Marshall Moritz is July09 Submeta ONS Award Winner

Marshall Moritz, a chemistry and math student at Syracuse University, working under the supervision of Jean-Claude Bradley at Drexel University over the summer, is the July 2009 Submeta Open Notebook Science Challenge Award winner. He wins a cash prize from Submeta.

Marshall started out using NMR to measure solubility and recently has made some important contributions to the Challenge by using the sequential precipitation technique to obtain solubilities in different solvent mixtures at various temperatures. See his experiments here:
http://onschallenge.wikispaces.com/list+of+experiments

Three more Submeta ONS Awards will be made during 2009. Submissions from students in the US and the UK are still welcome.
For more information see:
http://onschallenge.wikispaces.com
http://onschallenge.wikispaces.com/submetaawards08

Handling reactives in the solubility database

The discovery that aromatic aldehydes bearing electron withdrawing groups react with alcohols has forced us to create a new category in the ONS Challenge SolubilitySum spreadsheet: solute reacts with solvent. There is now a column on the far right to flag these.

Since there is no meaningful number for these mixtures we are assigning the value of -0.1M in the solubility column of the SolSum sheet. That has the advantage that it will not break any web services currently querying the sheet. We can also put an explanation in the notes column for a reason, such as "forms hemiacetal".

One of the benefits of this approach is that all solutes reacting with solvents can be queried using Rajarshi's web query setting the solubility range from -1 to -0.01 M.

Solubility surfaces in 3D

After a little bump in the road with attempting to measure the solubility of 4-nitrobenzaldehyde in methanol, Marshall Moritz extended the study (ONSC-EXP111) to chloroform and acetonitrile, where no hemiacetal can form. The sequential precipitation method seems to work quite well with a new thermostated bath that lets us go down to almost -30C.

The values in pure acetonitrile and chloroform were consistent with those obtained from Maccarone, E.; Perrini G. Gazetta Chimica Italiana. 1982, 112, p. 447. (private access). But Marshall went further and measured 9 points with mixed solvents and different concentrations. The result is this saddle shaped 3D surface plot.


I think the potential for extending the ONS Challenge to cover the full multi-dimensional space of mixtures of about 10 common solvents and temperature is very exciting. It would be foolish to think that we can map in extreme detail such large surfaces. However, I'll bet we can come up with some useful estimates of what the surface looks like in many areas of the space.

The long rage plan for this approach would involve coming up with at least an empirical model based on molecular descriptors of the solvents and solutes. This would help predict the space for completely new combinations.

Being able to predict the solubility of all starting materials and products would enable organic chemists to rationally select solvent systems and temperatures for their reactions maximizing product yield from simple precipitation. This is something that we are investigating for the Ugi reaction and I'll report on this as the data come in.

NMR integration progress for solubility measurements

In a previous post I reported about issues with using H NMR integrations for quantitative assessment of solute concentration to determine solubility. Using default parameters, a study by David Bulger revealed that integration of the methyl group on 2-phenylbutanoic acid lead to only 8.4% average error while the methine H gave an average of 26% under-integration.(ONSC-EXP102)

We have tried to select methyl or methylene groups whenever possible but obviously this won't work for many compounds, especially our series of aromatic aldehydes and carboxylic acids.

Khalid Mirza has just done a study using longer relaxation times and the results appear very promising (ONSC-EXP103). For 4-pyrenebutanoic acid using default parameters the integration of the aromatic vs. methylene hydrogens was off by 9-18% while extending the relaxation time (d1=50s) reduced the error to less than 1.2%.

Furthermore, Marshall Moritz used the new settings in a measurement of a known concentration of 4-nitrobenzaldehyde in acetonitrile and came within 3.2% using an aromatic hydrogen (ONSC-EXP111). Use of the aldehyde hydrogen was not as good, although much better than what we normally see with the default settings.

So I am cautiously optimistic that we are likely to get better data going forward.

Complications with solubility measurements of aldehydes in alcohols

Last week I mentioned that we had started measuring temperature solubility curves. Since 4-nitrobenzaldehyde in methanol also got flagged by our Outlier Bot we picked it as the next one to process. This one has bothered me for some time because our values have systematically come out to about half of those published by Maccarone, E.; Perrini G. Gazetta Chimica Italiana. 1982, 112, p. 447. (private access) In this paper temperature curves for the solubilities were also provided and so I thought this would be a great opportunity to validate our sequential precipitation method.

This experiment (ONSC-EXP110) turned out to be very puzzling. On the day that we tried to make solutions we could not get as much material to go in as expected from the paper, even by sonicating at 40C. The next day some of these samples went into solution and then we could not get precipitation to occur for some samples even at 0C.

However, an examination of the NMRs of the samples with lowest concentration revealed the problem. It turns out that they were about 50% converted to the methanol hemiacetal. The NMR clearly shows the coupling between the benzylic and hydroxyl protons at 5.6 and 6.8 ppm, each integrating for 1H each compared with 2H for each of the new peaks in the aromatic region.



It turns out that the hemiacetal was present in all our previous measurements for 4-nitrobenzaldehyde in methanol but we didn't spot it. Furthermore we found significant hemiacetal formation for 2-chloro-5-nitrobenzaldehyde, 2,6-dichlorobenzadehyde and 4-chlorobenzaldehyde but only trace on none for others like veratraldehyde (ONSC-EXP033 has several of these NMRs). So it appears that if the aromatic ring bears sufficiently electron withdrawing groups hemiacetal formation is facilitated without the presence of a catalyst. This makes sense from a mechanistic standpoint.

Since the hemiacetal forms so easily in these cases I wonder why there was no mention made of it in the Maccarone paper. They assayed concentration using GLC - perhaps the hemiacetal decomposed quickly under those conditions? (PNBA is para-nitrobenzadlehyde):

From a practical standpoint is it even possible to measure the solubility of 4-nitrobenzaldehyde in alcohols? If you try to make up a solution for a reaction the concentration will be much less than calculated. With an excess of alcoholic solvent it seems unlikely that a reaction consuming the aldehyde will shift the equilibrium enough to make the formation of the hemiacetal inconsequential.

I think that for the Ugi reaction the implication of this is that alcoholic solvents should not be used for aldehydes bearing electron withdrawing groups.

On the Advisory Board of Chemical and Engineering News

I have accepted an invitation to join the Advisory Board of Chemical and Engineering News. The three year appointment involves yearly meetings in Washington, D.C. where important trends in chemistry and the focus of the magazine are discussed.

Many thanks to Carmen Drahl for putting my name forward!

BrightTALK on ONS and Drug Discovery

I will be presenting at the BrightTALK seminar series on July 23, 2009 at noon ET. The virtual presentation will be on "Open Notebook Science for Collaborative Drug Discovery".

Temperature solubility curves using sequential precipitation

We were going to wait for a while to tackle temperature related solubility because it wasn't clear that our NMR technique was applicable. The main problem is that separating out the supernatant at a given temperature can be tricky for both filtration and centrifugation with our available equipment.

However, while discussing the issue with Marshall last week it occurred to me that we might be able to get the data by sequential crystallization. The idea is to prepare several solutions at known concentrations at a high temperature then let the bath cool down and note the temperature when precipitates are first observed. We can then intrapolate to report the solubility at room temperature if necessary.

Khalid and I made an attempt on Friday for pyrene in acetonitrile (EXP109) and obtained a value of 0.16 M at 22C, about twice the value found by Marshall in EXP108 using NMR. Part of the discrepancy is probably related to longer relaxation times of aromatic protons but we have to keep in mind that NMR is not particularly precise at such low concentrations. Hopefully we will soon figure out how to run our NMR experiments to allow full relaxation of all protons and address this issue more conclusively.

Crowdsourcing solubility requests from bots and people

Now that we have a reasonably routine way of measuring non-aqueous solubility and students trained to do the measurements, we can think about adding some structure to the workflow. By using an open Google Spreadsheet to list the next solute and solvent to measure we can easily crowdsource the requests. This is the dosol sheet and students are instructed to check it before planning their experiments for the day.

Requested experiments come from the following sources:

1) OUTLIER BOT: Andrew Lang has created a neat service that reports measurements exceeding a provided standard deviation to mean ratio (plug into the URL) and a Grubbs outlier threshold. Currently, the "bot" does not automatically write to the dosol sheet but eventually I see that it would make sense to complete that integration. On a daily basis I run it and process the flagged entries in the following ways:
a) If I investigate the corresponding lab notebook pages and find an error in the calculations I simply fix it.
b) If I find that one or more of the measurements are obviously in error I mark the entries as DONOTUSE in the SolSum sheet. This is often a low value that was obtained early on in the project before we appreciated how much mixing is required for some solutes.
c) If I cannot determine why there is a discrepancy I place a request on the dosol sheet. (note: solubilities that are very low (<0.1 M) may have relatively high standard deviation to mean ratios because the techniques we use are not precise at those solubilities and remeasuring won't help)

2) Internal Requests: If someone from within our group is planning a Ugi reaction and there is a missing solubility measurement for one of the reagents or Ugi product, this is a convenient way to request the missing information to make a solvent choice for the reaction.

