How many TV shows can you name that star a chemist as hero and feature references to reductive amination? I can think of only one.
Breaking Bad is by far and away my favorite show on TV. It’s got a truly addictive combination: intriguing premise, great scriptwriting, great directing and strong acting talent. And honestly, I’m hooked.
In addition to all the other things I love about BB, it occasionally gets around to some chemistry. Yeah, I know, the science of BB isn’t flawless, but let’s be fair: by Hollywood standards, it’s great. These folks did their research. In a way they had to, because the show is after all about a chemistry teacher who turns to cooking meth. And while the chemistry of a meth lab isn’t horrifically complicated, it’s more so than it appears at first glance.
Permit me to explain.
The structure of methamphetamine is very similar to a closely related illegal drug called amphetamine. The only difference is a methyl or -CH3 group. (Drawings below are borrowed from wikipedia since in this case they’re accurate and I’m feeling lazy right now.)
Why the squiggly line on that second carbon (I’ll call it C2) over from the ring? That squiggly line is actually the interesting part. Organic chemists usually leave out the hydrogens out of these drawings because there are so many hydrogens and it’s kinda obvious where they are — carbon atoms in organic compounds generally have a total of four bonds apiece. The ball-and-stick drawing (again from The Wiki) below includes the hydrogens and makes it obvious why the squiggly line is important:
Let’s focus on C2 for a minute (the carbon right next to the nitrogen, second carbon away from the ring). It’s got a methyl group (CH3) and a hydrogen attached to it. Let’s say I swap the hydrogen and the methyl group so the methyl group is now sticking back into the screen and the hydrogen is sticking out. The result is a mirror image of the original molecule called R-methamphetamine(the original molecule is S-meth)*. And it doesn’t matter how you rotate or flip R-meth and S-meth around — you can never superimpose the one on the other. Just like your hands, they are mirror images that will never align. Chemists call mirror-image molecules like these enantiomers.
My favorite example of cool enantiomers in nature is R-carvone, the molecule that gives spearmint its scent. The mirror image of R-carvone is S-carvone, the molecule that gives caraway seeds their scent. R-carvone and S-carvone are alike in every way except they’re mirror images of each other. And your nose can tell the difference.
So here’s the neat thing about meth. While S-meth is a highly addictive drug, R–meth is a legal decongestant you can buy at the supermarket. Same chemical formula, same structure except it’s a mirror image of the street drug. Each mirror image binds to different proteins, just like the way your right foot fits into your right shoe and your left foot into your left — but not the other way around. And that’s why one enantiomer causes vasoconstriction while the other gets you high.
For the Walter Whites of the world, that’s a problem.
If you could just take R-meth and magically swap that hydrogen and methyl group around, you could make meth from the stuff you have in Vicks inhalers. Unfortunately (or fortunately, perhaps?) it’s not that easy. Any time you want to alter a molecule, you have to do so by means of a chemical reaction — take it and react it with something else that will give you the change or alteration you want. There’s no simple sequence of reactions that will convert R-meth into S-meth, so you have to do something else. Walter uses two different methods. We’ll take a quick look at each.
In Season 1 Walter uses the most popular route. It starts with a compound called pseudoephedrine or pseudo, a decongestant found in medications like Sudafed.
The black wedge means a bond sticking out of the screen, while the dashed hash mark indicates a bond sticking into the screen. So the good news here is that the methyl group and hydrogen on C2 are already in the correct orientation we need for S-meth, the street drug. All we have to do is get rid of that pesky OH or hydroxyl group.
Walter opts to use hydroiodic acid (HI) and red phosphorus. Usually meth cooks get the red phosphorus from matchbook striker pads and combine it with iodine and water to make their hydroiodic acid. This approach is so popular the DEA monitors sales of iodine crystals and iodine tinctures to keep meth cooks away from the ingredients they need. Combining the HI with red phosphorus, water and pseudoephedrine replaces the -OH on pseudo with an -H, yielding S-meth.
Straightforward as it sounds, this method can be hazardous to the inexperienced. Heating red phosphorus and an acid like HI can generate a fish-scented, poisonous gas called phosphine or PH3. Indeed, red phosphorus actually reacts slowly with moisture in the air to make trace amounts of the gas at room temperature. And while it’s much less dangerous than white phosphorus, red phosphorus is still very flammable. Not to mention the hydroiodic acid, which is a strong acid and thus highly corrosive.
