Methanol Solubility Prediction Model 4 for Ugi reactions in the literature

Since non-aqueous solubility measurements have not become part of the standard characterization of organic compounds, it is not surprising that all the data we have for Ugi products originate from measurements that we made on our own compounds.

Since methanol is our most common solvent, Andrew Lang has collected the measurements that we have with values from the literature for a range of compounds, including our Ugi products, to generate a web service returning a predicted solubility based on a submitted SMILES string. The model (Model 4) was derived from a Random Forest algorithm, using molecular descriptors supplied by the CDK and VCC.

It would be nice to be able to test the model's ability to predict what will happen if a Ugi reaction is carried out in methanol. Although the actual solubility of Ugi products in the literature is typically not reported, reading the experimental sections in papers can still provide some validation of the model in some cases.

For example, consider the following Ugi products synthesized recently by Lezinska (Tetrahedron 2010)


Note that these images represent the azide group not following the octet rule. It is necessary to represent the structure SMILES without charges because the CDK and VCC web services used by the model do not process charges correctly. Stereochemistry also cannot be used and this can be removed from the SMILES simply by deleting slashes. Thus for the two molecules above the SMILES to be submitted to the prediction web service are:

O=C(NC1CCCCC1)C(Cc2ccc(C)cc2)N(c4ccccc4C(=O)c3ccccc3)C(=O)C(Cc5ccccc5)N=N#N
AND
O=C(NC1CCCCC1)C(C(=O)c2ccccc2)N(Cc3ccc(C)cc3)C(=O)C(C)CCN=N#N

The predicted methanol solubilities are respectively 0.004 M and 0.03 M.

Now if we look at the details in the experimental section, both of these Ugi products were synthesized in methanol at a limiting reactant concentration of about 0.1 M. Even though this is much more dilute than the usual 0.5-2.0 M generally recommended for Ugi reactions (Domling 2000), the products still precipitate and can be filtered off. This is consistent with the predicted solubilities above and the model would have suggested ahead of time that methanol might be a good solvent for isolation of the products by precipitation.

So far these are just anecdotal results but it does illustrate that solubility models can be evaluated without explicit determination of solubility in the literature.

ChemSpider SyntheticPages

I recently mentioned the Reaction Attempts project, which aims to collect organic chemistry experiments - especially those that are "failed", in progress or somehow incomplete.

For reactions where the desired product has been obtained and fully characterized, ChemSpider SyntheticPages also offers a very convenient publication vehicle. As I mentioned previously there is a need for enabling the publication of single experiments, especially when these are unlikely to become part of a traditional article.

We are in the process of submitting suitable reactions from the UsefulChem project to CS|SP. This will require some re-formatting of procedures and characterization data as they currently appear in the lab notebook.

Here is an example of one of our Ugi reactions: SyntheticPage 406 (UCEXP176C)


A nice feature of these pages is the automatic rendering of 2D structures upon hovering on top of chemical names.


Here are a few more reasons to use ChemSpider SyntheticPages:

* ChemSpider SyntheticPages takes you directly to a procedure. When you get a hit - you get a procedure.
* ChemSpider SyntheticPages provides information that may not generally be found elsewhere, such as frequently encountered problems, trouble-shooting tips, the number of times the reaction has been carried out, scale-variation etc.
* ChemSpider SyntheticPages is the only interactive chemistry database. Information is constantly updated and validated by comments from the user community (Peer Review in the Public Domain™).
* ChemSpider SyntheticPages can provide you with the most up-to-date method, we aim for 95% of submissions to be processed within 48 hours of submission.
* ChemSpider SyntheticPages is free of charge.

[Disclaimer: I am a member of the editorial group at CS|SP]

Reaction Attempts Book Edition 1 and UsefulChem Archive

I am pleased to report that Andrew Lang and I have published the first edition of the Reaction Attempts book. It currently contains most of the Ugi reactions from the UsefulChem project and is associated with an April 27, 2010 snapshot archive of the entire UsefulChem project, including NMR spectra, spreadsheets, images and the entire lab notebook from Wikispaces.


At 582 pages the printing cost from LuLu amounts to $26.28. Not meant to replace electronic searches, it should prove to be a handy reference book for the lab to quickly browse through what was attempted for a given reactant, what the outcome was and the researcher involved.

