In clandestine methamphetamine laboratories seized by the Drug Enforcement Administration (DEA) in recent years (1983-1985), the second most frequently encountered synthesis is the ephedrine to chloropseudoephedrine followed by reduction. In this paper we address the stereochemistry of the ephedrines, the ephedrine to methamphetamine conversion procedure, the mechanisms involved in the conversion, the impurities or by-products which arise during the conversion procedure, and the identification of starting materials based on final product analysis. Impurities addressed in this study have been detected by us in varying levels from clandestine (+)-methamphetamine samples utilizing the techniques of gas chromatography/ mass spectrometry (GC/MS) and ¹H-nuclear magnetic resonance (NMR).

Experimental Procedure

Standards of (-)-ephedrine and (+)-pseudoephedrine were obtained commercially from Sigma Chemical Co. The respective chloro analogs were prepared as described by Emde¹. The respective aziridines were prepared from the chloro analogs by addition of concentrated sodium hydroxide (NaOH), with gentle warming, allowing the aziridine to volatilize into a hanging drop of dilute hydrochloric acid.

Stereochemistry

Stereochemical refinements are best approached by a brief review of ephedrine and pseudoephedrine stereochemistry. Fisher projections of enantiomers and diastereomers of ephedrine and methamphetamine demonstrate their structural relationships.

Comparison of these structures shows that stereochemistry about the carbon alpha to the benzene ring is immaterial in methamphetamine production, this carbon becomes achiral methylene). Although all ephedrine enantiomers and diastereomers may be converted to methamphetamine, stereochemistry about the beta carbon to the benzene ring shows that only (-)-ephedrine and (+)-pseudoephedrine yield d-methamphetamine^1,3,4. The stereospecificity is one of the appealing features of this synthesis, since d-methamphetamine is physiologically more active than l-methamphetamine.

Ephedrine/Methamphetamine Conversion

The most commonly applied clandestine laboratory conversions of ephedrine to methamphetamine (1983-85) involve first converting the ephedrine to its chloro analog by reaction with SOCl₂, PCl₅, POCl₃, or PCl₃, secondly, the chloro analog is reduced by catalytic hydrogenation. Reaction of ephedrine with SOCl₂ yields the chloro analog with complete inversion of configuration around the carbon alpha (to the benzene ring), yielding chloropseudoephedrine to the extent of 99%³.

Reaction of pseudoephedrine with this reagent, in our hands as prescribed by Ref suited in a 60:40 mixture (quantitation via ¹H-NMR) of chloropseudoephedrine (retention) and chloroephedrine (inversion). These results suggest that a simplistic interpretation of overall mechanisms governing these diastereomeric conversions is dangerous. The usual reaction of alcohols with thionyl chloride to produce alkyl chlorides proceeds via a substitution nucleophilic internal (S_Ni) mechanism⁵. The S_Ni reaction proceeds in two steps: dissociation of the chlorosulfite into an ion pair, then immediate attack on the carbocation by chloride. Attack occurs from the front side; thus, S_Ni reactions result in end products which retain configuration of starting materials.

A second mechanism which yields products which retain configuration of starting materials is the neighboring group mechanism. In this mechanism, nitrogen functions as a nucleophile, attacking and forcing out the leaving group without giving up its own position in the molecule. This results in inversion of configuration at the carbon alpha to the benzene ring. Chlorine then attacks, negating nitrogen's effect and once again inverting configuration around the alpha carbon. This path amounts essentially to two serial S_N2 substitutions, each with inversion of configuration; the net result is retention of configuration. In this sequence the neighboring nitrogen group is said to lend anchimeric assistance.

The third mechanism is another two-step reaction. First SOCl₂ attacks nitrogen and oxygen, forming a bridged species and freeing chloride ion into solution. Free chloride ion may then attack from the back side, resulting in an inverted configuration at the alpha carbon. Support for this mechanism is found in the reaction of chiral alcohols, thionyl chloride with pyridine added⁵. Unlike S_Ni reactions, wherein the pyridine is absent, this reaction results in inversion of configuration around the chiral center. This is due to the immediate reaction of SO2⁺ with both pyridine and the alcohol, leaving Cl^- ion free to attack from the rear in an S_N2 reaction.