The key limitation from the meth cook’s point of view, however, is pseudoephedrine itself. You can’t go by your local drug store and pick up a couple hundred boxes of decongestant pills; the store clerk will call the cops, and you’ll have some explaining to do.
In Season 2 of Breaking Bad, Walter unwisely promises four pounds of meth to brutal drug lord Tuco — due by next week. Jesse is understandably horrified. He points out there’s no way they can get that much pseudo so soon. That’s why Walter and Jesse switch to plan B, the older P2P method. And here they run into a couple problems.
First, the ingredients. The P2P route starts with a chemical called phenyl-2-propanone or P2P. Don’t let ugly-sounding chemical names like these intimidate you, by the way — they’re just a “code” that tells you the structure of the molecule. Chemists name molecules using an internationally-agreed-upon system so that you can use the name of the molecule to draw its structure. (Molecular biologists are unfortunately a lot more random when it comes to naming things.) Phenyl is a particular kind of six-carbon ring, propan indicates a three-carbon chain just like propane, and 2-one means we have an oxygen double-bonded to carbon 2 of the three-carbon chain. Which gives us this:
All you need to do is replace that double-bonded oxygen with a nitrogen that has a methyl (CH3) group attached to it, and bingo! there’s methamphetamine. And there’s a name for a nitrogen (an amine) that has a methyl group attached to it: methylamine. Which is why Walter wants to get his hands on some of that stuff.
The DEA is keenly aware you can use P2P to make meth, so it’s a controlled substance. That’s why Walter chooses to synthesize his own P2P starting from phenylacetic acid.
How about the methylamine? A chemist of Walter’s talents could easily make methylamine from other readily available reagents, but instead he and Jesse decide to steal a barrel from a warehouse. I’m assuming the scriptwriters opted for theft just to add some more drama, because there’s no reason why Walter would take that kind of unnecessary risk. But hey, any excuse to make use of the thermite reaction is a good excuse, right? (The thermite reaction is a popular demo in undergrad chemistry classes, and as an undergrad I saw demos like this twice. The shower of white-hot sparks this violent reaction generates is undeniably impressive.)
The trademark blue color of Walt’s meth, by the by, is actually a little odd. High-purity meth is clear in color. A blue tint suggests an impurity, but there’s no impurities in the P2P process Walter is using that should color his final product blue. Is Walter deliberately adding a dash of something else? The show doesn’t say.
And now we come to the most puzzling thing of all.
When methylamine reacts with P2P, it initially forms a type of compound called an imine as shown below:
which looks like methamphetamine but with one key difference: the double bond between that nitrogen and our C2. We need to add two hydrogen atoms and two electrons — the equivalent of a molecule of H2 — to this molecule to get rid of that double bond. In other words, we need to reduce the molecule, and that’s what Walter means by reductive amination. He could do this in a number of different ways — by including aluminum-mercury amalgam in the reaction mix, for example, and in fact Jesse does precisely that when trying to copycat Walter’s recipe in Season 3. Walter doesn’t say, however, whether that’s what he is doing as well.
So here’s the interesting part. The pseudoephedrine method makes S-meth. If you make methamphetamine from P2P by reductive amination as I’ve described it, however, you unavoidably end up with a fifty-fifty mixture of the two enantiomers, which is undesirable because your product is now half drug and half decongestant. Yet Walter’s end customers and the DEA seem impressed with the potency of his product, which implies it contains only the S-meth enantiomer. And in an episode called “Box Cutter”, Walter says the following while quizzing Victor:
Walter: “And if our reduction is not stereospecific, then how can our product be enantiomerically pure?” (In other words: if our reduction generates both enantiomers, how does our product contain only one?)
Great question, Walt! Now could you answer it for us please?
True, there are techniques you can use to separate or “resolve” two enantiomers, but they’d make the whole process much more complicated and time-consuming. Moreover, Walt seems almost unnaturally proud of his formula, which seems to imply he’s thought of something clever. So what’s going on?
Come on, Walt. For the love of science, don’t hold out on us. Share your secret. The chemistry nerds in your audience would like to know.
Coming up in the next post: How a patented children’s cough suppressant became the world’s most dangerous illegal drug.
*Note to the chemists/biochemists & students out there: I prefer using the R and S naming convention to the old D- and L- except where sugars are concerned. That’s why I used R and S in this post. In case you’re wondering, though, S-meth is the dextrorotatory enantiomer, and if you go by the old D- and L- naming convention it’s D-.