All Bad Things…

Heads up: there are some chemistry terms you may or may not be familiar with in this post.  I’ve tried my best to explain as I go, and make everything as self-explanatory as possible.  If you find yourself lost, head over to the new glossary section, where I have compiled some simple definitions.

Part Three

Up until this point, the synthetic chemistry presented in Breaking Bad has been quite factual.  Conversion of pseudoephedrine to d-methamphetamine using reagents mentioned in the show is a well-known and documented synthesis.  You probably guessed there’s a “but” following the previous statement.  I’ll get to that, but first let’s talk about the synthetic route I propose Walt most likely used.

It is revealed in season one, in the episode “A No-Rough-Stuff-Type Deal,” that their process involves phenyl-2-propanone or phenylacetone, a chemical which Walt and Jesse initially make in a tube furnace.  Phenylacetone is a prochiral compound, meaning that while it is not chiral itself, it can be made chiral after only a single chemical reaction.

Chirality visual

A carbon with four bonds generally takes the shape of a tetrahedron (left) with the carbon in the center, and the four bonded substituents at the peaks of the tetrahedron. Skeletally, this is represented in the middle image. A carbon is said to be chiral if the four substituents it is bonded to are all different (right).

And that chemical reaction involves methylamine, a difficult to acquire chemical that is central to the plot of several episodes in the series.

“We’re going to use reductive amination to yield methamphetamine.  Four Pounds.”           -Walter White

This makes the homework pretty simple.  Walt and Jesse treat phenylacetone with methylamine, a reaction which yields an intermediate called an imine.

synth of imine

Phenylacetone or “P2P” (left) is treated with methylamine (above arrow) to yield an imine intermediate, shown in square brackets.

The process also releases one molecule of water for every imine formed.  You’ll notice the intermediate compound very closely resembles methamphetamine, except for one key detail: the carbon-nitrogen double bond.  With that bond in place, the intermediate is not chiral, and it certainly isn’t methamphetamine.  Luckily, we haven’t yet done the “reductive” part of the reductive amination.  If a mild reducing agent is added to the mixture (usually either gaseous hydrogen or sodium cyanoborohydride), methamphetamine results.

reduction

Reduction of the imine intermediate with hydrogen gas (or a number of other reagents) yields racemic methamphetamine.

Those of you following along since part one may notice a problem here.  We have indeed synthesized methamphetamine; however, we have done so as a racemic mixture.  That is, we have a mixture of dextro and levorotary methamphetamine.  A fifty-fifty mixture, in fact.  Then how is it that Walt claimed to produce 99.1% enantiomerically pure methamphetamine if the reaction cannot possibly do any better than 50%?  The short answer is, we don’t know.  They leave that part out of the methods described in the show.  At one point, Walt sends Jesse to acquire “40 grams of thorium nitrate,” which has catalytic uses, but no documented use in asymmetric synthesis.

From here on out, this discussion is purely speculative.  There is literature available on enantioselective reductive amination processes.  Instead of using either hydrogen gas or sodium cyanoborohydride, as mentioned above, a chiral hydride source could be employed.  However, the highest enantiomeric excess (ee.) found in literature for these products is only slightly better than 70%.  And if Walt could do better than that, so can we.  Certain chiral metal complexes, such as those of rhodium and titanium, have been demonstrated as incredibly expensive ways to achieve 90%+ selectivity.  But those catalysts would cost more than the meth would sell for.

There are some Lewis base catalysts that might do the job: they are relatively inexpensive, but the best yields are only in the 80% range.  After searching exhaustively, I found one procedure that might do the trick, but it’s going to cost you.  Using a catalytic mixture of (get ready for this) 1,1’-Bis{(S)-4,5-dihydro-3H-binaphthol[1,2-c:2’,1’-e]phosphino}ferrocene and Bis(1,5-cyclooctadiene)diiridium(I) dichloride you might be able to break into that ever elusive 99%+ range of purity.

catalysts

If you want to make Walt’s meth with his purity, you’ll need these catalysts, or similar ones. They aren’t cheap.

Therefore, the only possible conclusion is that Walter White is in fact a wizard.

I hope you’ve enjoyed reading about Breaking Bad chemistry; I’ve certainly enjoyed writing about it.  Hopefully, I’ll bring you all some new content early next week.  Thanks for reading!  And if you have any questions, concerns, or suggestions on what I should tackle next, check the about page for my contact info.

