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Death by Chocolate
For those of you who don’t know, Dr. Joe Vinson is iconic to the chemical community (believe it or not, even more so than Soderquist). The American Chemical Society frequently hosts his seminars on some of life’s guilty little pleasures, coffee and chocolate. I recently had the chance to sit in on his “Science of Chocolate” seminar. And after and hour of lecturing about the history and chemical make up of chocolate, he took questions from the audience. When I used to housesit for my aunt, I remember her telling me to be careful not to feed the dog chocolate because it could kill them. I also recall coming across a warning by the ASPCA about the dangers of cocoa bean fertilizer.
With my curiosity, I decided to ask the expert. “Why is chocolate toxic to dogs?” There was a bit of laughter behind me after I posed the question. Vinson claimed that the theobromine was responsible. “You would think that for a 100 pound dog it would be okay to feed them chocolate safely. But you can’t.” He then took the next question while I sat there completely unsatisfied with the response.
So (like my daschund and miniature pinscher) I went digging. Despite the name, theobromine has nothing to do with halogens. Theobromine (or more IUPAC-y, 3,7-dimethylxanthine) is a structural derivative of caffeine. In fact, several species of plants synthesize caffeine by converting xanthosine into theobromine. The biosynthesis is concluded by N-methylation of theobromine by caffeine synthase (using S-adenosyl-L-methionine or SAM). Recently, Crozier and co-workers mentioned that several groups have reported identical biosynthetic routes to caffeine (Coffea Arabica – coffee; Camellia sinensis – tea; Theobroma cacao – cacao; see Phytochemistry 2008, 69, 841-856). At any rate, both theobromine and caffeine are stimulants (caffeine much more so).
It appears that theobromine metabolism has only been moderately studied in the scientific community; most research has revolved around human metabolism. Arnaud and Welsch (two research chemists at Nestlé in Switzerland) used 14C-labeled theobromine to determine the metabolic breakdown of the alkaloid in rats (J. Agric. Food Chem., 1979, 27, 524-527). They determined that theobromine and methyl uracil were the major radioactive components in the urine (accounting for 85% of total radioactivity). Other side products included 7-methylxanthine, 7-methyluric acid, 3-methyluric acid and several others. Interestingly, they noted large similarities in the chemical composition of urine samples in both humans and rats that had been given theobromine. However, there were quantitative differences between the two species. Along with their paper, they actually printed pictures of 2D-TLC plates of urine samples of humans and rats.
By comparison, it appears that the canid (or canine) biochemistry for metabolizing theobromine is strangely unique relative to humans (and rats for that matter). The consensus opinion appears to be that dogs are unable to metabolize and then excrete theobromine efficiently. Upon ingestion of a theobromine-containing substance, dogs have been reported to excrete “small quantities of an unidentified but apparently unique metabolite” (Drug Metab. Disposition 1984, 12, 154-160). It also appears that the toxicity associated with the inability to metabolize theobromine causes an increased concentration of intercellular free calcium, which is consistent with significant CNS stimulation and tachycardia (J. Agric. Food Chem., 2005, 53, 4069-4075). Physiologically, theobromine ingestion in dogs is linked to epileptic seizures, heart attacks and death.
Bottom line: stick to the peanut butter. It’s much safer.
A Word on Research Misconduct
Dig out your dictionary and look up the word “hyperbole” (I know, it might be a while since you’ve last had English class)—exaggerated statement or claims not intended to be taken seriously. I tend to hyperbolize a bit when I replay an incident that happened at the bar or in class, which I attribute to the fact that I’m a terrible storyteller. I think we all do it to a certain extent. I know I’ve once said something to the effect of, “It was the greatest movie, ever…in the history of humans.” A hyperbole at its finest.
While most common vernacular is riddled with hyperboles, I’d argue that the majority of intellectual study makes an effort to stay away from gross exaggerations (with history being the exception). In particular, science is the observation and study of the physical world, and it leaves no room for hyperboles. Just facts. For example, if you mix an aqueous solution of silver nitrate with an aqueous solution of sodium chloride it is a fact that a precipitate will form. There are no equivocations about scientific facts. Though, science sometimes falls short when making assumptions that connect two or more facts into one coherent theory or proposal. Still, these assumptions, en route to a new theory, are usually reasonable if not simplistic (i.e. Occam’s razor).
