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Frank Ockenfels/AMC.
Disclaimer: Cooking and/or selling methamphetamine and other controlled substances is illegal unless you are working under the aegis of a pharmaceutical company.
As a chemist and someone interested in psychoactive drugs, I’m frequently asked if I watch the AMC series Breaking Bad and if the show accurately portrays clandestine chemistry. I am a huge fan of the show and frequently watch it while working in the lab late at night. Although the clandestine chemistry always appeared accurate at first glance, I desired a more detailed critique of Walter White’s syntheses. But season after season my thirst for technical analysis was left unquenched; I found a few articles that touched on the clandestine chemistry, but none were comprehensive. After dedicating the last seven years of my life to organic chemistry, it felt like a natural departure from writing my dissertation to examine this matter more closely.
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Nagai Nagayoshi(1844-1929)
N-methyl-1-phenylpropan-2-amine or methamphetamine was first synthesized from the naturally occurring alkaloid ephedrine by Japanese chemist Nagai Nagayoshi in 1893 while researching the structure of ephedrine [1]. Meth’s psychostimulant effect does not seem to have been noticed until the mid-30s when Friedrich Hauschild discovered it at the Berlin based pharmaceutical company Temmler. By the 1950s stimulants became a regular part of the American routine, and a flourishing black-market in diverted pharmaceuticals soon developed. This supply began to wither in the 1960s as law enforcement prosecuted over-prescribing doctors and placed pressure on pharmaceutical companies to withdraw certain products. Many believe the first clandestine labs originated in the California bay area from this environment around 1962 [2].
When it comes to making meth, the difference between cooking and synthesis should be acknowledged. In the same manner anyone can learn how to cook a fancy meal, anyone can be taught to cook meth regardless of chemistry education—cooking meth may be just a little more explosive. In fact, cooking meth can be extremely dangerous because a lack of chemical knowledge puts the cook (and anyone else nearby) at serious risk of injury. As Gus’s assistant Victor in “Box Cutter” (S.4E.1) states, “It’s called a cook, because everything comes down to following a recipe.” Walt appropriately asks him, “What happens when you get a bad barrel of precursor? How would you even know?” and “What happens in the summer when the humidity level rises and your product goes cloudy?” These are important points that someone just following a recipe may not be able to deal with. A skilled chemist like Walt understands the chemistry allowing him to alter or adapt the synthesis as necessary.
In early episodes, Walt and Jessie produce methamphetamine using the Nagai method—the same synthetic route used by Nagai Nagayoshi in the first recorded methamphetamine synthesis. The Nagai method employs pseudoephedrine as a precursor, which is reduced with hydroiodic acid (HI) to yield methamphetamine. This method was once the favorite of small scale meth operations in America—along with the misnamed “Nazi method,” which was most common in agricultural areas with access to liquid ammonia fertilizer (Li/NH3 reduction or Birch reduction). Today small-scale operators prefer the one pot “shake and bake” method, a modified form of the Birch reduction [3].
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Pseudoephedrine.
The Nagai method is portrayed twice in the pilot episode (S.1E.1): first when Walt's DEA agent brother in law, Hank Schrader, and his DEA pals raid Jessie's lab while Walt rides along, and then again during the Winnebago cook scene. The paraphernalia characteristic of this method is seen as the agents storm through the house: coffee filters, match books, road flares, iodine tinctures, boxes and blister packs of OTC cold medicine, and mason jars of transparent red and yellow solvents (from removing the red wax coating and extracting pseudoephedrine from cold medicine respectively).
As may now be obvious, the popularity of the Nagai method stems from the ease of obtaining the necessary chemicals. Pseudoephedrine is extracted (via water or alcohol and coffee filters) from OTC cold medicine. Red phosphorus needed to reduce elemental iodine (I2) to HI and to recycle reformed I2 [4], is collected from matchbook striker pads or road flares. (Walt and Jessie use both as phosphorus sources at different times.) I2 crystals can be extracted from readily accessible disinfectants. Once readied, pseudoephedrine, I2, and red phosphorus are placed in a boiling flask along with water and heated for varying lengths of time. The resulting deep purple solution, a result of I2, is a telltale sign of this reaction. (As acknowledged several times on the show, care should be taken—unless intentionally trying to kill a rival drug dealer who’s holding a gun to your head—to vent the toxic phosphine gas produced on heating.) Once complete the reaction is worked up.