We are hoping to include reaction attempts from other groups in future editions. More details can be found in the preface, reproduced below:

Reaction Attempts First Edition

Data Source: the UsefulChem project

Introduction

Open Notebook Science (ONS) refers to the practice of making the full contents of a laboratory notebook and all associated raw data files available in near real time.[1] This represents an opportunity for everyone to benefit from work in progress in an open research group. However, in order to make use of the information, it must be easily discoverable. A simple strategy to increase discoverability is redundancy over multiple communication platforms.

In another project - the Open Notebook Science Solubility Challenge[2] - we published non-aqueous solubility data in the form of physical and downloadable (PDF) books.[3] Although it is possible to search the solubility database using web query interfaces, exploration of a Google Spreadsheet, an XML feed, etc.[4], having a physical copy in the laboratory has proved to be very convenient in several instances. A similar format for reactions will also be useful.

The UsefulChem Project

UsefulChem started in 2005 as an organic chemistry Open Notebook Science project with a main goal of discovering new anti-malarial agents that can be prepared by simple and cheap syntheses.[5] Most of the reactions on UsefuChem are Ugi reactions, which involve the mixing of an amine, aldehyde, carboxylic acid and isonitrile in a solvent at room temperature generally for a few hours to days.[6] The multicomponent design of the Ugi reaction and the simple reaction conditions make it ideal for exploring large virtual libraries and selecting compounds of interest to make.[7]

Isolation of the Ugi products can be immensely simpler, cheaper and readily scalable if they precipitate in pure form from the reaction mixture. To this end, much of the research in the UsefulChem project focuses on reaction conditions that lead to this outcome.[8] This is in fact the origin of the ONS Solubility Challenge discussed above.[9]

The Reaction Attempts Database

In order to look for patterns in the reaction conditions which led to Ugi product precipitation, the CombiUgiResults Google Spreadsheet was set up.[10] Reactions indexed there can be sorted by precipitation outcome, solvent, reactant, concentration, etc. and links to the laboratory notebook pages can be followed for full details. However, this sheet is designed specifically for Ugi reactions and contains columns specifically for the aldehyde, amine, carboxylic acid and isonitrile.

In order to enable the tracking of other types of reactions, the information in the CombiUgiResults sheet was reformatted into two other sheets: ReactionAttempts[11] (containing reagents and reactants) and RXIDsReactionAttempts[12] (containing reaction conditions and results, such as solvent, concentration of limiting reactant, appearance of a precipitate, yield, etc.). The two sheets are connected via the use of a common ReactionID. This format permits the representation of any type of reaction, with an unlimited number of reactants and products.[13]

By definition, any Open Notebook Science project in a work in progress. The listing of a reaction in this database only means that the researcher attempted or is in the process of attempting it. Whatever the situation, a link to the laboratory notebook page is provided, where the most recent information is available. The philosophy used here is that partial information is always better than no information at all. Thus a researcher investigating the prior use a particular reactant in a Ugi reaction might find the report that a precipitate was obtained in methanol helpful for designing their own reactions, even if the characterization of the precipitate is still pending. At the very least, knowing that a certain researcher has at least attempted a similar reaction is enough information for initiating a discussion, which may lead to valuable insights.

Reaction Attempts on Chemspider

Although SMILES[14] are provided in the spreadsheets, the primary key to identify compounds is the ChemSpider ID (CSID)[15]. This allows us to render molecule images in the book automatically. In the case of the ONS Solubility Challenge book[3], use of the CSID enables a convenient way to calculate various descriptors for displaying values in the book.

In addition, the compounds in the Reaction Attempts database are indexed on ChemSpider as two Data Sources: ReactantsAttemptedReactions and ProductsAttemptedReactions[13]. In this way a substructure search for either reactants or products will identify indexed molecules. Clicking on the Syntheses tab in the ChemSpider record for a selected molecule will then reveal a list of hyperlinks to the relevant laboratory notebook pages.

Organization of the Book

In keeping with the layout of the ONS Solubility Challenge Book, the reactants are listed in alphabetical order. Each entry displays the list of reactions where the reactant was used. This includes a scheme with all reactants and product as well as key metadata: the researcher, reaction type, solvent, limiting reactant concentration, observation of a precipitate, comments and a reference (links to the laboratory notebook page).

