SYNTHETIC REDUCTIONS IN CLANDESTINE AMPHETAMINE AND METHAMPHETAMINE LABORATORIES

SYNTHETIC REDUCTIONS IN CLANDESTINE AMPHETAMINE AND METHAMPHETAMINE LABORATORIES:
A REVIEW.
ANDREW ALLEN and THOMAS S CANTRELL.Show more

Forensic Science International, Volume 42 (1989) Pages 183 to 199.
Elsevier Scientific Publishers Ireland Limited.

Summary.

A review of synthetic reductions utilized in the clandestine manufacture of amphetamine and methamphetamine is presented. General discussions on the mechanism of heterogeneous catalysis, dissolving metals, hydrides and non-metal reductions used in the manufacture of amphetamine and methamphetamine with over 80 references are presented.

Introduction.

This review addresses reductions in clandestine methamphetamine and amphetamine synthesis. Central to the diverse routes published for the synthesis of methamphetamine and amphetamine is a reductive step at some point in the synthesis. Of 95 references surveyed concerning the synthesis of these controlled drugs, all but ten utilize a reductive approach. Since such diversity exists in these approaches, we felt that a composite literature review and discussion of the chemistry involved would help forensic chemists charged with investigating these clandestine laboratories. Secondly, we felt that a composite reference list would be of assistance in correlating notes or procedures found in clandestine laboratory sites to the open literature.
Finally, only two open literature review articles in this forensic area have appeared and both were devoid of extensive references, reference one and two.
An overview of synthetic approaches to methamphetamine and amphetamine utilizing reductive routes is outlined in Tables one and two. Table one is organized by the type of catalytic surface or reductive species; meaning Palladium, Platinum, Lithium aluminum Hydride, Formic acid and so on.
Table two is organized by the synthetic route or intermediate; meaning Leuckart, Schiff base, oxime, nitrostyrene, and so on. Figures one to twelve illustrate the chemical formulas of the chemical reduction routes to amphetamine and meth-amphetamine. References three and seventy-two are annotated with the type of reductive catalyst, reagent and route utilized.

Chemical Abstract citations, C, A Volume, page and year, are included for each reference for ease of cross reference with cryptic notes often found in clandestine laboratory sites. Finally, the recurrent use of the terminology "open literature" refers to legitimate, accredited journals as opposed to underground publications or notes passed between clandestine manufacturers.

Heterogeneous catalysis.
The role of heterogeneous catalytic hydrogenation and hydrogenolysis in organic synthesis is replete in the literature. However, the mechanism of the catalyst's role has remained elusive due mainly to the difficulty of studying such heterogeneous systems. Recent research in this area has shown that a system charged with H, and D, in the presence of a catalyst yields HD. This has been interpreted as the catalyst's coordination with molecular H, and weakening or disruption of the H-H bond, reference eighty-seven and eighty-eight. Studies by Maier et al, in a personal communication, in which the catalytic surface has been coated with Silicon dioxide, have revealed that the H-H (which penetrates the SiO2, layer to coordinate with the catalytic surface) is truly ruptured, yielding singlet hydrogen.
Furthermore, hydrogenation of an organic species (incapable of penetrating the SiO2, layer) occurred. This suggests that coordination between the organic moiety and the catalytic surface may not be necessary. "Selectivity" for an organic substrate in some catalytic metal hydrogenation systems has recently been shown to be dependent upon the topology of the catalytic surface, reference eighty-nine. Further work in this area will be followed with interest.

Heterogeneous catalytic reduction of ephedrine to methamphetamine in clandestine laboratories is most often achieved with palladium, references three to eight, fifteen, seventeen, thirty-nine. The use of platinum (Adams Catalysis) is second in frequency (Figure one). Similar correlations apply to the reduction of phenylpropanolamine to amphetamine utilizing palladium, platinum and Raney Nickel.

