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Technical Note Reduction
of Phenylephrine with Hydriodic Acid/Red Phosphorus
KEYWORDS: 3-Hydroxy-N-methylphenethylamine, Phenylephrine, Reduction, Methamphetamine, Pseudoephedrine, Reduced Phenylephrine, Reduced PE, Hydriodic Acid, Red Phosphorus, Iodine, Clandestine Laboratories, Forensic Chemistry
Clandestine methamphetamine laboratories are epidemic in many areas of the United States. One of the primary synthetic methods that has been used for production of methamphetamine over the past 25 years is the reduction of ephedrine or pseudoephedrine with hydriodic acid/red phosphorus (HI/red P) [1]. In past efforts to combat illicit methamphetamine production, federal and state authorities restricted the sale of bulk ephedrine and pseudoephedrine, and closely monitored the sale and use of hydriodic acid and red phosphorus [2]. In response, clandestine laboratory operators began utilizing Over the Counter (OTC) consumer products containing ephedrine or pseudoephedrine, began generating hydriodic acid in situ with iodine and red phosphorus (I2/red P) [3], and also turned to alternate syntheses, notably the lithium/ammonia reduction [4]. A number of states countered these initiatives with a variety of additional restrictions on the sale of ephedrine- and pseudoephedrine- containing OTC products, including purchase limits, access restrictions, and identification/signature requirements, and also further restricted sales of I2 and red P. In turn, clandestine laboratory operators in those states resorted to so-called “road trips” to purchase ephedrine- and pseudoephedrine- containing OTC products, either traveling to states that had no restrictions, or purchasing the maximum allowable amounts at dozens or even hundreds of stores within states that had restrictions in place. In addition, as acquisition of I2 and red P became increasingly problematic, clandestine laboratory operators turned to a variety of I2 and red P containing consumer products, and also began using other phosphorus compounds as substitutes for red P. Most recently, the Combat Methamphetamine Epidemic Act (enacted in March 2006) placed federal restrictions on the sale of ephedrine- , pseudoephedrine- , and phenylpropanolamine- containing OTC products (again, purchase limits, access restrictions, and identification/signature requirements) [5]. In total, federal and state imposed restrictions have dramatically reduced the number of methamphetamine laboratories in some states. Initially, the pharmaceutical companies that produced ephedrine- and pseudoephedrine- containing OTC products were strongly opposed to the imposition of restrictions on their sale. However, as they began to recognize the extent and increase of methamphetamine abuse, and the salient role that ephedrine- and pseudoephedrine- containing OTC products played in illicit methamphetamine manufacture, they began to create alternate formulations that contained phenylephrine (3-(1-hydroxy-2- methylaminoethyl) phenol, sometimes abbreviated as “PE”), as a substitute for ephedrine/pseudoephedrine. The structures of phenylephrine and ephedrine/ pseudoephedrine are shown below.
Phenylephrine-containing products have been available for OTC sale in Europe for many years. The first of these reformulated products became available to consumers in the United States in January 2005, and has gained rapid acceptance among American consumers. However, because many clandestine laboratory operators are chemically naïve, and do not understand that phenylephrine and ephedrine/pseudoephedrine are different compounds, it is expected that these new phenylephrine containing OTC products will eventually be utilized in erroneous efforts to produce methamphetamine. The purpose of this study is to identify the products, byproducts, and intermediates formed during the reduction of phenylephrine with HI/red P or I2/red P.
Reactions Gas
Chromatography Gas
Chromatography/Mass Spectrometry Infrared
Spectrophotometry
One popular preparation of the reformulated OTC “PE” allergy/cold medications contains 10 milligrams of phenylephrine hydrochloride per tablet, which is easily extracted with methanol. The base was precipitated from a saturated solution of the hydrochloride by basifying to pH 11 with ammonium hydroxide (pH control is important, see below). The infrared spectra of phenylephrine hydrochloride and base are shown in Figures 1 and 2, respectively. The full scale and expanded mass spectra of phenylephrine are shown in Figures 3 and 4, respectively. Based on the analogous reduction of ephedrine/pseudoephedrine [1], the HI/red P reduction of phenylephrine was expected to result in loss of the benzylic hydroxyl, thereby producing 3-hydroxy-N-methylphenethylamine, also known as “Reduced Phenylephrine” or less commonly, “Reduced PE”. The structures of 3-hydroxy-N-methyl-phenethylamine and methamphetamine are shown below.
