Posts Tagged IBM

The Story of Olympicene from Concept to Completion

The story of Olympicene, and our intention to try and get it synthesized and analyzed, was first reported in August 2011 here. The original conversation was between Prof Graham Richards and I over a drink in Belgium at the RSC Editors Symposium in March 2010. The concept of having someone synthesize a small organic molecule that would be a molecular representation of a famous symbol of sport was a fascinating challenge. And, always one for a challenge, it was one that was pursued with great gusto!

Since we had started the ChemSpider SyntheticPages (CSSP) platform recently I thought it was appropriate to kick off a grand vision discussion with Peter Scott, one of the editors of CSSP. My original idea that I bounced off of Peter was a big one…an international competition exposed to the chemistry community. Encourage chemistry labs around the world to submit their step-by-step syntheses to CSSP. We would be able to collect and expose all of this work to the entire chemistry community. We would set up a voting scheme for the community to give their input on what was the most elegant synthesis, the greenest, what had the best analytical data, what had the best write up. Not all categories were detailed at that time and would come later but the concept of bronze, silver and gold medal winners in an international chemistry competition made sense. We were really excited by the possibilities but for many reasons (read that as many distractions) we rolled the announcement out as a smaller announcement and encouraged participation as best as we could with a small engagement profile via this blog. It did seem to garner a lot of attention but as is common with such projects the participation was not as high as we expected. Nevertheless one lab did step up to participate in the project, the lab of David Fox Group at the University of Warwick. David is a colleague of Peter Scott’s…small world…

David had one of his students pursue the synthesis, not only because the olympicene molecule might be an elegant piece of synthetic work, but also because some of the envisaged properties could well be of value (more on that later!). Anish started publishing his syntheses to CSSP in November of last year as listed here. You can see the Olympicene compound coming together step by step and yes, the final step is not yet reported! Once the compound was made then the possibilities of having it analyzed seemed rather interesting, especially having seen the work reported by IBM in 2009 regarding the single molecule imaging of pentacene. Also, I had followed the work of Marcel Jaspars, who I had known during my time working at ACD/Labs when I was working on Computer-Assisted Structure Elucidation [1,2]. Marcel had recently worked on an NMR and microscopy imaging project to confirm a chemical compound structure. Again, small world. I asked Marcel for an intro to the researchers at IBM and we started a dialogue. Researchers at University of Warwick had already applied Scanning Tunnelling Microscopy (Dr Giovanni Costantini and Ben Moreton at Warwick) and they then connected with Leo Gross with the idea of using the noncontact atomic force microscopy approach.

Within a fairly short period of time IBM had performed the very elegant work of imaging olympicene…just one of the images is shown below but there are others shown on the Flickr account.

A single olympicene molecule is just 1.2 nanometres in width, about 100,000 times thinner than a human hair. This is beautiful! For whatever reason it looks like a molecule with a smile at the success of the work too!

The story of the work is described in this video below.

The work is not over yet! There is a research paper to come from the University of Warwick and IBM Research labs as there is definitely unique science that has come out of this work and definitely needs to be reported. That molecule, as it were, is “NOT just a pretty face”. We will submit all the appropriate images and available analytical data onto ChemSpider and CSSP as time allows.

For now I simply smile at the story of a concept discussion between Graham and I that was taken into the hands of superb scientists and brought to fruition. Congratulations to ALL of those who worked on the project in David Fox’s and Leo Gross’s labs. Thanks to the marketing people at IBM, RSC and Warwick for bringing together all of the materials in a tight time frame to tell the story. My thanks to my colleagues at RSC who believed in the potential of this project and especially to Peter Scott for seeing the potential and willingly participating! This project is a great example of international collaboration and pushing science to its extremes. It was a pleasure to be involved if only at a concept level and HOPEFULLY I will get to meet the scientists who did the work sometime!

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How are NMR Prediction Algorithms and AFM Related?