How to prepare l2 from Iodine tinctures.
In the pilot episode, Walt does this by making the solution basic and then extracting it with an organic solvent. His use of a plastic syringe to remove the organic solvent layer is typical of clandestine cooks—an easier alternative favored by legitimate chemists is a seperatory funnel. By bubbling the HCI gas into the solution, the resulting d-methamphetamine is then precipitated as the HCl salt.
In the Nagai method, the β-hydroxyl group on ephedrine or pseudoephedrine is protonated forming a hydronium ion leaving group. A nucleophilic substitution reaction then occurs with an iodide anion. Water is lost to give iodoephedrine, which then undergoes reductive dehalogenation by liberated H2 producing methamphetamine [4]. The mechanism of the “emede method,” a previously popular clandestine procedure, is equivalent; however, in this case it is performed in two separate reactions, isolating the ephedrine halide, usually Bromo- or Chloro-ephedrine, and then reducing it to methamphetamine.
By the seventh episode of Season 1 (“A No Rough-Stuff-Type Deal”), obtaining pseudoephedrine for the large-scale production that Walt desires becomes an issue. To circumvent this, Walt decides on an alternate synthesis—reductive amination using P2P (phenylacetone) and methylamine. Upon hearing he no longer has to smurf pseudoephedrine, an infamously tedious process, Jessie enthusiastically exclaims, “Yeah, science!” The synthesis of methamphetamine using reductive amination is not new; Japanese chemist Akira Ogata first used it in 1919 [5] with various modifications appearing in the scientific and patent literature ever since. Obtaining methylamine required for this reaction—which is on the DEA watch list, a list of chemicals the DEA has classified as having use in drug manufacture—becomes a major plot line throughout the seasons.
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Methylamine.
In reductive amination, a ketone or aldehyde is condensed with an amine to form an imine or Schiff base intermediate, which is then reduced to an amine. In this case, P2P and methylamine are condensed forming the imine; this is then reduced by adding hydrogen to methamphetamine. The steps can be performed in separate reactions or together (one-pot). In Secrets of Methamphetamine Manufacture 7th edition, author and former meth cook Uncle Fester discusses several possible reduction methods for reductive amination—including NaCNBH4, mercury aluminum amalgam reductions, and Hydrogen bomb using H2/PtO2 or Raney nickel [6]. Based on several scenes referencing or depicting aluminum metal and mention of “mercury amalgam,” Walt and Jesse use the former where aluminum foil is “activated” with HgCl2 to give aluminum amalgam. As Uncle Fester outlines, Walt and Jessie use a one-pot reaction where P2P, 40 percent aqueous methylamine, and alcohol are mixed with mercury amalgam—mercury amalgam reductions have a characteristic foaming cloudy grey appearance, as portrayed in the cook scene from “Hazard Pay” (S.5E.3).
Although H2 is generated, the reduction actually involves an internal electrolytic process involving electron transfer from the metal that forms a radical carbon and subsequent hydrogen abstractions from solvent. Once complete, the reaction is worked up and product-obtained by vacuum distillation. This is Walt’s preferred reduction. In “Green Light” (S.3E.4) Walt criticizes Jessie’s product, derogatorily stating he probably used a platinum dioxide reduction. However, Jessie states he used “mercury aluminum amalgam” because “dioxide's too hard to keep wet,” which surprises Walt.