In this edition, only Ugi reactions are included. The reaction schemes are laid out in the following order: carboxylic acid, amine, aldehyde and isonitrile. This should allow for easy comparison between schemes within a given record. Reactions where the Ugi product was isolated and characterized are marked with a green check and the percent yield is noted. Since the Ugi products do not have simple common names, they are not included as separate entries. However, all reactions where the synthesis of a specific Ugi product was attempted can be found by looking up the entries for any of the four reactants.

Although this compilation is not exhaustive, it does cover the vast majority of reactions in the UsefulChem project to date. Future editions will include other reactions from UsefulChem and other sources.

Archive

This edition is linked to the UsefulChem data archive (ZIP)[16], (DVD)[17] and interactive hosted archive format[18], ReactionAttempts (XLS)[19] and RXIDsReactionAttempts(XLS)[20] taken on 2010-04-27.

References

1. Open Notebook Science Wikipedia Entry http://en.wikipedia.org/wiki/Open_Notebook_Science
2. Open Notebook Science Solubility Challenge Wiki http://onschallenge.wikispaces.com
3. Bradley, J.-C. First Edition of ONS Solubility Challenge Book UsefulChem Blog (2009)
http://usefulchem.blogspot.com/2009/12/first-edition-of-ons-solubility.html
4. Open Notebook Science Solubility Challenge List of Experiments page http://onschallenge.wikispaces.com/list+of+experiments
5. UsefulChem Wiki http://usefulchem.wikispaces.com
6. Ugi Reaction Wikipedia Entry http://en.wikipedia.org/wiki/Ugi_reaction
7. Dömling, A., & Ugi, I. (2000). Multicomponent Reactions with Isocyanides. Angewandte Chemie International English Edition, 39(18), 3168-3210. http://www3.interscience.wiley.com/journal/73500473/abstract.
8. UsefulChem List of Experiments http://usefulchem.wikispaces.com/All+Reactions
9. Bradley, J.-C. Open Notebook Science Challenge UsefulChem Blog (2008)
http://usefulchem.blogspot.com/2008/09/open-notebook-science-challenge.html
10. CombiUgiResults Google Spreadsheet http://spreadsheets.google.com/ccc?key=plwwufp30hfpUERhse9y5Kw
11. ReactionAttempts Google Spreadsheet
http://spreadsheets.google.com/ccc?key=0Ak1R8T6wt4YQdG9NejNLcDNUMkVBVURGM01TR0NxdXc
12. RXIDsReactionAttempts Google Spreadsheet
http://spreadsheets.google.com/ccc?key=0Ak1R8T6wt4YQdGVENVFMWjdzaGd2REJTTnA4RG5vblE
13. Bradley, J.-C. Reaction Attempts on ChemSpider UsefulChem Blog (2010)
http://usefulchem.blogspot.com/2010/03/reaction-attempts-on-chemspider.html
14. SMILES Wikipedia Entry http://en.wikipedia.org/wiki/Simplified_molecular_input_line_entry_specification
15. ChemSpider Web Site http://www.chemspider.com/
16. UC archive Drexel server (ZIP) http://showme.physics.drexel.edu/usefulchem/archives/usefulchem2010-04-27.zip
17. UC archive on lulu.com (DVD) http://www.lulu.com/product/dvd/usefulchem-archive/10791847
18. UC interactive hosted format http://showme.physics.drexel.edu/usefulchem/archives/usefulchem2010-04-27/All%20Reactions.html
19. Bradley, J.-C.; Lang, A.. Reaction Attempts Reactants and Products. UsefulChem. 2010-04-27.

URL:http://spreadsheets.google.com/pub?key=toMz3Kp3T2EAUDF3MSGCquw&output=xls. Accessed: 2010-04-27.

(Archived by WebCite® at http://www.webcitation.org/5pIsFEbT9)
20. Bradley, J.-C.; Lang, A.. Reaction Attempts RXIDs. UsefulChem. 2010-04-27.

URL:http://spreadsheets.google.com/pub?key=teD5QLZ7shgvDBSNp8DnonQ&output=xls. Accessed: 2010-04-27.

(Archived by WebCite® at http://www.webcitation.org/5pIs2eh62)

Reaction Attempts on ChemSpider

Just as we have done with the Open Notebook Science Solubility Challenge, we are adding more structure to the UsefulChem project.