What about bad data? Of course, there are ways to make our raw data more “natural” without exaggerating. In the event that we have to plot data points, for example, as scientists we can exclude data that “doesn’t belong.” We call these anomalies “outliers” and there is statistical rationale as to why a stray might be “bounced” from the data set without any bias to the result. But even in these cases, the data point is often so far away from the others that including it might be a detriment to a fact about Mother Nature.
What irritates me to no extent is a term I refer to as “hyperbolized research.” We have all seen these situations before: yields that are bumped a good 5 to 10 to 50%, data that is fit just right, patent procedures that are not reproducible. Why are these practices tolerated? Contemporary science is themed “publish or perish,” which essentially means that if you are not producing enough results (nevermind quality) you will soon be unemployed. I recall hearing stories about early 20th century scientists who studied science without the proverbial gun to their respective heads and still made great findings. A lot of these experiments were groundbreaking, marvelous and truly beautiful.
It’s no surprise that this issue of “publish or perish” rears its ugly head in science. Society is incredibly fast-paced, and science is certainly trying to keep up. But, it’s really hard to do so with a tiny, bankrupt research group (where most if not all members are teaching) versus a behemoth firm with hundreds of years of experience and millions of dollars of materials to use.
So, what do groups do to keep pace (or at least appease the boss)? “How did you do with that reaction you couldn’t get to work last week?” “Um…I got 98% yield with 95% ee.” “Great, let’s write up a manuscript and submit to JACS.” I’ve heard stories of “big name” research groups who’s members purposely inflate their yields to keep “the man” happy. In these cases, researchers keep two sets of lab notebooks: the real one (usually under lock and key with the actual experimental results) and the boss’ one (usually kept in the open, so the boss can see how his researcher got a 90% yield on chemistry that is next to impossible to reproduce). The bottom line is that papers get published, lectures are given and proposals are funded—criminality is rewarded. How is this right? Furthermore, how is it fair to another researcher who needs to repeat the results?
Have we not learned anything from the Bell Lab incident? For those not familiar, Hendrik Schön was a groundbreaking physicist working for Bell Labs in the late 1990’s. He was purportedly on par to win a Nobel Prize with his creation of an “organic molecular transistor.” The papers describing this work were met with criticism in the scientific community and at some point (c. 2001), Bell Labs launched an internal investigatory committee to examine Schön’s work. Their final report ultimately alleged 24 accounts of misconduct that were essentially fit into three categories: “Substitution of data,” “unrealistic precision of data,” “Results that contradict known physics.” In the end, he was ultimately stripped of his doctoral degree. But think about the repercussions of not investigating Schön’s findings. Had Schön’s work not been policed, potentially millions of dollars would’ve been invested into falsified research. While I’m aware that Bell Labs was recently closed, without insinuating anything, it makes me wonder if this Schön incident had any weight in the lab’s termination.
Rex Dalton covered the aftermath of this incident along with several other examples of research misconduct (Nature 2002, 420, 728-729). He ultimately offered up the following observation:
“Science may be self-correcting, but sometimes it is a painfully slow process.”
Perhaps he’s right. Sure, several papers are going to be questioned in the future. And of those papers, a few might be blatant lies. How much time is it going to take to correct these mistakes? According to Corey: “Occasionally, blatantly wrong science is published, and to the credit of synthetic chemistry, the corrections usually come quickly and cleanly.” Case in point? The hexacyclinol incident that was excellently covered by C&EN and by a couple of fellow bloggers: Derek Lowe and Paul Docherty. In this case, there was a rapid turn around (possibly due to public interest). However, this case might be the exception. It could be years before a questionable project is proven incorrect.
I know…you want me to provide a solution. Maybe there isn’t an immediate, reasonable answer. But, alas, here’s what I’ve uncovered: there are a few wonderful articles in J. Chem. Ed. about scientific misconduct, which both hover around the LBNL and Bell Lab incidents (see: J. Chem. Ed. 2002, 79, 1391; ibid. 2005, 82, 1521). The authors’ messages (albeit bluntly or implied) were that ethics and empathy should be at the forefront in the early years of scientific training. Some people cannot discern between right and wrong and teachers should do their jobs by teaching students about the rights and responsibilities of being a scientist. While I did not receive formal training on scientific misconduct, I was given a lambasting for bordering on plagiarism my freshman year of college. I learned my lesson early—you and your lab partner need to keep separate lab notebooks. Perhaps this experience has formed me into the scientist that I am today (I’m anal-retentive about my lab notebook).