The reduction mechanism was similarly expected to parallel that of the HI/red P reduction of ephedrine/pseudoephedrine; that is, through an iodophenylephrine intermediate that can be inferred by detection of the corresponding aziridine. The phenolic hydroxyl was not expected to be reduced by HI/red P [6]. Similarly, phenylacetone-like and naphthalene-like compounds (that are detected as byproducts during the HI/red P reduction of ephedrine/ pseudoephedrine [7]) were not expected to form during the HI/red P reduction of phenylephrine, due to the presence of the phenolic hydroxyl group. The analytical results were consistent with these postulates. An iodophenylephrine intermediate was apparently formed, as verified by detection of the corresponding aziridine compound, 1-methyl-3-(meta-hydroxyphenyl)-aziridine (mw = 148.1), confirmed by mass spectrometry (see Figure 5). This iodo intermediate was in turn reduced to 3-hydroxy-N-methylphenethylamine (hereafter “Reduced PE”). The full scale and expanded mass spectra of Reduced PE are shown in Figures 6 and 7, respectively. As expected, no phenylacetone-like or naphthalene-like byproducts were observed.
Presumed Reaction Sequence for the HI/red P Reduction of Phenylephrine Interestingly, the reduction of phenylephrine was much more facile than the corresponding reduction of ephedrine/pseudoephedrine. In fact, the aziridine was already present in the aliquot that was removed prior to heating (see Figure 8), and Reduced PE was already the major product after just 5 minutes of reflux (see Figure 9). Some trace level intermediate peaks were also noted, but were not identified. Complete conversion to Reduced PE, with essentially no byproduct formation, occurred within 30 minutes of reflux (see Figure 10). In additional experiments, phenylephrine that was added directly to 57 % HI sitting at room temperature, without applied heat or added red P, formed some of the aziridine and Reduced PE within one day. This facile conversion is most likely due to the influence of the phenolic hydroxyl group. Mass spectrometry and NMR data (not shown) also confirm that only the benzylic hydroxyl was reduced, in agreement with previous work on compounds containing both an alkyl amine and phenolic hydroxyl [6]. The extraction process for Reduced PE was more challenging than the corresponding extraction of methamphetamine. Because Reduced PE can form a phenolate salt, the extraction can only be accomplished in a narrow pH range (expected to be between the pKa’s of methamphetamine hydrochloride and phenol; that is, corresponding to about pH 11). To determine the optimal extraction pH, a series of test solutions were made, each using a set amount of reaction mixture adjusted to different pH values via dropwise addition of ammonium hydroxide. The resulting solutions were then extracted with a chloroform/isopropanol (2:1) mixture, and the extracts analyzed by GC. As expected, as the pH in the respective test tubes approached pH 11 (as measured by multi-range pH paper), the amount of Reduced PE in the extracts increased, but as the pH increased past pH 11, the amount of Reduced PE in the extracts decreased. The solvent system used for the above extractions was unusual. Reduced PE does not readily extract from a pH 11 solution into ether, hexane, or camping type fuel (extraction solvents that are typically used at clandestine methamphetamine laboratories). It is thought that a zwitterion is formed between the phenolic hydroxyl and the free amine. Since a zwitterion has salt-like characteristics, its solubility in water and polar solvents is enhanced. The chloroform/isopropanol (2:1) mixture improves the partition coefficient of Reduced PE, allowing its extraction from the aqueous solution. This solvent mixture has previously proven effective in extracting similar zwitterionic substances form aqueous solutions, including morphine, psilocybin, and lysergic acid. The infrared spectrum of Reduced PE base (as obtained by evaporation of the above chloroform/isoproanol (2:1) extracts) is shown in Figure 11.
As the availability of ephedrine/pseudoephedrine-containing OTC products decrease, it is expected that some chemically naïve clandestine laboratory operators will attempt to produce methamphetamine from substitute phenylephrine-containing OTC products, thereby producing Reduced PE. It is in fact quite likely that such substitutions have already been attempted; however, it is also quite likely that these syntheses failed due to the loss of Reduced PE during the extraction procedures typically utilized in illicit methamphetamine production. Similarly, some clandestine laboratory operators will attempt to produce methamphetamine from mixtures of pseudoephedrine- and phenylephrine- containing OTC products, but these efforts will only result in lower apparent yields of methamphetamine, again due to the loss of Reduced PE during extractions. Furthermore, the reduction of phenylephrine-containing OTC products using the lithium/ammonia process (Birch reduction) will likely be attempted, and will probably yield Reduced PE - though some other unknown product is also possible (this will be addressed in future research). Regardless of the reduction technique, however, the use of phenylephrine as a substitute for ephedrine/pseudoephedrine in illicit methamphetamine production will probably be short-lived, since Reduced PE is believed to have no significant CNS stimulant effects [8], and clandestine laboratory operators will quickly become educated about phenylephrine through drug abuse websites, bulletin boards, and chat rooms on the Internet, consumer complaints, and discussions with fellow laboratory operators. Nonetheless, it is necessary for forensic analysts to be able to identify these products, and understand their sources.