This statement likely refers to the fact that PtO2, or Adam’s catalyst, is prophetic, meaning it ignites if exposed to open air. (A clandestine meth chemist using the pseudonym Loius Feech writes of his own experience with PtO2 spontaneously exploding in his lab [7] in his guide Large Scale Methamphetamine Manufacture.) PtO2 is a perfectly good reducing agent and was at one point common in clandestine methamphetamine labs [8]. However it’s pyrophoric nature and cost are downfalls. There is some suggestion Walt may have even used PtO2 at one point—perhaps in the first P2P cook in “A No Rough-Stuff-Type Deal” (S.1E.7). One of the listed items Jessie gets for Walt is hydrogen gas. (This wouldn't be used with a mercury amalgam reduction but would be useful for a heterogeneous reduction employing a reducing agent such as PtO2.)
In 1980 the DEA placed P2P into Schedule II of the Controlled Substances Act, making it illegal to buy, sell, or possess without a controlled substance license. This is one of the earliest examples of the odd and unfortunate habit of making pharmacologically inert chemicals illegal because career criminals “could” misuse them. Although P2P became harder to purchase, this did little to impact methamphetamine’s availability, because clandestine chemists began synthesizing P2P themselves. Meanwhile clandestine operations became more complex, dangerous, and environmentally hazardous. The resourceful clandestine chemists adopted several well-known methods to synthesize P2P [9]. (Details of these are available in the latest edition of Uncle Fester’s Secrets of Methamphetamine Manufacture or his Advanced Techniques of Clandestine Psychedelic and Amphetamine Manufacture.) The clandestine favorite for P2P synthesis has always been phenylacetic acid (PAA), which is also that used by Walt and Jessie [8, 9]. PAA is mentioned in “Sunset” (S 3.E.6) when Gale asks Walt about tapering its addition rate and in “Salud” (S4.E10) when Jessie criticizes the cartel, whom he’s visiting in Mexico for not having PAA ready.
There are a number of ways to make P2P from PAA. The list Walt gives Jessie in “A No Rough-Stuff-Type Deal” (S.1E.7) contains two items: thorium nitrate and a tube furnace indicative of a dehydrocarboxylation reaction. Thorium nitrate is used to generate thorium dioxide (ThO2), a radioactive metal oxide catalyst used in the relatively complex—though high yielding—gas phase reaction in a heated tube furnace. Mention of “thorium oxide,” a moniker of ThO2 and a “catalyst bed” in “Más” (S3.E.5), further supports this. In dehydrocarboxylation, two carboxylic acids are vaporized—in this case PAA and acetic acid—and passed through a catalyst bed enclosed by a heated tube furnace. These form the desired asymmetric ketone (P2P), some undesirable symmetric ketones, acetone, dibenzylketone, and the side products CO2 and water. The resulting crude brownish oil is collected. After separation from the aqueous water layer, the P2P is purified via vacuum distillation.
From the 1960s to the mid-1980s, reductive amination was the method of choice for clandestine methamphetamine production. Enterprising biker gangs who dominated the trade at this time mostly ran these operations. (The slang term “crank” for methamphetamine allegedly originated from Biker’s transporting meth in the crankshafts of their bikes.) Reductive amination is less common today. Reference to this occurs in “Seven Thirty-Seven” (S.2E.2) when Hank shows his surprise after being shown the video of the methylamine heist. He says, “P2P––they’re cooking old school biker meth.” Increased DEA restrictions, including placement of PAA on its “watch list,” led to a switch to ephedrine based syntheses. While ephedrine was the initial choice, additional controls led to greater use of pseudoephedrine. While pseudoephedrine remains available over-the-counter today, the 2005 Combat Methamphetamine Epidemic Act (CMEA) title VII limits retail purchases and keeps records on all sales. Aside from limited short-term impacts, these legislative efforts failed to reduce availability of methamphetamine—the DEA Domestic Drug Seizure Statistics indicate meth availability may have even increased in recent years with 3,898 kgs confiscated in 2012 from 2,481 in 2011. While domestic large-scale clandestine labs have been impacted, small-scale (less than two ounces) labs have become increasingly common, representing 81 percent of seized domestic laboratories in 2006 [3]. These small-scale domestic labs only provide a minor portion of the current US meth supply—the majority originating in Mexican cartel operated super-labs [2,3]. Showing the scale of these operations, one 2012 bust of a Guadalajara based super-lab allegedly confiscated 15 tons of high purity methamphetamine [10]. The Mexican government’s new controls have effected ephedrine and pseudoephedrine availability, leading to a significant portion of Mexican super labs switching back to reductive amination, specifically P2P prepared from PAA [11,12].