I guess there is a remaining question still looming. What sparked this rant about “doing the right thing”? I’ve been repeating experiments for the past couple of months that were reported to be exceptionally clean (requiring no chromatography) and high yielding. Most of these reactions have tanked—miserably—even with exceptional preparation and precision. So, I’m painstakingly re-optimizing experimental procedures so someone else doesn’t have to. It’s taking a while—much longer than it reasonably should. But, hey, “sometimes (correcting science) is a painfully slow process.”
You are getting sleepy…
Just dropping a note to check out the new Ambien CR commercials that are playing on American television (not sure if they’re playing in other countries). You can find the commercials by clicking on the link entitled “Watch the Clips” on this webpage.
For those who are not aware, Ambien (now sold generically as zolpidem tartrate) is a pharmaceutical manufactured by Sanofi-Aventis that is used to treat bouts of insomnia. The controlled release (or “CR”) formulation is a combination of two drugs where one puts you to sleep immediately and the second signals your body to stay asleep.
Ambien’s generic version was recently approved by the FDA for sale in the United States. In many of these cases (as patent life expires) pharmaceutical companies will try to “improve” their formulation to extend the life of a patent (by filing another application). In this particular case, Sanofi was awarded a US patent on February 4, 2003 for a “controlled-release dosage forms comprising zolpidem or a salt thereof” (US patent #6,514,531). I’m guessing that Ambien CR is Sanofi’s attempt to prolong the life of their “Ambien” drug.
At any rate, Ambien CR’s new add campaign is being hailed as a revolutionary marketing strategy, predominantly because the commercials are simple, entertaining and urge you to want to check out their website without actually mentioning the drug they’re marketing. Truly brilliant.
First Day of Classes
Regardless of wheter you’re an undergrad, grad student, professor, industry worker, retired or anyone else who reads this blog, I wanted to wish everyone a happy start to the new school year! Though I openly admit I am tired of University life, there’s something refreshing about the first day of classes. As a scientist, I’m naturally curious to know what you all see on your campuses the first day of classes. I now present my experience in the first 20 min of the 2008-2009 academic year:
WARNING: MY CAMPUS IS HEAVILY GREEK
- The want-to-be sorority girl wearing shorts that are, well, just a little too high (these ones are sort of difficult to pick out, but they make you laugh).
- Two random guys talking about how [the University] has “a good shot” at winning a national championship this year (in football)
- The cookie cutter sorority girls complimenting each other’s shirts (“Your top is so cute!” I heard that 3 times between the 200 yards from where I park to where my research building is located)
- The freshmen girls decked out in Greek letters (shirt, flip-flops and tote bag) wearing huge sunglasses (it’s cloudy today)
- The fraternity guys wearing either bright, lime green or pink shirts while donning sunglasses (believe me, it’s incredibly cloudy today)
- I had to register my laptop 3 times with the University network even though I’ve been using the same computer for the past 3 years
- A full parking lot by 7:45 am (classes start at 8 am)
- People in suits passing out bibles
- The poster people in the student union (campus center)
- The only day you’ll actually see most professors dressed nice
- The only day you’ll actually see most professors on campus before 9 am
- The people at Starbucks were actually nice this morning (though somewhat groggy)
The Interface of Rose Bowls and Priestly Medals
Few equate chemistry with (American) football. You could imagine my surprise to see that this year’s chemistry SURP program featured a guest lecturer that would cover the symbiotic relationship between ethics and athletics. My freshman year of college, I had a philosophy professor that taught Aristotle’s Nicomachean ethics through a football analogy, but that’s the closest I’ve ever made a connection between scholarly aptitude and a rugged manly sport. After getting “special permission” from the department to attend (I’m definitely not a SURP student), I got the rare opportunity to sit in the same room with a prominent sports figure—the head coach of our University’s football team.