3) External Requests: When people think about crowdsourcing, usually the first thing that comes to mind is how others can help solve their problem. But in addition to asking what the science world can do for you why not ask what you can do for the science community? We have done so last week and received 3 requests (via a form created by Andy). One for the solubility of iodine in 1,1,2-trichloroethane, one for the solubility of nitric acid in water and another for pyrene in acetonitrile.

For the first request, iodine has no hydrogens so we can't use our standard NMR technique to do it so I set the priority of that request lower. For nitric acid - it is well known that it is miscible in water so we won't be doing that experiment. We also want to focus on non-aqueous solubilities. However the third request was a good fit and Marshall Moritz from our lab processed it right away - he found a value on 0.08M for pyrene in acetonitrile at room temperature (EXP108).

Hadas Joseph from the Agricultural Volcani Center in Israel made the third request. He is a masters student investigating the degradation of pyrene in soil and needs the measurements for extraction experiments. The contacts we make via this route might turn into more involved collaborations or just end up being interesting people to interact with. Either way it benefits science.

4) Implicit requests by keyword searches: We know from our Sitemeter and Google Analytics the keywords that people use to find our site. Most of the time they find the solvent and solute combination that they are looking for but occasionally a combination arises that we have not yet tried. In fact we set up this page with all of the compounds and solvents in my lab to catch new combinations that we could run. This is how the request for phthalic acid in chloroform found its way on the dosol sheet. If someone or something searched for it there is a need for it to exist.

Ultimately, whether entered by human or machine agency, the requests on the dosol list are simply that - requests. It is still left to me to assign the priority in a logical way, allocating resources in proportion to their importance in the portfolio of projects that we are pursuing. One of those projects involves listening to what the global chemistry community is asking for and betting that it will be useful to answer.

Recent insights about solubility measurements

Over the past several months we have learned a lot more about measuring non-aqueous solubilities. (see experiment list) Here is a summary:

1) Sonication: It can be really difficult to reach saturation for some compounds. Since we started the ONS Challenge project in the fall of last year students have used all kinds of methods to mix the solvent and solute. For a while we required that solid remain during 10 minutes of vortexing. However, this proved problematic for doing lots of samples in parallel and required the researcher to stand there holding the vials on the vortexer.

So to be able to leave samples mixing unattended we started using a sonicator. This certainly seems to be a major improvement over vortexing. But, as an unintended benefit, sonication also caused the temperature to rise. Upon cooling to room temperature, additional solid is often observed to come out of solution - the only sure guarantee that saturation has been reached. Our current protocol is to continue to add solute until 30 minutes of sonication leaves solid in the vials. Temperature of the bath is also taken before and after to ensure reproducibility.

2) Screw Cap Vials: One of the problems with sonication and increasing temperature is that standard one dram vials with caps that snap in often pop out. Using half-dram vials with screw caps completely solved that problem.

3) Filtration, centrifugation and decantation: Coming up with a common protocol to separate the supernatant after saturation is reached is not as straightforward as it might seem. The problem is that saturated solutions can behave quite differently. The easiest behavior to deal with is when the solute just settles on the bottom and simple decantation can be used. This typically happens for low solubility cases where the solute is much more dense than the solvent. In other situations a suspension forms that does not settle quickly. Centrifugation for a few minutes often resolves that issue and then the supernatant can be decanted. However, there are more difficult suspensions that do not settled after centrifugation. The worst of these actually form a gel. We have found that filtering through as Pasteur pipette packed with a small piece of cotton usually does the trick. The gel or suspension is transferred into the pipette and a bulb is carefully squeezed to try to get at least a drop of supernatant out. Even getting a single drop can be challenging sometimes so it is fortunate that our NMR method does not require accurate volume measurements.

4) Evaporation of supernatant: Sometimes we observe higher solubilities than the known saturation values. This was puzzling because looking at the NMRs it was clear that the ratios of the solute to solvent were real. We traced back this problem to the way the supernatant is handled. When the drop is introduced at the top of the NMR tube it rolls down and a significant amount of solvent can evaporate. When the deuterated solvent is then added the ratio of solute to solvent will appear to be much higher than it was in the saturated solution. This is especially problematic for volatile solvents like THF. A similar effect can be caused by waiting too long to take the NMR as solvent does evaporate slowly even with a cap on. The solution to this problem is to transfer the drop of saturated solution directily into a vial containing the deuterated solvent and taking the NMR immediately.

5) Deuterated solvent considerations: We have also had problems with solutes precipitating out when diluted into the deuterated solvent. Polyphenols in DMSO or THF tend to do this when diluted in CDCl3. In this case diluting in DMSO-d6 resolves the issue. If a solvent other than DMSO is used non-deuterated DMSO can be added to DMSO-d6 to conserve deuterated solvent. Its only purpose is to enable locking during NMR acquisition.

6) Additivities of volumes and density predictions: There are two assumptions made in the way we measure solubility - that volumes are additive and that the predicted densities (via ChemSpider) of solid solutes are accurate. If one or both of these assumptions is a dominant contributor of error, we would expect the maximum deviation to occur at higher concentration. To investigate this issue (EXP102) David Bulger made up known concentrations of 2-phenylbutanoic acid and measured the SAMS solubility using the integration of the terminal methyl and the methine proton. Then the error was plotted against concentration.

It turns out that the error does not increase with increasing concentration suggesting that - at least in this system - those two assumptions hold up to 3M.



However there was a marked difference in the error of the methyl (8.4% average) and the methine H (26% average). Clearly the methine proton is systematically under-integrating, a feature of a longer relaxation time. The solution to this in general would be allow sufficiently long relaxation times during NMR acquisitions and we are looking into this.

Still, lets put these results into context. Is a 26% error that bad? Well it depends on the application. The purpose of this project is to give chemists guidelines in choosing solvents for carrying out their reactions. Whether the solubility is 1M or 1.26M is not going to be of much concern to plan a reaction at 0.5 M and rules out reactions at 1.5M.

Also note that very small temperature changes can have very large effects on solubility. For example if we look at the solubility of 4-nitrobenzaldehyde in various solvents between 26C and 19C we find differences of 45% in acetonitrile, 34% in benzene, 59% in carbon tetrachloride, 42% in methylene chloride and 36% in toluene. This temperature range is within the variation of what could be considered "room temperature" in a lab (at least the ones I have worked in).

Sometimes temperatures are reported in solubility studies but often they are not. For example, the solubility of aspirin is reported as 1:5 in ethanol in this book. No exact temperature is given and this is not a very precise measurement. But there is enough information there to plan a reaction or to gain an appreciation for roughly how much solvent to use for a recrystallization.

We will never control for all parameters. For example, even if we have an exact measure of temperature (and recently we have been leaving vials equilibrate in 23C water baths), we don't degass solvents or work under rigorously anhydrous conditions.

The key question to consider: Is it more useful to make our results available immediately and improve them over time as we learn - or is it more helpful to keep them closed until an arbitrary standard has been reached?

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.

Matthew Federici is June09 Submeta ONS Award Winner

Matthew Federici, a mechanical engineering student working under the supervision of Jean-Claude Bradley at Drexel University, is the June 2009 Submeta Open Notebook Science Challenge Award winner. He wins a cash prize from Submeta.

Matt has applied an NMR technique to measure solubility. See his experiments here:
http://onschallenge.wikispaces.com/list+of+experiments

Four more Submeta ONS Awards will be made during 2009. Submissions from students in the US and the UK are still welcome.
For more information see:
http://onschallenge.wikispaces.com
http://onschallenge.wikispaces.com/submetaawards08

ONS talk at AI conference in July 2009

I've been invited to talk at the IJCAI'09 Workshop on Abductive & Inductive Knowledge Development in Pasadena on July 12, 2009. This will be a great opportunity to focus what might become possible on the machine side of Open Notebook Science.

Although Ross King (of Robot Scientist fame) won't be there in person, his collaborator Oliver Ray will be giving a talk on their project. That should be quite interesting.

