Chemistry Blog

Distractions

While sitting on the couch watching TV last night, I got to thinking about what I consider one of the most important parts of grad school: what you do when you are not in lab. The rest of the working world takes this time for granted. No matter how many times I tell my parents the hours I work, everytime I call them at 7 pm, they are shocked when I say that I still have to go back to lab to do some more work. Would anyone be shocked by the hours I work if I were an I-banker? Probably not. So why is this so confounding to people?

Both of my parents went to grad school in humanities fields, and they admit that they worked really hard, and harder than they work in the jobs that they went to grad school to obtain. This seems to be a common occurrence: you have to work your ass off to get a job where you don’t have to work your ass off. The exception, of course, is if you go into the academics side of things and have to get tenure before you start sitting on your thumbs all day. As one of my former colleagues said, “once you get tenure, you can stop wearing pants.” Beautiful.

To the point, chemistry differs from humanities because you have to actually be in lab doing something for anything to get done. If you were, say, a historian, then everything has already been done, you just need to compile and make sense of it. Don’t get me wrong, I’m not saying that is an easy task, but at least you can work on that at home in sweat pants. A task like chemistry really invades your life. You have to be present for every part of the process, from set-up to work-up to data collection. Automated instruments help some, but they really just make the process of collecting the data more efficient.

So what is the difference here? Does this mean that a chemist does comparatively more work than a historian to get a PhD? Maybe, but then again a chemistry student probably gets paid more and will finish in 5-6 years instead of 7-10. Sounds like a wash to me.

The big question is how does the quality of life in those years compare? Please add some comments about how you spend your “free time” and how this helps you cope with all the time you commit to the lab. Some bloggers have made mention of their distractions on their blogs already including fish and beer.

And no, reading blogs about chemistry doesn’t count!

movies

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Let’s Talk About Quinine

Quinine is one of the most important molecules in history (see the C&EN feature as one of The Top Pharmaceuticals That Changed The World.  Nowadays the closest most of us come to this wonder-drug is the bitter taste in those fantastic gin & tonics at the local bar.  Modern tonic water doesn’t contain enough quinine to be clinically effective, so it is only added for that great alkaloid taste.

Quinine was originally used by the Incas to treat malaria, and was later used throughout the world by conquerors from the Europe (a couple of other blogs have been discussing the merits of folk remedies versus pharma developed drugs: @The Chem Blog,  @Chemical Musings).  Anyway, this compound has saved countless lives, although now other remedies (e.g., chloroquine) have replaced quinine as a usual malaria treatment for cheapness and synthetic accessibility.  Resistance to chloroquine may put quinine back into the spotlight, however. Beyond its importance as a medicinal compound when isolated from natural sources (the bark of the cinchona tree), this has been a fascinating molecule for synthetic chemistry.  Most of the history of this story can be found in chapter 15 of Classics in Total Synthesis II, possibly the best chapter in either of the Classics books.  I’ll summarize some of this history here. Let’s begin with Hofmann, who decided it might be possible to synthesize quinine from components of coal tar, and he talked his student, Perkin, into trying this.  The idea was to take two equivalents of N-allyltoluidine (C₁₀H₁₃N) and three atoms of oxygen and, since you have the right number of all the atoms you would need for quinine (C₂₀H₂₄N₂O₂), they might spontaneously assemble and make the natural product (with water as a byproduct).

Those of us who are familiar with total synthesis will recognize that this is a low-yielding reaction.  Perkin ended up with a bunch of tar.  When cleaning his glassware with alcohol, he found that a purple compound was extracted from the tar, and this could effectively dye cloth a royal purple color.  The dye, mauveine (actually a mixture of two compounds), led to Perkin becoming a very rich man. Around the same time, Pasteur found that treating natural quinine with H₂SO₄ led to a different compound, now known as quinotoxine.  In 1918, Rabe reported the conversion of quinotoxine back into quinine.  Then some 25 years later, the great R. B. Woodward and his post-doc Doering synthesized quinotoxin, thereby completing a formal synthesis of quinine (details on the route here).

Now it gets interesting.  This synthesis was a landmark for Woodward, and would certainly ensure that he get a tenured faculty position at Harvard.  However, there arose some questions about the validity of the formal synthesis, because the work of Rabe had not been repeated in Woodward’s lab.  There is a fantastic review in Angew. Chem. by Seeman which investigates this debate at length.  I highly recommend reading this article.  It’s 30 some pages, but worth every letter (DOI link also featured in C&EN here).  Seeman ultimately concludes that Rabe did in fact convert quinotoxin to quinine in 1918, but these results may be difficult to reproduce since the experimental details are not very extensive. This is a very interesting example of prominent figures questioning the validity of results reported in chemistry journals.  This of course has been a hotbed of activity recently in light of Sames/Sezen-gate and hexacyclinol-gate.  The difference is that now RBW is not around to explain his actions and decisions.  Seeman did interview Doering (now an emeritus prof. at Harvard) and did get some insights.  It is hard to say with certainty with a 60 year gap in the record. We should all learn from this story.  Chemistry is done by human beings, and that can be a good thing or a bad thing.  Was Woodward knowingly skipping over steps he knew would be difficult to reproduce, if they were reproducible at all?  Was this a situation where the most important factor was publishing in order to get tenure?  We can’t know what was going through his head.  Another point that Seeman makes, which is perhaps the most powerful in the whole debate, is that it is astonishing how quickly opinion turned against the Woodward report.  As we get more and more skeptical of published results, we also run into the danger of becoming too quick to judge something false.  The suggestion that results may be fabricated are certainly not a conviction, and the community must keep that in mind.  Suspicious results are one thing, proving them wrong is quite another. Since the Woodward route was published, several others have appeared, notably one by Stork, who was one of the principle figures in questioning the validity of the Woodward/Rabe route.  Each of these syntheses is a great achievement.  Over the years quinine has touched the fields of medicine, synthetic dyes, politics, and ethics.  See, chemistry and history aren’t all that different after all! By the way, the Stork paper has the greatest abstract of all time. – movies

