Posts Tagged ‘chemical diagrams’

Organocatalytic cyclopropanation of an enal: (computational) mechanistic understanding.

Saturday, August 25th, 2018

Symbiosis between computation and experiment is increasingly evident in pedagogic journals such as J. Chemical Education. Thus an example of original laboratory experiments[1],[2] that later became twinned with a computational counterpart.[3] So when I spotted this recent lab experiment[4] I felt another twinning approaching.

The reaction under consideration is that between dec-2-enal and 2,4-dinitrobenzyl chloride as catalysed by an α,α-diphenylprolinol trimethylsilyl ester with addition of further base (di-isopropylamine?). The proposed mechanism can be seen in figure 7‡ of the journal article[4] and also scheme 2 of an earlier article.[5] The following is my interpretation of their published mechanism (the compound numbering is the same as in Figure 7).

  1. The initiating step is the condensation between the alkyl enal (1) and the prolinol derivative (3), with elimination of water and the formation of a positive iminium cation (5). One might wonder at this stage what the counter ion to this cation is.
  2. 5 then reacts with 2,4-dinitrobenzyl chloride (2) with apparent elimination of HCl to form 6. This corresponds to 1,4-Michael addition to 5 with the formation of the first new  C-C bond and the creation of two new stereogenic centres.
  3. 6 then cyclises to form a second new C-C bond and a third new stereogenic centre as in 7.
  4. 7 is then hydrolysed to give the final product 4.

A total of three (starred) stereogenic centres are therefore created in 4, implying 23 = 8 steroisomers, arranged as four diastereomers and their enantiomers. A computational mechanistic analysis might strive to cast light on the following questions.

  • Is the sequence shown in figure 7 reasonable? If not can a more reasonable cycle be constructed that has energetics corresponding to a facile reaction at 0°C?
  • What are the predicted relative yields of the four possible diastereomeric products and do they match those observed?
  • If  R=α,α-diphenylprolinol trimethylsilyl ester, then this fourth chiral centre increases the total number of stereoisomers to 16, arranged in eight pairs of diastereomers. Does this result in the diastereomers of 4 forming with an excess of one enantiomer over the other (an ee ≠ 0)?

This post addresses just the first question (R=R’=H, R”=isopropylamine) leaving the other two questions for later analysis.

My analysis (figure above)♥ of the mechanism, as cast for computational analysis†, differs in various details from Figure 7/Scheme 2 of the published articles.[4],[5]

  1. The issue of defining a counterion to 5 is solved by in fact starting the cycle with proton abstraction from 2 by di-isopropylamine♦ to form a benzylic anion, as stabilized by the 2,4-dinitro groups and with the positive counter-ion being the protonated amine base.
  2. The next step is reaction between 1 and 3 to form an aminol 10, a tetrahedral intermediate.
  3. To remove water from this to form an iminium cation 5, one has to protonate the hydroxy group and this can now be done using the cationic ammonium species formed in step 5 above.
  4. The benzylic anion can now react with the iminium cation to form the first C-C bond and the first two stereocentres via 1,4-Michael addition to form 6
  5. The species 6 can now eliminate chloride anion to form the cyclopropyl iminium cation/anion pair 7, generating the 3rd stereogenic centre.
  6. Hydrolysis forms the product 4 and returns the system to the starting point in the catalytic cycle.
  7. Also included is whether an alternative mechanism is viable, involving elimination of Cl– from 8 to form a “carbene”, which could then potentially add to the alkene in 1.

Species (transition state)

FAIR Data DOI
10.14469/hpc/4642

ΔG273.15, Hartree
(ΔΔG‡273.15, kcal/mol)

Structure
(click for 3D model)
Reactants -1837.174744♣ (0.0)
TS1 -1837.150502 (15.2)
TS2 -1837.154923 (12.4)
TS3 -1837.147927 (16.8)
TS4 -1837.175723 (-0.6)
TS5 -1837.101534 (45.9)

The (relative) free energies of the transition states at the B3LYP+GD3BJ/6-311G(d,p)/SCRF=chloroform level shown in the table above (click on the thumbnail images to show the 3D model of each transition state) reveal that the highest point corresponds to TS3, a C-C bond forming reaction. This is noteworthy because it constitutes the reaction between an ion-pair, albeit ions which are both heavily stabilized by delocalisation. Since the reaction is known to proceed over 3 hours at 0°C, the activation barrier of 16.8 kcal/mol is also entirely reasonable. TS5, the putative formation of a carbene from the benzyl chloride, has a very high barrier and in fact cyclises to form 9. This pathway can therefore be safely ignored.

The next stage would be to investigate the stereochemical implications of this mechanism (atoms in 4 marked with a *) using the actual substituents for R and R’. Because the mechanism includes ion-pairs throughout, this does actually present some tricky issues. Unlike molecules with covalent bonds, where the shapes are relatively easy to predict, ion-pairs are more flexible and can often adopt a variety of poses, the relative energy of which is frequently determined simply by the magnitudes of their dipole moments.[6] If I manage to sort this out, I will report back here.