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Phenylacetic acid.
Assuming all else is equal, most clandestine chemists would choose a pseudoephedrine/ephedrine reduction over reductive amination, because reduction of pseudoephedrine produces the more potent d-methamphetamine where reductive amination produces the much less potent racemic l-methamphetamine. The potency difference is due to a chemical phenomenon called chirality, not purity. Using the analogy of handedness, Walt correctly explains chirality to his class in “The Cat’s in the Bag” (S.1E.2): “Just as your left hand and your right hand are mirror images of one another… identical and yet opposite, well so two organic compounds can exist as mirror image forms of one another.” Since methamphetamine has one chiral center, it can exist as two different mirror forms called enantiomers (R- and S-based on an assigned priority of substituent and d- and l- or + and - based on interaction with plane polarized light). Since pseudoephedrine and ephedrine are themselves chiral—containing the (S-) configuration at the α-carbon—reduction produces exclusively d-methamphetamine. On the other, reductive amination produces a racemic or 50:50 mixture of d- and l-methamphetamine. This is because the planar P2P-methylamine imine is not chiral and hydrogen addition occurs equally from either side of the planar imine bond. Enantiomers often have distinct biological effects. Walt explains, “Although they may look the same, they don’t always behave the same.” He then illustrates this with the textbook example of thalidomide, the morning sickness pill that caused major birth defects, when sold as the racemic mixture, due to the activity of the less active enantiomer. Despite being a common pedagogical illustration, the enantiomers of thalidomide interconvert in the body because of the acidic hydrogen at the chiral center. This means Walt’s statement regarding R-thalidomide being safe to give to a pregnant women is technically false as the R-thalidomide would convert to the mutagenic S-thalidomide in the body. Walt could have better illustrated this phenomenon with methamphetamine, since d-methamphetamine induces classic stimulant effects, whereas l-methamphetamine is only a weak stimulant but an excellent decongestant ,which is sold over-the-counter in Vicks® inhalers under the pseudonym les-desoxyephedrine. The enantiomers do not easily interconvert, because the chiral center of methamphetamine does not have acidic hydrogen.
Despite using reductive amination, Walt implies his product is enantiomerically pure in “Box cutter” (S.4E.1). He asks Victor, “If our reduction is not stereospecific, then how can our product be enantiomerically pure?” Since he's not a chemist, Victor was unable to answer, and anyways, before he could try, Gus slits his throat with a box cutter. Unfortunately, we don’t know if Walt is just bluffing to try and save his and Jessie’s life. If Walt’s product is pure d-methamphetamine, we can assume he must use some technique to separate or “resolve” the isomers, because the starting material is not chiral and the reduction not stereospecific. Crystallography (derivatization with a chiral group followed by physical separation) and chiral chromatography are both possibilities. Crystallography is relatively easy and high yielding, and the resolving agent can be recycled, making it a green option. We also know that Walt has professional experience in crystallography, further pointing to this method. In a crystallographic resolution, a diasteromeric crystal or complex is formed between a chiral acid (like D-tartaric acid) and the compound so they can be separated. Unlike enantiomers, diastereomers have distinct physical properties that allow cooks to separate them using physical means like solubility. One chiral acid used to resolve methamphetamine is Di-p-toluoyl-tartaric acid [13]. One last point of pertinence—stereoselective reductive aminations has been performed to synthesize enatiomerically pure amphetamines, which containing a primary amine, using asymmetric synthesis with chiral auxiliary (R-) or (S-)-α-methylbenzylamine [14].