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Catalytic Antibodies and Addiction

At the risk of sounding too much like a narc, I have picked a controversial subject for my inaugural post on the Chemical Forums Blog. Before I get underway, I want to thank Mitch for the invitation to contribute here, and I also welcome Maz to the fold. I’m sure that each of us will highlight very different, but interesting topics. As for background, I am a grad student in synthetic organic chemistry in the US.

On to the post. This was inspired by a recent paper by Dickerson and Janda (at Scripps) regarding a catalytic antibody approach to the treatment of addiction (ACS link). Now I am no chemical biologist, so I admittedly have not followed any of the catalytic antibody literature, but here is my understanding: these antibodies are just like the normal antibodies our bodies produce to fight of infection and the like, except that these antibodies do more than just bind the offending molecule, they catalyze a chemical reaction changing the structure and, hopefully, the bioactivity/degradation of that molecule. Catalytic antibodies are great for pharmaceutical applications because they avoid many of the toxicology problems that plague non-natural therapeutics.

This is a powerful concept for addiction therapy since, for many drugs, the specific molecule responsible for the intoxicating effect is well known (e.g., LSD, cocaine). Although this idea is striking, what really caught my eye was the selection of the target in the Dickerson and Janda work: delta⁹-tetrahydrocannibol (THC).

I love to read the intro paragraphs of papers like this because they always talk about the sweeping socioeconomic effects of whatever particular ailment they are targeting. As someone who is in a first-world ivory tower academic institution, most of the time the reality of these diseases and effects are at arms-length; they do not directly touch my life. So this topic really struck me because everybody knows someone who just smokes weed all the time. Say what you want about the way some people choose to live/waste their lives, I have always thought it is not really my place to judge these people too harshly. More annoying to me is that a quick search of the Internet will give you a laundry list of reasons why marijuana should not be a controlled substance because, for one reason or another, some people think it just isn’t that bad, some even saying that it is not addictive (One from each side: DEA (pdf file), NORML). I have read all the arguments for legalizing marijuana, and I have not found one that really convinces me; it is still an intoxicant with demonstrated addictive properties (don’t give me the “so is alcohol” straw-man argument either).

As a scientist, I would really like to see some facts on the matter, and the intro to this paper gives some great scientific data on the subject. To paraphrase: the now famous “cannabis gateway hypothesis” does, in fact, have some real experiments that show that delta⁹-THC specifically changes opiod receptors in the body, perhaps making them more susceptible to other drugs (link to that study). Not proof positive, but a start that is not just based on surveys and statistical manipulation. To summarize the results in the paper, Dickerson and Janda have identified catalytic antibodies which do effect oxidative degradation of delta⁹-THC, mostly to cannabitriol (which is not the predominant metabolite in humans). Some detailed kinetic studies suggest that these antibodies may drop the effective half-life of delta⁹-THC from ~20 hours to less than 40 minutes. They have some preliminary biological data on the effect of cannabitriol (which incidentally is also a naturally occurring compound in cannabis) but they need some more extensive studies to shore up the efficacy of this approach in reality.

I guess my point is that while at one end of the spectrum pervasive drug use has slowly become a more acceptable part of our society, I am very happy to see that there are prominent scientists looking to address these problems as they would any other ailment. Kudos to these researchers for taking on an unpopular problem.

- movies

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Targets vs. Science

Most of the projects you see nowadays are directed at achieving a particular goal, and that’s a good thing. It can be easy to get distracted by other, unimportant details when there is a big difficult puzzle set out in front of you.  But what is the cost of this approach to science?

Suppose two groups are working on the same molecule.  One group goes with the brute force method and makes the molecule in a perhaps predictable and inelegant fashion.  The other group comes up with a beautiful idea and takes the time to execute that idea well, optimizing conditions so that there are no major weaknesses in the synthesis.  Which is better?  They both attained the same goal (making the molecule).  To complicate things, suppose the former group reports their synthesis 3 months before the latter.  Then what?

I am of the mind that the appearance of one synthesis shouldn’t cheapen the impact of a later synthesis, but it’s hard to argue that the chemical community thinks the same way.  How often do you see a second synthesis of a natural product show up in Org. Lett. instead of JACS simply because it was second?

