synthetic chemistry

Calling Out the Synthetics

The dirty truth in the synthetic literature is that reaction yields are inflated. After many long discussions with my synthetic friends, they all admit that the yields reported in their papers or the yields they report to the boss are often the maximum yield they ever obtained. I will admit that when I was a stereotypical synthetic, I too would always report the highest yield during group meeting or to fellow colleagues. Regardless of those acts, it is still wrong and highly unscientific.


Average

It would be far more appropriate to report the average yield obtained for the reaction along with the standard deviation. When would we ever allow our g-chem students to only report their “best” titration for one of their labs? When did reporting the most statistically aberrational data-point become the norm? This behavior has become far too common for synthetics. Reaction yields should not be the yardstick used to measure one’s scientific manliness or ego.

I’m often comforted by my friendly synthetics that if a yield was abnormally high, they would investigate further and probably not trust it. I usually follow up those types of statements with, “do you check to see if that abnormal yield could be q-tested out?” The usual answer I get back, “q-test?”

This rant is meant to respectfully ask the synthetics in the audience to boldly begin reporting the average yield obtained for a reaction along with the standard deviation. By doing this, the stellar yields would still be deducible from this combination of yield + standard deviation, and the new format would be more scientifically meaningful.

Standard Deviation

– Mitch

By March 29, 2007 0 comments synthetic chemistry

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

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.

By August 16, 2006 0 comments synthetic chemistry