November 23rd, 2015
This reaction emerged a few years ago (thanks Alan!) as a tutorial problem in organic chemistry, in which students had to devise a mechanism for the reaction and use this to predict the stereochemical outcome at the two chiral centres indicated with *. It originates in a brief report from R. B. Woodward’s group in 1973 describing a prostaglandin synthesis,[1] the stereochemical outcome being crucial. Here I take a look at this mechanism using computation.
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References
- R.B. Woodward, J. Gosteli, I. Ernest, R.J. Friary, G. Nestler, H. Raman, R. Sitrin, C. Suter, and J.K. Whitesell, "Novel synthesis of prostaglandin F2.alpha.", Journal of the American Chemical Society, vol. 95, pp. 6853-6855, 1973. https://doi.org/10.1021/ja00801a066
Tags: activation energy, animation, energy, learning tool
Posted in Interesting chemistry, reaction mechanism | 4 Comments »
November 12th, 2015
Derek Lowe has a recent post entitled "Another Funny-Looking Structure Comes Through". He cites a recent medchem article[1] in which the following acetal sub-structure appears in a promising drug candidate (blue component below). His point is that orally taken drugs have to survive acid (green below) encountered in the stomach, and acetals are famously sensitive to hydrolysis (red below). But if X=NH2, compound "G-5555" is apparently stable to acids.[1] So I pose the question here; why?
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References
- C.O. Ndubaku, J.J. Crawford, J. Drobnick, I. Aliagas, D. Campbell, P. Dong, L.M. Dornan, S. Duron, J. Epler, L. Gazzard, C.E. Heise, K.P. Hoeflich, D. Jakubiak, H. La, W. Lee, B. Lin, J.P. Lyssikatos, J. Maksimoska, R. Marmorstein, L.J. Murray, T. O’Brien, A. Oh, S. Ramaswamy, W. Wang, X. Zhao, Y. Zhong, E. Blackwood, and J. Rudolph, "Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-p
<i>K</i>
<sub>a</sub>
Polar Moiety", ACS Medicinal Chemistry Letters, vol. 6, pp. 1241-1246, 2015. https://doi.org/10.1021/acsmedchemlett.5b00398
Tags: Cambridge, Derek Lowe, HTML, HTML element, medchem, medical chemistry
Posted in reaction mechanism | 2 Comments »
October 23rd, 2015
Steve Bachrach on his own blog has commented on a recent article[1] discussing the structure of the trimer of fluoroethanol. Rather than the expected triangular form with three OH—O hydrogen bonds, the lowest energy form only had two such bonds, but it matched the microwave data much better. Here I explore this a bit more.
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References
- J. Thomas, X. Liu, W. Jäger, and Y. Xu, "Unusual H‐Bond Topology and Bifurcated H‐bonds in the 2‐Fluoroethanol Trimer", Angewandte Chemie International Edition, vol. 54, pp. 11711-11715, 2015. https://doi.org/10.1002/anie.201505934
Tags: Atoms in molecules, chemical bonding, Diagram, Hydrogen bond, low energy structure, lowest energy form, microwave, Steve Bachrach
Posted in Interesting chemistry | 4 Comments »
October 23rd, 2015
Posted in Historical | 1 Comment »
October 14th, 2015
In Jingdezhen an Imperial Kiln was built in 1369 to produce porcelain that was “white as jade, thin as paper, bright as a mirror and tuneful as a bell”. It’s the colours of the glazes that caught my eye, achieved by a combination of oxidative and reductive firing in the kiln, coupled with exquisite control of the temperature.
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Posted in Historical, Interesting chemistry | No Comments »
October 9th, 2015
This comes to you from China, and the city of Suzhou. To set the scene, cities in China have a lot of motorbikes. Electric ones. With their own speed units, a % of Panda speed. 