Cheers,

Mitchell

Sources:

Angew. Chem. Int. Ed. 2001, 40, 3425

Organometallics 1998, 17, 3308

Angew. Chem. Int. Ed. 1990, 29, 558.3

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11 thoughts on “All Bad Things…

  1. Is P2P not achiral as its obviously 2 steps away from a chiral compound and the imine being the prochiral one? I am though absolutely not sure if imines are really not chiral, but I admit this is all somewhat confusing for me.
    I would really like to know why P2P is not chiral, cannot be it seeems, but the related alcohol suddenly is very well chiral? What makes the difference? One hydrogen? How comes.

    regards

    • Hi, I’d be happy to explain the chirality issues around P2P. Firstly, let’s define some terms: chiral, prochiral, and achiral.

      Chirality: In the context of organic chemistry, a compound is chiral if and only if it contains an asymmetric carbon. Now, if you are familiar with the hybridization of carbon, it can be SP, SP2, or SP3 hybridized. Carbon atoms that are either SP or SP2 hybridized are planar in geometry, which means they automatically have a plane of symmetry and therefore CANNOT be chiral. It therefore follows that only SP3 hybridized carbons can be chiral.

      Achirality: In the case of achiral carbon atoms, it is easiest to think of them in contrast to chiral carbons. Achiral carbons contain some sort of symmetry element. In the case of SP or SP2 hybridized carbons, that symmetry element is the internal plane of of the carbon.

      Prochiral: The term prochiral is really just a designation that separates a subset of achiral compounds. ALL prochiral compounds are also achiral. BUT, not all achiral compounds are prochiral. It’s sort of like how all squares are rectangles, but not all rectangles are squares. A compound is considered to be prochiral if and only if it can be transformed into a chiral compound in a single step.

      Now that we have better defined the necessary terminology, we can begin to address your questions. P2P is achiral. It is also prochiral. It is achiral because every single carbon in the molecule has an internal symmetry element. It is prochiral because one carbon (the carbonyl) can be made chiral by a single step (a nucleophilic addition, for example). It does not matter that in this particular synthesis we are using an imine intermediate; that carbonyl carbon is still prochiral. The imine intermediate is ALSO both achiral AND prochiral, since a single step (reduction, in this case) converts it to a chiral carbon.

      You ask why is it that P2P is a chiral, but if we replace the ketone (C=O) with an alcohol (C-OH) it becomes chiral? As I have already explained, the hybridization of the carbonyl makes it achiral. However, when the ketone is replaced by a hydroxyl group (alcohol), the carbon is no longer SP2 hybridized: it becomes SP3. In doing so, the carbon no longer has an internal plane of symmetry. Since it no longer has any symmetry element, it is now chiral.

      Hope this clarifies things, feel free to ask if there’s anything you’re still unclear about.

      -Mitch

  2. I am by now means a chemist and my experience is limited to classroom lecture, and have had to do my fair share of reading. I recall one thing in particular, and that is 1-phenylethan-1-amine can be used to form diastereomic salt with ketones, which allows one to perform a stereospecific reduction, and the result being an enantiopure amine. I realize the imine must be formed, but I am not sure what effect this would have on its formation, or if it could form at all.

    I am probably completely off base here, so please correct me if I am wrong.

    • It is indeed possible to perform a reductive amination using 1-phenethylamine as a substrate. However, you’d need to start with enantiomerically pure material in order to maintain the proper stereochemistry.

      The main problem with employing this chemistry toward methamphetamine synthesis would be your starting material; you’d need to start with enantiomerically pure amphetamine, which you would then methylate with formaldehyde to methamphetamine using reductive amination. The costs associated with procuring amphetamine (especially in the context of illicit drug manufacture) would be prohibitive.

      But good catch nonetheless!

  3. Pingback: Non-“Breaking Bad” methamphetamine | The Unemployed Chemist

  4. Hi, I was wondering how Vick’s goes about separating the l- and d-methamphetamine, or produce only l-methamphetamine, and was wondering if a similar process could be used to produce/separate only the dextro version. Do they synthesize the levo- by itself, and if so, could the same be done for dextro-? Obviously, it is able to be done within reasonable financial means, seeing as how they’re able to sell it as a cheap decongestant. Thank you for your time.

  5. This method would be worth way more than the meth. Stereospecific reductive amination would be a billion dollar idea if it were patented and licensed. If Walt were rational he’d have stopped cooking the instant he thought of it.

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