This is a little bit more difficult because the UC notebook represents mainly chemical reactions, while the ONSC data are simply solubility measurements. Since most of the UC reactions are Ugi reactions, we have been keeping summary data in the CombiUgi Google Spreadsheet, which is completely specialized for this reaction and variations in our reaction conditions. This lets us search or sort by reactant, concentration, solvent, etc. However, we cannot do substructure searching directly using the CombiUgi sheet and we cannot add other types of reactions.

In order to enable substructure searching and add other reactions, Antony Williams has created 2 new data sources in ChemSpider: Attempted Reactions - Reactants and Attempted Reactions - Products. The data represented in the CombiUgi sheet has been restructured into 2 new Google Spreadsheets: RXIDs Reaction Attempts and Reaction Attempts.

Both of these sheets use a common Reaction ID to tie together an unlimited number of reactants and products (Reaction Attempts) and other pertinent reaction conditions (RXIDs Reaction Attempts), such as the concentration of the limiting reagent, the solvent, yield, notes, etc.

Currently only the data in the Reaction Attempts sheet has been imported into ChemSpider. But this alone gives us new functionality: we can perform substructure searches for either reactants or products.

For example lets say we want to search for all reaction attempts using aromatic carboxylic acids. First we simply do a substructure search on ChemSpider drawing benzoic acid and selecting Attempted Reactions - Reactants as the Data Source.


This pulls up 8 compounds that were used as a reactant at least once.


Clicking on one of these hits brings us to the ChemSpider entry. Selecting the Syntheses tab in the Data Sources shows links to the lab notebook pages where this compound was used.


The system is configured to accept reactions with fully characterized products to reactions where products were not isolated or even reactions in progress. I'm not using the term "failed reaction" because the term has no meaning without the context of the objective of the reaction. In our Ugi reactions we are typically looking for the product to precipitate out. By our criteria, reactions where no precipitate was observed after a few days would be classified as "failed". However it may well be that product was formed but did not precipitate. Even when product is obtained, some might consider 30% isolated yields to be failures, while others would not. Context is everything in qualifying success.

But even with a clear definition of success, many reactions are simply neither successful or failures. Reactions in progress fall into that category. The student may have even completed the reaction but not yet analyzed the results. But that doesn't matter so much if the raw monitoring data has been provided.

The general structure of this database means that we can add not only our reactions but those of anybody. Even in cases where someone does not have an Open Notebook, just providing a link to contact information of the researcher could be very useful to start a conversation. In that case the system would function more as a social networking platform - connecting researchers who work on similar molecules.

I don't think people are willing to do extensive write-ups for what they consider to be "failed experiments". However, if all that is requested is the list of reactants and target products that may not be such a burden if it potentially means connecting up with another researcher who can help or even start a new collaboration.

Currently ChemSpider does not take into account the information in the RXIDs Reaction Attempts sheet but we hope to be able to make use of that at some point. That would let us do more sophisticated searches like - search for any reaction attempt where an aromatic carboxylic acid was reacted with an aliphatic amine in methanol.

Andrew Lang has also provided the information of the 2 spreadsheets as XML:
http://showme.physics.drexel.edu/onsc/Services/OData.svc/Reactions/
http://showme.physics.drexel.edu/onsc/Services/OData.svc/ReactionCompounds/
[Note: if viewing on FireFox select View Source to see all the XML]

We will likely use these live feeds for performing more sophisticated queries and we welcome others to use them for any purpose.

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.

CombiUgi virtual library generation via Google Spreadsheet

Andrew Lang has just created a service that lets anyone create a virtual library of Ugi products by entering the SMILES of the starting materials in a Google Spreadsheet.

First copy this template sheet (you must use File -> create a copy - copying and pasting cells will not work). Then publish the Google Spreadsheet under the Share tab.


Next add the key of your new Spreadsheet (as it appears in the URL) to a URL of this form:
http://showme.physics.drexel.edu/onsc/combiugi/combiugi.php?key=tR6lhYF_iqGdmceaAg-WRLg

The resulting page, which could take a long time to load for large libraries, can then be saved as a CSV file. On Firefox this is done by selecting Save As Text File.

If you put a CSV extension in the name you can then open the file directly in Excel:


All the results are in SMILES format and using all the tricks of Excel can be sorted or filtered even by reactant. One could also copy and paste to another Google Spreadsheet to manipulate the dataset.

