How does Walter White make pure crystal meth using a non-stereospecific reaction?

Question

In the highly-rated TV series, Breaking Bad, Walter White, a high school chemistry teacher recently diagnosed with cancer, takes to making the illicit drug, crystal meth (methamphetamine), by two main routes.

First, along with his RV-driving accomplice, Jessie Pinkman, Mr. White uses the common small-scale route starting with (1S,2S)-pseudoephedrine (the active ingredient in Sudafed®️). This method features the use of an optically active starting material to make an optically active end product, (S)-methamphetamine. However, making (S)-methamphetamine on a large scale is limited because it is hard to get sufficient quantities of (1S,2S)-pseudoephedrine.

In the second route, Mr. White uses his knowledge of chemistry to move to an alternative synthesis starting with phenylacetone (also know as P2P or phenyl-2-propanone):

Racemic methamphetamine was obtained by the Winnebago-based chemists by reductive amination of P2P using methylamine and hydrogen over activated aluminum.

While his blue-colored product is considered by his customers to be exceptionally pure, Mr. White clearly knows about the issue of producing the correct enantiomer. In fact, he raises this topic more than once in the series.

Since the show might not want to tell us the answer, I am wondering what what other possible methods Mr. White could have used to obtain an enantiomerically pure product?

Answer 1

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).

Answer 2

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.

Answer 3

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.

Answer 4

Regarding user55119's comment about methylamine: about the train scene, they didn't steal methylamine per se from that train, they stole aqueous methylamine, i.e. a 40% methylamine solution in water.

This solution has a different density than water, thus explaining the need to compensate with a slightly different volume of water, and explaining why WW talks about "China sending a marginally weaker batch".

However, for meth synthesis most underground chemists prefer using the hydrochloride salt of methylamine rather than an aqueous solution, as it is easily prepared in small batches with precursors that are way easier to obtain than methylamine in any form -which is a surefire way of attracting you close attention from the authorities. Just like P2P, phenylacetic acid and acetic anhydride (which is needed for total conversion of the morphine contained in opium to heroin), methylamine isn't a restricted compound per se, but it is a watched chemical...

Which brings me to another gaping plot hole in the show: many of the items WW & Jesse have to obtain for their production (e.g. 10 L round-bottomed glassware and the right-sized mantle-heater, catalytic bed for thorium oxyde, chemicals etc) are actually very conspicous items that are usually only found in specific places: student or semi-industrial -testing the scaleability of a reaction before scaling it up to industrial production for example- chemistry labs or clandestine drug labs. Even a chemistry teacher would raise suspicion by buying these items for himself rather than on behalf of a school (and with proper paperwork and clearance from the DEA), so a tattoed street punk like Jesse showing up at a chemical or labware retailer and asking to buy them (in cash, no less!) would be sure to raise a lot of red flags at all levels, and would probably be woken up at 6 AM by a bunch of assault troops one of the following mornings. It just doesn't add up in the real world. :)