Experimental Plans

I have started to record proposed experiments with detailed step by step instructions. This should help students who are just starting out in the lab get going. I am also hoping that this will reduce confusion at group meetings. With students coming from vastly differing levels of lab experience, everyone has different assumptions during communication and those are rarely made explicit.

In the first experiment plan, I am proposing a protocol to monitor the formation of an imine by NMR so that we can better understand the kinetics of the Ugi reaction. We have been speculating about the rate and extent of this reaction for some time now and it is time to put the issue to rest with hard numbers. Also, with the CMR and HMR values for the imine, it will be much easier to monitor the rest of the Ugi reaction by NMR.

I am also hoping that publishing our experimental intentions can save us from making unnecessary mistakes by obtaining feedback from others before we start executing.

Titanium Tease

In response to a query by James on ChemUnpub about hints on doing the Ugi reaction, Francesco Mazzini responded:

Regarding aromatic aldehydes in Ugi reaction, I think that this paper

"Titanium Catalysis in the Ugi Reaction of r-Amino Acids with Aromatic Aldehydes"
Thomas Godet, Yannick Bonvin, Guillaume Vincent, Daphne´ Merle, Alain Thozet, and Marco A. Ciufolini
Org Lett 2004,6, 3281-3284

can help you (if have not already read it)

This actually looked like a really promising way of accelerating the Ugi reaction using titanium tetrachloride. We discussed it for a while until we realized that the HCl liberated by the reaction of TiCl4 with methanol would knock off the BOC group required in the synthesis of all our diketopiperazines. Doh...

At least we got a solid reference for the noted slower reaction of aromatic aldehydes in the Ugi reaction, which supports what we are finding.

PubChem Chat

Chemical information expert Gary Wiggins of Indiana University has announced that the PubChem discussion group is close to critical mass with well over 100 users now signed up. There are representatives from Abbott, ACDLabs, ACS, Astrazeneca, and Arizona State University as well as Xemistry, but no one beginning with a Z yet, he says.

The PubChem archives are online and you can find information there on how to join.

Murray-Rust talk at Google

Peter Murray-Rust's talk at Google in September 2006 is now available on Google Video. It is a nice summary of the state of cheminformatics and his vision for the future, similar to his talk at the ACS in the fall. A handy thing about Google Video is that you can export the video in mp4 format for playing on video ipods.

The Semantic Chemical Web: GoogleInChI and other Mashups

The millions of scientific papers published each year are an amazing source for scientific discovery but in most of them the experimental data is destroyed by the publication process. Publishers insist on converting semantic data into PDF which effectively destroys everything. We have been developing social and technical strategies to preserve and liberate this data and where this has happened have been able to create completely new mashups and other semantic resources

NMR Spectra on Browser with JCAMP

Our quest for a good browser-based JCAMP viewer for our NMR spectra is over: JSpecView. Dave also looked at SpectreView and did manage to put up a spectrum but it required decompressing and editing the dx file coming off of our Varian 500 MHz instrument. The advantage of JSpecView is that it can handle the compressed dx file directly. The procedure is very simple:

1) Copy the dx file from the NMR and rename it to something meaningful (like a UsefulChem experiment ID)
2) Download a template html file by right clicking this link and selecting to save on your desktop (on Firefox it would be Save Link As)
3) Edit the html file using Notepad to change the reference to the new dx file
4) Rename the html file to something meaningful
5) upload the dx and html files to our server under the Software/JCAMP folder

This is what the JCAMP file looks like when all done (just left click here). This should start JAVA and display the NMR spectrum. To expand left click on the spectrum and drag to the end of the desired expansion. To display the integral, right click and select the integration. (This particular spectrum of 5-methylfurfurylamine is underintegrating the furan protons by half - we'll investigate to see if the problem is with JCAMP or shows up on the printout from the NMR as well.) The metadata is automatically posted under View->Show Header.

The advantage of using this type of display for NMR is that there is no need to do peak picking or expansions during the NMR time. This is especially nice for determining the J constants on the fly. For example in the above example, the coupling of the furan H's can be measured at 3.0 Hz by expanding the left doublet at 5.99 ppm enough to measure a 0.0060 ppm difference and multiplying by 500 MHz/ppm. (The peak at 5.86 is not showing up as a clean doublet, probably due to phasing issues that may be related to the integration problem in this spectrum).

We can currently only copy files from our 500 MHz machine, which still does not have C NMR running. Hopefully that situation will get resolved shortly and we'll be able to post all of our NMR data in this interactive format.

UsefulChem at NERM 2006

I have the great privilege to be the vice president of Drexel's ACS-Student Affiliates organization. Back in August, I was tipped off that, to entice ACS-SA groups to go to the NERM in Binghamton NY, there was going to be a $200 travel grant given to the first 8 who registered with the intension of presenting a poster. Well, this was not a difficult decision, especially since Binghamton was not far and the grant could go to other applications besides travel reimbursement...like a trip to the MARM in May :)
Anyway, it was a pretty good experience. The president elect, Catherine Hunt gave a really great talk and we are currently attempting to get her to come to Drexel to speak. Check out the Drexel ACS-SA website for further developments.
I put a link to the poster I presented so it is attached for anyone to take a look at along with a pic of yours truly doing a pose in front of it. Sorry it is cheesy. Unfortunately the lighting in the hall wasn't great, and it was at this point I thought to myself that a different color font would have been better. There were no judges so I just explained it to anyone who wanted me to or to anyone who was thoroughly confused... Basically I gave further insight to the DOPAL chronicles, and Ugi trial and errors that Khalid and myself have been through. I also mentioned that we are partnered with Beth Ritter-Guth and The UsefulChem writing partners to try an make what we do easier for everyone to understand. Also how we have become more automated with our CMLRSS feed thanks to Dave Strumfels...so check it out!

