Posts Tagged ‘web browsers’

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

Tags:, , , , , , , , , , , , , , ,
Posted in Interesting chemistry | 9 Comments »

Ten years on: Jmol and WordPress.

Wednesday, May 16th, 2018

Ten years are a long time when it comes to (recent) technologies. The first post on this blog was on the topic of how to present chemistry with three intact dimensions. I had in mind molecular models, molecular isosurfaces and molecular vibrations (arguably a further dimension). Here I reflect on how ten years of progress in technology has required changes and the challenge of how any necessary changes might be kept “under the hood” of this blog.

That first post described how the Java-based applet Jmol could be used to present 3D models and animations. Gradually over this decade, use of the Java technology has become more challenging, largely in an effort to make Web-page security higher. Java was implemented into web browsers via something called Netscape Plugin Application Programming Interface  or NPAPI, dating from around 1995. NPAPI has now been withdrawn from pretty much all modern browsers.‡ Modern replacements are based on JavaScript, and the standard tool for presenting molecular models, Jmol has been totally refactored into JSmol.† Now the challenge becomes how to replace Jmol by JSmol, whilst retaining the original Jmol Java-based syntax (as described in the original post). Modern JSmol uses its own improved syntax, but fortunately one can use a syntax converter script Jmol2.js which interprets the old syntax for you. Well, almost all syntax, but not in fact the variation I had used throughout this blog, which took the form:

<img onclick=”jmolApplet([450,450],’load a-data-file;spin 3;’);” src=”static-image-file” width=”450″ /> Click for 3D structure

This design was originally intended to allow browsers which did not have the Java plugin installed to default to a static image, but that clicking on the image would allow browsers that did support Java to replace (in a new window) the static image with a 3D model generated from the contents of a-data-file. The Jmol2.js converter script had not been coded to detect such invocations. Fortunately Angel came to my rescue and wrote a 39 line Javascript file that does just that (my Javascript coding skills do not extend that far!). Thanks Angel!!

In fact I did have to make one unavoidable change, to;

<img onclick=”jmolApplet([450,450],’load a-data-file;spin 3;’,’c1′);” src=”image-file” width=”450″ /> Click for 3D structure

to correct an error present in the original. It manifests when one has more than one such model present in the same document, and this necessitates that each instance has a unique name/identifier (e.g. c1). So now, in the WordPress header for the theme used here (in fact the default theme), the following script requests are added to the top of each page, the third of which is the new script.

<script type=”text/javascript” src=”JSmol.min.js”></script>
<script type=”text/javascript” src=”js/Jmol2.js”></script>
<script type=”text/javascript” src=”JmolAppletNew.js”></script>

The result is e.g.

Click for 3D

Click for 3D structure of GAVFIS

Click for 3D

Click for 3D interaction

This solution unfortunately is also likely to be unstable over the longer term. As standards (and security) evolve, so invocations such as onclick= have become considered “bad practice” (and may even become unsupported). Even more complex procedures will have to be devised to keep up with the changes in web browser behaviour and so I may have to again rescue the 3D models in this blog at some stage! Once upon a time, the expected usable lifetime of e.g. a Scientific Journal (print!) was a very long period (>300 years). Since ~1998 when most journals went online, that lifetime has considerably shortened (or at least requires periodic, very expensive, maintenance). For more ambitious types of content such as the 3D models discussed here, it might be judged to be <10 years, perhaps much less before the maintenance becomes again necessary. Sigh!

‡ At the time of writing, WaterFox is one of the few browsers to still support it. †An early issue with using Javascript instead of Java was performance. For some tasks, the former was often 10-50 times slower. Improvements in both hardware and software have now largely eliminated this issue. Thus using Jquery.

Tags:, , , , , , , , , , , , , , , , , ,
Posted in Interesting chemistry | 6 Comments »

Electronic notebooks: a peek into the future?

Tuesday, September 16th, 2014

ELNs (electronic laboratory notebooks) have been around for a long time in chemistry, largely of course due to the needs of the pharmaceutical industries. We did our first extensive evaluation probably at least 15 years ago, and nowadays there are many on the commercial market, with a few more coming from opensource communities. Here I thought I would bring to your attention the potential of an interesting new entrant from the open community.

My very first post on this blog six years ago related to incorporation of the Jmol molecular viewer into posts, and it has been a feature of many since. A little more than two years ago, Jmol was recast into JSmol. This had become possible because JavaScript engines built into modern web browsers were finally getting the sort of performance needed to display molecules (years and years ago, lets say ~1990, such display required very fancy hardware kit such as Silicon Graphics workstations). Around the same time, another well-established Java-based molecule sketcher, JME (Java molecular editor) also became JavaScript based. My own interest in this sort of Web-based behaviour actually crystallised last December, when I decided to refactor my own lecture notes into a tablet-friendly format using JSmol, with some questions directed at the  formidably excellent Jmol discussion list. One of these related to how students might annotate such lecture notes with chemical sketches and store the results for future study or revision. Otis Rothenberger starting exploring various mechanisms for such local storage (using Web browsers), and in the last month or so has found a way of exploiting something called  HTML5 local storage, which allows the sort of capacity needed.  These three technologies have now come together on Otis’ site, which you can now view as CheMagic Notebook (this might be a .com site, but I believe the concept is very much open).

NBTogether with the Virtual model kit (VMK, itself now part of JSmol) this combination is starting to resemble a very interesting mechanism for creating an immersive lecture note environment, almost you might say a lecture note ecosystem. I would argue that for the first 30 years of the digital document era, most people preparing lecture notes became mesmerised (distracted?) by the need to print the outcomes with complete fidelity. It is only recently that the focus has turned to “beyond the PDF” (or beyond the PPT) and much richer mechanisms. So now we have lecture notes morphing into an ecosystem where:

  1. the objects themselves can be interactive (3D models, spectra, animations etc)
  2. or reference further models and associated data held in digital repositories
  3. or built from scratch in response to stimulation from peers, tutorials, workshops or lectures (using eg VMK or JME)
  4. and such annotations in effect themselves can be spliced into the student’s own copy of these notes,
  5. with the whole being regarded as a running notebook created from the initial seed of a lecturer’s materials augmented by the student’s own annotations.

I have focused here on where I started, i.e. refactoring my own lecture notes. But the above concepts could easily morph into eg a research project notebook, a rebundling into smaller segments which are themselves published into digital repositories (and there assigned their own persistent digital object identifiers) and ultimately further morphing into scholarly articles submitted to say a journal. These could represent a continuum, not discrete (and non-communicating) objects.

So will “lecture notes” actually start to change from their conventional (printable) form into something related to the above? Well, I have not addressed the largest hurdle preventing this; giving the content creators (i.e. the lecturers) the training, skills and most importantly the motivation to start to venture down this pathway. Otis has shown it should be technically possible. Come back and revisit this post in ten years time to see what actually did happen!

 

 

 

 

Tags:, , , , , , , , , , ,
Posted in Chemical IT | No Comments »