1. Skinner HF. Methamphetamine synthesis via hydriodic acid/red phosphorus reduction of ephedrine. Forensic Science International 1990;48:123. 2. The Chemical Diversion and Trafficking Act of 1988. Anti Drug Abuse
Amendments Act of 1988, Subtitle A. 3. Skinner HF. Identification and quantitation of hydriodic acid manufactured from iodine, red phosphorus and water. Journal of the Clandestine Laboratory Investigation Chemists Association 1995;5(4):12; Microgram 1995;28(11):349.* 4. (a) Heegel RA, Northrop DM. “One Pot” methamphetamine manufacture via the lithium ammonia method with multi ingredient, liquid, and/or soft gel pseudoephedrine preparations. Journal of the Clandestine Laboratory Investigating Chemists Association 2006;16(1):25.* (b) Angelos SA, Raney JK. Methamphetamine by the Birch reduction. Proceedings of the International Association of Forensic Sciences 15th Triennial Meeting 1999:61. (c) Clandestine Laboratory Investigating Chemists Association. Monograph: A Review of the Birch Reduction Method. Fresno, CA:1998.* 5. Combat Methamphetamine Epidemic Act of 2005 (Final: 3/9/06; Effective 4/8/06) [Title VII of the USA PATRIOT Improvement and Reauthorization Act of 2005, Pub. L., No. 109-177, Tit 7, 120 Stat. 192 (2006)]. 6. Oulton SR, Skinner HF. Reaction byproducts of common cold tablet ingredients via hydriodic acid/red phosphorus. Journal of the Clandestine Laboratory Investigating Chemists Association 1999;9(4):21; Microgram 1999;32(10):257.* 7. (a) Windahl KL, McTigue MJ, Pearson JR, Pratt SJ, Rowe JE, Sear EM. Investigation of the impurities found in methamphetamine synthesized from pseudoephedrine by reduction with hydriodic acid and red phosphorus. Forensic Science International 1995;76(2):97. (b) Cantrell TS, John B, Johnson L, and Allen AC. A study of impurities found in methamphetamine synthesized from ephedrine. Forensic Science International 1988;39:39 53. 8. Susan Carr, Drug Enforcement Administration, Office of Diversion Control, Arlington, VA, Personal Communication, 2005. * Law Enforcement Restricted. [Figures 1 - 11 and Table 1 Follow.]
Figure 1. Infrared Spectrum (ATR) of Phenylephrine HCl.
Figure 2. Infrared Spectrum (ATR) of Phenylephrine Base.
Figure
3. Mass Spectrum of Phenylephrine.
Figure 4. Expanded Mass Spectrum of Phenylephrine.
Figure 5. Mass Spectrum of 1-Methyl-3-(meta-hydroxyphenyl)aziridine
Figure 6. Mass Spectrum of 3-Hydroxy-N-methylphenethylamine (Reduced Phenylephrine).
Figure 7. Expanded Mass Spectrum of 3-Hydroxy-N-methylphenethylamine (Reduced Phenylephrine).
Figure 8. Gas Chromatogram of the Initial Mixture of Phenylephrine and Hydriodic Acid.
Figure 9. Gas Chromatogram after 5 Minutes of Reflux of Phenylephrine and Hydriodic Acid.
Figure 10. Gas Chromatogram after 30 Minutes of Reflux of Phenylephrine and Hydriodic Acid.
Figure
11. Infrared Spectrum of 3-Hydroxy-N-methylphenethylamine
Base ----------------------------------- Table 1. Methamphetamine Relative Retention Times (RRT’s) for Gas Chromatography Column: DB - 10 m, 0.32 mm, 0.52 µm; Temperature
Profile: 130 OC for 1 Minute,
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