More than just the implications for publication records and C.V.’s, how does this cause scientists to change their approach?  Some investigators are really embracing the approach where they just care about getting to the target first, no matter what the cost.  It seems that the chemical community is rewarding these types with high profile publications and certainly with funding, so it is a self-aggrandizing process.  What really irks me about this approach is how much thought gets lost in the process.  How many new reactions do scientists miss because they are only looking to get to that end product?  I’d bet there are a lot!

I can’t help but make the comparison to the business end of science.  Think about the med. chem. approach to chemistry: make a ton of compounds, yields or direct routes are irrelevant, just get the compounds to the bio assay.  It’s good business, and it certainly works, but a lot of elegance is lost in this approach.  Elegance is somewhat unimportant in med. chem. though because that’s not the point, but I see that mindset spilling over into academic chemistry and that is a poison to the field.

Academic chemistry should be about investigating new ideas in order to learn new things.  If professors think that the goal is just to serve industry, then we aren’t learning anything.  Industry does what industry needs to do, and it does it well.  The academic end should be pure and free of the dollars and cents involved, but if all you think about is finishing targets while ignoring the learning, you’ve missed the point.

Call me an idealist, but somewhere people need to be doing science for the sake of science.

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The Brick Wall of Science (with Aerogel!)

In contrast to the joy of crystallization,  there is always that sinking feeling when you can’t get something to work.

In light of recent events, chemists are becoming much more skeptical about the veracity of the results they see in print, and to a large extent, that’s a good thing.  In some cases, however, this can be problematic as well.  For example, recently I’ve been trying to carry out what should be a simple, routine reaction.  I won’t give any details, but the reaction is the very definition of “textbook.”  I can’t get it to work worth a damn.  I’ve tried everything I can think of, I’m following literature procedures to the T, but it just won’t work out the way it’s reported.

Here’s the real dilemma: this reaction was reported to work, but I can’t reproduce the results.  I even know other people who have had trouble reproducing these results.  So what is the problem?  I have to wonder whether it’s a failing in my abilities as a chemist, but at the same time, at what point do you say “These reported results can’t be right.”  I’m definitely not to that point with my chemistry, but if I were working with a reaction that wasn’t so firmly established I would have to seriously consider the possibility that the reported results were false.

So am I jumping the gun on this?  Did I just miss something in those papers I read?  I feel like I may be more likely to accuse falsification just because there have been some high profile reports of such things.

Then try to think of yourself on the other end of things.  Any chemistry that I publish will be true to the best of my knowledge, but what if someone questions my results?  I know I have evidence to back it up, but how do you tell someone that their inability to reproduce my results must be some fault on their end.  Worse yet, what if I made an honest mistake and misidentified something?  Is that forgivable, or would my carelessness mar all of my accomplishments.  These are serious issues and I think that some of this may have gotten lost in the fray of competing accusations.

So what am I to do, with a textbook reaction that doesn’t behave like it should?  How long do I pound my head in to the brick wall of science before I give up on it?  And perhaps a more ominous concern is what happens when someone asks why I didn’t just use this obvious textbook reaction instead of my obviously circuitous work around!!

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Crystals

You ever have one of those days where you do something in lab that’s totally routine, but then you encounter something that just makes you happy to be a chemist?  I had one of those today.  Most of the compounds I deal with are oils or liquids, but today I made a compound that crystallized after concentrating the organic layer after the reaction.  Nice white crystals with no purification at all.  That freakin’ rules.

I kinda want to try to sublime it now, because sublimation is easily the best part of chemistry.

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Blogging: An Outlet for the New Generation of Chemists.

Maybe I am selling the whole world short, but this blog thing is just exploding in the chemistry community. I’m a pretty avid blog reader, especially the chemistry ones, but that has been a recent development. I have to credit Dylan over at Tenderbutton for that. Dylan has approached his blog in a way that fellow grad students can really appreciate: the day-to-day difficulties in the lab, fascinating little observations, and a healthy shot of irreverant criticism of the chemical literature. This though process is nothing new, grad students have these conversations amongst themselves all the time, but Dylan seems to have made it okay for everyone to write these things on the internet. This is really great because you get to see what other people are thinking about the issues that are out there and see a little slice of how other people perceive chemistry. I like to read a bunch of the chemistry blogs just to get a feel for how new ideas are being accepted.

The blog atmosphere is very different from some of the other chemistry focused sites out there. Most of them are informational (e.g. organic-chemistry.org) and some are for teaching (e.g. Chemical Forums), which is all fine and good, but those sites don’t leave a lot of room for discussion with real experts (or aspiring experts) in the field. The key is that these blogs allow chemists to see how to think about problems (and solutions) in chemistry in a very critical way. It’s easy to pick up the latest issue of a journal and talk about how great some newly discovered reaction is, but it is perhaps more important to be able to identify the short comings of that chemistry because in doing so you will identify the next set of problems. Perhaps we chemists should look at these blogs as a way to better our own ability to look at the way we do science so that we can do it better!

Vivo el blogosphere de la química!

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