Thanksgiving with the Rents

Tetrabromo Anthracene from the Ground Up

Anthracene looks a lot like a big version of benzene, and to a large degree it is. If you wanted to make benzene with additional groups attached to it, such as bromine atoms, the chemistry is pretty well-established. If you want to add more than one group, and the exact positions of the groups are important, then it gets a little more complicated but it is still quite doable.

Anthracene on the other hand is rather less cooperative than benzene. The 9 and 10 positions on anthracene are very easy to modify, but the positions on the outer edges are a lot harder to get at with the same chemistry you would use on benzene. So how would you go about making anthracene with four bromines on the outer edges and not modify the 9 and 10 positions?

A recent article in the online Beilstein Journal of Organic Chemistry, the authors describe a synthesis of 2,3,6,7-tetrabromoanthracene in just four steps starting with benzene.

First they attach four iodines to benzene by reacting it overnight with I2, periodic acid and concentrated sulfuric acid. These seem like pretty forcing conditions, but they are necessary since iodine is the least reactive of the halogens. The periodic acid is necessary to oxidize the iodine to an "I+" species which then reacts with the benzene ring.

Next they use a coupling reaction to replace the iodines with tetramethylsilyl acetylene groups. The tetramethyl silyl (TMS)groups are protecting groups to prevent the acetylene from reacting at both ends. The coupling reaction itself is quite interesting and involves a palladium complex in which the palladium is effectively in the zero oxidation state - that is, chemically it is a palladium atom rather than being an ion. In the Sonogashira coupling reaction that they use, the Palladium complex and a Cu(I) ion interact with the pi-bonds to stitch together the acetylenes and the benzene ring in place of the iodines.

To remove the TMS groups they react the compound with a catalytic amount of Ag(I), which initially forms a silver acetylide compound. The acetylide ion does a nucleophilic attack on the bromine atom in N-bromo succinimide. In this case the bromine is effectively acting like Br+, with the succinimide acting as a leaving group.

At this point we have all the carbons and bromines needed for the tetrabromoanthracene, all that needs to be done is to make the rings on the ends. To do this they simply heat the compound in a high-pressure bomb. This is an example of a double Bergman cyclization, which can occur when you have an alkene with two alkyne groups attached to it - an "enediyne." This is a radical mechanism in which each of the alkynes donates one electron to make a new carbon carbon bond and close the ring. This produces a diradical. The cyclohexadiene is added as a hydrogen donor: when it donates two hydrogen atoms to the anthracene molecule the cyclohexadiene is converted to benzene.

Anthracene can undergo many of the same Electrophilic Aromatic Substitution reactions that are routine for benzene, but selectiviely modifying only the "end" positions is very difficult - the other positions on the rings are much more reactive - especially the middle 9 and 10 positions. So usually, any new additions end up in the 9 and 10 positions preferentially.  To get around this the somewhat counterintuitive solution is: don't start with anthracene.

Christian Schäfer, Friederike Herrmann, Jochen Mattay (2008). Synthesis of 2,3,6,7-tetrabromoanthracene Beilstein Journal of Organic Chemistry, 4 DOI: 10.3762/bjoc.4.41

Advice for Students

Have you ever had a hard time keeping up with all the things you need to do as a student?  Take a look at the Alpha Student web site.  It is run by a couple of college students in England.  The articles are listed in catagories: Academic, Career, Financial, Fun, Personal, Practical and Social.

Most of the articles are written by Ali Hale who is in a masters program in creative writing.  Take a look at this interview with Ali.  It makes me tired just reading about all of the different things she is doing while in graduate school - she writes for a bunch of blogs in addition to Alpha Student, and she did all of the coding for Alpha Student (html, css, and php).  

Why Do I Blog

I started this blog for the same reasons that I went to graduate school and that I teach. I think chemistry is really cool and would like to tell other people about it. As a lifelong science nerd and a chemist I've always been little frustrated the chemistry seems to get short shrift in the media. When you hear about science in the news it's seldom about chemistry. And when you DO hear about chemistry it's all about how bad chemicals are.

I have three main goals in writing for this blog. First of all I want to write about chemistry that I think is really interesting in a way that is accessible to anyone with an interest in science, in particular the students in my classes. Second, since I spend all of my time with college students, I'll write about things that I think might be helpful for them as students. Finally, for my own edification I plan to write about current research in chemistry.

