Introduction to the Forensic Chemistry of Methamphetamine Manufacture

The literature on the organic synthesis and medicinal chemistry of phenethylamines, phenylisopropylamines and phenylisopropylmethylamines is truly voluminous. The most complete review of the unsubstituted prototypes amphetamine and methamphetamine is that of Allen et al., Synthetic Reductions in Clandestine Amphetamine and Methamphetamine Laboratories: A Review. Forensic Science International, 42, 183-99 (1989). The most extensive review of the substituted amine compounds is the landmark PiHKAL: A Chemical Love Story by Alexander Shulgin and Ann Shulgin (Transform Press, 1991). For an older review, see Haley, Desoxyephedrine - A Review of the Literature. Journal of the. American Pharmaceutical Association, 36, 161-9 (June 1947). For a very complete review of pharmaceutical chemistry, see Lednicer et al., The Organic Chemistry of Drug Synthesis, Volumes 1-4 (John Wiley & Sons, New York). The interested forensic chemist may find the following references useful in the analysis of impurities: LeBelle et al., Identification of a Major Impurity in Methamphetamine. J. Pharm. Sci., 62(5), 862 (1973); Barron et al., Identification of Impurities in Illicit Methamphetamine Samples. J. Assoc. Off. Anal. Chem., 57(5), 1147-58 (1974); Sinnema et al., Impurities in Illicit Amphetamine: A review. Bull. Narc., 33(3), 37-54 (1981); Huizer et al., Impurities in Illicit Amphetamine. J. Forensic Sci. Soc., 21, 225-232 (1981); Huizer et al., Di-(beta-phenylisopropyl)amine in Illicit Amphetamine. J. Forensic Sci., 30, 427-438 (1985); Bailey et al., Identification and Synthesis of Bis-(1-phenylisopropyl)- methylamine, an Impurity in Illicit Methamphetamine. J. Pharm. Sci., 63(10), 1575-8; Theeuwen et al., Impurities in Illicit Amphetamine. 7. Identification of Benzyl Methyl Ketone Phenylisopropylimine and Benzyl Methyl Ketone Benzylimine in Amphetamine. Forensic Science International, 15, 237-41 (1980); Hider, Preparation of Evidence in Illicit Amphetamine. J. Forensic Sci., 9, 75-9 (1969); Noggle, Jr. et al., Liquid Chromatographic Determination of the Enantiomeric Composition of Methamphetamine Prepared from Ephedrine and Pseudoephedrine. Anal. Chem., 58, 1643-8 (1986); Allen et al., Methamphetamine from Ephedrine: I. Chloroephedrine and Aziridines. J. Forensic Sci., 32, 953-62 (1987); Skinner, Methamphetamine Synthesis Via Hydriodic Acid/Red Phosphorus Reduction of Ephedrine. Forensic Sci. International, 48, 123-34 (1990); Windahl et al., Investigation of the Impurities Found in Methamphetamine Synthesised from Pseudoephedrine by Reduction with Hydriodic Acid and Red Phosphorus. Forensic Sci. International, 76, 97-114 (1995). The forensic chemist who desires a more complete review of potential synthetic methods must also consult the various "underground" manuals of varying quality that are available as well as the materials available via the Internet (e.g., Psychedelic Chemistry, Secrets of Methamphetamine Manufacture, Total Synthesis, alt.drugs.chemistry and the HIVE at www.the-hive.ws) in order to be fully apprised of the methods potentially utilized in clandestine manufacture.

Hydrogenolysis and Related Reactions

Reduction of ephedrine may be accomplished via catalytic hydrogenation or via red phosphorus and hydriodic acid or iodine. It is of interest that reduction of ephedrine via red phosphorus and hydriodic acid utilizing a technique previously applied only to other benzylic alcohols appeared in "underground" laboratories prior to publication in the "open" or "scientific" literature. The intermediates in both red phosphorus/hydriodic acid reduction and catalytic reduction are hydroxy-substituted analogs. The by-products of aziridines are common to both synthetic routes. However, there are significant mechanistic and by-product differences between these two routes, primarily due to the ambient aprotic medium of catalytic hydrogenation as compared to the heated protic acid medium of phosphorus/hydriodic acid reduction, which make further rearrangements unique to each reaction.