Those who know me will probably know which coach I’m talking about, but for the sake of anonymity, I’ll simply refer to him as “Coach.” Arriving a few minutes late, “Coach” darted through the door and up to the head of the classroom avoiding eye contact. Truthfully, I saw no difference between his social manner and most other profs (no smiling, reasonably polite yet focused). Rather than stand in a traditional lecturing position, Coach elected to sit at eye level with the 20 of us (some of whom were there to bombard him with football questions). He started the discussion by saying, “I’m not really sure what I’m supposed to talk about, but this’ll be pretty informal. I figure I’ll talk about ethics from my perspective then answer any questions you guys have, except about the football team.” That was a pretty reasonable request because if I were hypothetically in a room with Terry Francona, he probably wouldn’t want me to ask why he hadn’t benched Manny Ramirez weeks ago.
The crux of Coach’s discussion was two-fold and actually quite simple: (a) goal setting is paramount to excellence and (b) you have to learn to overcome anything that gets in the way of preventing you from reaching your goals. He offered up this story:
“I asked one of my wide receivers, ‘what’s your goal for the year.’ And, he says, ‘Coach, I want to catch 50 passes this season.’ That’s not a goal. That’s an end result. His goal should be to push himself to become a better player so that you are able to catch 50 passes…Now, if you mix distractions into the equation, you’ve introduced another hurdle to cross for you to reach your goal.”
At one point, Coach drew on King’s street sweeper quotation. For those of you who are not familiar here it is:
“If you are called to be a street sweeper, sweep streets even as Michelangelo painted, or Beethoven composed music, or Shakespeare wrote poetry. Sweep streets so well that all the hosts of heaven and earth will pause to say, ‘Here lived a great street sweeper who did his job well.’”
Coach’s overall message? Give it everything you have and you can sleep easy at night knowing you did your best. “It” in his case is defined as hard work on the football field.
That night I tried to distill away the football and civil rights references to understand how I could apply Coach’s lessons to my job/education as a chemist. I asked myself, “should I focus on making sure I have 25 papers before I leave grad school (I know, it’s a dream) or should I spend more time on developing my skills to be the best chemist I can be so that I can give my best at trying to get 25 papers before graduate school.” Ultimately I arrived at the later option.
I realize that while I do give an honest effort on most days, there’s always room for improvement. I argue that the blogging, literature searching and even podcasts I listen to are making me become a smarter scientist. But, do I really need to be listening to the new Tantric album while I’m trying to think my way through a reaction, for example? Should I eliminate my distractions (including occasional, social interaction) and maintain focus at all times? When do you call it a day? 8 hours? 13? 20? When is the job truly done? How do you correctly balance work and family/personal time? Perhaps I don’t have a good objective answer to any of these questions. But I’ll tell you that my lab bench and desk are now the cleanest and distraction-free they’ve been in a while. Let’s see how long this lasts.
P.S. I definitely plan on seeing the new X-Files movie this weekend (I own an “Asian Collectors Edition” of seasons 1-9). It appears to have bad reviews, but I’m a diehard fan, so I’ll go see it anyway. How about you?
Pushing the Envelope
When I was taking organic chemistry as a sophomore, the lecturing professor encouraged students to ask questions in his class. His reason? “If you have a question about something, chances are that someone else in the class has the same question.” Likewise, I believe in open communication, particularly in learning the rudiments of organic chemistry. Anyone who has taken a class with me will instantly recognize my trademark closing inquiry: “does anyone have any questions, comments or concerns.” I give students one last chance to bring up any issues before the lab begins. Usually, 95% of the time you can clearly hear a pin dropping on cotton during this time.
The problem I’ve encountered over the past couple of years is the lack of preparedness by the average student. Granted, the procedures will deviate from what’s in the book on occasion, but these concerns are addressed either in the prelab lecture or in my final instructions right as the lab period begins; I also leave notes about these issues on the whiteboard. Remember the old cliché, “there’s no such thing as a stupid question”? Some students recidivistically abuse this rule to the point of criminality. Here are a few conversations between students (S) and teaching assistants (TA) over the past few years of teaching organic chemistry. I’m sure you can supply your own examples.
S: “I spilled my product in the hood. What should I do?”
TA: “A celebratory dance?”
S: “My book says to add…um…sodium…brine…when the color changes. Do I add it?”
TA: “Did the color change?”
S: Pause. Smile. “Yeah.”