‡I would love to show you figure 7 here, but the publisher asserts that I would need to pay them $87.75 to do so and so you will have to acquire the article yourself to see it.

†Various guiding rules include constructing the entire catalytic cycle using exactly the same number of atoms so that the cycle can show only relative (free) energies and using neutral ion-pair models rather than just charged species alone.

♥Almost all the chemical diagrams on this blog for some ten years now have been in SVG (scalable vector graphics) format. Most modern web browsers for a number of years now have had excellent support for SVG. Until recently SVG could not be generated directly from a drawing program such as e.g. ChemDraw. Instead I saved as EPS (encapsulated postscript) and then used a program called Scribus to convert to SVG. In fact with Chemdraw V18.0, the direct conversion to SVG seems to be working very well, including honoring color maps. To scale up a diagram, click on it to open a new browser window containing only it and then use the browser zoom-in control to magnify it. Unlike e.g. a pixel image, SVG images magnify/scale correctly.

♣This relates to metadata as described in this post in performing a global search of any species matching this Gibbs Energy.

♦If the mechanism is set up without any base, then proton abstraction must occur directly from the benzyl chloride. Under these circumstances, the barrier for proton removal is 27.5 kcal/mol, whilst that for C-C bond formation is only 13.6.

References

  1. A. Burke, P. Dillon, K. Martin, and T.W. Hanks, "Catalytic Asymmetric Epoxidation Using a Fructose-Derived Catalyst", Journal of Chemical Education, vol. 77, pp. 271, 2000. https://doi.org/10.1021/ed077p271
  2. J. Hanson, "Synthesis and Use of Jacobsen's Catalyst: Enantioselective Epoxidation in the Introductory Organic Laboratory", Journal of Chemical Education, vol. 78, pp. 1266, 2001. https://doi.org/10.1021/ed078p1266
  3. K.K.(. Hii, H.S. Rzepa, and E.H. Smith, "Asymmetric Epoxidation: A Twinned Laboratory and Molecular Modeling Experiment for Upper-Level Organic Chemistry Students", Journal of Chemical Education, vol. 92, pp. 1385-1389, 2015. https://doi.org/10.1021/ed500398e
  4. M. Meazza, A. Kowalczuk, S. Watkins, S. Holland, T.A. Logothetis, and R. Rios, "Organocatalytic Cyclopropanation of (<i>E</i>)-Dec-2-enal: Synthesis, Spectral Analysis and Mechanistic Understanding", Journal of Chemical Education, vol. 95, pp. 1832-1839, 2018. https://doi.org/10.1021/acs.jchemed.7b00566
  5. M. Meazza, M. Ashe, H.Y. Shin, H.S. Yang, A. Mazzanti, J.W. Yang, and R. Rios, "Enantioselective Organocatalytic Cyclopropanation of Enals Using Benzyl Chlorides", The Journal of Organic Chemistry, vol. 81, pp. 3488-3500, 2016. https://doi.org/10.1021/acs.joc.5b02801
  6. J. Clarke, K.J. Bonney, M. Yaqoob, S. Solanki, H.S. Rzepa, A.J.P. White, D.S. Millan, and D.C. Braddock, "Epimeric Face-Selective Oxidations and Diastereodivergent Transannular Oxonium Ion Formation Fragmentations: Computational Modeling and Total Syntheses of 12-Epoxyobtusallene IV, 12-Epoxyobtusallene II, Obtusallene X, Marilzabicycloallene C, and Marilzabicycloallene D", The Journal of Organic Chemistry, vol. 81, pp. 9539-9552, 2016. https://doi.org/10.1021/acs.joc.6b02008

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Blogbooks, e-books and future proofing chemical diagrams.

Monday, October 31st, 2011

Most of the chemical structure diagrams in this blog originate from Chemdraw, which seems to have been around since the dawn of personal computers! I have tended to use this program to produce JPG bitmaps for the blog, writing them out in 4x magnification, so that they can be scaled down for display whilst retaining some measure of higher resolution if needed for other purposes. These other purposes might be for e.g. the production of e-books (using Calibre), the interesting Blog(e)book format offered as a service by Feedfabrik, or display on mobile tablets where the touch-zoom metaphor to magnify works particularly well. But bitmap images are not really well future proofed for such new uses. Here I explore one solution to this issue.

I have previously mentioned scalable vector graphics (SVG) as an alternative, and fortunately the production of such has become routine.3 The diagram above2 is indeed SVG (and if you cannot see it, then try a modern SVG-capable browser1). It was produced thus:

  1. Drawn in Chemdraw
  2. Exported as Encapsulated postscript
  3. Imported into  Scribus, an Open Source desktop publishing program (where it can be annotated/edited if need be)
    • This program will also need Ghostscript installed to handle the EPS
  4. and exported from Scribus to SVG.
  5. Notice how the diagram above automatically scales to fill the width of the page. If you click on it, you get the diagram on its own. If you zoom the browser window, it should scale perfectly.
  6. I note that these SVG diagrams work well in e-books or blogbooks.
There seem to be many other (open) programs out there which support SVG, so the above combination is not necessary the only one, or indeed the best. There is one other aspect which might be mentioned. The old GIF or JPG bitmap formats do have good meta-data support, such as  EXIF, GPS or XMP. These invisible data have often been used to embed a molecular connection table into a GIF or JPG file, such that the original molecular data can be reconstituted from the image file. Unfortunately, there are no real standards for doing this, and so round-tripping the data is probably a closed process within a specific software environment. However, because SVG is an XML format, it can be readily made to carry such information in a fully inter-operable manner. For example, one could easily embed a CML description of the molecule into its own container (namespace) in the SVG file. For the purposes of rendering an on-screen image, this extra information is of course ignored.

