Ugi Reaction as Mettler-Toledo Application Note

Our JoVE paper Optimization of the Ugi Reaction Using Parallel Synthesis and Automated Liquid Handling (Jean-Claude Bradley, Khalid Baig Mirza, Tom Osborne, Antony Williams, Kevin Owens) was adapted as an Application Note for Mettler-Toledo. Lots of interesting things can be done easily when you publish in a journal with an Open Access option.


I just noticed that our number of views is almost at 8000 on JoVE. After a little over a year the views are still coming in at a fairly steady pace. Article-level metrics are one of the best things in the scientific publication process to have come along for authors.

Laboratory Automation Talk at Drexel

Tom Osborne from Mettler-Toledo will give a talk on laboratory automation at 10:30 a.m. on Tuesday July 1, 2008 in Disque 109 (32^nd and Chestnut streets).

The presentation will focus on chemistry applications of the MiniBlock, MiniBlock XT, and MiniMapper systems, including some results from the Bradley lab on the optimization of the Ugi reaction. A laboratory demonstration will follow in Disque 511.

RSVP Jean-Claude.Bradley@drexel.edu to attend.

MiniBlock® is a flexible, easy to use tool designed for parallel synthesis. MiniBlock® is the only compact parallel synthesizer that allows synthesis via Solid Phase or Solution Phase to be carried out on the same platform. Originally designed by medicinal and combinatorial chemists at Bristol-Myers Squibb Company, the MiniBlock® has been further developed to address a wide range of chemistry methodologies.

Ugi Reaction on MiniMapper - Trial 1 Preliminary Results

After receiving the MiniMapper two weeks ago we now have some numbers to look at from Trial 1.

The idea here was to repeat a Ugi reaction known to work in methanol at 0.5M concentration (EXP099) and explore the experimental space varying solvent, concentration and an excess of some of the reagents.

All 48 reactions gave precipitate (EXP189). We still have to optimize the lighting and camera angle to see this clearly for all tubes:

In reviewing the results I noticed an inconsistency between the experimental design and the information in the GoogleDoc used to plan the details of the experiment. But because the MiniMapper stores the log of its actions in an XML log file, Khalid was able to make corrections to the worksheet.

Based on the weight of product and the limiting reagent, a yield for each reaction was calculated (column AC).

The best 4 yields (48-61%) were found for 4:1 acetonitrile/methanol solutions at the lowest concentration (0.1 M). It is counterintuitive that a multi-component reaction should work better at lower concentration but this is an effect that I noted previously.

Ironically, the absolute lowest yield (1.4%) was found for the 0.5M methanol reaction that was supposed to be the positive control!

This may be due to a malfunction in the delivery of one of the reagents. However, the other reactions carried out at this concentration in methanol were all low yielding (10-15%), compared to when it was run manually in EXP099 (37%).

I must stress that these results are very preliminary since we have not yet shown that the isolated materials are all pure Ugi products. As the NMRs come in I'll update the status.

But I think that this was a good first trial to demonstrate what kind of questions can be asked with the power of automation and the importance of reporting automated logs in Open Notebook Science.

MiniMapper in Lab

As I mentioned previously, Mettler-Toledo is giving us a trial with their MiniMapper/MiniBlock system. Tom Osborne was in my lab yesterday to set it up. We got as far as setting up the software to recognize the positions of bottles and racks and pumping through some methanol.


Once we're set up it looks like we'll be able to come pretty close to just copying columns from the Google spreadsheet of planned experiments to the MiniMapper software. This will make it very convenient for crowdsourcing Ugi experiments.

Actually the worksheet for trial #3 is already set up to accept suggested experiments from anyone - no login required. Just note your name in the contributor column and put in a little explanation for your reasoning. For example, after looking at the master table of Ugi reactions, you may have a hypothesis that aromatic aldehydes lead to Ugi product precipitates at 0.5 M concentration in methanol. Just set up a dozen experiments probing that question. See the MettlerTrial wiki page for more info. I'll explain more about this later but if anyone wants to discuss collaboration contact me.

We have the capacity of doing 96 experiments in parallel but Khalid will probably start with a dry run with pure methanol or a small section from Trial #1.

Tom made a good point about how organic chemists need to think differently when designing experiments in parallel with automation. We have done parallel runs in vials but it gets tricky for people to keep track of everything. Machines are much better at this type of thing. You have to ask different questions when faced with 96 reaction tubes vs. a round-bottomed flask.

And it looks like the MiniMapper software keeps a log in XML format - obviously more on that after our first trial...

UsefulChem Automation Trial with Mettler Toledo

Kevin Owens and I have been looking into equipment to automate some UsefulChem experiments.

This is something that I feel strongly will become important in Open Science applications, especially as it relates to Open Notebook Science. I think it is one of the paths of least resistance for the automation of the scientific process.

Industry is automated to the gills but it will probably be easier to convince academic practitioners of Open Science to automate their procedures rather than to get industry to open their data. Can you imagine a company allowing crowds to design and analyze experiments run on their machines? That is what we've been proposing and it would be difficult to reconcile that with a business model based on IP protection.

In that NSF proposal, we planned to use ChemSpeed's technology. Kevin and I recently visited ChemSpeed at their Princeton location and we were impressed with the capabilities of their reactors. We're in the process of planning a trial run of the Ugi reaction on their system and we'll post on the progress of that on this UC wiki page. The idea is to couple a digital camera within the robot's workflow to be able to generate results comparable to those manually generated by my students.

ChemSpeed's systems are quite powerful but also expensive (200-400K). In order to take advantage of more funding opportunities, we've also been looking at Mettler-Toledo's MiniMapper/MiniBlock solutions. We're planning this out openly on this wiki page - any feedback is welcome.

I've had a good discussion with Frank Schoenen at the University of Kansas, where they run both systems as part of servicing the NIH Roadmap Program. Based on his feedback I think this trial run should be successful.