Sunday, January 22, 2017

Crystal Structure Determination of the Pentagonal-Pyramidal Hexamethylbenzene Dication C6(CH3)62+

Malischewski, M.; Seppelt, K., Angew. Chem. Int. Ed. 2017, 56, 368-370
Contributed by Steven Bacharach
Reposted from Computational Organic Chemistry with permission

Hypercoordinated carbon has fascinated chemists since the development of the concept of the tetravalent carbon. The advent of superacids has opened up the world of hypercoordinated species and now a crystal structure of a hexacoordinated carbon has been reported for the C6(CH3)62+ species 1.1

The molecule is prepared by first epoxidation of hexamethyl Dewar benzene, followed by reaction with Magic acid, and crystallized by the addition of HF. The crystal structure shows a pentamethylcyclopentadienyl base capped by a carbon with a methyl group. The x-ray structure is well reproduced by the B3LYP/def2-TZVP structure shown in Figure 1. (While this DFT method predicts a six-member isomer to be slightly lower in energy, MP2 does predict the cage as the lowest energy isomer.)

Figure 1. B3LYP/def2-TZVP optimized geometry of 1.

The Wiberg bond order for the bond between the capping carbon and each carbon of the five-member base is about 0.54, so the sum of the bond orders to the apical carbon is less than 4. The carbon is therefore not hypervalent, but it appears to truly be hypercoordinate. (A topological electron density analysis (AIM) study would have been interesting here.) NICS analysis indicates the cage formed by the apical carbon and the five-member ring expresses 3-D aromaticity. This can be thought of as coming from the C5(CH3)5+ fragment with its 4 electrons and the CCH3+ fragment with two electrons, providing 4+ 2 = 6 electrons for the aromatic cage.


1) Malischewski, M.; Seppelt, K., "Crystal Structure Determination of the Pentagonal-Pyramidal Hexamethylbenzene Dication C6(CH3)62+Angew. Chem. Int. Ed. 2017, 56, 368-370, DOI: 10.1002/anie.201608795.

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Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats

Harriman, G., Greenwood, J., Bhat, S., Huang, X., Wang, R., Paul, D., Tong, L., Saha, A.K., Westlin, W.F., Kapeller, R. and Harwood, H.J., (2016)
Contributed by Jan Jensen

This paper describes the development of ND-630 (aka NDI-010976) which is currently in Phase 2 clinical trials and could help cure a serious liver disease called non-alcoholic steatohepatitis and potentially other diseases. I am highlighting it here because computational chemistry had a lot to do with its discovery both directly and indirectly.

The development of ND-630 is spearheaded by Nimbus Therapeutics, which is basically an off-shoot of Schrödinger, i.e. a company that uses Schrödinger's software to discover new drugs. One of the co-founders (at the VC company Atlas) writes:
Back in the spring of 2009, Atlas (where I'm a partner) founded the company with Schrödinger, a leading computational chemistry software company, after almost a year-long dialogue between myself and Ramy Farid, Schrödinger’s president. At this time, Schrödinger was launching a novel computational tool called WaterMap, an apt name for a technology that maps the energetics of water sites at the receptor-ligand interface, providing a potential roadmap for efficient ligand-receptor interactions. As this cutting-edge technology catalyzed some of our initial thinking, we called it Project Troubled Water Inc (PTW) for the first year or so. 
So in a way, this is also highlight of this article. To summarise: the company was founded because these people believed in computational chemistry as the main driving force behind drug discovery. Did the success of ND-630 prove them right?

Here's how they discovered ND-630 according to the article. They started with the crystal structure of Acetyl-CoA carboxylase with the natural product Soraphen A bound and identified two pockets with high-energy hydration sites using SiteMap and then WaterMap. Then they did a structure-based virtual screen of commercially available compounds using GlideXP and kept only compounds that hit the high-energy hydration sites in both pockets. Soraphen A and these compounds where then used to build two pharmacophore models, which, in turn, where used for a ligand-based virtual screen with hits further refined with GlideXP. "A combined virtual hit-list of a few thousand compounds was clustered to maximize diversity, and 300 representatives were chosen after visualization of the poses. This process led to the identification of ND-022 ... Subsequently, lead optimization proceeded rapidly, guided by WaterMap and Prime/MM-GBSA v. 2.2 estimates of binding free energy." Which finally led to ND-630.

So not exactly Derek Lowe's unicorn dream come true, but I think it's fair to call this computer aided drug design.

Thanks to Victor Guallar for bringing the article to my attention.

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Saturday, January 7, 2017

A Thermally Populated, Perpendicularly Twisted Alkene Triplet Diradical

Wentrup, C.; Regimbald-Krnel, M. J.; Müller, D.; Comba, P., Angew. Chem. Int. Ed. 2016, 55, 14600-1460
Contributed by Steven Bacharach
Reposted from Computational Organic Chemistry with permission

Wentrup and co-workers examined the strained, non-planar aromatic 1.1

The UKS-BP86-D3BJ/def2-TZVP optimized geometry of the singlet 1 is shown in Figure 1. The molecule is decidedly twisted, with an angle of about 52°. This large twist, weakening the π-bond between the two aromatic fragments, suggests that the triplet state of 1 might be easily accessible. The geometry of 31 is also shown in Figure 1, and the two aromatic portions are orthogonal.


Figure 1. UKS-BP86-D3BJ/def2-TZVP optimized geometries of 11 and 31.

The proton and 13C NMR studies of 1 show increasing paramagnetism, observed as line broadening, with increasing temperature. Confirming this is ESR which shows increasing signal with increasing temperature. The triplet state is clearly present. The experimental ΔEST=9.6 kcal mol-1 and the computed singlet-triplet gap is 9.3 kcal mol-1. This is in excellent agreement, and much better than previous computations which predict a gap of 3.4 kcal mol-1, but omitted the D3 correction. This dispersion correction stabilizes the singlet state over the triplet state, as might be expected. (The triplet has the two aromatic components orthogonal and so they have minimal dispersion interactions, while the aromatic planes are much closer in the singlet state.)

For comparison, the computed ΔEST of isomer 2 is much larger: 17.9 kcal mol-1. The energies of the triplet states of 1 and 2 are nearly identical. Both of these structures have orthogonal, non-interacting aromatic moieties. However, the energy of 12 with the twist angles of 11 is 8.2 kcal mol-1 lower than that of 11. This the twisting causes a significant strain to the singlet state, but not to the triplet, and that gives rise to its small singlet-triplet gap.


1) Wentrup, C.; Regimbald-Krnel, M. J.; Müller, D.; Comba, P., "A Thermally Populated, Perpendicularly Twisted Alkene Triplet Diradical." Angew. Chem. Int. Ed. 2016, 55, 14600-14605, DOI: 10.1002/anie.201607415.


1: InChI=1S/C42H24/c1-5-13-29-25(9-1)17-21-33-34-22-18-26-10-2-6-14-30(26)38(34)41(37(29)33)42-39-31-15-7-3-11-27(31)19-23-35(39)36-24-20-28-12-4-8-16-32(28)40(36)42/h1-24H
2: InChI=1S/C42H24/c1-5-13-29-21-37-33(17-25(29)9-1)34-18-26-10-2-6-14-30(26)22-38(34)41(37)42-39-23-31-15-7-3-11-27(31)19-35(39)36-20-28-12-4-8-16-32(28)24-40(36)42/h1-24H

This work is licensed under a Creative Commons Attribution-NoDerivs 3.0 Unported License.