For (-)-ephedrine the alkyl sulfite is sterically hindered from front side attack and is unhindered from back side attack. The final chloroproduct shows inversion of configuration. Conversely, the front and back side approaches to the intermediate sulfite of (+)-pseudoephedrine are equally hindered. Both retention and inversion of configuration is in the final chloro product. Note that the inversion product has the larger number of gauche interactions, therefore the product with retention of configuration will predominate.

This last rationalization, that of alternate anchimeric assistance, is consistent with experimental facts. We feel justified in identifying alternate anchimeric assistance as the parable mechanism involved in the synthetic conversion of ephedrine to chloropseudoephedrine with thionyl chloride. The principal impurities in the conversion of ephedrine to methamphetamine which we have analyzed from clandestine samples are the unreduced chloro analog of ephedrine and 1,2-dimethyl-3-phenyl-aziridine.

Aziridines result from internal substitution of chloro ephedrines. This rearrangement can be catalyzed by alkali or by heat. These aziridines have stereospecific qualifiers since internal substitution of nitrogen for chlorine is via backside attack. The geometric and stereospecific consequences of HCl elimination from (+)-chloropseudoephedrine (derived from (-)-ephedrine) leading to cis-1,2-dimethyl-3-phenyl aziridine. Similarly, (-)-chloroephedrine (derived from (+)-pseudoephedrine) rearranges to trans-1,2-dimethyl-3-phenyl aziridine⁷. Unfortunately, results of analysis are not unambiguous. This is due to the fact that the trans-1,2-dimethyl-3-phenyl aziridine is unstable and easily polymerizes, a feature not equally shared by the more stable cis isomer^7,8.

Simple rationalization of experimental results based on steric repulsion would draw the opposite conclusion, that is, cis would be rationalized to be less stable that trans. The explanation for experimental fact, trans is less stable that cis, comes from the symmetry rules governing molecular orbital theory. In this concept, ring opening of the aziridine system is viewed as a four-electron conrotatory process. The sterics involved in the cis structure would tend to favor a disrotatory opening, which is not allowed by these symmetry rules. Stated another way, one might consider the vicinal steric repulsion in the cisisomer to be, in effect, holding the molecule together. This steric repulsion is not present in the trans aziridine, and the symmetry-allowed conrotatory ring opening may proceed. Furthermore, a close look at the ring-opened products show the trans isomer to be more linear than the cis product and consequently the more favored ring opening⁹.

Analysis

From the discussion in the previous section one may conclude that clandestine samples of (+)-methamphetamine synthesized from ephedrines may contain complex mixture of components. Less numerous in components and thus easier to analyze are samples prepared from (-)-ephedrine. Impurity components prominent from this precursor route are (+)-chloropseudoephedrine and cis-1,2-dimethyl-3-phenyl aziridine. On the other hand, samples of (+)-methamphetamine which had as their origin (+)-pseudoephedrine pose more of an analytical problem. Components to be expected from (+)-pseudoephedrine route are (-)-chloroephedrine, (+)-chloropseudoephedrine, cis/trans-1,2-dimethyl-3-phenyl aziridine, and retro-ring openings of aziridines, that is, dimers and polymers of aziridines and the hydrolysis product phenyl-2-propanone¹⁰.

Conclusion

The mechanism of conversion for ephedrine(s) via SOCl₂ to its alkyl chloride has been rationalized as proceeding by alternate anchimeric assistance. Clandestine d-methamphetamine samples which are prepared by way of these alkyl chloride(s) have been analyzed to determine the stereo-identity of the precursor. Spectral data via ¹H-NMR spectroscopy and GC/MS spectrometry have been presented to aid in the analysis of these precursors, intermediates and rearrangements.