My abstract:

The Role of Openness in Scientific Automation: a case for Open Notebook Science

The use of Open Notebook Science to collect and make publicly available non-aqueous solubility measurements and the synthesis of anti-malarial agents will be described. ONS involves the real time sharing of all experiments and associated raw data by a community of collaborators who are geographically distributed and may have never communicated using channels other than these shared projects. Monthly cash prizes are awarded to participating students by means of the ONS Challenge Submeta Awards for solubility measurements. The laboratory notebook pages are recorded on a public wiki and the solubility measurements, including relevant calculations, are stored in public Google Spreadsheets. A combination of ChemSpider, the GoogleDoc visualization API and web services is used to enable flexible searching and display of desired subsets of the data.

The use of such a distributed and open platform with virtually zero read/write costs for the communication of science creates new opportunities for rapid collaboration. By using a redundant information dissemination system, channels that are more human friendly can be integrated with those that are more geared to machine readability. For example a publicly editable Google Spreadsheet tied to the operation of a robotic liquid handling system opens up the possibility of integrating crowdsourced intelligence with human workflows. In another example, web services called from within a publicly editable Google Spreadsheet to perform calculations on NMR spectra can be integrated readily with manually executed steps to accelerate progress and minimize the possibility of errors.

The advantages and disadvantages of ONS and related bottom-up Open Science strategies will be discussed. The key concerns revolve around intellectual property, trust, reference-ability, publication in traditional academic vehicles and other implications for collaborations.

Two new ONS Challenge Judges: Andrew Lang and Troy Milliken

Bill Hooker and I have been contacting the chemistry departments in the US to recruit new students to the Open Notebook Science Challenge. As a result, I have the pleasure of reporting that today we have a new judge: Troy Milliken from Jackson State University. Troy is a polymer chemist and will look out for some promising students to supervise to contribute to our solubility measurements.

Andrew Lang from Oral Roberts University also agreed to participate as a judge this month. As a mathematician and creator of many of our web services to calculate and display solubility measurements, Andy is in a unique position to provide valuable feedback to our students.

This brings our total judge count to 7.

Baseline correction for automated integration of NMR JCAMP-DX files

We were initially getting a surprisingly large solubility measurement for one of our solutes (spectrum from ONSC-EXP077). After investigating, it was clear that the discrepancy was originating from a peak with a sloping baseline:


The web service was integrating all of the area beneath the peak and the raised baseline. After discussing the situation with Andrew Lang, he modified his code to exclude the area beneath a linearly sloping baseline. Andy's code is Open Source and made available here, including detailed instructions for anyone wishing to implement it themselves. This modified web service is included in the most recent Google Spreadsheet template for semi-automated measurement of solubility using NMR.

The progress of science is a clumsy walk toward a non-attainable ideal of full understanding and control. With every experiment we have to re-question what think we know as variables change. This is why I am so passionate about Open Notebook Science and having all stakeholders interact at the level of the individual experiment. We caught this issue early and we were able to deal with it because our computational collaborator was engaged in details with the chemists and responsive.

Leaders and Pushers in Open Science projects

Fred Zimny just posted an interesting piece on open scientific collaborations: Your (r)evolution will be digitized: online tools for radical collaboration — DMM

The article tries to give a balanced view of radical sharing and our Open Notebook Science projects (ONSchallenge and UsefulChem) get a mention.

Some good discussions about what it takes to have an open collaboration succeed have emerged from it. Deepak Singh has posted about the requirement for a benevolent dictator. There is also a healthy discussion on FriendFeed where Andrew Lang argues for an organizer.

I think that open projects function very much like any other projects, with the advantage of it being easier for people to join in and make use of the results.

People often mention leadership as the key ingredient to making projects work. Leadership is associated with that nebulous concept of vision, a type of flexible long range planning that probably does work best when coming from a single individual.

Leaders with a clear vision are known for giving inspiring speeches and presentations. But vision by itself does not get things done. For that you need pushers - people who relentlessly push themselves and others to execute.

In the book "The Dip", Seth Godin explores the value of strategic perseverance and quitting. In anything worth doing there is a period after initial enthusiasm and before one can see the light at the end of the tunnel where most people quit - this is the dip. Godin argues that the key to being successful is to being able to tell the difference between a true dip and a pit leading nowhere. Winners strategically quit the dead ends and persevere through the dips. That is exactly what pushers do.

People often think that successful leaders attract followers - people who are subservient. In my experience successful projects result from a collaboration of colleagues who share common values. Within the group there may be individuals with less experience who can best contribute by trusting those with more experience and making a firm commitment to learn quickly so that they can initiate contributions that count.

Of course leaders have to be pushers themselves. But since people have a limited ability to maintain simultaneous goals with equal urgency, it is helpful for collaborating colleagues to act as pushers in a complementary fashion.

To give a few concrete example of this, consider our Open Notebook Science projects.

Andrew Lang has been a close collaborator for a long time and has written code that enables us to visualize our solubility results (with Rajarshi Guha) and process NMR files automatically. The project would be missing key components without Andy pushing to make things happen. But Andy has also initiated other high impact actions that are unrelated to writing code: our ONS Wikipedia entry, recruiting David Bulger at ORU to do solubility measurements and adding our measurements to common chemicals in Wikipedia - which has ended being a popular portal to our data.

Bill Hooker, in addition to writing in depth about Open Science, has recently stepped up to help with emailing all of the chemistry departments in the US to get some more students to participate in the ONS Challenge. Shirley Wu volunteered to assist Andy in making ONS logos. Brent Friesen included the solubility challenge as part of his sophomore organic chemistry lab at Dominican University.

Cameron Neylon has done a tremendous amount - recently he pushed to get a group of us to publish a chapter in the upcoming O'Reilly Media book Beautiful Data. Organizing my trip to the UK last fall was another major accomplishment that he made happen. Cameron speaks extensively about Open Notebook Science and although there is a significant overlap in our objectives, he has a clear vision about what needs to happen that focuses on slightly different - and complementary - priorities.

There are many other people and examples that I could have used but I think those highlight the point I am trying to make about open collaborations. Pushers make things happen without being asked and that keeps projects alive.

My most pressing objectives often involve making sure key lab experiments get done and results processed into a usable format, including publications. Sometimes my collaborators need to push me about other issues and I am generally appreciative of that. It is when you have people that don't share your values pushing you that conflict arises.

As I mentioned previously, the point of open collaborations is the shared experience with others with similar values. At the end of the day it is their opinion that matters most.

Streamlining automated solubility measurements with NMR JCAMP-DX files

Two months ago I reported on a protocol for measuring solubility using NMR JCAMP-DX files and a web service set up by Andrew Lang called from within a Google Spreadsheet. Things were going well until David at ORU was a little too productive and crashed the server from too many requests.

Andy had to change the way the script worked and used this as an opportunity to make the service more broadly usable. It turns out that the compressed JCAMP-DX files produced by different NMR instruments are not created with exactly the same standards. A way to address that issue is to convert the files to an uncompressed XY format. Unfortunately, there was a glitch in JSpecView which created XY formatted spectra displaying in Hz instead of the standard ppm.

Now all of these issues have been resolved and the process is simpler than ever. Robert Lancashire fixed the glitch in the April 26, 2009 release of JSpecView. And Andy not only made his integration web service work for the new release but also created another service to display JCAMP-DX spectra directly from the the DX file (see here for an example). In the past students had to create an associated HTML file to display JCAMP-DX files and this was just another point in the process to introduce errors and slow things down.

The new process for the semi-automated measurement of solubility (SAMS) using NMR is as follows:

1) Make a saturated solution in a given solvent (sonicate for at least 30 mins - more on this in a separate post)
2) Transfer about 0.1 mL to an NMR tube with some compatible deuterated solvent (for locking)
3) Take the NMR spectrum and export the JCAMP-DX file (on our machines these are in a compressed format)
4) Open the initial JCAMP-DX files in JSpecView and save as JCAMP-DX XY format
5) Upload the converted file to the ONSC server in the spectra folder
6) Fill out the requested information in the SAMS spreadsheet and you have the solubility calculation (first open the SAMStemplate and save as a copy with a new name)

We can now easily finish processing the backlog of measurements that the ONSchallenge participants have been obtaining and record them in the SolubilitySum spreadsheet for querying.

Chemistry in Second Life April 09 Talks

Andrew Lang and I just did two presentation on applications of chemistry in Second Life.

The first was on April 24, 2009 at the "Virtual Worlds: Libraries, Education and Museums" (VW LEM) conference on Infotainment Island. The second was on April 29, 2009 at "Education Days" on Orange Island.

This was basically an updated version of the talk we gave at the ACS last summer. We showed how the ChemTiles and Spectral Games evolved from Second Life. That is interesting because usually Second Life applications are adaptations of projects initially conceived elsewhere.

As I mentioned previously, giving talks on Second Life or using some other form of tele-presence certainly has its advantages. It does not replace face to face interaction but I think people get a good idea of what we do and they can follow up later for more discussion or possibly even collaborations.