Two sites that made a big impression on me in starting this blog are Mike Kaspari's blog Getting Things Done in Academia, and Researchblogging.org. Dr. Kaspari is a biologist who writes advice for grad students in biology, but his advice is good for any student. Unfortunately he hasn't been posting much this semester, I hope to see more from him soon.  Researchblogging.org is a web site that collects blog posts about peer-reviewed research in all areas of science.  I recommend both sites highly.

I'm still new at this and don't have many readers at the moment, but if you see something you like or have a suggestion I would like to hear from you.  Please leave a comment.

Well, how did I get here?

A musical interlude courtesy of David Byrne.

I miss the big suit, but I'm glad he's enjoying himself now.

Ask Questions - Stepcase Lifehack

Ask Questions - Stepcase Lifehack

When I was an undergrad I tutored Organic Chemistry.  One of the students I tutored was a biology major and a friend - Kathy was also in the karate club,  but that's another story.  She was a challenging person for me to tutor - because she asked questions.  Specifically - "Why does that reaction happen?" and "How do you know that is the product?" and other inconvenient questions.  I could tell her the answers to her homework problems, but answering these questions took effort.

I'm grateful to her - she made me think.  And trying to answer her questions forced me to understand them myself.  Asking questions and trying to answer them is an important step in learning new things. Even asking yourself questions and trying to answer them yourself.  Don't be complacent!  Be curious!  Ask questions!

How Do You Know It's a Mutagen?

How do you know if a compound will be a mutagen before you test it. Before you even make it?

Drug companies make lots of new molecules that they hope will be useful as drugs. But there are a lot of other things that can happen when a biologically active molecule gets inside you. A lot of potential drugs just don't work, or work poorly. Many work well enough for the task at hand, but have side effects that are unpleasant. Some side effects are inconvenient but tolerable, others are deal breakers. 

Making a new molecule and testing it is a time consuming process. Just making the molecule will involve several reactions run sequentially, and each step can require careful purification before you can go on to the next step in the process. Once the molecule has been made, there is a battery of tests to run both to see how well it works on the drug target, and to find out if it is likely to make the patient sicker through side effects.

It would be helpful if you could predict the toxicity of a compound before you go to the trouble of making it in the lab, or at least ruling out compounds that are likely to be highly toxic. In Accurate and Interpretable Computational Modeling of Chemical Mutagenicity, Langham and  Jain describe their work on predicting whether a compound is a mutagen just based on the types of atoms in the molecule. And they get pretty good results.

To do this properly you will have to look at lots of molecules, so you need a simple way to describe your molecules quickly without running lots of complex calculations. Langham and Jain had a computer program list all possible pairs of atoms in each molecule, and made a

 list of these atom pairs. The example they give in their paper is an atom pair found in aspirin described as O3_1_D5_C2_Ar2. This describes an sp3 hybridized oxygen attached to one heavy atom (not hydrogen) that is 5 bonds away from an aromatic carbon with two heavy neighbors.

Next you have to look for a pattern of atom pairs in a molecule that seems to be related to whether or not it is a mutagen. Just looking at the data would probably not be very effective, so the authors used three different Machine Learning techniques to look for a pattern: support vector machines (svm), RuleFit, and K-nearest neighbors (KNN). They analyzed a training set of 4337 diverse compounds, 2401 of which were mutagens and 1936 were not and found that the SVM method gave an accuracy of 0.77, and RuleFit was a little better with an accuracy of 0.79.

The real test is how well the model works in predicting the activity of completely new molecules. So next they used their SVM and RuleFit results to try to predict the mutagenicity of a completely different set of compounds taken from the Carcinogenic Potency Database (CPDB). With this new set of compounds, SVM (accuracy 0.770) worked a little better than RuleFit (accuracy 0.718).  This is far from ideal, but it's a pretty good start.  And it is interesting to see that such a simple criterion as pairs of atoms can be predictive of a complex behavior like causing mutations.

James J. Langham, Ajay N. Jain (2008). Accurate and Interpretable Computational Modeling of Chemical Mutagenicity Journal of Chemical Information and Modeling, 48 (9), 1833-1839 DOI: 10.1021/ci800094a

More Eric, Plugged In This Time

Same song as the previous post, but electric.  Watch the bass player to Clapton's left about 40 seconds into the clip.