Wednesday, June 26, 2019

The logic of translating chemical knowledge into machine-processable forms: A modern playground for physical-organic chemistry

Karol Molga, Ewa P. Gajewska, Sara Szymkuć, and Bartosz A. Grzybowski (2019)
Highlighted by Jan Jensen
Figure 11 from the paper (c) RSC

This paper offers a, to me, fascinating "look behind the scenes" of Chematica. At the core this program has 75,000 handcrafted reaction rules (SMARTS and Reaction SMARTS strings as shown in the above figure) extracted from the literature (which took over a decade). The authors estimate that there ca 3000-5000 new reaction classes/types appearing in the literature each years and "that there are on the order of 100,000 distinct reaction classes constituting the body of modern organic chemistry. So their work is almost done :).

The paper does a really excellent job of outlining the challenges involved in constructing these rules and present several cases where the rules must be augmented by ML, MM, and Hückel calculations in order to take non-local structural (e.g. strain and steric hindrance) and electronic effects (e.g. on regioselectivity) into account. Such calculations must be done on the millisecond time scale as many thousand intermediates must be inspected during a retrosynthetic search. At the same time they must be very accurate as inaccuracies accumulate with each step on the retrosynthetic path.

It will be very interesting to see if purely ML-based alternatives can beat this approach!

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Wednesday, June 12, 2019

Vibrational Signatures of Chirality Recognition Between α-Pinene and Alcohols for Theory Benchmarking

Medel, R.; Stelbrink, C.; Suhm, M. A., Angew. Chem. Int. Ed. 2019, 58, 8177
Contributed by Steven Bachrach
Reposted from Computational Organic Chemistry with permission

Can vibrational spectroscopy be used to identify stereoisomers? Medel, Stelbrink, and Suhm have examined the vibrational spectra of (+)- and (-)-α-pinene, (±)-1, in the presence of four different chiral terpenes 2-5.1 They recorded gas phase spectra by thermal expansion of a chiral α-pinene with each chiral terpene.

For the complex of 4 with (+)-1 or (-)-1 and 5 with (+)-1 or (-)-1, the OH vibrational frequency is identical for the two different stereoisomers. However, the OH vibrational frequencies differ by 2 cm-1 with 3, and the complex of 3/(+)-1 displays two different OH stretches that differ by 11 cm-1. And in the case of the complex of α-pinene with 2, the OH vibrational frequencies of the two different stereoisomers differ by 11 cm-1!

The B3LYP-D3(BJ)/def2-TZVP optimized geometry of the 2/(+)-1 and 2/(-)-1 complexes are shown in Figure 2, and some subtle differences in sterics and dispersion give rise to the different vibrational frequencies.


Figure 2. B3LYP-D3(BJ)/def2-TZVP optimized geometry of the 2/(+)-1 and 2/(-)-1

Of interest to readers of this blog will be the DFT study of these complexes. The authors used three different well-known methods – B3LYP-D3(BJ)/def2-TZVP, M06-2x/def2-TZVP, and ωB97X-D/def2-TZVP – to compute structures and (most importantly) predict the vibrational frequencies. Interestingly, M06-2x/def2-TZVP and ωB97X-D/ def2-TZVP both failed to predict the vibrational frequency difference between the complexes with the two stereoisomers of α-pinene. However, B3LYP-D3(BJ)/def2-TZVP performed extremely well, with a mean average error (MAE) of only 1.9 cm-1 for the four different terpenes. Using this functional and the larger may-cc-pvtz basis set reduced the MAE to 1.5 cm-1 with the largest error of only 2.5 cm-1.

As the authors note, these complexes provide some fertile ground for further experimental and computational study and benchmarking.


1. Medel, R.; Stelbrink, C.; Suhm, M. A., “Vibrational Signatures of Chirality Recognition Between α-Pinene and Alcohols for Theory Benchmarking.” Angew. Chem. Int. Ed. 201958, 8177-8181, DOI: 10.1002/anie.201901687.


(-)-1, (-)-α-pinene: InChI=1S/C10H16/c1-7-4-5-8-6-9(7)10(8,2)3/h4,8-9H,5-6H2,1-3H3/t8-,9-/m0/s1
(+)-1, (-)-α-pinene: InChI=1S/C10H16/c1-7-4-5-8-6-9(7)10(8,2)3/h4,8-9H,5-6H2,1-3H3/t8-,9-/m1/s1
2, (-)borneol: InChI=1S/C10H18O/c1-9(2)7-4-5-10(9,3)8(11)6-7/h7-8,11H,4-6H2,1-3H3/t7-,8+,10+/m0/s1
3, (+)-fenchol: InChI=1S/C10H18O/c1-9(2)7-4-5-10(3,6-7)8(9)11/h7-8,11H,4-6H2,1-3H3/t7-,8-,10+/m0/s1
4, (-1)-isopinocampheol: InChI=1S/C10H18O/c1-6-8-4-7(5-9(6)11)10(8,2)3/h6-9,11H,4-5H2,1-3H3/t6-,7+,8-,9-/m1/s1
5, (1S)-1-phenylethanol: InChI=1S/C8H10O/c1-7(9)8-5-3-2-4-6-8/h2-7,9H,1H3/t7-/m0/s1

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