TA: “Congratulations! You answered your own question. You’re one step closer to being a synthetic organic chemist.”
S: “No. This is my last semester of chemistry.”
TA: “Really?”
S: “What’s the molecular weight of anisole?”
TA: “What’s the chemical formula?”
S: “C…9…8…7…H…”
TA: “What does your book say?”
S: “I didn’t bring it.”
S: “Can I go to the bathroom?”
TA: “You’re in college. You can do whatever you want.”
S: “So, I don’t have to do the lab if I don’t want to?”
TA: “I don’t care.”
S: “So you’ll gimme an A?”
TA: “No, I don’t care if you do the lab or not. But you have to do the lab to get an A.”
S: “That’s not fair.”
S: “The book says use ‘dichloromethane,’ but there isn’t any in the hood.”
TA: “You’re better off using ‘methylene chloride.’ It’s better for the environment.”
S: “Is NMR-chloroform a halogen?”
TA: “What do you think?”
S: “I think it’s halogenated…no, wait, it’s non-halogenated.”
TA: “Why?”
S: “Didn’t you say ‘H’ is replaced by a ‘D’ or something?”
S: “I have a question.”
TA: “Okay.”
S: The student holds up a flask with a boiling stick in it, waiting for an answer. “What should I do?”
TA: “Yes.” He walks away. The TA makes his way around the room and returns to the student 20 minutes later.
S: “Should I add the hydrochloric acid or the sodium stuff?”
TA: “Yes.”
S: Sigh. “That’s not helping.”
TA: “True?”
S: Sigh.
TA: “Oh, wait, you wanted me to say ‘no.’”
Just a Suggestion
Picture this: you are expected to do a cross-metathesis, Mitsunobu, hydrolize the ensuing ester and cross-couple with (s)-proline. Not necessarily a difficult order to an experienced organic chemist. The challenge is finding a procedure/reference that will work on your substrate. You crawl through several Google searches (because you’re too lazy to get to walk across campus to the library and use SciFinder) and come up with ballpark, unreasonable hits. Are you seriously going to do a cross-metathesis in cresol just because the paper says there was a “noted rate enhancement”? How many total syntheses will you crawl through to find the right tosylation procedure? I encounter this frustrating problem on a weekly basis. Isn’t there a middle of the road procedure or set of procedures someone can consult?
Look no further than Li, Limberakis and Pflum’s relatively recent book entitled Modern Organic Synthesis in the Laboratory (ISBN-13: 978-0195187991). Truthfully, I’m not one for plugging media (movies, music, books, etc.), but this text rocks! It’s on par with Li’s Named Reactions (ISBN-13: 978-3540300304) book, which got me through cumes a few years back.
Those who know me well also know that I’m obsessed with Leonard, Lygo and Proctor’s Advanced Practical Organic Chemistry (ISBN-13: 978-0748740710)—a splendid reference covering the ins and outs of any organic laboratory. It’s full of useful information ranging from how to set up a laboratory notebook to Grignard preparation to anoxic techniques. I’m living proof that any idiot can consult APOC and have a vague idea of how to correctly conduct a majority of laboratory techniques.
Similarly, Li’s MOS puts a modern twist on most of what APOC covers then throws in generic procedures for running a cross-metathesis or doing a EDCI-mediated peptide coupling, for example. There’s even a section on lab coats! (SPOILER ALERT: baggy is not the way to go). My only criticism is that I wish there were even more information. Though, both references are conveniently concise (~200 pages) and cut through the BS that most technique books love to cover.
My boss received a desk copy of MOS a few months back, and I think it’s spent more time on my desk than his; I just added the book to my Amazon wishlist. I encourage you to do the same (even all you nuclear chemists…you never know).
Better Living through K-Carb - My Salting out Saga
I have run this reaction nearly 20 times; it’s a known procedure that takes ~5-7 days to run, and I do it once every 2-3 months to bring up starting material. Though the reaction offers mediocre yields (~70%), it’s a cheap and effective way of making a synthon I need for research. In one of my previous projects, I realized that adding a fresh portion of reagent to a drawn out reaction could sometimes be the difference between 60% and 85% yields. With that in mind, I added a second, freshly distilled portion of my reagent and let the reaction go another 24 h. Like a charm, the remaining starting material vanished from my TLC plate, and I was left exclusively with the desired product!