I enjoy presenting with Andy - we go back and forth depending on the content on the slide and when it is relevant Andy does a demo of how to rez a molecule right on stage. So far we have not had any technical problems with that and I think it drives home the message of how easy it is to use the orac rezzer.

The talk on Orange Island was recorded and I'll update a link to it here when available.

Chemistry on Second Life April 09

View more presentations from Jean-claude Bradley.

Is it becoming dangerous to NOT blog?

It wasn't so long ago that the big discussion about scientists blogging was whether or not it would hurt your career. Granted, some the examples used involved personal content that would have been problematic on any platform. Still, many scientists chose to blog anonymously, even for the most uncontroversial scientific musings.

Recently I have noticed a change in the tone. The question doesn't seem to be "Is blogging bad?" anymore but rather "Is blogging a waste of time?". Often this involves the rather ironic situation of naysayers using a blog to express their opinion that blogging is a waste of time. There are many examples of this but a particularly controversial discussion took place on Nature Network recently.

And then yesterday I came across a particularly good example of why blogging is not a waste of effort. I was checking my Sitemeter referring links and found a few from Nature Chemistry. Unfortunately the article is toll access but I was able to get my hands on a copy. It was Michelle Francl's article about the history of the periodic table and all the creative ways that people have used to demonstrate order in the elements.

Michelle used my blog post about Andrew Lang's 3D representation of the periodic table in Second Life as a reference for this type of table. This is a very short (4 sentence) post but it has the key elements of a good reference - answers to who? what? and where?. That is enough information to visit the exhibit and contact the creator for a copy.

Now Andy and I are witing this up as part of a larger article on chemistry in Second Life (see draft here). If that article had been completed and published, it is likely that Michelle would have used that as a primary reference. But it can take a really long time for the journal publication process to reach completion. If I had not blogged this I am sure Michelle could have adapted her article and found another similar reference.

The point is that mainstream scholarship (Nature Chemistry is certainly an example of that) is able and willing to use Web2.0 references when these are the most appropriate.

There are very few examples of mindblowingly original ideas. People working in related areas tend to come up with similar ideas. In a world where any of your competitors can blog their ideas as soon as they think of them, hoarding ideas might be the more dangerous choice.

It doesn't matter what you think about the professional status of blogs. It doesn't matter most scientists don't blog. The only thing that matters is that at least one of your competitors is willing to blog their research and that the traditional journals in your field are willing to accept blog posts (and other Web2.0 publication formats) as valid references.

NASA Open Notebook Science Talk April 09

On April 15, 2009 I had an opportunity to give a talk at the NASA Goddard Space Flight Center. I talked about Open Notebook Science and all of the Web 2.0 tools that we use to operate. There were no chemists in the audience but hopefully the overall patterns of how all the components interconnected made enough sense to be useful.

I had a full hour so this talk is a pretty comprehensive summary of our projects, including the most recent work on the Spectral and ChemTiles games and the automated backing up of Google Spreadsheet documents and semi-automated solubility calculations using web services called from within Google Spreadsheets. All of this work was only possible because of Andy Lang's rapid development efforts. Tony Williams also assisted greatly with the Spectral Game.


slides

We had a very nice conversation over lunch with a few NASA people. I found it interesting that many apparently very different user environments (librarians, educators, molecular biologists, cosmologists, etc.) share very similar needs for Web2.0 technologies. For example delicious was lauded as a very convenient alternative to email for sharing content. The distribution of personalities seems to be similar everywhere: a few early adopters within a larger more skeptical population.

After lunch Emma Antunes gave me a tour of the facilities. Despite the annoying rain to get between buildings, it was well worth it. Here are some of the cool things that I saw:

An enormous room housing very large speakers for testing the effect of vibrations on spacecraft and equipment. Emma stands next to one of the several speakers.



A huge centrifuge for testing the robustness of instruments. Emma said that they were able to put an SUV on there to how much force was required to tip it over.



I saw one of the satellites for the Solar Dynamics Observatory under construction. The idea of this project is to use the different perspectives from satellites at different positions in orbit around the sun to calculate the direction of solar flares and other potentially detrimental activity on the sun.

Next to the largest clean room in the world, there is a display of the guts of the Hubble telescope. Apparently the astronauts had to fix some components in there that were not designed to be accessible so they had to do a lot of practice on a duplicate before attempting the task in space.

Automatic Back-Up of ONS files: Google Spreadsheets, JCAMP-DX, Flickr

As many of you know, we have been heavily dependent upon publicly editable Google Spreadsheets for storing results and calculations relating to our Open Notebook Science projects. We have recently integrated automated processing of NMR files in JCAMP-DX format to calculate solubility data by using web services called directly from within the Spreadsheets.

That represents a lot of distributed technology that is susceptible to network or server problems. Andy Lang, who wrote the web services that currently calculate the solubility, has enabled the recall of previously calculated values via a quick database look-up. While this substantially reduces server load by avoiding lengthy calculations, it does mean that the final numbers do not exist in the Spreadsheets themselves.

In addition to these concerns, every time I give a talk to a group of librarians the issues of archiving and curation of new forms of scholarship are raised. These are valid concerns and I've been trying to work with several groups to deal with the problem in as automatic a way as possible.

We had initially considered a spidering service that would automatically follow every file linked to the ONS wikis and download the documents on a daily basis. This has turned out to be problematic because many of the links don't terminate directly on files, but rather user interfaces. For example, a typical link to a Google Spreadsheet does not lead to a simple HTML page that can be copied but rather to an interface to add data and set up calculations.

It turns out we can take a semi-automated solution that gets us to where we want to be but requires a bit more manual work. Google Spreadsheets can be exported as Excel spreadsheets, which store the results of web service calculations as simple values and include the link to the web service as a cell comment. All calculations within the Spreadsheet are also retained in this way. The trick is to "publish" the spreadsheet using the advanced option of exporting as an Excel file. This then becomes a simple URL.


Now, the only manual step left in the process is to copy these URLs to another BackUp Google Spreadsheet. Andy has created a little executable that steps through a list of these URLs and creates a backup on any Windows computer under a C:\ONS directory. It is simply then a question of setting up a Windows Scheduler service to run once a day and call the executable. All the files are named with the date as a first part of the name for easy sorting.



Besides Google Spreadsheets backed-up as Excel files, spectral JCAMP-DX files and Flickr images can be processed in the same way. In both these cases the user must specify the JDX or DX or JPG file directly. In Flickr you have to go through a few clicks to the download page for a given image but once you have that it works fine.

Andy has versioned this as V0.1 for good reason. It does do exactly what we want but there are a few caveats:

1) Any errors in specifying a file will abort the rest of the back-up. In future versions there would be tolerance for errors, with appropriate reporting of problems, perhaps by email.

2) Files don't necessarily have the correct extensions. For example, backed up Wikispaces pages have to be renamed with an HTML extension to be viewed in a browser. Note that Wikispaces has its own sophisticated back-up system that will put the entire wiki with all files directly uploaded onto the wiki into a single ZIP file - in either HTML or WIKITEXT format. Of course this will not include files residing outside - like Google Spreadsheets. Still I think there is no harm in including the wiki pages in the the list of files to be backed-up by Andy's system.

Going forward there are two types of collaborations that could help a lot:

1) Librarians who would be willing to archive UsefulChem and ONSChallenge files. Right now these are just a few Megs a day but this will increase as we continue to add to the list. To be reasonable about space I could see a protocol of keeping only one back-up per week or month for dates more than 30 days in the past. This is about what the Internet Archive does I think. It would certainly be unambigous to know for certain what was known at what time with multiple libraries maintaining archives.

2) Someone who knows how Google creates URLs for downloadable XLS exports would be mightly helpful. Similar for Flickr and JPG exports. Even just writing a script to spider all HTML pages linked to the wikis and blogs would save a lot of manual labor. The nice thing is that the results of the spidering code would just have to be dumped into the Back-Up Google Spreadsheet - which already backs itself up conveniently.

Is the Human Ego good for Science?

I have just finished reading the fascinating book "The Emperor of Scent" by Chandler Burr. It starts off describing the world of perfume with a focus on Luca Turin, a man with the unusual talent of being able to review perfumes with great eloquence, conjuring up beautiful metaphors of experiencing their scent.