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Posted in Interesting chemistry | 1 Comment »
October 1st, 2015
A fascinating re-examination has appeared[1] of a reaction first published[2] in 1960 by Wittig and then[3] repudiated by him in 1964 since it could not be replicated by a later student. According to the new work, the secret to a successful replication seems to be the presence of traces of a nickel catalyst (originally coming from e.g. a nickel spatula?). In this recent article[1] a mechanism for the catalytic cycle is proposed. Here I thought I might explore this mechanism using calculations to see if any further insights might emerge.
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References
- S.A. Künzi, J.M. Sarria Toro, T. den Hartog, and P. Chen, "Nickel‐Catalyzed Cyclopropanation with NMe<sub>4</sub>OTf and <i>n</i>BuLi", Angewandte Chemie International Edition, vol. 54, pp. 10670-10674, 2015. https://doi.org/10.1002/anie.201505482
- V. Franzen, and G. Wittig, "Trimethylammonium‐methylid als Methylen‐Donator", Angewandte Chemie, vol. 72, pp. 417-417, 1960. https://doi.org/10.1002/ange.19600721210
- G. Wittig, and D. Krauss, "Cyclopropanierungen bei Einwirkung von <i>N</i>‐Yliden auf Olefine", Justus Liebigs Annalen der Chemie, vol. 679, pp. 34-41, 1964. https://doi.org/10.1002/jlac.19646790106
Tags: activation free energy barriers, Cambridge, energy, energy relative, nickel-carbene product
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September 24th, 2015
How does an anaesthetic work? Surprisingly, it is only recently[1] that the possible binding sites of the anaesthetic propofol (2,6-di-isopropylphenol) have been identified using a technique known as photoaffinity labelling.[2] A propofol analogue was constructed[1] by replacing one of the isopropyl groups with a trifluoromethyl diazirine group (R=CF3, X=Y=N below). Upon photolysis, this species looses nitrogen and forms a carbene as a reactive species, which with further chemistry binds covalently[2] to adjacent amino acids in the binding pocket.These modified segments could then be analysed by mass spectrometry.[1] An isomer of diazirine is diazomethane, which is some 11 kcal/mol lower in free energy, but fortunately the diazirene is preventing from thermally isomerising to this species by a large kinetic barrier. That was the intro; now for a connection.‡ I recently attended a presentation on another medical topic, the therapeutic uses of carbon monoxide.[3] In higher concentrations it is notoriously lethal, but with appropriate delivery it can be therapeutic. So, intertwingling, I asked myself what the properties of the carbon monoxide isoelectronic analogue of a diazirine might be (X=C, Y=O below).
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References
- G.M.S. Yip, Z. Chen, C.J. Edge, E.H. Smith, R. Dickinson, E. Hohenester, R.R. Townsend, K. Fuchs, W. Sieghart, A.S. Evers, and N.P. Franks, "A propofol binding site on mammalian GABAA receptors identified by photolabeling", Nature Chemical Biology, vol. 9, pp. 715-720, 2013. https://doi.org/10.1038/nchembio.1340
- L. Dubinsky, B.P. Krom, and M.M. Meijler, "Diazirine based photoaffinity labeling", Bioorganic & Medicinal Chemistry, vol. 20, pp. 554-570, 2012. https://doi.org/10.1016/j.bmc.2011.06.066
- R. Motterlini, and L.E. Otterbein, "The therapeutic potential of carbon monoxide", Nature Reviews Drug Discovery, vol. 9, pp. 728-743, 2010. https://doi.org/10.1038/nrd3228
Tags: anaesthetic, Diazirine, GABAA receptors, photo affinity labelling, propofol
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September 13th, 2015
Previously, I explored deviation from ideal tetrahedral arrangements of four carbon ligands around a central (sp3) carbon using crystal structures. Now it is the turn of digonal (sp1) and trigonal (sp2) carbons.
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Tags: chemical phenomena
Posted in Chemical IT, crystal_structure_mining | No Comments »