The layout of floor 2 of the chemistry department here contains a number of small rooms which function as tutorial areas. Each has a (non-interactive) whiteboard used by students and tutors for, inter-alia, thought-showering. It was in one such room that I found myself with three colleagues this monday afternoon. We soon all sensed something not quite right about the room; it slowly dawned that the whiteboard was entirely devoid of thoughts (it is normally left adorned with chemical hieroglyphics). Before we departed, one of our number crept up to the board and showered the following (the red bit only followed by a ?; thanks Willie!). The chemistry equivalent you might say of Guerrilla gardening. The product shown in blue below is for your benefit here. It is an example of a double fragmentation reaction; by an odd coincidence following on nicely from the previous post.
Archive for the ‘reaction mechanism’ Category
More stereo electronics: the Eschenmoser double fragmentation and guerrilla tutorials.
Thursday, December 10th, 2015A tutorial problem in stereoelectronic control. The Tiffeneau-Demjanov rearrangement as part of a prostaglandin synthesis.
Monday, November 23rd, 2015This 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.
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
The roles of water in the hydrolysis of an acetal.
Wednesday, November 18th, 2015In the previous post, I pondered how a substituent (X below) might act to slow down the hydrolysis of an acetal. Here I extend that by probing the role of water molecules in the mechanism of acetal hydrolysis.
How to stop (some) acetals hydrolysing.
Thursday, November 12th, 2015Derek 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?
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
Isoelectronic games: the CO analogue of diazirines as an intriguing species?
Thursday, September 24th, 2015How 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).
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
Reproducibility in science: calculated kinetic isotope effects for cyclopropyl carbinyl radical.
Saturday, July 11th, 2015Previously on the kinetic isotope effects for the Baeyer-Villiger reaction, I was discussing whether a realistic computed model could be constructed for the mechanism. The measured KIE or kinetic isotope effects (along with the approximate rate of the reaction) were to be our reality check. I had used ΔΔG energy differences and then HRR (harmonic rate ratios) to compute[1] the KIE, and Dan Singleton asked if I had included heavy atom tunnelling corrections in the calculation, which I had not. His group has shown these are not negligible for low-barrier reactions such as ring opening of cyclopropyl carbinyl radical.[2] As a prelude to configuring his suggested programs for computing tunnelling (GAUSSRATE and POLYRATE), it was important I learnt how to reproduce his KIE values.[2] Hence the title of this post. Now, read on.
References
- H.S. Rzepa, "KINISOT. A basic program to calculate kinetic isotope effects using normal coordinate analysis of transition state and reactants.", 2015. https://doi.org/10.5281/zenodo.19272
- O.M. Gonzalez-James, X. Zhang, A. Datta, D.A. Hrovat, W.T. Borden, and D.A. Singleton, "Experimental Evidence for Heavy-Atom Tunneling in the Ring-Opening of Cyclopropylcarbinyl Radical from Intramolecular <sup>12</sup>C/<sup>13</sup>C Kinetic Isotope Effects", Journal of the American Chemical Society, vol. 132, pp. 12548-12549, 2010. https://doi.org/10.1021/ja1055593
Reproducibility in science: calculated kinetic isotope effects for the Baeyer-Villiger reaction.
Wednesday, July 1st, 2015Recollect this earlier post on the topic of the Baeyer-Villiger reaction. In 1999 natural abundance kinetic isotope effects were reported[1] and I set out to calculate the values predicted for a particular model constructed using Quantum mechanics. This comparison of measurement and calculation is nowadays a standard verification of both experiment and theory. When the two disagree either the computational model is wrong or incomplete, or the remoter possibility that there is something not understood about the experiment.
References
- D.A. Singleton, and M.J. Szymanski, "Simultaneous Determination of Intermolecular and Intramolecular <sup>13</sup>C and <sup>2</sup>H Kinetic Isotope Effects at Natural Abundance", Journal of the American Chemical Society, vol. 121, pp. 9455-9456, 1999. https://doi.org/10.1021/ja992016z
Natural abundance kinetic isotope effects: mechanism of the Baeyer-Villiger reaction.
Wednesday, June 10th, 2015I have blogged before about the mechanism of this classical oxidation reaction. Here I further explore computed models, and whether they match the observed kinetic isotope effects (KIE) obtained using the natural-abundance method described in the previous post.