This service replaces the one Rajarshi Guha had set up a while back at Indiana University. A key difference with this service is that it requires SMILES to be constructed as shown in the template sheet:

• N to the left for amines
• C(=O)O to the right for carboxylic acids
• O=C to the left for aldehydes
• [C-]#[N+] to the left for isocyanides

This requires a little knowledge of SMILES, especially for aromatic rings. I left a few examples with polysubstituted aromatics to show how this is done.

David Bulger's Drexel visit

David Bulger (February 2009 Submeta ONS Challenge winner) from Oral Roberts University just completed a two week visit in my lab at Drexel - thanks to the generous efforts of Andrew Lang. It was truly a pleasure to finally meet him in person and for the students in my group exchange tips and techniques for working in the lab.

David got a lot done in that short time. On his first day he repeated a Ugi reaction (EXP223) known to work well so that he could learn how to do it and carry that knowledge back to ORU. He attempted several other Ugi reactions (EXP226 and EXP229) to add to our knowledge of conditions leading to precipitates. One of the experiments (EXP230) involved using a 96 well plate for rapid screening. Unfortunately, it was difficult to properly seal the wells and solvent evaporation was too problematic. We are always looking for methods to accelerate the execution of experiments so it was certainly worth trying and we learned something from the trial.

David also did several solubility experiments and resolved conclusively previously contradictory solubility measurements for 1-pyrenebutanoic acid (EXP091). Finally, he looked at the accuracy of our NMR technique for measuring solubility using known concentrations of 2-phenylbutanoic acid (EXP102). I'll be posting about this in more detail shortly as part of a post on what we have learned recently about measuring solubility. For more of David's solubility experiments see our experiment list.

David is now in the UK in Cameron Neylon's lab. His current experiments are reported here.

Interactive Visualization of ONS Solubility Data

Rajarshi Guha and Andy Lang have been very busy during the past few weeks developing visualization interfaces for the Open Notebook Science Challenge solubility data.

Information in a database is only as useful as the tools to explore it. We are striving to create interfaces that enable synthetic organic chemists to find actionable information in as intuitive a manner as possible.

To search for specific solubility measurements for a given solute in a given solvent (or to search for all solvents for a given solute), we have been using Rajarshi's handy web browser interface providing drop-down menus of available selections. The query results directly link back to the relevant pages from the laboratory notebook for further analysis. (For details of the coding see Rajarshi's blog)

We now have to ability to look for patterns in the dataset. Solubility measurements can now be plotted on a surface using Andy's service. First select a solvent, 2 molecular descriptors, a solubility cutoff value and the maximum point size from drop-down menus:

Then explore the chemical space.

In this example the solvent is methanol and molecular weight is plotted on the x axis and ALOGP is plotted on the y axis. Up to a maximum defined above, the size of the points relates to the value of the solubility, averaged from all available valid measurements. Measurements that have been judged invalid as marked as DONOTUSE in the SolubilitySum spreadsheet. That way researchers can investigate for themselves the reason for rejection of the data point. As an example, insufficient mixing time has been a cause of invalidation.

As synthetic organic chemists, we are mainly interested in how our reagents and products will behave in a given solvent. The compounds in this chemical space are starting materials for Ugi reactions and are color-coded by functionality. Red points are aldehydes and blue points represent carboxylic acids. We selected 2M as the cutoff point for point shape because it is a convenient concentration to use to mix reagents participating in the Ugi reaction, especially when considering automation. (see JoVE article) With this selection, disks are below 2M and diamonds are above.

Some interesting insights can be gleaned quickly from this plot. There are three low solubility disks among a group of diamonds near the top of the plot. The diamonds in this region represent mainly highly soluble aromatic aldehydes. By positioning the mouse over each point we can discover the details of each compound and its solubility. As shown, 2 of the disks are aromatic nitroaldehydes.

We may infer from this that methanol may not be a good solvent choice for nitroaldehydes in general. At the very least we can formulate the hypothesis and follow it up with additional measurements or re-investigate outliers. Such a pattern is difficult to observe when measurements are stuck in tables - or worse - only in lab notebook pages.

One of the limitations of a 2D plot like this is overlap of points. We can control this to some extent by making the points smaller but that doesn't eliminate the problem in all cases. One trick that we can use is introduction of a third molecular descriptor to separate points in 3D space.

