I recently picked up Nick Reding’s book Methland, which is about the blight of a small Iowa town due to methamphetamine use. I was interested in it because I had heard about it from NPR; I was interested in what Reding had to say about the chemistry of meth synthesis. What I found was pretty amusing.

I should pause to say that Reding was not focused on the chemistry at all — rather, his thesis was that meth was a mere symptom of the devastating effects of global economic forces on a small Iowa town. It’s well written and pretty gripping stuff.

I’m sure I’m not the only chemist who can get distracted by chemical explanations that’s just obviously wrong. But some of the explanations were just terribly, terribly wrong:

“Mirror imaging is a process whereby a chemical’s molecular structure is reversed, moving, for example, electrons from the bottom of a certain ring to the top, and vice versa. Pseudoephedrine, ephedrine, and methamphetamine are already near mirror images of one another. To make meth from ephedrine, it is necessary to remove a single oxygen atom from the outer electron ring. Thus ephedrine and methamphetamine not only look the same under a mass spectrometer, but both dilate the alveoli in the lungs and shrink blood vessels in the nose-hence ephedrine’s use as a decongestant while raising blood pressure and releasing adrenaline. The key difference is that meth, unlike ephedrine, prompts wide-scale releases of the neurotransmitters dopamine and epinephrine.

What the 1997 tests at the University of North Texas showed was that, at least in lab animals, mirror-image pseudoephedrine was equally as effective as regular pseudoephedrine as a decongestant. Unlike regular pseudo, however, the mirror-image version didn’t cause any side effects to the central nervous system, such as high blood pressure and a racing heart: the common “buzz” that one associates with cold medicine. Better yet for Warner-Lambert, mirror-image pseudoephedrine could only be synthesized into mirror-image methamphetamine, which, according to the Oregonian, had no stimulant effects and could not then be made into regular meth.” (quote thanks to Mike the Mad Biologist.)

Where to begin? First of all, “mirror imaging” is not a term; the word you’re looking for is, of course, enantiomers. The explanation about electrons is not correct; you can’t move electrons willy-nilly around rings. The comparison of ephedrine and methamphetamine as mirror images is wrong — they’re not even structural isomers. To make meth from ephedrine, you don’t “remove a single oxygen atom from the outer electron ring” (that sounds like something you do on the planet Zefu), you remove an oxygen and a hydrogen from a side chain by reduction. Ephedrine and methamphetamine most certainly DO NOT look the same under a mass spectrometer; I imagine it’s quite easy to distinguish the peaks from one another. Did Reding’s editor basically make a pass on the science stuff?

Reding’s book relies heavily on a series of articles on the meth epidemic written by Steve Suo of the Portland Oregonian. (If you look in Suo’s articles, you’ll see that Reding basically reworded the somewhat-more-correct chemistry explanation from Suo’s article.) Reding and Suo’s larger point  is that (-)-pseudoephedrine does not generate CNS-active methamphetamine, and that Warner-Lambert (and subsequently, Pfizer) were not interested enough in the larger public health issues to spend the money to push (-)-psuedoephedrine through the FDA approval process when the enantiomer they had was already quite lucrative.

So now that we’ve had a laugh about bad chemistry explanations, a question for everyone: how easy is it to get (-)-pseudoephedrine? The companies in India contacted by Suo said that they could supply ton quantities, no problem. I’m skeptical, but not that skeptical. Anyone out there know about this?

Link: Wolfram|Alpha Chemistry 101

Mitch

Although chemists don’t have a chemistry rock star, Youtube has made Martyn Poliakoff as close as we’ll get. Unless someone is bold enough to go the Paris Hilton route.

Safety Note: The cake baker, Samantha Tang, has no gloves on although she has a lovely accent and introduces me to a new interjection, “Pants!” In the background there are other lab workers without lab coats and their personal protective equipment.

Phil first covered the website earlier this year: The Periodic Table of Videos

Mitch

We’re going to be taking time out of our regular blogging schedule to remind everyone about better lab safety practices. Recently at Lawrence Berkeley National Laboratory someone poured isopropanol into an acid waste container of aqua regia. Aqua regia contains nitric acid, and the reaction for those unfamiliar with nitric acid’s oxidizing power is thus,

Due to the pressure in the waste container, the bottle blew and spewed its golden goodness throughout the room. It fractured the safety sash, and could have really hurt someone.

The lessons you should take home:

• Get rid of strong oxidizing acid waste as you generate it.
• Do not trust others near your waste bottles. Don’t let others add to them.
• If you generate strong acid wastes, probably a good idea that everyone from the undergrads and lab techs to the postdocs are made aware of the incompatibility of organics and nitric acid. You can’t expect chemists to have this knowledge anymore.

Mitch

All of which allowed the opportunity to uncover some really, um, interesting bottles of things.

Talc.  Maybe we’ll refinish our lab counter tops.

Chunk marble.  Seriously.  Quarter sized chunks of marble.  In a labeled bottle.

But the best…..

