1. Table of Contents
1. Introduction
2. Synthesis Routes
1. The Reductive Amination Route
2. The Leuckart Reaction
3. The Nitropropene Route
4. The Bromopropane Route
3. Applications
4. Conclusion
5. References
6. About the Author

I. Introduction

Clandestine manufacturing of 3,4-(methylenedioxy)amphetamine (MDA) analogs and homologs was thoroughly discussed by Dal Cason¹. Central nerve system activities, synthesis potentialities, ease of chemical handling, and availability of precursors were reviewed. Achieving synthesis of the desired compounds through the reductive amination route (with several hydrogenation steps), the Leuckart reaction, the bromopropane route, the Ritter reaction, the nitropropene route, and the substituted cinnamic acid route were also focused on¹.

As MDA and 3,4-(methylenedioxy)methylamphetamine (MDMA) are nearly always illicitly produced in clandestine laboratories, the preparations produced very often contain precursors, intermediates, or other impurities in addition to the targeted drugs. In fact, the presence of these contaminations derived from different origins in MDA or MDMA preparations can assist in establishing the route of synthesis² adopted by the individuals illegally producing these amphetamines.

Structure elucidation of the impurities in MDA and MDMA preparations by mass spectrometric and other methods can be found in literature: the reductive amination route^3,4, the Leuckart reaction^4,5, the nitropropene route^5,6, and the bromopropane route^7,8. In this article the MS data of the impurities present in preparations of MDA and MDMA are collected and arranged in tables, in according to the synthetic routes used.

II. Synthesis Routes

A. The Reductive Amination Route

The most frequently used method to prepare MDMA in The Netherlands can be described as a low pressure reductive amination at slightly elevated temperatures^3,4 (Scheme 1).

The structural information and eight-peak MS data of the impurities that are reported for this route of synthesis are summarized in Table 1. The compounds given in the table include starting materials and their impurities, hydrogenated compounds originating from starting materials, and nitrogen-containing compounds - intermediate substances resulting from the reaction of phenylpropanone with impurities in methylamine such as ammonia and higher alkylated amines.

Besides these impurities relating to chemical synthesis and the substances used in it, the MDA and the MDMA preparations can be contaminated by a host of strange compounds⁴ including caffeine, cocaine, ketamine, quinine, and amphetamine; the latter substance also contains typical impurities aziridines, pyrimidines, and di-(β-phenylisopropyl)amine.

B. The Leuckart Reaction

This reaction is seldom used for the synthesis of the substituted amphetamines^4,5. Using safrole as a starting compound in order to produce the phenylpropanone, the reaction can be schematically depicted as shown in Scheme 2.

The structural information and eight-peak MS data of the impurities that are reported for this route of synthesis are summarized in Table 2. Again, many impurities derive from starting materials and accompanying chemicals; others originate from condensations between the starting material and the end product.

C. The Nitropropene Route

The condensation reaction (Scheme 3) between nitroethane and piperonal has been adopted for the production of MDA^5,6.

The structural information and eight-peak MS data of the reported impurities that are known for this route of synthesis are summarized in Table 3. Again, the presence of impurities in the starting materials was noticed, while the most of the other impurities found can best be explained by assuming condensation reactions between starting materials, intermediate, and final products.

D. The Bromopropane Route

The reaction of safrole (obtained from sassafras oil) with hydrobromic acid shown in Scheme 4 was intensively studied^7,8.

All bromination products of the other essential oils associated with the starting chemical safrole can be found in MDA or MDMA preparations, depending on the extent of purification attained by the individuals that are producing the illicit drugs. The structural information and eight-peak MS data of the impurities that are reported for this route of synthesis are summarized in Table 4. The impurities given here refer to various compounds present in safrole; the brominated products of these substances resulting from the reaction of different compounds in safrole with hydrobromic acid; and the amino compounds originating from the amination of the bromine-containing substances.

III. Applications

The information collected in the tables was used in the author's laboratory⁴ to differentiate between the various routes of synthesis followed for the production of MDMA samples. During the past year, very limited use of the data from the tables was made in cases in which the origin of different samples was questioned. These so-called "signature investigations" which utilize gas chromatographic profiles are now in a mature state of development. They are often used in cases in which amphetamine was involved. In particular, Strömberg's group at Linkoping University has reported signatures of amphetamines of different origins for many years^9-12. The literature^13-15 provides more of an overview of the subject. It stands to reason that the information from the tables can be used for similar purposes, depending on the popularity and future availability of these kinds of drugs.

IV. Conclusion

Mass spectral information in the tables is given about the different impurities found in either MDA or MDMA preparations that are produced along several routes. In most cases the nature of the impurities can be ascribed to starting chemicals, intermediates, and substances originating from condensations of reaction products in the various stages of the reaction. Some impurities are route specific, e.g., N-formyl MDA, 1-[3,4-(methylenedioxy)phenyl]-2-nitro-1-propene, and the bromo compounds of the bromopropane route. Although there are other possible synthetic routes, only those the impurities of which are described in the literature, are reviewed in this article. In our opinion, proper use of information in the tables can assist in elucidating the nature of a reaction route that may be used for producing an MDA analog preparation.

About the Author

A. M. A. Verweij

Dr. Anthonie M. A. Verweij is senior chemist in the mass spectrometric service group of the Department of General Chemistry at the Forensic Science Laboratory of the Ministry of Justice at Rijswijk. He studied chemistry at the Free University of Amsterdam, where he received his Ph.D. in organic chemistry in 1970. His current research interests center on studies of the synthesis of illicitly prepared drugs, structural elucidation of impurities found in them, and the application of liquid chromatography/mass spectrometry in forensic science.