The book then takes an unexpected turn into the description of Turin's theory about the mechanism of olfaction. There is some truly interesting science there, such as Turin's discovery of a binding site for NADPH and another for zinc on a protein thought to mediate smell. This supports his hypothesis that the protein functions as an electron tunneling spectroscope detecting differences in vibrational modes. Further evidence is provided by comparing the different smells of deuterated molecules like acetophenone and the similarity of the stench of boranes with thiols, which share similar IR spectral bands. This idea is at odds with the conventional view that molecular shape is responsible for the activity of odorants. (For a summary of Turin's theory I would suggest watching his recent TED talk "The Science of Scent" and his Wikipedia entry)

This is all very interesting stuff and would have made for a good read but what makes this a truly fascinating story is that Burr spends the rest of the book detailing the way the scientific community responded to his findings. As Turin waits a year to finally get rejected by Nature, the reviews, rebuttals and other communications with the editor are examined to expose the intense emotional components that can arise from the peer review process. The author even follows Turin to conferences and reports in detail how various members of the audience react and comment during his talk and at informal meetings over lunch.

People who are not in science may find this disturbing. All too often science operates like the judicial system, where winning can take on more importance than finding the truth.

The fundamental problem is conflict of interest. If you have patents or run a company it may not in your financial best interest to look under every rock, except as required by law. If you have built your career on a certain theory it may not be in your professional best interest to open every can of worms. Burr actually wrote a chapter explaining why the book appeared to be so one sided: it was hard to get detailed comments from Turin's detractors because, although they disagreed with his theory, they had not read his paper and did not have time to do so.

But Turin was really not that different in his conflict of interest related to ego. There are descriptions of him reading articles in a state of dread and delaying experiments for fear that he might be proved wrong. Still, I like to root for the underdog, so the book did have me hoping that he would be vindicated.

If most scientists are motivated by ego, is it possible to do egoless science - and what would that look like?

For starters I think that keeping a true Open Notebook (All Content shared Immediately) does a lot to keep your ego in check. If you report on what you find, when you find it, you don't have time to succumb to the temptation to cherry pick results and embellish the story of what happened.

Another trend that I think will emerge in the next few years and will change the way science gets done is machine-driven science. It will probably prove too much trouble to take into account a researcher's ego and career objectives when coding for AI to plan and analyze experiments to solve problems. Just like Turin, a lot of researchers (including myself, especially early in my career) procrastinate doing certain experiments for fear of not liking the outcome. The key again here is making the experimental logs of those machines public in real time.

When I refer to egoless science, I am speaking at the level of experimentation. I am driven by ego, like everyone else. But I have found it more useful to place its focus at the meta level. Instead of taking pride in appearing to run a perfect operation - and of getting high yields for our reactions - I am most pleased when the members of my group do their best to record exactly what happened, as they do science.

And being a strong proponent of Open Science, my ego is linked to those activities. Even though it is somewhat ironic, I do enjoy competing at being as openly collaborative as I can.

The ChemTiles Game

In another example of code and content re-mixing for educational purposes, Andrew Lang and I have adapted many of the elements of the Spectral Game and tiles from the Second Life quizzes I traditionally gave for my introductory organic chemistry course. Many of these tiles were originally created for use in Unreal Tournament.

The concept is simple: tiles represent images or statements that are either true or false in any context. By marking them as true or false and ensuring that one true tile is present in a mix of a number of false ones, games can be designed that vary from rooms within a maze to obelisks offering a selection of floating images in Second Life.

In the current implementation, the tiles appear in a web browser. Clicking on the correct tile produces a new random selection. Clicking on a false tile stops the game and records the player's score. Following the same structure as the most recent implementation of the Spectral Game, the first 10 queries present only two tiles. As the game progresses the difficulty level increases and more tiles are included.

Whereas the Spectral Game obtained spectra and molecules from ChemSpider, this game taps into a set of 256 x 256 pixel images in a Flickr group. Using Flickr lets us leverage the ability to easily tag images, which can then be used by players to select different topics to practice.

I'll be giving a prize to the student in my current CHEM241 class who scores highest by 10:50 ET April 10, 2009. The student must play under the "all tags" option, which covers all the material before test 1, given the following week. Students can also practice different modules by selecting tags like Lewis Structures, Hybridization, Nomenclature, Newman Projections, etc.

I think that this approach of rapid remixing of code and content on free hosted platforms (like Flickr or ChemSpider) is really the future of technology in education. It will be difficult for heavy top down - and expensive - systems to compete against the incredible flexibility of these lighweight and loosely connected initiatives led by educators with the simple motivation of just experimenting with teaching in a better way.

My Open Notebook Science talk at NASA in April 09

I will be speaking at the Goddard Space Flight Center at 11:00 on April 15, 2009. NASA has a long history of sharing data and it will be interesting to see how their experience compares with what we have been doing in chemistry. Certainly the much larger amount of telescope generated data presents different problems and opportunities.

Crowdsourcing solubility measurements using Open Notebook Science

Jean-Claude Bradley

The use of Open Notebook Science to collect and make publicly available non-aqueous solubility measurements will be described. This involves the real time sharing of all experiments and associated raw data by a community of collaborators who are geographically distributed and may have never communicated using channels other than this project. Monthly cash prizes are awarded to participating students by means of the ONS Challenge Submeta Awards. The laboratory notebook pages are recorded on a public wiki and the solubility measurements, including relevant calculations, are stored in public Google Spreadsheets. A combination of ChemSpider, the GoogleDoc visualization API and web services is used to enable flexible searching and display of desired subsets of the data.

Tim Bohinski is the April 09 Submeta ONS Award winner

Tim Bohinski, a Chemistry undergraduate student working under the supervision of Jean-Claude Bradley at Drexel University, is the April 2009 Submeta Open Notebook Science Challenge Award winner. He wins a cash prize from Submeta.

Tim mainly focused on evaporation techniques to measure solubility. He also wrote a review paper on non aqueous solubility. See his experiments here:
http://onschallenge.wikispaces.com/list+of+experiments

Five more Submeta ONS Awards will be made during 2009. Submissions from students in the US and the UK are still welcome.
For more information see:
http://onschallenge.wikispaces.com
http://onschallenge.wikispaces.com/submetaawards08

Wendy Warr report on ONS from Fall 08 ACS meeting

Wendy Warr has provided a thorough report from the Fall 2008 American Chemical Society meeting in Philadelphia. My talk "Processing drug discovery raw data collaboratively and openly using Open Notebook Science" is summarized on p.10 as part of a special extract of talks and companies.

Wendy has covered a lot of material related to cheminformatics in the full report and is worth looking over if you missed the conference.

Chemistry publication - making the revolution

Steven Bachrach has just published a very interesting commentary "Chemistry publication - making the revolution" on March 17, 2009 in the new Journal of Cheminformatics (I am on the editorial board).

The article does a great job of highlighting the current state of affairs in chemistry which is creating a chasm between researchers and the data they could be using. There are suggestions of steps that can be taken by researchers, reviewers and editors. Although Open Notebook Science is mentioned, there are several less intensive steps that can be taken to still benefit the community. Steven mentions the submission of JCAMP-DX files instead of PDFs when submitting spectra as supplementary materials for publications. I agree that this is a very low barrier step that chemists can take to gain immediate benefit - whether they share their spectra or not. At that point it also becomes trivial to contribute spectra to databases like ChemSpider that supports the open JCAMP-DX format - hopefully as Open Data (so that it can be used in applications such as our SpectralGame)

CDD's Pay for Privacy Model

Barry Bunin and co-authors Moses Hohman, Kellan Gregory, Kelly Chibale, Peter J. Smith and Sean Ekins just published an article in the March 2009 issue of Drug Discovery Today: Novel web-based tools combining chemistry informatics, biology and social networks for drug discovery.

This is a must-read for the Open Science community involved with drug discovery. Barry reviews several relevant online resources and details the workings of the Collaborative Drug Discovery system.

The point that I thought was most interesting is that Barry reports that CDD now has a policy of allowing unlimited uploading of data by non-subscribers. Researchers pay for privacy, which is a model that I think works well for a number of Web2.0 applications. For example, Wikispaces works that way. Since most users will likely want to limit their data sharing between selected collaborators, this is a good way to get the word out by groups who don't mind sharing publicly.

There are a few case studies in the article, including our UsefulChem project and our collaboration with Rajarshi Guha at Indiana University and Philip Rosenthal at UCSF to find new anti-malarial compounds. Barry illustrates the point with the assay results for one of our Ugi products:

Spectral Game Winners

Following up on my last post about the SpectralGame, I have given out 2 molecular model kits to the highest scoring students in my CHEM242 class.

The first winner was Scott Beaudoin with 24 points followed by HaeJi Choi with 17 points.

The current high scores for the Drexel students can be accessed here. High scores from everyone in the world can be found here. The top score is currently 40 by VK.

Andy and Tony continue to fine tune the operation of the game. The recent introduction of a "Reload Spectrum" button below the molecules prevents the game from stopping prematurely if the spectrum won't load for any reason.

We still welcome contributions of spectra (NMR, IR, UV, MS, etc.) and players!