Oh… 50-75 milliletrs of elemental mercury.  Nice.

Have a great week, everyone.

I didn’t know that Avogadro’s constant has changed slightly. IUPAC and IUPAP were embroiled in controversy over whether to consider the mole to be the number of oxygen atoms in a sample of oxygen-16 or as the physicists preferred, the number of atoms in a fixed sample of carbon-12. By adjusting the standard, the atomic mass unit slid a little, so that hydrogen was no longer 1.0000 amu, but became 1.0083 amu. To me, Avogadro’s number was a constant, an unvarying and mysteriously established number in the universe like pi or Euler’s number. In reality, it’s nothing more than the definition of an arbitrary unit of measure unvarying only so long as the units chosen to measure it. Technically so are approximations of pi and Euler’s number, since they are written in the base 10 system we use for counting.

The physicist Richard Feynman, arguably well known for his antics as much as his science, wrote of “fragile knowledge” in his book, “Surely, You’re Joking Mr. Feynman”. I’ve only recently read it, I sort of happened upon it at the bookstore. He recounts how he capriciously got some people to look in astonishment over a french curve and note how the lowest point at any of its curves was designed to have a horizontal tangent, no matter which way it was turned. The trick was of course, that it wasn’t designed that way, the lowest point of any curve has a slope of zero! Yet here were a bunch of students who had taken calculus and were all using pencils to establish for themselves this peculiar whim of french curve makers. The story struck a chord with me, since it set the lower bound for the harm caused by fragile knowledge: Looking like a fool.

Yet this is the way I was taught the number–as a number–not as a relationship or standard. When you think about it, this is the way we’re taught many other things, like pi as 3.14, instead of  “the ratio of the circumference of a circle to its diameter”. My question is, why insist on this sort of teaching? So that students can focus on calculations and thereby “learn what they need to know?” That’s foolish and short-sighted, as demonstrated by my experiences fooling teachers into believing I knew anything about stoichiometry and getting Bs (which stood for Better than I deserved). So what if the time available in a semester or school year is limited, isn’t the measure of how well something is “taught” the extent to which it is “learned” (as in- not simply memorized)?

In fact it was only after reading Asimov on Chemistry a long time ago, that I was able to finally get a handle on constants, the real tragedy being that this information is not something I could have gotten from a class or even my college level chemistry textbook. I could not have even developed an interest an chemistry (or math- another story) were it not for my readings outside the classroom. It’s easy to understand why it’s important for students to learn to manipulate numbers in chemistry, but what is the point if they’re doomed to be obsolete calculating machines who can give you the recipe for 1M sodium acetate, but have no clue what that information means?

The video was made by Christopher Hendryx as his thesis for Ringling College of Art & Design.
Link: http://vimeo.com/4433312

Mitch

“Can Reaction Mechanisms Be Proven?” generated spirited responses from its reviewers. The reviews were approximately evenly divided, and all were of very high quality. The authors agreed with the editor’s proposal that the reviewers convert their reviews into rebuttals or affirmations of the authors’ position for publication along with the article, which has been revised based on the reviews. Most agreed to such a process and their comments appear here. We hope that publication of this paper and well-reasoned rebuttals such as those provided here will initiate a wide-ranging discussion. JCE will provide an online forum for further discussion of the issue. Our hope is that both faculty and students will contribute their opinions and ideas to this discussion. -JWM

Huh.  You don’t usually hear about that happening too often.  So now I had to read the article.  It’s pretty fascinating, and I encourage you to read it all.  I’ll summarize and give my thoughts below the jump

The paper starts out with a bit of philosophy: how do we know when we “know” something?  Note that textbooks routinely tell us  reaction mechanisms can never be proven.  That is, we always talk about the “proposed” mechanism, and we never leave out that adjective and refer in the definite to “the” mechanism.  The authors conclude this is ultimately a philosophical limitation to knowledge: inductive reasoning cannot actually prove the mechanism of a reaction.  Repeated observations may suggest a mechanism operates a certain way, but 100 observations does not guarantee the 101st observation will definitely be the same.

The only correct way to theorize and “prove” a reaction mechanism – according to this philosophy of knowledge – is to postulate all plausible mechanisms… then run experiments to refute as many as possible.  The last mechanism standing doesn’t even win, though, as it only claims the title of “proposed” mechanism.  This sort of Survivor: Mechanisms mentality implies that “all knowledge is negative.”  We cannot Know (capital K) the mechanism of a reaction, we can only Know every mechanism the reaction does not follow.

The authors criticize this theory of knowledge sometimes referred to as “strong inference.”  We as scientists might think about atoms and bonds and orbitals and electrons and trajectories and charges……. but these are all just pictorial metaphors and mental constructs of the physical attributes of molecules and molecular motion.  Thus, all mechanistic observations are made through these man-made representations.  Does a negative result really negate the hypothesis?  Or is there a flaw in our representation and interpretation of the data?  Furthermore, the “strong inference” model also downplays experiments supporting a proposed mechanism.  They do have merit and deserve to be supporting evidence for a mechanisms – not just a lack of evidence against a mechanism.