UsefulChem NERM ppt slides

Left to right: me, Leslie Mann (ACS-SA Secretary), Pereen Ghayal (ACS-SA President)

Yes the flash was not on, but What am I pointing to?...I think it is the Molecules Blog

Deep Linking in UsefulChem Molecules RSS Feed

eMolecules now provides deep links for many of its suppliers, and this information has been incorporated into the UsefulChem molecules RSS feed.  The feed also now only shows commercial suppliers.  To view this new information, you can either subscribe to the feed with Bloglines (or any other feed reader), or check the Useful Chemistry Molecules web pages.  The latter also provides both Excel workbook and text versions of the data.

Docking Progress

Sean has made some really good progress on the docking front. He learned how to use THINK software to reproduce the docking of some of our anti-malaria targets. This is important because we want to see if some of our intermediates or potential synthetic targets have a chance of inhibiting enoyl reductase.

This morning Dave put up a page enabling the viewing of the diketopiperazine UC0010 docking in enoyl reductase with Jmol. This is very nice because it allows for interactive rotation and zooming into the docking site. Right click on the image to change settings and left click to rotate. Jmol is not showing the hydrogen bonds to the catechol moiety so we still have some work to do but this is certainly orders of magnitude better than what we previously had to work with.

CSLC Versus eMolecules -- Round One

I've finally updated the UsefulChem Molecules blog (subscribe to with BlogLines here) to show eMolecules as the supplier instead of chmoogle.  I've also added a link to perform searches for sub-structures (there are simply too many in most cases to be included directly in the feed).

Using the updated feed, I performed several comparisons between Chemical Structure Lookup Service (CSLC) and eMolecules, and eMolecules came out the clear winner.  For example, for the SMILES
"C(C(NC(=O)OC(C)(C)C)Cc1ccccc1)(=O)O" (which is UC0005 in the UsefulChem Molecules blog), CSLC returned 17 hits, whereas eMolecules gave 46.  Other SMILES gave similar results.  Sheer number of results, of course, may not be the whole story.

Chromatography of Polar Stuff

Since we have been faced with purifying very polar materials lately (such as Khalid's amines), here is a solvent system recommended on Org Prep Daily that might help avoid streaking. It is interesting that in this case methylene chloride does not work as well as chloroform. Also read the suggestions in the comments.

Questions for Group

I am working on a definition of "open chemistry" in terms of philosophy and practice. If you have a chance, please offer your ideas about these questions:

1. How do you define "open chemistry"?

2. In your experience, is chemistry, as a discipline, "open" or "closed"?

3. Why do you believe there is opposition to "open" science (specifically, chemistry)?

4. Are you aware of funding agencies requiring open access to publicly funded research? How do you feel about that movement?

5. What is the root "philosophy" of sharing data?

6. How is sharing best practiced (in your opinion)?


Thanks!

Beth RG

The Isonitrile Problem

We had a UsefulChem group meeting yesterday Oct 2, 2006 with James, Khalid, Alicia, Dave and a new member Sean.

On the laboratory front, we finally have access to both C and H NMR. With the synthesis of DOPAL solved, the obstacle to getting our anti-malarial compounds made remains carrying out a Ugi reaction followed deprotection then cyclization (UDC). We have been following a paper with limited experimental data which has made it difficult to tell where things are failing. It would be helpful to replicate a prior published example of a UDC strategy to generate a diketopiperazine and compare NMRs to make sure that we can at least do that. So far we have not found such a paper or report but here is a place where we are collecting references. Please add relevant links.

So I think we need to make a better effort to make, isolate and characterize a Ugi product and then worry about the deprotection and cyclization. Having access to C NMR is going to make this much easier. In fact Lin is analyzing a simple Ugi reaction with piperonal so we may be close to getting a handle on this first step.

I spent some time going over Armstrong's paper on the convertible isonitrile in the Ugi reaction. Every lab member working on this project needs to read this paper carefully. There are some detailed experimental procedures for carrying it out the Ugi reaction and some discussion about the mechanism. Note especially that the proposed mechanism on p. 2577 shows a protonated imine serving as a leaving group to drive the reaction. I don't think a protonated amine, which we would have during the cyclization step using our benzyl isonitrile derived Ugi products, should behave that differently. I'm willing to accept that it might but I don't know why. Any ideas? Unfortunately Armstrong did not test another isonitrile in this paper and he did not make diketopiperazines, although he does demonstrate cyclizations to seven membered rings.

In case we do need the cyclohexenyl isonitrile used by Armstrong, Khalid has located a company and is awaiting pricing info. When we looked previously it was not commercially available.

Otherwise Dave talked about his progress on the cheminformatics front and Sean had to leave before reporting on his docking calculations. More on this later.

Org Prep Daily

I just posted a little review of the OrgPrepDaily blog compared to Synthetic Pages for the publication of organic chemistry procedures.