THE BLUE STUFF
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Photo of blue meth from Kansas City Police Department chief's blog.
Walt's methamphetamine becomes blue when he switches from pseudoephedrine reduction to reductive amination. When delivering this new product to cartel drug dealer Tuco, in “Seven Thirty-Seven” (S.2E.1), Walt says, “I used a different chemical process but it is every bit as pure.” In his own vernacular, Jessie also attests to the quality saying, “It may be blue but it’s the bomb.” After a short snort, Tuco agrees. “Tight, tight, tight, tight, yeah, blue, yellow, pink, whatever man just keep bringing me that,” he yells.
As the pure HCl salt, methamphetamine is a colorless-white crystalline solid. Illicit methamphetamine exists in a number of colors, although colorless, white, and yellow are most common. In the early days of clandestine production, a brown waxy product called peanut butter crank was common. Like Walt’s blue, the colors result from impurities formed during the reaction.
While I don’t know why the writers chose blue, there may be some logic. In the fifth chapter of Uncle Fester’s Secrets of Methamphetamine Manufacture 7th Edition (2005), Uncle Fester describes an internet conversation he had with “another cooker.” During the pressure gassing of a solution of 100 grams of methamphetamine freebase in 1000 milliliters of Et2O, the “process generates blue-colored product.” During any chemical reaction, “side reactions” occur which produce impurities. Identity and quantity of impurities vary by synthesis. Profiling the impurities, an analytical chemist can often determine the method used to produce a sample. However, the analytical chemist should take care—P2P is actually produced as a side product in the Nagai reduction of pseudoephedrine [15]. Crystallization, chromatography, and other purification methods can remove some impurities, but it is impossible to remove all, and even a minor amount (less than one percent) can influence a sample's color.
Despite its light blue coloration, Walt's product is highly pure. “Box-cutter” (S.4E.1) opens with flashback to Gale giddily setting up equipment in the laundromat super-lab. He tells Gus that he has the sample he asked him to analyze saying it is “quite good.” He then lets us know it was Walt’s product: “I can not as of yet account for the blue color.” Gale goes on to guaranty Gus a purity of 96 percent for his own product. Walt’s sample was 99 percent pure and “maybe even a touch beyond that.” Gale says to know for sure, he would “need an instrument called a gas chromatograph.” (A gas chromatograph or gc vaporizes and separates the components of a sample allowing impurities to be detected and quantified.)
Although at least one forensic report of blue methamphetamine, an unimpressive powdered sample adulterated with “blue chalk,” predates Breaking Bad [16], the show has certainly influenced the international methamphetamine trade. A quick search of posts from the last few years of various online drug discussion forums shows that there has been many encounters of high quality crystalline blue meth. In 2010, Kansas City MO police chief Darryl Forté posted an entry on his blog, saying blue meth was encountered several times in the previous two months.
Surprisingly many of the law enforcement personal and reporters in Kansas City failed to make the connection to Breaking Bad. Two news reports speculated the blue color might have been an ineffective attempt to fool the chemical reagent field tests, which give a blue color when tested positive for methamphetamine. It seems very unlikely that highly successful criminals would think dying their product blue would be sufficient to fool police detection efforts. Another explanation was the blue color was a marketing technique—drug dealers do use a variety of methods to brand their products and colored drugs are not new. Saint Patrick’s day in Marietta, Ohio apparently includes green crack cocaine [17]. Similarly pink strawberry flavored cocaine has been encountered by the DEA [18], and methamphetamine has been available in a rainbow of colors and flavors [16].
The best source of information on the phenomenon is a 2010 “el Paso” intelligence bulletin which describes a potential influence of Breaking Bad on the appearance of blue methamphetamine in several states including Texas, California, and Washington beginning in December 2009. This “blue meth” or “blue ice” was allegedly more potent and expensive—with two samples found to be an impressive 98.4 and 98.2 percent pure d-methamphetamine. The nature of the blue color was unfortunately not determined but speculated to be an additive dye. Attesting to the power of entertainment, Mexican drug cartels are believed to be responsible for these samples [19].
