A recent NPR article discussed the business of fentanyl synthesis in China. But it's not just fentanyl. There is a cottage industry in making and selling some of the chemicals that are used to synthesize the drug. What would happen if some of the chemicals that are used to synthesize the drug were banned? Would this shut down its production?
Last week NPR ran a disturbing article about a large network of Chinese vendors that are supplying both fentanyl and its chemical precursors to the U.S., Europe, and Mexico. Emily Feng, the author of this darkly fascinating piece, describes an organized, savvy network of manufacturing facilities within China. The chemists who run these places are able to skirt the Chinese 2019 crackdown on fentanyl production by using plain old organic chemistry, something I wrote about in 2018 (see Organic Chemistry Can Defeat Any Fentanyl Agreement).
In the 2018 article, I showed how making simple changes in the fentanyl molecule (this is called analoging) can produce "designer fentanyls", aka novel fentanyl derivatives that can be many times more potent than fentanyl itself. This makes it impossible to outlaw specific drugs because they may be so new that they've never been seen in the US before. Or even "newer" – these drugs might not even exist yet except in the mind of a chemist.
How can this be controlled? The Chinese banned the "fentanyl class" (fentanyl and fentanyl-like substances) from being made or sold. This term is somewhat subjective; two different chemists may have two different ideas about what "fentanyl-like" means (see the original article for a discussion of this). Despite some potential ambiguity it is usually easy to tell from the chemical structure whether a new drug is fentanyl-like.
The NPR report touches on another strategy; banning the precursor chemicals that are used to make fentanyl and its analogs. What isn't included in the NPR articles is a discussion of the chemicals involved and whether one could make a dent in the fentanyl supply by controlling the chemicals that are used to make it. It's not easy. Here's why (1):
First, let's divide the fentanyl molecule into four obvious (2) fragments (Figure 1). On the left side of the blue line is fentanyl. Each fragment is designated by a number. The black hatch line indicates where one fragment ends and the next begins. On the right are the four precursor chemicals needed to synthesize fentanyl (3). Note that the chemicals are very similar but not identical to the four fragments (4).
Figure 1. One of the many possible synthetic routes used to make fentanyl involves four common, commercially available chemicals. (I'm not giving out any information that can't be found online in 5 seconds. And it's in an academic paper with the not-so-subtle title "An Efficient, Optimized Synthesis of Fentanyl and Related Analogs.")
The Fentanyl Chemicals - How Can We Control Them?
Phenethyl bromide (#1)
Phenethyl bromide isn't an especially common lab chemical. While you might find a bottle now and then in a chemistry lab it's not something that would be used very often – except to make fentanyl. So it is not unreasonable to categorize it as a fentanyl chemical. If I'm a drug enforcement agent and see that someone ordered gallons of this chemical it will raise a red flag. But it's simple for the fentanyl makers to get around this. Any competent organic chemist knows that phenethyl bromide can easily be synthesized from a very common, commercially available chemical called phenethyl alcohol. So even if phenethyl bromide is banned entirely this will not stop fentanyl production. Here's the reaction.
Phenethyl alcohol (L) can easily be converted into phenethyl bromide (R)
What about banning phenethyl alcohol as well? No way.
Phenethyl alcohol is a very common chemical that has dozens of uses. It's an artificial (and also natural) flavor. It smells like roses so it's used in perfume. It's also used in lipstick, toothpaste, makeup, and skincare products. It's just not feasible to ban this widely-used chemical.
But even if phenethyl alcohol were banned (which is ridiculous), a chemist can simply back up one step and start with benzene, which can easily be converted to phenethyl alcohol. There is no way on earth benzene can be banned. It's all over the place. So you cannot stop fentanyl synthesis by banning phenethyl bromide, phenethyl alcohol or benzene. There are too many ways around it.
Benzene can be converted to phenethyl alcohol
4-Piperidone is a very common chemical – but only for people making fentanyl. Otherwise, it is only used for specific purposes by chemists. There are a number of companies that sell it but you better believe that you're going to get yourself on a DEA list if you order it. And it's expensive as hell. Even if the chemical was banned there are a number of ways to synthesis 4-piperidone from very common chemicals using literature procedures. These methods will work but require far more work than making phenethyl bromide from phenethyl alcohol. If I go into the details of the synthesis of this chemical not one single person, not even an Olympic Class masochist will finish this article.
Propionyl chloride (#3)
Propionyl chloride is a rather common, readily available chemical. Let's say it gets banned. It would make no difference. This is because it is so easy to make it from can be made from propionic acid that a dyslexic sloth could do it. And propionic acid is widely available. Why? Because of bread. Propionic acid (more commonly its salt form sodium propionate) is a very common and safe preservative for baked goods. It is sold by more than 20 vendors. No, you can't stop fentanyl production by banning propionyl chloride. Even a chemist with modest skills can just go back one simple step and synthesize it from propionic acid.
Propionic acid (L) can easily be converted into propionyl chloride (R)
It's almost ridiculous to even mention aniline in this article. Aniline is so widely used to manufacture polymers, rubber, pesticides, plastics dyes, drugs, and more. I'm guessing that half of the organic chemistry labs in the US have a bottle of aniline lying around. It cannot be banned.
Chemistry 1, Law Enforcement 0
This article is not intended to be a comprehensive examination of all the syntheses of fentanyl. It serves more to illustrate the power of organic synthesis and how it can be used to nullify efforts to reign in chemicals and drugs.
Bet you didn't know how powerful we were.
(1) Keep in mind that there are other synthetic schemes that use different chemicals, making the job of tracking fentanyl chemicals even more difficult. I am only discussing one of these schemes.
(2) It may not be obvious to you, but one of the skills required by organic chemists is called retrospective synthetic analysis – the ability to look at a molecule and figure out how to put it together from (usually) smaller pieces.
(3) There are plenty of other ways to do this, but I'm focusing on the simplest method.
(4) This is because the chemicals undergo a transformation in a chemical reaction.