There’s a really nice News piece over on Nature News regarding “Feeling the Shapes of Molecules“. The work reports on how Atomic Force Microscopy is being used to deduce chemical structure directly, one molecule at a time. It is, quite simply, stunning. This work is an extension of the original work reported on pentacene that many scientists thought was spectacular. This work is even one step closer to the dream of single molecule structure identification. The work is entitled “Organic structure determination using atomic-resolution scanning probe microscopy” and as well as the IBM group responsible for the AFM work involves Marcel Jaspars, someone who’s work I have watched for many years as I am trained as an NMR spectroscopist and have spent a lot of time working on computer-assisted structure elucidation (CASE) approaches to examine natural product structures (see references in here…).

The molecule that they studied was cephalandole A  that had previously been mis-assigned. Interestingly my old colleagues from ACD/Labs, where I worked for over a decade, and myself had published an article in RSC’s Natural Product Reviews where we studied “Structural revisions of natural products by Computer-Assisted Structure Elucidation (CASE) systems“. The basic premise of the article is that there are incorrect structures making it into the literature because of the misinterpretation of the analytical data and that computer algorithms, specifically NMR prediction and CASE algorithms, can be used to rule out structures elucidated by the scientists.It is hard to do justice to the entire review article as we detail the approaches to CASE and NMR prediction and doing it in a blog post is tough. So, I do recommend reading the NPR article. However, I am extracting the part that applies to the elucidation of the structure of cephalandole A and how algorithms would be of value in negating the incorrect structure.

“In 2006 Wu et al isolated a new series of alkaloids, particularly cephalandole A, 16. Using 2D NMR data (not tabulated in the article) they performed a full 13C NMR chemical shift assignment as shown on structure 16.

Mason et al synthesized compound 16 and after inspection of the associated 1H and 13C NMR data concluded that the original structure assigned to cephalandol A was incorrect. The synthetic compound displayed significantly different data from those given by Wu et al. The 13C chemical shifts of the synthetic compound are shown on structure 16A.

Cephalandole A was clearly a closely related structure with the same elemental composition as 16, and structure 17was hypothesized as the most likely candidate. Compound 17 was described in the mid 1960s and this structure was synthesized by Mason et al.The spectral data of the reaction product fully coincided with those reported by Wu et al. The true chemical shift assignment is shown in structure 17. For clarity the differences between the original and revised structures are shown in Figure 17.

We expect that 13C chemical shift prediction, if originally performed for structure 16, would encourage caution by the researchers (we found dA=3.02 ppm).Figure 18 presents the correlation plots of the 13C chemical shift values predicted for structure 16 by both the HOSE and NN methods versus experimental shift values obtained by Wu et al. The large point scattering, the regression equation, the low R2 =0.932 value (an acceptable value is usually R2 ≥ 0.995) and the significant magnitude of the g-angle between the correlation plot and the 45-grade line (a visual indication for disagreement between the experiment and model) could indicate inconsistencies with the proposed structure and should encourage close consideration of the structure.Our experience has demonstrated that a combination of warning attributes can serve to detect questionable structures even in those cases when the StrucEluc system is not used for structure elucidation.

Figure 18. Correlation plots of the 13C chemical shift values predicted for structure 16 by HOSE and NN methods versus experimental shift values obtained by Wu et al. Extracted statistical parameters: R2(HOSE)=0.932, dHOSE=1.20dexp-25.6.

So, for those NMR jocks who don’t have access to the genius of IBM scientists performing AFM, and yet want to have tools to help in the elucidation process you’d be doing well to use NMR prediction algorithms and CASE systems to help….it’s rather embarrassing to have to issue a retraction on a paper with your name on.

Meanwhile I am in awe of the work reported by Marcel and his colleagues at IBM. Clearly there’s a long way to go before such approaches are mainstream but the flag is in the sand…this is where things will speed up and we are surely destined, I hope (!) to see many more reports of this type of work and how it is progressing. Let’s hope. Feedback on the NPR article welcomed!!!

Organic structure determination using atomic-resolution scanning probe microscopy

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