Andy has done this recently in Second Life - here is a picture we took yesterday with our friend Viv on Drexel island (SLURL). The balls we are sitting on are the solubility points. The larger the ball the greater the solubility. Clicking on the balls opens a browser window to the measurements in the laboratory notebook.

Our eventual goal is to provide robust quantitative models to predict non-aqueous solubility. To see where we stand on that front see Rajarshi's recent report.

In the meantime I think we can continue to provide intuitive tools to get non-theoretical organic chemists to play with the visualization of solubility. Almost all organic reactions are performed in non-aqueous solvents so solvent selection is a very important part of the process of doing chemistry. This is especially important if one wants to engineer non-chromatographic product isolation.

NSF proposal: Crowdsourcing Chemistry and Modeling using Open Notebook Science

On December 8, 2008 I submitted the pre-proposal "Crowdsourcing Chemistry and Modeling using Open Notebook Science" with Rajarshi Guha and Antony Williams to the NSF CDI program.

Last year we submitted to the same initiative and the reviewer comments were positive for the most part. The main criticism was the lack of a more fully developed computational component. I think we've addressed that this year by including Rajarshi and his plans to carry out modeling of the non-aqueous solubility data and Ugi reaction optimization.

We also have the ONS Challenge in place and the sponsorship by Submeta, Nature and Sigma-Aldrich should help.

I posted the PDF version of the proposal on Scribd, linked to it from Noam Harel's SCIEnCE wiki and put up a text version on the ONSC wiki. In some ways proposals can be more important than papers to connect up collaborators and gain an appreciation of where science is headed. Ironically the only people to see proposals (the reviewers) are typically a research group's closest competitors. So making them public makes sense. It could also help funding agencies connect up with researchers.

I think it would be helpful to have a Web2.0 database of research proposals. The SCIEnCE project aims to do this but doesn't currently have a structured interface. I created a "Research Proposal" group on Scribd that is open for anyone to drop in proposals. That gives us the standard Web2.0 functionalities like commenting, visitor count, favorites, etc. One of the most convenient features of this strategy is that it provides an RSS feed for new submissions. I've added this feed to my FriendFeed account.

From ONS to Peer Review: our JoVE Article is Published

Our article "Optimization of the Ugi Reaction Using Parallel Synthesis and Automated Liquid Handling" is now published on the Journal of Visualized Experiments (JoVE). I am very pleased with this because it showcases some interesting approaches to communicate science that were not possible not so long ago.

First, and foremost, this demonstrates that lab notebook pages and blog posts can be used to support claims made in a peer reviewed article. In a way this isn't drastically new since it has been possible for a while now to cite web pages in the peer reviewed literature. The key question is whether the reference is appropriate, regardless of its format. When providing a reference for a melting point or spectrum, nothing is more relevant that the lab notebook page where the specific batch of product was obtained and characterized.

Second, we have demonstrated that it is possible carry out research under Open Notebook Science conditions, write an article openly on a wiki, post it on a pre-print server (like Nature Precedings) and finally publish it in an peer reviewed journal. No, this won't work with every publisher. But if communicating science openly (beyond the confines of the regular Open Access model) is important to you, there are options out there that don't take anything away from the traditional system of academic validation.

Third, this is a good example of the use of video to enhance the communication of a protocol for a chemical reaction. But this is not a shortcut by any means. The process of writing a script and preparing for the shoot was very time-consuming because we were describing a whole workflow. When using video as raw data to record details of a specific experiment, it can actually save time that would otherwise be required to describe using text.

Finally, JoVE is an example of an Open Access journal with some Web2.0 capabilities, like the ability to leave comments and label them as agreeing or disagreeing with the authors. The final article can now also serve as a location for continuing the scientific conversation.

Webinar on Ugi Reaction Optimization Available

The webinar I gave for Mettler-Toledo on Sept 23, 2008 is now available here as a Flash presentation. It is 19 minutes and covers the Optimization of the Ugi reaction using parallel synthesis and automated liquid handling. The related paper is currently available from Nature Precedings. (authors: Jean-Claude Bradley, Khalid Mirza, Kevin Owens, Tom Osborne & Antony Williams)

Thanks to Andrew Lang for the slide with the 3D plot showing the reaction yield space.

