In the fantastic TV series Breaking Bad, Walter White, the dying chemistry teacher, takes to making crystal meth (d-methamphetamine) by several routes.

Initially, he uses the common small-scale route starting with pseudo-ephedrine which uses a stereospecific starring material to make a stereospecific end product (d-methamphetamine is the active compound). But doing this on a large scale is limited because it is hard to get large quantities of the pseudo-ephedrine.

Walter uses his knowledge of chemistry to move to an alternative route starting with phenyl-acetone(or P2P as it often called): wikipedia reaction method for P2P routes

There are several ways of doing the reduction to produce the final product (White first seems to use a Thorium dioxide dehydrocarboxylation in a tube furnace but later seems to favour the aluminium amalgam reduction).

But all the P2P methods produce racemic products. White clearly knows this as the issue of getting the right enantiomer is raised more than once in the show. His product is considered to be exceptionally pure.

So how does he get an enantiomerically pure product? Or perhaps, since the show might not want to tell us the answer, what possible methods could he have used?

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    The simpler answer is that TV/movie/book depictions of illegal actions are often simplified/sabotaged in an effort to discourage people from trying to take these as instructions. Anyone whose expertise overlaps any such area -- in my case, computers and locksmithing -- gets used to seeing deliberately wrong depictions and simply saying "that's OK, it's only a plot device anyway". In other words, if you're asking this question you're asking the wrong question. It's entertainment. Let it go. – keshlam Dec 24 '13 at 5:08
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    While you are right, I think of this as an excuse to discuss some really interesting chemistry. – matt_black Dec 24 '13 at 10:09
  • WW hijacked the methylamine from the train replacing it with water to compensate for the density difference. How did they store methylamine (bp 21 degrees F) in Albuquerque no less? – user55119 Apr 29 at 2:08

Intriguing question.

First, the best yield would be achieved by selectively producing one enantiomer instead of the other. In this case, White wants D-methamphetamine (powerful psychoactive drug), not L-methamphetamine (Vicks Vapor Inhaler). Reaction processes designed to do this are known as "asymmetric synthesis" reactions, because they favor production of one enantiomer over the other.

The pseudoephedrine method for methamphetamine employs one of the more common methods of asymmetric synthesis, called "chiral pool resolution". As you state, starting with an enantiomerically-pure sample of a chiral reagent (pseudoephedrine) as the starting point allows you to preserve the chirality of the finished product, provided the chiral point is not part of any "leaving group" during the reaction. However, again as you show, phenylacetone is achiral, and so the P2P process cannot take advantage of this method.

There are other methods of asymmetric synthesis, however none of them seem applicable to the chemistry shown or described on TV either; none of the reagents or catalysts mentioned would work as chiral catalysts, nor are they bio- or organocatalysts. Metal complexes with chiral ligands can be used to selectively catalyze production of one enantiomer, however the aluminum-mercury amalgam is again achiral. I don't remember any mention of using organocatalysis or biocatalysis, but these are possible.

The remaining route, then, is chiral resolution; let the reaction produce the 50-50 split, then separate the two enantiomers by some means of reactionary and/or physical chemistry. This seems to be the way it works in the real world. The advantage is that most of the methods are pretty cheap and easy; the disadvantage is that your maximum possible yield is 50% (unless you can then run a racemization reaction on the undesireable half to "reshuffle" the chirality of that half; then your yield increases by 50% of the last increase each time you run this step on the undesirable product).

In the case of methamphetamine, this resolution is among the easiest, because methamphetamine forms a "racemic conglomerate" when crystallized. This means, for the non-chemists, that each enantiomer molecule prefers to crystallize with others of the same chiral species, so as the solution cools and the solvent is evaporated off, the D-methamphetamine will form one set of homogeneous crystals and the L-methamphetamine will form another set. This means that all White has to do is slow the evaporation of solvent and subsequent cooling of the pan, letting the largest possible crystals form. Then, the only remaining trick is identifying which crystals have which enantiomer (and as these crystals are translucent and "optically active", observing the polarization pattern of light shone through the crystals will identify which are which).

Meth doesn't have to be optically pure to be "pure". A mixture of d,l-methamphetamine is still pure, but I get where you're going with this.

He has a few options:

  1. Chiral resolution - he could make the racemic meth and they resolve it by selectively crystallizing out the desired enantiomer. Chiral acids like tartaric acid can be used to do this.

  2. He could perform a stereoselective reduction of the intermediate imine. You couldn't do this with Al/Hg, but there are other methods to do it (stereoselective hydrogenation using a chiral catalyst).

Also, the thorium oxide furnace was not used to reduce the imine intermediate, it was used to make the P2P. Phenyl acetic acid + acetic anhydride over thorium oxide will give you P2P.

  • Very good point as to the possibility of asymmetric imine reduction. If I remember my reading correctly, some of the best catalysts are relatively pricey and exotic Rh, Ru, and Ti-metallocene complexes. I think there are various cheaper and more mundane chiral auxiliaries that can effect similar asymmetric reduction, though probably with poorer yield and %ee. – Greg E. Dec 25 '13 at 21:41
  • Expensive yes, but possibly still practical, as the catalyst isn't consumed and so theoretically can be reclaimed and reused; also, most chiral complex catalysts are only needed in relatively small doses. – KeithS Dec 26 '13 at 21:31
  • @KeithS, yes, that's true. I suppose the fact that catalysts of this type (e.g., the Noyori and Knowles Ru chiral complexes) are routinely used in industry is evidence enough of their cost-efficiency. – Greg E. Dec 27 '13 at 19:53

In a tube furnace phenylacetic acid and acetic acid are heated run through a catalytic bed (a number of different catalytic substances can be used). Reduced using aluminum. The product cleaned up then using d- tartaric acid crystallizing out the desired enantiomer.

  • That's very incomplete. You might want to include more details about what happens (equations/structures etc.) and some idea of the remaining steps. – matt_black Sep 12 '17 at 15:57

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