As to the history of the elucidation of a mechanism, early mechanistic studies certainly failed to offer conclusive proof of a mechanism – especially the structure and conformation of transition state species.  Steady-state kinetics rely on observations of reactants, intermediates and products.  With no direct observation of transition state species (which have lifetimes on the order of molecular vibrations, or dozens of femtoseconds), definitive conclusions about those species and their formation and subsequent degradation can only be speculative.

However, advances in technology are now allowing the ability to resolve molecular motion to the femtosecond scale.  The field of femtochemistry has allowed observation of some of these exceedingly short lived structures.  Zewail received the 1999 Nobel Prize in Chemistry for his work in femtochemistry utilizing ultra-short laser pulses.  His Nobel lecture is adapted into print here.

So what can we say about mechanisms?  Can we prove them?  The authors conclusion is ultimately a dogmatic one: reinforcing a negative view on the study of reactions and their mechanisms (all we can conclusively do is prove them false) potentially discourages aspiring students from utilizing all possible tools (and very powerful tools, at that) at their disposal.  But they also note that, philosophically speaking, “we can never “prove” a mechanism – or any other scientific theory – absolutely.” (emphasis added).

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I think I tend to agree with reviewer David Lewis of Wisconsin-Eau Claire.  In his review, his answer to the title question is: it depends on what your definition of the word “proof” is.  It’s basically semantics.  Do we mean “proof” in the mathematical, Absolute Certainty sense of the word; or do we mean “proof” in the jurisprudence, Beyond a Reasonable Doubt sense of the word?  The answer to the title question changes depending on how you mean “proof.”  A sufficient body of support gleaned from a series of properly constructed experiments can serve to “prove” a proposed mechanism beyond a reasonable doubt … until such time as new knowledge or new technology allows for the construction of more and more thorough experiments to be carried out.

Two interesting case studies: the SN2 and the Mitsunobu reaction.  We all know how the SN2 reaction works, right?  Or do we?  The nucleophile should approach the electrophile from the back face, and – to preserve momentum – the leaving group should continue along the same trajectory as the incoming nucleophile, right?  Well, new evidence from the Wester and Hase labs suggests there might be more to it than originally thought.  Certain leaving groups were travelling significantly slower than expected by conservation of momentum.  The research team concludes that the nucleophile spins the electrophile 360 degC before undergoing SN2 addition.

The Mitsunobu reaction is a favorite quiz question for first year organic graduate students.  Next time you get asked the Mitsunobu mechanisms, tell your inquisitor, “it depends.”  Really.  The mechanism (click image for larger) changes depending on the nature of the azodicarboxylate, the nature of the phosphine, the pKa of the acidic proton, the phase of the moon, and the record of the Cleveland Indians.  Who’s to say the mechanism of the Mitsunobu reaciton has been “proven?”

I guess my final point would involve the conditions under which a reaction mechanism was “proven.”  A good mechanistic study will survey pH, concentration, electronic effects of the reactant molecules, etc.  But even still, all we can say is this is the postulated mechanism under these conditions.  Or, more melodramatically, this is the postulated mechanism on Earth. Remember, a reaction can theoretically proceed under any number of ionic, radical, diradical, and fragmentation pathways.  The energy surface for a reaction to occur is more like a mountain range.  The pathway requiring the lowest energy is the “accepted” mechanism.  But given sufficient energy and reaction conditions, other mechanistic pathways are attainable.  Given that the possibility for alternative mechanistic pathways exists to me says we cannot “prove” one mechanism as the mechanism.

In fact, this is kinda what the paper is talking about when it discusses eliminating all other possible mechanisms.  We can think of all sorts of crazy mechanisms to get to the product, and each of them will take a different path through our mountanous region of the energy surface.  We probe each mechanism to test its validity, and only the strongest mechanism surives.  This is why I liken this approach to Survivor.

Ya, know, I think we need a logo for Survivor: Mechanisms.  I’m no good with photoshop (or GIMP, for the open-sourced among us). But if you are, and you want to put together a logo for our Survivor island, you can email it to me, and I’ll post them here on the blog.  We’ll also need a name for our Survivor island.  I suggest Gibbs Free Pass (slogan: Minimal Energy Required).

Oh, and what do you think?  Can a mechanism be proven given our advances in technology?  Or is this all just a semantic triviality?

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I notice Sabbaitcal Epistles also covered this paper

The Basics
s-blocks are blue, d-blocks are green, p-blocks are shades of purple-pink, f-blocks are red. Black are for the elements that have never been studied chemically.

The Exceptions
The d-metals that are missing an s-electron in their octet are teal (green + blue). The f-metals that have an extra d-electron are brown (green + red). The super brights Palladium and Thorium gained or lost two electrons not in their native octet.

It was always difficult for me to remember where in the periodic table the electron configurations do not conform to what I would naively assume. I would hope this type of periodic table keeps it more in the mind of students.

Mitch