Andy and Shirley's new ONS Logos

Some new ONS logos are available to specify a researcher's intent in making their lab notebook available online. Options include full Open Notebook Science (All Content - Immediate) or more restrictive forms (Selected Content or Delayed).

Andrew Lang updated his logos, including options for multiple sizes:




Shirley Wu also contributed these:





The logos can be downloaded from the ONS claims website. Clicking on them should link either directly to the lab notebook or to the ONS claims page, where a brief description of the intended meaning can be found.

Semi-automated measurement of solubility using NMR

Over the past few days Andrew Lang and I have been discussing ways of streamlining the measurement of non-aqueous solubilities using NMR. Inspired by David Strumfels' VBA code on Excel to automatically measure kinetics, Andy found a way to directly extract the integration values from the H NMR spectra hosted on our server in JCAMP-DX format.

We have set up a Google Spreadsheet (see ONSC-EXP062B for an example) that automatically calculates solubility based on information that the researcher provides. What is required:

• A link to the NMR spectrum (the HTML file linking to the JCAMP-DX file)
• Density and molecular weight of the solute
• Density and molecular weight of the solvent
• A range in the solute to integrate with the number of corresponding Hs
• A range in the solvent to integrate with the number of corresponding Hs

The spreadsheet calculates the molar ratio of the solute to solvent then the molarity by making use of the assumption that the volumes of the two components are additive. The volume of solids is typically not available experimentally but ChemSpider gives a reasonable prediction. We have been using this assumption to convert published solubility values from g solute/ 100 g solvent to molar. In order to prevent taxing the server, once the measurements are computed they are stored in a database so that the spectrum and calculations don't have to be performed again.

The beauty of this approach is that there are no volume measurements. A saturated solution is made then, generally diluted in a deuterated solvent. When using an internal standard the volume of the saturated solution and the volume (or weight) of the standard must be known exactly. It is often difficult to micropipette some solvents and there is always the possibility of making an error in the handling of the micropipette. In general the fewer variables there are the more likely the results will be reproducible.

This is method can save a lot of time but it is not as automated as it could be. The densities must be looked up manually, although the molecular weight is automatically calculated from the common name using a web service by Rajarshi Guha run directly from within Google Spreadsheets. It also requires students to define solvent and solute ranges manually. All of the input cells are colored green, the output red and the intermediate calculations are in yellow.

However, once a range for a solute or solvent (and corresponding number of hydrogens) has been determined it can be used as a handy default and we will be collecting these and storing them in this sheet.

Does this mean that students don't need to think anymore?

Used properly, this system should actually elevate the level of thinking, in much the same way that the calculator did not remove the need for thought in data analysis. It just removed a lot of the tedium of manually calculating square roots and all of the associated sources of error in manual calculations of that type.

Students should use this tool to handle more measurements - faster - and think about their results in aggregate form. The ability to detect systematic errors becomes an essential skill to be developed. Also students need to spot problematic results quickly, for example where solvent and solute peaks overlap - or where there are baseline anomalies.

Of course even these last issues of quality can control can probably be automated to a large extent and we will report on this as we go. For example, it is conceivable that the NMR of a solute and solvent can be predicted or looked up automatically (on ChemSpider for example) and probable peak overlaps could be flagged. Software could also probably detect a mislabeling error.

At this point, we are getting closer to scientific progress by machine-to-machine communication on the free open read/write web. All we would need are a few groups around the world who see the value in endeavors such as this and donate a part of their NMR autosampling time. I am sure we could come up with simple ways of automatically converting files on their local computers to JCAMP-DX format and automatically upload them. We also need people to make up saturated solutions - but with the decoupling of tasks in this new workflow - these don't necessarily have to be the same people who process the NMR spectra.

Cedric Tchakounte is March09 Submeta ONS Award Winner

Cedric Tchakounte, a Biological Sciences and Biotechnology undergraduate student working under the supervision of Jean-Claude Bradley at Drexel University, is the March 2009 Submeta Open Notebook Science Challenge Award winner. He wins a cash prize from Submeta.

Cedric is focusing on NMR techniques to measure solubility. He has also done several experiments to verify the miscibility of liquid solutes in methanol. See his experiments here:
http://onschallenge.wikispaces.com/list+of+experiments

Six more Submeta ONS Awards will be made during 2009. Submissions from students in the US and the UK are still welcome.
For more information see:
http://onschallenge.wikispaces.com
http://onschallenge.wikispaces.com/submetaawards08

Spectral Game update

The end of February 09 has come and gone and nobody hit the 100 points to win the molecular model kit I announced earlier for the Spectral Game. The highest score in that time period was 75.

Since my CHEM242 class is having 2 tests and one exam in the next 3 weeks I thought I would make the next prize available to them exclusively. The student from that class who scores highest by 9:50 Wednesday March 4, 2009 will win a molecular model kit. That happens to be the end of class on that day. The scores have been reset.

The game has been improved considerably during the past few weeks. A few security flaws were fixed, including modifying what metadata can be viewed via JSpecView and preventing the refresh button from selecting a new set of molecules. The game play was also changed to get increasingly more difficult over time, including adding more molecules and a timeout after the first set of ten spectra. This work was a collaboration between Andrew Lang, Antony Williams, Robert Lancashire and myself.

We are very excited by what we have put together so far. There are currently 457 H NMR, 389 C NMR, 11 IR and 29 NIR spectra. This is only possible because of people who submitted their spectra to ChemSpider as Open Data - please keep uploading!

The game has been played 1,824 times, viewing the spectra a total of 8,652 times - with a lot of curation by users. (If you see something wrong with a spectrum you can write a note and that helps us clean up the database). We have had 612 unique visitors from 37 different countries - a total of 13,919 page views in just over two weeks!

We now have a wiki with key links relating to the game. I also added the NMR notes from my CHEM242 class and we'll keep collecting resources. This could become a helpful resource to learn about NMR and practice it by playing the game.

ONS Solubility Challenge on Sigma-Aldrich tech sheet

The Open Notebook Science Solubility Challenge has made it onto the Solubility Information for Products technical sheet of Sigma-Aldrich:

Sigma-Aldrich are currently collaborating with Nature and Submeta in an Open Notebook Science Challenge. This is a project aimed at facilitating the generation of solubility information for chemicals. Please follow this link 'Open Notebook Science Challenge - Solubility' for more information on this project.

This is a great example of how synergies between academia, industry, publishers and foundations can take place quickly and in the open.

There is some other interesting information on that page - notably a table translating written descriptions of solubility terminology - like "freely soluble" - into numbers.

Open Notebook Science Claims and Logos

I have recently posted about definitions relating to Open Notebook Science. When I discuss ONS without qualification I generally refer to providing access to the entire lab notebook and associated supporting raw data in near real-time. As I explained in that post, only when these two criteria are met do you get the full benefit that anyone (human or not) can see what you have and have not done and can realistically contribute the next step in a project without having to contact the researcher (human or not) for more information.

I have also conceded that this is not necessarily an option for everyone interested in performing research more openly. Others (Dave Bacon for example) have suggested that more restrictive forms of ONS could be useful, especially when intellectual property protection is involved. Dave called this Pseudo-ONS and I have suggested Partial-ONS: both abbreviate to PONS.

This has been a tricky distinction to make quickly and the idea of logos for ONS has been kicked around. When Hope Leman asked me for an ONS logo I thought I would ask Andy Lang to create something and deal with this issue at the same time.

Inspired by the Creative Commons system, we set up an ONS claims page to link from the logos to descriptions. The options are AC (All Content) vs SC (Selected Content) and I (Immediate) vs D (Delayed).

Let us know what you think.

ONS talks at the British Library, ACRL and a Slideshare feature

Update: the Columbia panel on Open Science video is now available.

This past week I gave two talks and participated in one panel discussion - with no jetlag or airport burn-out. Gotta love technology for allowing for that to happen.

My first talk was on Feb 11, 2009 at a session on Digital Lives at the British Library. This was a hybrid conference with a presence in the physical world as well as Second Life. I could see and hear the speakers in London from within Second Life and I'm assuming they saw my presentation just as clearly. Joanna Scott from Nature coordinated the SL session.

I then participated in a panel in Second Life on "Stepping into Science" on Feb 13, 2009. There was as good discussion about using Second Life for educational applications. The other panelists included:

• - Troy McConaghy (Scientist and Educator who has been involved with Second Life for over three years)
• - Dr. George Djorgovski (Caltech and Meta Institute for Computational Astrophysics (MICA))
• - Joanna Scott (Writer for Nature and manages Second Nature on Second Life)
• - Adrienne J. Gauthier, M.Ed. (Instructional Technology Specialist, Steward Observatory)
• - Tony Crider (Elon University)

Then on Feb 17, 2009 I presented for the Association of College and Research Libraries using Acrobat Connect Pro. Hope Kandel from LearningTimes did a great job in coordinating the technology and people several weeks before the event. The attendees used chat to ask questions during my talk then John Howard moderated by summarizing some of the questions verbally at the end. It went well I think.

