken discussed in New Orleans) in this post.

The Cope rearrangement, a fundamental organic reaction, has been studied extensively by computational means (see Chapter 4.2 of my book). Mackey, Yang, and Houk examine the degenerate Cope rearrangement of 1,5-hexadiene with molecular dynamics at the (U)B3LYP/6-31G(d) level.¹ They examined 230 trajectories, and find that of the 95% of them that are reactive, 94% are trajectories that directly cross through the transition zone. By this, Houk means that the time gap between the breaking and forming C-C bonds is less than 60 fs, the time for one C-C bond vibration. The average time in the transition zone is 35 fs. This can be thought of as “dynamically concerted”. For the other few trajectories, a transient diradical with lifetime of about 100 fs is found.

The dimerization of cyclopentadiene finds the two [4+2] pathways merging into a single bispericylic transition state. ² Only a small minority (13%) of the trajectories sample the region about the Cope rearrangement that interconverts the two mirror image dimers. These trajectories average about 60 fs in this space, which comes from the time separation between the formation of the two new C-C bonds. The majority of the trajectories quickly pass through the dimerization transition zone in about 18 fs, and avoid the Cope TS region entirely. These paths can be thought of as “dynamically concerted”, while the other set of trajectories are “dynamically stepwise”. It should be noted however that the value of S² in the Cope transition zone are zero and so no radicals are being formed.

Finally, Yang, Dong, Yu, Yu, Li, Jamieson, and Houk examined 15 different reactions that involve ambimodal (i.e. bispericyclic) transition states.³ They find a strong correlation between the differences in the bond lengths of the two possible new bond vs. their product distribution. So for example, in the reaction shown in Scheme 1, bond a is the one farthest along to forming. Bond b is slightly shorter than bond c. Which of these two is formed next is dependent on the dynamics, and it turns out the P_ab is formed from 73% of the trajectories while P_ac is formed only 23% of the time. This trend is seen across the 15 reaction, namely the shorter of bond b or c in the transition state leads to the larger product formation. When competing reactions involve bonds with differing elements, then a correlation can be found with bond order instead of with bond length.

Scheme 1

References

1) Mackey, J. L.; Yang, Z.; Houk, K. N., "Dynamically concerted and stepwise trajectories of the Cope rearrangement of 1,5-hexadiene." Chem. Phys. Lett. 2017, 683, 253-257, DOI: 10.1016/j.cplett.2017.03.011.

2) Yang, Z.; Zou, L.; Yu, Y.; Liu, F.; Dong, X.; Houk, K. N., "Molecular dynamics of the two-stage mechanism of cyclopentadiene dimerization: concerted or stepwise?" Chem. Phys. 2018, in press, DOI: 10.1016/j.chemphys.2018.02.020.

3) Yang, Z.; Dong, X.; Yu, Y.; Yu, P.; Li, Y.; Jamieson, C.; Houk, K. N., "Relationships between Product Ratios in Ambimodal Pericyclic Reactions and Bond Lengths in Transition Structures." J. Am. Chem. Soc. 2018,140, 3061-3067, DOI: 10.1021/jacs.7b13562.

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