CONCLUSION
As should now be clear, Breaking Bad accurately portrays methamphetamine synthesis. From pronunciation of complex chemicals to the appearance of specific reactions, they get it right—Bryan Cranston pronounces chemical names better than some graduate students I know. This is all possible because the staff at Breaking Bad “do their homework,” consulting experts like associate chemistry professor Dr. Donna Nelson from University of Oklahoma. No, they aren’t perfect. Details are sometimes overlooked, like condensers not being connected to a water source and the order of synthesis steps sometimes being wrong. The industrial scale crystallization technique shown is unfamiliar to me, but my synthesis experiences are on the relatively small scale. While entertainment doesn’t have to always get it right, it is nice that it can. With the final episodes starting, I hope that Breaking Bad continues to set a new standard in narco-entertainment.
Sources
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5. Ogata A. Constitution of ephedrine – Desoxyephedrine Journal of the Pharmaceutical Society of Japan. 1919; 451:751-54
6. Uncle Fester. Secrets of Methamphetamine Manufacture 7th Edition. Loompanics Unlimited. 2005
7. Freeh L. Large-Scale Methamphetamine Manufacture. Reductive Amination of P2P through Catalytic Hydrogenation Using Adams Catalyst.https://www.erowid.org/archive-/rhodium/chemistry/meth.louisfreeh.html
8. Allen A. Cantrell TS. Synthetic Reductions in Clandestine Amphetamine and Methamphetamine Laboratories: A Review. Forensics Science International. 1989;42:183-199.
9. Frank RS. The Clandestine Drug Laboratory Situation in the United States. Journal of Forensic Science. 1983;28:18-31.
10. Stevenson M. Perez A. Mexico Meth Bust: Army Finds 15 Tons Of Pure Methamphetamine. Huffington Post. 2012. http://www.huffingtonpost.com/2012/02/09/-mexico-meth-bust_n_1266251.html
11. Maxwell JC. Breecht ML. Methamphetamine: here we go again? Addictive Behaviors. 2011;36:1168-73.
12. Koop DW. Pseudoephedrine Crackdown Forces Mexican Meth Cartels To Go Back To Basics. Huffington Post. 2009. http://www.huffingtonpost.com/2009/12/14/-pseudoephedrine-crackdown_n_390894.html
13. Kozma D. Fogassy E. Optical Resolution of Methamphetamine by O,O'-Dibenzoyl-R,R-Tartaric Acid in Dichloroethane-Water-Methanol Solvent System. Synthetic Communications. 1999;29:4315-4319.
14. Nichols DE. Barfknecht CF. Rusterholz DB. Benington F. Morin RD.
Asymmetric synthesis of psychotomimetic phenylisopropylamines. Journal of Medicinal Chemistry. 1973;16:480-483.
15. Windahl K.L. McTigue M.J. Pearson J.R. Pratt S.J. Rowe J.E. Sear E.M. Investigation of the impurities found in methamphetamine synthesized from pseudoephedrine by reduction with hydriodic acid and red phosphorus. Forensic Science International. 1995; 76:97-114.
16. Leinwand D. DEA: Flavored meth use on the rise. USA TODAY. 2007. http://usatoday30.usatoday.com/news/nation/2007-03-25-flavored-meth_N.htm
17. Zachariah H. Drug suspects dye crack cocaine green for St. Patrick's Day. The Columbus Dispatch. 2008. http://www.dispatch.com/content/stories/local/-
2008/03/20/green.html
18. US Department of Justice. Drug Enforcement Administration. Microgram Bulletin. July 2008;41(7):59-67. http://www.justice.gov/dea/pr/micrograms/2008/mg0708.pdf
19. El Paso Intelligence Center. Tactical Bulletins Team – Bulletin EB10-25. Blue Meth. 2010. http://publicintelligence.net/el-paso-intelligece-center-blue-methamphetamine-report/
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