This is my first time using Camtasia 5 - it lets you zoom into areas of the screen that are under discussion. I think that is pretty handy for screencasts involving web pages, where there can be a lot of small text.

Mettler-Toledo Webinar on Ugi Reaction

I am presenting a webinar courtesy of Mettler-Toledo tomorrow - Optimization of a Ugi Reaction Using MiniBlock® - presented by Dr. Jean-Claude Bradley of Drexel University taking place tomorrow, Tuesday, September 23 at 9am and 2pm US EDT. If you have not already registered, click here. (See related Nature Precedings report)

The Ugi reaction involves the mixing of four components: an aldehyde, an amine, a carboxylic acid, and an isonitrile. The Ugi reaction is a convenient reaction to generate diverse libraries and has been used in the past to generate antimalarial compounds. The particular Ugi reaction that we consider involves the reaction of furfurylamine, benzaldehyde, boc-glycine and t-butylisonitrile. This reaction produces a Ugi product as a precipitate when run at 0.5M concentration in methanol. We will describe the optimization of this reaction by varying the solvent, concentration, and excess of some reagents.

This webinar will last for 30 minutes and at the end there will be an interactive Q&A session providing you with the opportunity to ask questions relevant to your particular application.

Register for the webinar on Tuesday, September 23.

Solubility and 96 well Ugi plates

Following up on the objectives I outlined last week concerning making progress on our ability to model solubility and Ugi product precipitation, I have created a spreadsheet for solubility and one for 96 well plates for quick screening of Ugi product precipitation.

Both spreadsheets are open for crowdsourcing. Anyone requesting a solubility or Ugi reaction must include their name and rationale. We'll prioritize the runs based on chemical availability and fit with ongoing projects.

The solubility runs will be carried out by evaporating 1 ml of a saturated solution of the given compound and solvent using the SpeedVac in the Owens lab.

Unless otherwise stated the Ugi screening runs will consist of 50 microliters from 2 M methanol solutions of the specified amine, aldehyde, acid and isonitrile. The 96 well plates we are using hold about 300 microliters and have a flat transparent bottom ideal for scanning or photography. Precipitate detection will take place 16 hours after mixing. As I discussed previously, this standardization should facilitate modeling and speed up testing.

I have briefed our new undergraduate researchers Aneta and Cedric last week and they will start with the solubility runs.

The BCCE, research discussions and good friends

I've just returned from the Biennial Conference on Chemical Education 2008.

I wasn't able to record my first talk on Communicating Results from Undergraduate Research because my computer crashed. However, I repeated many of the same concepts in my second talk on Open Notebook Science and Cheminformatics.

It was very fortunate that the BCCE was held in Bloomington at Indiana University this year because it was a great opportunity for me to meet up with Rajarshi Guha, David Wild and Amar Flood.

Amar and I discussed Open Notebook Science with his lab people and it may make sense to do this for some of their projects. We set up a wiki to explore that possibility.

Rajarshi and I discussed at length our collaboration on the prediction of Ugi precipitates and docking against falcipain-2. It is certainly easier to pour over the relevant papers and online documents when face to face.

These are the outcomes:

1) We're going to separate the problem of predicting the solubility of Ugi products from the problem of generating the best enzyme inhibitors. Our initial plan was to try to make the top ranked Ugi products for a given enzyme and hope that we generate enough precipitates from those results for Rajarshi to model. We're just not getting enough positive results that way to generate a reliable model in a reasonable amount of time. To stack the deck in our favor we're going to start with a well behaved Ugi reaction (EXP099) and modify the reagents one at a time.

2) We're going to separate the performance of the Ugi reaction from the solubility of Ugi products in various solvents. Once we have Ugi products in hand in pure form from a reaction in methanol we will simply measure their solubility in other solvents, starting with ethanol, acetonitrile, THF and toluene. Low solubility will not guarantee that the Ugi reaction will proceed smoothly to produce a precipitate when carried out in a given solvent but it will certainly be a great starting point.

3) We're going to actually measure the solubility instead of just noting soluble or insoluble, as we have been doing in our Ugi master table. This will make it much easier for Rajarshi to come up with a robust model. Kevin Owens is already set up with a SpeedVac in his lab and that will help immensely. Rajarshi made the point that models predicting solubility in non-aqueous systems are needed and could be quite helpful to the chemistry community. He will be using the crystallographic data of our precipitates in his calculations. More on this later...