And I just heard that my ACRL presentation on Open Notebook Science is currently showcased on Slideshare under the Education category.

Now I'm on my way to a physical conference at Columbia with Bora: Open Science: Good For Research, Good For Researchers?

Prize for Spectra Game

Tony Williams and Andy Lang have been busy over the weekend adding a pile more spectra to the Spectra Game on the web. I used it this morning in my workshop for CHEM242 and I think it is time to announce a prize.

During the month of February 2009, the first student in the US (undergraduate or high school) to score 100 on the H NMR web version of the Spectra Game will win a molecular model kit. Obviously all of my students taking organic chemistry CHEM242 are eligible but I invite the rest of the country to give them some healthy competition.

Make sure to add your email when you start playing the game so that we can contact you if you win.

Play the Spectra Game
Instructions

Web based Spectra Game

Yesterday I used the NMR game in Second Life during our 2-hour Friday workshop in CHEM242. (We used a new location on Drexel island SLURL) The students who attended had looked at little or no material prior to the workshop. By the end I ended up explaining chemical shifts, complex coupling patterns and diastereotopic hydrogens differentiated by the presence of a chiral center. The only concept we didn't cover is integration, although we used peak size to take a guess about groups with lots of hydrogens (like trimethyl).

I think it was a very efficient way to teach NMR and the students can now go off and continue to practice till our next workshop Monday. Second Life has some advantages - such as the ability to mediate group study sessions where students from remote location can come together to play and discuss spectral assignments using either voice or chat. It is also nice to see the molecules in 3D, especially for bridged cyclic systems.

However, there is a bit of a learning curve to get into Second Life and not all computers have a suitable video card. So it is nice to now have the ability to play the game on a web browser. Andy set up the game play so that the score reflects the number of correct answers obtained in a row. There are also only 3 molecules to choose from instead of 5 in Second Life.

We're using JSpecView to render the spectra so expanding peaks simply requires dragging the mouse across the area of interest. It is also possible to integrate and view the metadata by right clicking.

Currently we mainly have H NMR spectra but we'll be adding lots more C NMR, IR, UV, MS, etc. It all depends on how many Open Data contributions we can find. If anyone has spectra to donate please upload them to ChemSpider and don't forget to check the box for Open Data.

This has been a wonderful example of rapid collaboration by Andrew Lang, Rajarshi Guha, Antony Williams, Robert Lancashire and myself.

Give the web Spectra Game a spin and see if you can beat the high score....

Substructure searching on ONS solubility data

Jenny recently reported that one of her values seemed low and was going to repeat it. She obtained 0.9 M for 4-hydroxybenzaldehyde in THF (ONSC-EXP057). Compared against the previous value of 3.5M (UC-EXP208) it certainly seems like one of the values is off.

To get a better idea of which it might be it can be useful to look at the solubility of structurally similar compounds. We can now do this using Rajarshi's web query tool by entering information in the SMARTS box. In this case we want to do a substructure search based on the skeleton of 4-hydroxybenzaldehyde. Putting the SMILES of that compound (O=Cc1ccc(O)cc1) in the SMARTS box and selecting THF returns 6 results.

It certainly does seem that 0.9M is low for that group. More measurements will settle the issue.

Open Notebook Science, Reproducibility and Exclusion

There has been a fairly active conversation about Open Notebook Science over the past few days on FriendFeed. Some of the points I have wanted to make wont fit there so I'll post them here.

A short definition of ONS on Wikipedia: Open Notebook Science is the practice of making the entire primary record of a research project publicly available online as it is recorded.

I have repeatedly said that Open Notebook Science is probably not the best choice - at least initially - for most researchers interested in dipping their toes into Open Science. So why do I care so much about pursuing it?

It has to do with taking us past the tipping point to runaway real time open collaborative crowdsourcing in science.

There are two properties of ONS that at least set the stage for such a scenario.

1) Reproducibility: The primary purpose of a laboratory notebook is to make experiments reproducible for the researcher who recorded it. You can't improve on a process if don't keep a detailed record of what exactly happened in a given trial. A secondary purpose is to prove what a researcher knew and did at a specific point in time. This can be useful for patent enforcement if the notebook is kept private. There are other applications, but in general the sharing of experimental details is typically extremely limited in science.

I believe that this is an artificial barrier still standing to a large extent because of inertia. In the past, even if they wanted to, researchers could not realistically make this information public because of the absence of a convenient publication vehicle. But that is changing right now - technology is no longer the bottleneck. Very high quality free hosted services exist now that permit sharing with very little additional effort. All we have to do is record our laboratory notebook (which has to be kept anyway) on media that are easy to share and automatically indexed on major search engines.

By definition, the notebook should have all the information necessary to reproduce the results you obtained. If it is published in close to real time, someone who doesn't know you can read the details of an experiment you did today and contribute to the advancement of your project tomorrow. Or they may use your information for their own project. As long as they also maintain an Open Notebook knowledge can spread extremely rapidly. The efficiency of such a system between strangers is probably far greater than most scientific collaborations between researchers who already know each other.

2) Exclusion. If I come across an experiment you did yesterday and I have a desire to contribute meaningfully to your project, before executing the next experiment, I will want to look at all of the related experiments in your notebook. Of particular interest will be "failed experiments" to avoid repeating the same attempts. Or I may want to repeat one of your failed runs because I don't think that you properly controlled some parameter or made a mistake in the analysis.

The point of an Open Notebook is to get the truth - the whole truth about what you did and did not do. If I don't find what I am looking for in your notebook - and you have declared it to be an Open Notebook - then I can safely assume that you have not done it and I will feel confident to invest my resources to do that next experiment.

For an example of this system at work consider the Open Notebook Science solubility challenge. If I want to contribute to the project, the first thing to do is take a look at what has not been extensively measured yet. I can do this via the web query or directly on the experiment list page. By using the web query tool I can also look for contradictory results and try to resolve them. Or I may wish to include a control in my measurements and pick a compound that has been measured reproducibly using different techniques. I probably also want to look at the minute details of exactly how previous researchers applied their technique.

Now what would happen if we had adopted a Partial Open Notebook Science approach where we delayed recording lab notebook pages until a paper was published? Or what if we used the PONS variant of only recording experiments that "worked"?

Had we done anything short of a fully Open Notebook the project would have never gotten off the ground.

NMR game on Second Life

Andrew Lang and I have been discussing publishing our work on chemistry and Second Life. We're working on the draft here. When going over the game section, it became clear that we'll probably need to make two manuscripts out of this. This is an opportunity to wrap up my previous work on the EduFrag project - using Unreal Tournament to teach organic chemistry. I had submitted that article but as it was going through the peer-review process the approach was essentially made obsolete when we adapted the quizzes to Second Life.

So Andy and I brainstormed some new chemistry games that we could introduce to Second Life to leverage our recent tools. One of the applications is the NMR game. By combining the orac molecule rezzer, the SL spectral viewing tool and ChemSpider Open Data spectra I think we have a pretty good game.

The idea simple: click on the molecule that is represented by the spectrum. If it is correct you get 2 points and get another spectrum. You lose a point by clicking on an incorrect molecule. After going through all the spectra your score gets posted on the web to a top10 list. For equal scores the best time takes it.

From an educational perspective this is useful I think on several levels.

First the ability to look at the molecule in 3D makes it easier in many cases to demonstrate the relationship between Hs, which is critical in NMR.

Second we are using real spectra - not simulations. That is a great opportunity to teach students about how to deal with impurities, solvent peaks or quirks in the peaks. The viewer allows for easy zooming by typing commands like "zoom 1.5-2.5" in the chat box.

Third this spectrum viewer uses Open Source JCAMP-DX files so it can (and will) be adapted to all kinds of spectra - like IR, UV, MS, C NMR, etc. I'm teaching (CHEM 242) all of those techniques this term so I'll have an opportunity to see how well it works.

There is currently a copy of the game on ACS island (SLURL) - give it a try and give us some feedback.

Here is picture of the game area (Viv is sitting on the molecule and I'm on the spectrum):

C&E News article on ONS and FriendFeed

Carmen Drahl's article following her visit to my lab has just appeared online on Chemical and Engineering News:
(February 9, 2009 Volume 87, Number 06 p. 34).