Hydrogenolysis of ephedrine or phenylpropanolamine, here hydrogenolysis is defined as reduction of C-X) is not a result of reduction of the benzylic carbon-OH bond. The actual moiety reduced is C-X, where X refers to halogen, sulfate, phosphate or perchlorate esters, figure one. This moiety (C-X) may be produced in situ, or synthesized externally, isolated and then reduced.
The stereochemistry and analytical methodology for methamphetamine prepared from ephedrine and pseudoephedrine has recently been addressed, reference ninety-two and three.

Heterogeneous catalysis has been used to reduce the imine bond of Schiff Bases formed with phenyl-2-propanone and ammonia or methylamine in order to produce amphetamine, references twenty six to nine, or methamphetamine, references nine, ten, twenty to twenty two, twenty-five, figure two. When heterogeneous catalysis is utilized in this Schiff’s base reduction, a Competing reaction, that of P-2-P reduction to 1-phenyl-2-propanol limits the yield of amphetamine or methamphetamine. Additions of large excesses of the amine component in these reactions have been employed to suppress the ketone reduction.

This has limited applicability, since the optimum pH for the Schiff’s base production is between pH 6 and 7. Other clandestine routes, although less popular, which have open literature references utilizing heterogenous catalysis for the synthesis of amphetamine are oxime reduction, figure three, nitro-styrene reduction, figure four, 2-keto-oxime reduction figure five and hydrazine reduction, figure six.
Precursors to amphetamine (phenylpropanolamine) and methamphetamine (ephedrine) have been synthesized with the aid of heterogeneous catalysis references sixteen, thirty-eight, figure five.

Dissolving metal reductions.

Dissolving metal reductions, in particular aluminum, continue to be the most popular synthetic routes to methamphetamine and amphetamine in clandestine laboratories in the United States. Although molecular Hydrogen, is produced as the metal dissolves, this is generally considered a detriment to the reduction of the organic species. The actual reductive mechanism does not involve molecular Hydrogen, but is, in fact, a result of an "internal electrolytic process".
Electron transfer from the metal to a heteroatom results in a radical carbon which abstracts hydrogen from solution to complete reduction. In metals where higher oxidation states are present, meaning Al, Mg, Zn, dimers may form as a result of intramolecular radical combination.
Poisoning of catalysis is one approach used to minimize rapid dissolution of the metal and to abate evolution of Hydrogen gas. Amalgams made between sodium and mercury have the effect of diminishing the activity of the parent metal thus slowing dissolution of the reducing species. Amalgamation between aluminum and mercury has the added benefit of preventing oxide formation on the surface of aluminum in contact with air. Aluminum-mercury amalgam serves to poison the metal somewhere between the extremes of the over-active metal and the inactive metal oxide.
In the clandestine manufacture of amphetamine and methamphetamine the most popular route is via aluminum-mercury amalgam reduction of the Schiff base adduct of phenyl-2-propanone, P-2-P, and the appropriate amine, see references forty to forty five and figure two.
This popularity persists despite U.S. Government control (Schedule Two) of P-2-P in 1980. This controlled status has resulted in an upsurge in the clandestine manufacture of P-2-P. A variety of synthetic routes have surfaced in clandestine laboratories, primarily through phenyl-acetic acid, reference seventy-three to seventy seven figure seven. Alternatives to the phenyl-acetic acid, now on a reporting schedule in some states, synthesis of P-2-P have appeared.
One approach to P-2-P utilizes a dissolving metal reduction of nitro-styrene with iron and hydrochloric acid, as shown in figure four.
Clandestine laboratories which utilize other dissolving metal reduction routes have been infrequently encountered. However, reduction of a Schiff base to meth-amphetamine, figure two and of 5-phenyl-4-methyl-thiazole to amphetamine, figure nine using sodium in alcohol are cited in the open literature.