The workup, however, was disastrous. Instead of a typical bilayer upon quench, I had this cloudy, colorless solution—much more worse than any emulsion I have ever encountered. Instincively, I figured that I could use NaCl to salt the hell out of the reaction and separate the two layers. Two problems: (1) in retrospect I realize that this technique really only works on non-polar solvents (like hexane) and water; I had methylene chloride and water. (2) My aqueous layer was already saturated to begin with. Dilution with additional DI water did nothing productive.
Then it hit me. We encountered a similar problem this past semester while we were trying to hydroborate octene in the undergraduate organic labs (see: J. Chem. Ed. 1990, 67, 975-976). Kabalka’s solution to the mono-phasic cloudiness? Saturate the reaction mixture with K2CO3. I thought it was one of the coolest tricks I’ve ever seen in an organic lab (and I’ve seen Grignards go in wet ether). Sure enough, the technique worked well in my case. The cloudy, colorless solution transformed into a clear, bilayer with a tinted-yellow aqueous layer and a clear, colorless organic layer.
A word of caution! Be careful using this technique with base-sensitive reactions! Remember that while pKa of carbonic acid is ~6.5, H2CO3 dissociates to CO2 and H2O, and the pKa of water is 15.6.
A Proverbial Fork in the Road
I hate knocking on my boss’s door. I hate it even more when I have to beg for money so I can buy a reagent/reactant. Fortunately for him, I’ve been good though in my years as a graduate student (relative to other colleagues). Why buy the acid chloride when we have 3 L of SOCl2 and a kilo of the carboxylic acid? Similarly, why pay $200/night for a hotel room on the Strip in Vegas when we can pay $75.95 on a side street? I call my actions “pennywise”; my wife calls them “cheap.”
The reality of research, especially for a fledgling group, is the almighty dollar. All of the countless columns, long hours and the associated b.s. yields more breakthroughs and, with them, more papers. With more papers comes more exposure; with more exposure comes more money (i.e. for the University, unless you know a damn good IP attorney…à la Robert Holton). So, we work long ours, run numerous columns, attempt to cure cancer, etc., and at the end of the road, what’s left? Typically, a meeting with your boss where he says the following gem: “The American Cancer Society ranked our proposal 6th out of 47. So, I’m glad about that. But they’re only funding the top 5 projects.”
As chemists, we perpetually attempt to improve our standing by spending more hours in the lab, running more columns, washing more disposable test tubes, using other groups NMR time, etc. I’ll drag myself back to point by reiterating the old cliché, “Necessity is the mother of invention.” With respect to our research group, as the money tree becomes less fruitful, I’ve been forced to think outside the box and rely on other methods besides picking up a Sigma-Aldrich catalog. “I’m a synthetic chemist,” I tell myself, “I can make crystal meth in my bathtub if I feel so inclined.” The overall message is pretty clear: why buy it if you can make it?
Most synthesis geeks, are probably familiar with Rochester’s Not Voodoo website—a resource promising to demystify the magic that is organic synthesis. Out of all of the pages, I’m a huge fan of, “Buy it or Make it Yourself.” On this page, scientists are encouraged to vote over whether you’d make LDA or buy it, for example. While most of these reagents are no-brainers to a synthetic chemist with a few years under his or her belt, what about the borderline reagents? Sure, you can buy 9-BBN, or you can make it from borane and 1,5-cyclooctadiene (if your technique is good enough). Are you confident enough to handle as expensive as a task of making Wilkinson’s catalyst, or is it more advantageous to buy it? Would you really derivatize Hoveyda/Grubbs-II or contract Strem to make the water-soluble version?
Though chemists can argue over whether you should buy or make a reagent, I’m surprised at how many of my colleagues favor the catalog to the benchtop. It’s refreshing to open up a brand new bottle of 6-methoxytetralone. But, at what point do you suck it up, make the damn synthon, and save your group $200? My philosophy is simple. While I’m in grad school, learning new techniques anyhow, why not make a reactant if I can?
P.S. My previous readers love to play the game “which one doesn’t belong.” Good luck with this one:
Yamaguchi, Lester, Corey, Keck, Nicolaou, Buchholz
P.P.S. There’s actually 2 that don’t belong.