Reduction of either (-)-ephedrine or (+)-pseudoephedrine will yield the dextro (+)-methamphetamine, regardless of whether reduction is by catalytic means or by means of phosphorus and hydriodic acid. The stereospecificity of the reduction results from mechanistic factors as well as the diastereoisomeric nature of the ephedrines. Ephedrine and pseudoephedrine are 1-phenyl-1-hydroxy-2-methylamino-propane; each contains two chiral centers at the No. 1 and No. 2 carbons of the propane chain. Reduction to methamphetamine eliminates the chiral center at the No. 1 carbon. The dextro isomer of phenylisopropylamine and phenylisopropyl-methylamine is the d, (+), D or S isomer; the levo isomer is the l, (-), L or R isomer. The racemic mixtures may be referred to as d,l or (±) or (+,-) or DL.

Catalytic Reduction of Ephedrine and Pseudoephedrine

The stereochemistry and analysis of methamphetamine prepared by the catalytic hydrogenation of ephedrine and pseudoephedrine has been reviewed. Noggle, Jr. et al., Liquid Chromatographic Determination of the Enantiomeric Composition of Methamphetamine Prepared from Ephedrine and Pseudoephedrine. Anal. Chem., 58, 1643-8 (1986); Allen et al., Methamphetamine from Ephedrine: I. Chloroephedrine and Aziridines. J. Forensic Sci., 32, 953-62 (1987).

Reduction of (Pseudo)Ephedrine with Red Phosphorus and Hydriodic Acid or Iodine

When ephedrine or pseudoephedrine is heated with hydriodic acid, with red phosphorus or without, initially the hydroxyl is replaced with iodine. From this point the rearrangement chemistry of trace impurities starts. The halo compound is subject to reduction in the hydriodic acid medium leading to the target compound, methamphetamine. Hydrogen iodide dissociates at higher temperatures to iodine and hydrogen. The reaction is reversible. Its equilibrium is shifted in favor of the decomposition by the reaction of hydrogen with organic compounds (iodoephedrine in this case) in the reduction, but it can also be affected by removal of iodine. This can be accomplished by allowing iodine to react with phosphorus to form phosphorus triiodide which decomposes in the presence of water to phosphorous acid and hydrogen iodide (a cyclic oxidation of the iodide anion to iodine and reduction of iodine back to the anion by the red phosphorus, the latter being converted to phosphorous or phosphoric acids). In this way, by adding phosphorus to the reaction mixture, hydrogen iodide is recycled and the reducing efficiency of hydriodic acid is enhanced.

Cantrell et al., A Study of Impurities Found in Methamphetamine Synthesized from Ephedrine, Forensic Science International, 39, 39-53 (1988), found the halo compound may undergo an internal substitution reaction, whereby nitrogen replaces iodine, producing 1,2-dimethyl-3-phenylaziridines, both cis- and trans- in a 2:1 ratio (aziridines could also be formed directly from ephedrine by acid dehydration, however, formation from iodoephedrine is more likely). The aziridines can be reduced to methamphetamine or react to form the impurities found in the reaction. Due to the extreme acidity of the reaction mixture, further reactions are via the protonated aziridine only. The protonated nitrogen of the aziridine controls retro ring-opening to produce a highly favored zwitterion intermediate with resonance overlap to the aromatic ring. The product of retro ring-opening, followed by hydrolysis of 1,2-dimethyl-3-phenylaziridine is phenyl-2-propanone. Thus phenyl-2-propanone is a common impurity in clandestine laboratory preparations of methamphetamine, an anomaly that had puzzled a number of forensic scientists where the synthesis was known to start with ephedrine and not the phenyl-2-propanone/methylamine reduction via aluminum foil/mercuric chloride (the non-acidic reduction of halo-ephedrines produces the aziridines but no P-2-P). The major portion of the phenyl-2-propanone produced in the reaction undergoes self-condensation (aldol) to afford hydrocarbon impurities. These impurities are 1-benzyl-3-methylnaphthalene and 1,3-dimethyl-2-phenylnaphthalene. Both compounds incorporate two molecules of phenyl-2-propanone as result of an aldol condensation, followed by dehydration, followed by a second internal condensation and dehydration.

Windahl et al., Investigation of the Impurities Found in Methamphetamine Synthesised from Pseudoephedrine by Reduction with Hydriodic Acid and Red Phosphorus. Forensic Sci. International, 76, 97-114 (1995), also found the diastereoisomers of N-methyl-N-(alpha-methylphenethyl)amino-1-phenyl-2-propanone and the cis-cinnamoyl derivative of methamphetamine to be present in the reaction mixture.

If the hydriodic acid/red phosphorus reaction is incomplete, ephedrine HI or pseudoephedrine HI will also be present. It should be noted that the reaction is said to proceed quite well in the absence of the phosphorus but in slightly lower yields. Windahl et al., supra.