Additionally, Sodium alcohol reduction of an oxime, figure three, Sodium Mercury amalgam reduction of a nitro-styrene, figure four or a 2-keto-oxime, figure five to amphetamine and zinc, HCl reduction of Chloro analogs of ephedrine to methamphetamine, figure one are also cited in the literature.

Metal hydride reduction.

Metal hydride reductions have not captured the imagination of clandestine laboratory chemists like the remainder of the scientific community. This fact is probably the result of their inability to utilize current Chemical Abstracts nomenclature, wherein most literature references to metal hydrides appear.
Metal hydrides function by transfer of a hydride to the electron deficient center (typically carbon) of a double bond. Protonation is effected on the electron rich center via the solvent media in the case of Sodium Borohydride or product workup in case of Lithium Aluminum Hydride.
The infrequent use of metal hydride reducing agents in clandestine laboratories cannot be attributed to the lack of open literature references in these agents, references fifty-five to sixty-two. Methamphetamine has been produced in clandestine laboratory sites via Sodium Borohydride reduction of the Schiff Base adduct of P-2-P and methylamine following a procedure outlined by Weichet et al, figure two.
Unfortunately, the activity of Sodium Borohydride is sufficient to reduce the ketone of P-2-P and this is a competing reaction. This is not the case with the more selective reducing agent NaCNBH3 whose activity is dependent on the pH of the reaction media, reference fifty-seven.
Lithium aluminum hydride, whose activity is greater and therefore less selective than Sodium Borohydride, has been used to produce methamphetamine or amphetamine through the reduction of a variety of functional groups; meaning formyl, figure eight, carbamate, figure ten, oxime, figure three,
Nitro-styrenes figure four and halogen analogs, figure eleven. Sodium borohydride has also been used in a de-mercuration procedure route followed by acid hydrolysis to amphetamine (in a clandestine laboratory) as outlined in Figure twelve.

Non-metal reductions.

Non-metal reduction routes to methamphetamine and amphetamine have been what might be termed as "fads" in clandestine laboratory synthesis within the United States. In the early and mid-1970’s, the Leuckart Synthesis, which employs formic acid, was the most popular clandestine route to amphetamine and methamphetamine. For whatever reason, this route, which is still very common in Western Europe, lost popularity in the United States by the end of the 1970s. In the early 1980s, the hydriodic acid reduction of ephedrine to methamphetamine began increasing in frequency in the Southwestern and Western areas of the United States. Although several literature references link the Leuckart synthesis figure eight, to amphetamine references sixty seven to nine, and methamphetamine, reference sixty four to six, "no" open literature reference directly links hydriodic acid reduction of a benzylic alcohol to the production of methamphetamine figure one.

Several general benzylic alcohols have been reduced to their aliphatic counterparts. However, this “Cross application” of chemical syntheses would require a level of chemical knowledge not common among clandestine chemists.
The mechanism of the Leuckart reaction has been studied and shown to be a free radical process initiated by formic acid. Unfortunately, the mechanism of the hydriodic acid reduction has not been established. It seems clear that the benzylic alcohol of ephedrine undergoes a substitution reaction with iodine. However, the mechanism of the carbon-halogen reduction is in conjecture; i.e. hydride transfer, internal electrolysis via disproportionation of iodine, or elevated temperature decomposition of HI to H, and I, whereby H, reduces the C-I bond.

Conclusion.

In this review we have addressed reductive approaches to amphetamine and meth-amphetamine via heterogeneous catalysis, dissolving metals, metal hydrides and non-metal reductions. The chemistry of these varied approaches has been highlighted with emphasis on the role of the reducing species. It may be concluded that there are many options available to clandestine chemists, see Figures one to twelve.
However, in actual practice, the three most frequently encountered routes in the United States are:
One, the aluminum foil reduction of the Schiff Base adduct of P-2-P and methylamine, reference forty to forty four.
Two, the palladium catalyzed reduction of the Chloro analog of ephedrine to methamphetamine, references four and five, and.
Three, the hydriodic acid reduction of ephedrine to methamphetamine.