4) We're going to require the reactions to be easily amenable to automation, even if we can carry them out manually sometimes. For example, some of the reactions had starting materials that were not very soluble in methanol by themselves, even though they went into solution when combined with the other starting materials and then generated a product. This is interesting behavior but extremely inconvenient for automation because we can't make up stock solutions of reagents at 2M concentration in methanol.

5) We're going to require the reactions to be fast. Some reactions required several days to complete. These will now be considered to be negative for precipitation at the 16 hour mark.

JoVE shoot at Drexel

On Saturday July 12, 2008, in my lab at Drexel, we recorded our JoVE shoot for the use of Mettler-Toledo's MiniBlock and automated liquid handler for optimizing a Ugi reaction.

It took about 6 hours and I was very impressed with the professionalism of Ian, the camera man JoVE sent us. The preparation time was much more than that and I appreciate JoVE's flexibility in compressing their regular operating timeline because of our limited time with the equipment.

One of the main challenges was finding an appropriate level of detail and selecting illustrative video sequences to describe the protocol. After working with Tom, Khalid and Aaron from JoVE I think the resulting script should be helpful for people wishing to repeat the experiment. Khalid and I recorded the intro and conclusion and the rest of the script will be recorded by JoVE.

The good news is that the shoot went well I think. Multiple takes were recorded for most sequences so it should be possible to piece together a decent video. However, we discovered flaws in the way we have been programming the MiniMapper, which would explain the strange and inconsistent results we obtained at first.

Thanks to Tom Osborne digging through the log files of our runs to identify the problems, I think we have a liquid handling protocol that is correct now. The first experiment using it (EXP199) is showing reasonable results so far, with the higher concentrations 0.2M and 0.4M and methanol or methanol/ethanol methanol/acetonitrile mixtures showing the higher yields. We'll see if we can get good reproducibility in next few runs. Once that is done we can wrap up the JoVE paper.

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.

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...

NMR prediction on ChemSpider

As Tony recently mentioned, there is a new button on ChemSpider to predict H NMR spectra based on the nmrdb.org web service:


To give it a spin I am posting the experimental spectrum of Ugi product UC-150D underneath the predicted one.


This is going to be extremely helpful and yet another reason for using ChemSpider in active chemistry research. However, this tool does not replace the need for understanding how to interpret NMR spectra.

First, two of the predicted peaks - the phenanthrene H at 8.5 ppm and the benzylic H at 5.7 ppm - are off by almost half a ppm. Second, the algorithm does not take into account the diastereotopic nature of the methylene group centered at 4.8 ppm. This is predicted to be a singlet but appears, as expected, as a pair of doublets.

With this new tool there is a danger that students might think that they don't need to learn the finer details of NMR analysis since the predicted spectrum just pops up so conveniently. I hope people will report on what they find to be most and least reliable as they work on real problems.

The beauty of ChemSpider is that both the theoretical and experimental spectra can be stored in the same record. Yet another reason to continue to routinely upload our spectra.

Tag: InChIKey: PBZQTKRWYXTXIS-WLRTZDKTBU

Not a Ugi Product

As I mentioned previously, one of the objectives of our research is to determine the conditions required for precipitation of pure Ugi products. Until recently, every precipitate we obtained could be characterized as the expected product.

It looks like the situation is not so simple.

For example consider Khalid's attempt (EXP171) to make Ugi product 171 H:

A nice precipitate was obtained...



But it does not correspond to the expected product. For one thing the tosyl group is missing - no non-exchangeable protons past 7.0 ppm. It clearly has the 3,5-dimethoxybenzaldehyde and possibly the methylamine and 2,4,6-trihydroxybenzoic acid components. It is insoluble in all common solvents except for DMSO. Although I'm not completely satisfied with the integration of the H NMR, the MS seems to match an iminium salt:


If this is the case it may be because of the significantly increased acidity of ortho-hydroxybenzoic acids. 2,6-dihydroxybenzoic acid has a pKa of about 1.5 (Papadopoulos 1991), compared with benzoic acid's 4.2 value.

The problem may be with the isonitrile component TOSMIC. However, according to Chris Hulme, it should participate in Ugi reactions, even if it gives lower yields.

We'll just have to do more examples and see if a pattern emerges.

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.