1 I notice that Internet Explorer 9 (both 32- and 64-bit versions) will display (and save) the above diagram if you click on it, but it cannot (yet) be inlined into the post, although the documentation implies it should.
2 The version below is the conventional JPG form (click on it to see the original 4x version).

Diagram displayed using JPG.

3. Historical note. Peter Murray-Rust and I have been promoting SVG for use in chemistry for 11+ years now. For one ancient page, see here. The syntax has decayed somewhat, but some of the diagrams still work!

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Data-round-tripping: moving chemical data around.

Saturday, November 20th, 2010

For those of us who were around in 1985, an important chemical IT innovation occurred. We could acquire a computer which could be used to draw chemical structures in one application, and via a mysterious and mostly invisible entity called the clipboard, paste it into a word processor (it was called a Macintosh). Perchance even print the result on a laserprinter. Most students of the present age have no idea what we used to do before this innovation! Perhaps not in 1985, but at some stage shortly thereafter, and in effect without most people noticing, the return journey also started working, the so-called round trip. It seemed natural that a chemical structure diagram subjected to this treatment could still be chemically edited, and that it could make the round trip repeatedly. Little did we realise how fragile this round trip might be. Years later, the computer and its clipboard, the chemistry software, and the word processor had all moved on many generations (it is important to flag that three different vendors were involved, all using proprietary formats to weave their magic). And (on a Mac at least) the round-tripping no longer worked. Upon its return to (Chemdraw in this instance), it had been rendered inert, un-editable, and devoid of semantic meaning unless a human intervened. By the way, this process of data-loss is easily demonstrated even on this blog. The chemical diagrams you see here are similarly devoid of data, being merely bit-mapped JPG images. Which is why, on many of these posts, I put in the caption Click for 3D, which gives you access to the chemical data proper (in CML or other formats). And I throw in a digital repository identifier for good measure should you want a full dataset.

It is only now that we (more specifically, this user) understand what had happened under-the-hood to break this round-tripping. In 1984, when Apple produced the Mac, they also produced a most interesting data format called PICT. A human saw the PICT as a PICTure, but the computer saw more. It (could) see additional data embedded in the PICT. The clipboard supported the PICT format, which meant that both picture and data could be transferred between programs. And ChemDraw and Word also understood this. Hence the ability to round-trip noted above (it has to be said between specifically these programs).

Times moved on and the limitations of PICT set in. Apple refocussed on the PDF format. Related, notice, to the Postscript format that Adobe had introduced in order to allow high quality laserprinting. PICT support was abandoned, and the various components no longer carried recognisable data (specifically the clipboard or the ability of Word to recognise the data). Round-tripping broke. Does this matter? Well, one colleague where I work had accumulated more than 1000 chemical diagrams, which he decided to store in Powerpoint (and yes, he threw the original Chemdraw files away). The day came when he wanted to round trip one of them. And of course he could not. He was rather upset I have to say!

PDF was not really a format designed to carry data (see DOI: 10.1021/ci9003688). But, bless their hearts, the three vendors involved in this story all agreed to support data embedded in the PDF hamburger (and Abobe to tolerate it) and now once again, a structure diagram can move into an Office program (on Mac) and out again and retain its chemical integrity. What lessons can be learnt?

  1. Firstly, out of side, out of mind. The clipboard is truly mostly out of sight, and it was not really designed from the outset to preserve data properly. Nowadays I wonder whether clipboards in general recognise XML (and hence CML) and preserve it. I truly do not know. But they should.
  2. Secondly, any system which relies on three or four commercial vendors, who at least in the past, devised proprietary formats which they could change without warning, is bound to be fragile.
  3. We have learnt that data is valuable. More so than the representation of it (i.e. a 2D or 3D structure diagram). But when its lost, the users should care! And tell the vendors.
  4. Peter Murray-Rust and his team have produced CML4Word (or as Microsoft call it, Chemistry add-in for Word). At its heart is data integrity. Fantastic! But I wonder if it survives on Microsoft’s clipboard (I know it does not on Apple’s, since CML4Word is not available on that OS. And is unlikely to ever become so).
  5. And I can see history about to repeat itself. The same seems about to happen on new devices such as the Apple iPad. It too has copy/paste via a clipboard. I bet this will not round trip chemistry (or much other) data! Want to bet that the lessons of this story have not yet been learnt?

Oh, for those who wish to round-trip chemistry on a Mac, you will have to acquire ChemDraw 12.0.2 and Word 2011 (version 14.01), as well as OS X 10.6 for it to work.

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