I think she really captured the essence of our Open Notebook Science solubility project and how to make those results available in an intuitive way via web queries and Second Life tools. Rajarshi Guha and Andrew Lang's work is demonstrated here. The text description is very helpful but it is her video recordings that really stand out. There are two screencasts from Second Life: one from my class where I ran an organic chemistry quiz race and another demonstrating the Ugi solubility explorer.

Carmen also recorded a very good overview of how we use FriendFeed to collaborate with other researchers. The life science and Open Science communities are very strong right now on FriendFeed and hopefully this demonstration will encourage more chemists to participate. To illustrate how easy it is to connect with new people she shows how the "like button" enabled a link to be formed when Egon Willighagen liked one of her posts.

Sigma-Aldrich ships ONS solubility challenge batch

A while back I reported that Sigma-Aldrich was sponsoring the Open Notebook Science challenge by donating compounds when necessary. That was a very generous offer and we have just made use of it. The first batch has shipped yesterday to Jenny Hale at Southampton University. Since she is using a SpeedVac to measure solubility, we made a list of lower cost Ugi product reactants with higher boiling points. Here is the collection:

Every solubility measurement technique has its pros and cons. Evaporation based methods are very direct but are limited to high boiling solutes. UV is sensitive to low concentrations but requires a calibration curve and a chromophore. (for example EXP024)

NMR is less sensitive than UV but has the advantage that it can handle solutes of any volatility and does not require a chromophore - and from an efficiency standpoint - it does not require a calibration curve. At our concentration range of interest (>0.1M), NMR does seem to be the most convenient method in my lab: make a saturated solution in the solvent of interest then dilute with a deuterated solvent (generally CDCl3) then add an internal standard (acetonitrile is handy) then take one spectrum and analyse. For an example see Khalid's EXP030.

For an sampling of all the methods see our experiment list.

David Bulger is Feb09 Submeta ONS Award Winner

David Bulger, a chemistry undergraduate student working under the supervision of Robert Stewart at Oral Roberts University, is the February 2009 Submeta Open Notebook Science Challenge Award winner.

In addition to a cash prize from Submeta, he will receive a one-year subscription to Nature magazine. David is focusing on NMR techniques to measure solubility. See his experiments here:
http://onschallenge.wikispaces.com/list+of+experiments

Seven more Submeta ONS Awards will be made during 2009. Submissions from students in the US and the UK are still welcome.
For more information see:
http://onschallenge.wikispaces.com
http://onschallenge.wikispaces.com/submetaawards08

Maintaining Solubility Data Provenance from Wikipedia to Lab Notebook

I recently noticed a bunch of incoming clicks from the Wikipedia entry for benzoic acid to our Open Notebook Science solubility challenge wiki on the ONSC sitemeter.

It turns out that Andrew Lang added a link from the Properties section covering the solubility of benzoic acid in a few organic solvents.

Instead of pointing directly to the individual notebook pages for each measurement, clicking on the reference takes us to a page summarizing all of the solubility measurements of benzoic acid in various solvents. The values are averaged and a standard deviation is provided.

Clicking on one of these links takes us to a summary page of each measurement for one of the solvents.
Clicking a link from that collection takes us to the laboratory notebook page (for example EXP005) on the wiki and ultimately to a Google Spreadsheet (for example) with all of the calculations for that measurement.

The beautiful thing is that the original url can't be any easier to create:
http://oru.edu/cccda/sl/solubility/allsolvents.php?solute=benzoic acid

And this same link will always link to the best possible values as more measurements are made and erroneous values are removed if found. With Andy's current code, if measurements at different temperatures are made, a plot is provided.

Now we're getting into some interesting territory. It is now so simple to refer to the solubility data of the ONS challenge that people who don't know the first thing about wikis, blogs or coding can start to partcipate in the use of ONS measurements.

The Open Notebook can be thought of like insurance. We don't want to have to use it - but if there is a problem we have to ability to trace the chain of provenance all the way to the source.

By the way notice that this is the only link in the Properties section of this Wikipedia article with a reference...

The ChemSpider Journal and ChemMantis

The ChemSpider Journal of Chemistry is about to go live. This is not just another chemistry journal. Not only does it boast the option of an open peer-review in addition to Open Access, but it takes us tantalizing closer to the promise of Web3.0: the semantic web. This is achieved by a sophisticated mark-up system generated by ChemMantis. The automatic identification of molecules is impressive enough. But it also marks up functional groups, reactions, spectral data and even biological entities.

For an example consider this article, which was actually a proposal that I wrote with Rajarshi Guha and Tony Williams. Simply by hovering over the marked-up text "Ugi reaction", it pulls up a brief summary from Wikipedia. What makes this semantic is that it already knows that this is a chemical reaction and not a molecule or a virus.

When you hover over the name of a molecule it knows to render it accordingly and provide appropriate links. Consider this example:
This makes the experience of reading a chemistry article a lot richer. But another payoff is coming in what machines will do when they are able to associate concepts instead of just text. Most importantly it does not require authors to do any extra work.

Tony has more information on his blog - and new submissions are welcome.

Solubility on Google Books and the ONS challenge

Andrew Lang has brought something very interesting to my attention: there are some solubility measurements on Google's Library project, providing access to the full text of books that are old enough to be part of the public domain. This means that certain measurements can be referenced directly and openly, without excluding people (and machines) who don't have subscriptions.

For example, Atherton Seidell compiled extensive collections of solubility information in 1907 and 1919. Specific pages can be referenced directly, which makes it easy to track upon inclusion into our Open Notebook Science solubility challenge.

Consider the solubility of benzoic acid in methanol at room temperature. Either using Rajarshi's drop-down menus or Andy's direct URL method, we find that there are currently 5 measurements, 4 from the ONS project and one from the Seidell compilation.


Clicking through the last link takes you directly to the table in the book where the information was obtained.
It is comforting to see that all the values are consistent. But to view all the measurements expressed as molar concentrations required a bit of fiddling. The Seidell book reports the solubility of benzoic acid in methanol at 23C as 71.5g/100g solvent. In order to convert to molar we have to make two assumptions.

First we assume that the volume of the solute and solvent are additive. This is clearly not the case but until someone proposes a better model that's what we will use. Second we must estimate the density of the solute. For a liquid that is not a problem but experimental values of the density of solid organic materials is scarce. Luckily, ChemSpider provides such estimates - and for benzoic acid that turns out to be 1.197 g/ml.

We're performing all the calculations directly in the SolubilitySum spreadsheet (columns N-W) and making these assumptions explicit. If anyone has a better model let me know.

Optimally, we would like to provide links to the public domain as much as possible when comparing our results with the literature. But that probably won't be the case. For example, many of the values for 4-nitrobenzaldehyde are from toll-access sources and the best we can do freely is provide a text citation: Maccarone, E; Perrini, G. Gazzetta Chimica Italiana vol 112 p 447 (1982).

By the way this particular search nicely showcases Andy's graphical representation of the temperature dependence of solubility in various solvents. Just scroll to the bottom.

Carmen Drahl visits my lab at Drexel

On Wednesday Jan 21, 2009 I had the pleasure of spending the day with Carmen Drahl from Chemical and Engineering News. She showed up bright and early an hour before my class (CHEM242) started at 9:00. And this was helpful because we had to get her computer set up on the Drexel wireless system.

That morning I was running a Second Life "race", where students compete to complete a series of questions about basic material they should recall from last term's organic chemistry course (CHEM241). Nobody completed the quiz within the duration of the class so there was no actual winner. Regardless of the motivation, the exercise of actually attempting these quizzes certainly can't hurt for the upcoming test this week. Carmen is to my right in this picture and the others next to the quiz obelisks are students:


Carmen spent the rest of the day trying to get an idea of what my students and I do on a typical day. She looked at the equipment we use to measure solubility and we discussed the Open Notebook Science Challenge in detail. This was a good opportunity to demonstrate the value of the interactive ways we have of querying the solubility data, mainly thanks to Rajarshi Guha and Andrew Lang. Finally I showed her how I use FriendFeed to collaborate and rapidly share scientific information with colleagues. This should make for an interesting read when it comes out in a few weeks.

ONS Solubility Challenge in Teaching Lab

Last year Brent Friesen started to experiment with using his organic chemistry teaching lab at Dominican University to carry out new reactions in the pursuit of making new anti-malarial agents, as part of the UsefulChem project.

This year, Brent is involving his class in the Open Notebook Science Challenge to measure the solubility of a variety of organic compounds in non-aqueous solvents (CHEM254). He took the time to write up a comprehensive laboratory handout on the topic so I'm hopeful that this exercise will go smoothly.

As we've discussed repeatedly during the past year the potential for university teaching labs to contribute real new science while training students is immense. It only requires instructors like Brent to take the time to make appropriate changes in the curriculum.

The lab is scheduled to run Jan 21-23, 2009.

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.