METHAMPHETAMINE SYNTHESIS INHIBITION: DISSOLVING METAL
REDUCTIONS
*
Craig A. Kelly , David S. Lawrence, George M. Murray, and O.
Manuel Uy
Johns Hopkins University Applied Physics Laboratory
11100 Johns Hopkins Road, Laurel, Maryland 20723
*
240-228-8631, 240-228-6914 (Fax), Craig.Kelly@jhuapl.edu
1 Abstract
Of all the drugs of abuse, methamphetamine
In this paper, we report the status of our in- is the only one so simple to prepare that the
vestigation into the feasibility of introducing individual user can make it independently
a chemical agent into agricultural grade an- [1]. It is estimated that 99 % of the clandes-
hydrous ammonia that will render the am- tine laboratories in this country are involved
monia useless for methamphetamine synthe- in the illicit manufacture of methamphet-
sis. Our goal is to provide a means to re- amine. An increasing number of the clan-
duce the number, ease, and stealth that clan- destine methamphetamine laboratories (cur-
destine methamphetamine laboratories using rently estimated at 20 % [2]) use a procedure
the dissolving metal, or Nazi, synthetic known as a dissolving metal reduction [3],
method currently enjoy. often referred to as the “Nazi” method, of
over-the-counter cold medications ephedrine
We have conducted investigations of addi- or pseudoephedrine [2]. The details for the
tives that span the broad classes of organic, synthesis are readily available from the lit-
inorganic, and organometallic reagents. We erature [5] and the Internet. Unlike other
have identified numerous compounds and synthetic drugs, less than 10 % of those ar-
classes of compounds that effectively inhibit rested for the illicit synthesis of metham-
methamphetamine synthesis. Feasibility phetamine are trained chemists [1].
evaluations of these compounds are ongo-
ing. However, we have identified two can- The relative ease with which methamphet-
didate reagents that possess properties useful amine is manufactured has led to a prolif-
for consideration as additives for anhydrous eration of small-scale “mom and pop” op-
ammonia: ferrocene and 1,1,1,2-tetrafluoro- erations. The small-scale labs produce only
ethane. Details of the reactivity of these a small amount of the methamphetamine
compounds and issues relating to their ap- available in this country [4]. However,
plication for the inhibition of methamphet- clandestine laboratories, often operated by
amine synthesis will be presented. criminally minded individuals untrained in
the handling of dangerous chemicals, pose
2 Introduction threats of fire, explosion, poison gas, booby
traps, and the illegal dumping of hazardous
2.1 Background waste [4]. The solvent of choice used for
the Nazi synthesis is anhydrous ammonia, equipment will easily fit into the trunk of a
often obtained by theft from farmers’ fields. car. The methamphetamine synthesis can be
The thieves normally pilfer only a few gal- carried out in a hotel room or on the side of
lons of anhydrous ammonia but too often are the road before disposing of the waste and
the cause of major ammonia spills. Such concealing the laboratory equipment. The
spills not only result in the loss of thousands Nazi method enjoys the advantage of pro-
of gallons of ammonia for the farmer, but ducing relatively little odor compared with
have resulted in the evacuations of entire other synthetic methods, greatly minimizing
towns due to the toxic cloud of ammonia the risk of detection.
produced [6].
With these points in mind, the objective of
The handling of anhydrous ammonia is an our work is to increase the level of diffi-
extraordinarily dangerous activity. The liq- culty, time, equipment, and supplies neces-
uid is extremely cold (-28 oF) and the vapor sary to synthesize methamphetamine by the
is highly volatile. Contact of the liquid with Nazi method. Because the average metham-
skin or mucus membranes causes a combi- phetamine producer has relatively low
nation of frostbite, direct ammonolysis of chemistry skills, increasing the level of dif-
the skin by ammonia, and saponification of ficulty is expected to significantly decrease
the epidermal fats by ammonium hydroxide the number of individuals capable of con-
formed by the reaction of ammonia and ducting the procedure. Additionally, by in-
water [7]. A very real concern is severe in- creasing the time, equipment, and supplies
jury to children who obtain the methamphet- required for the synthesis, the risk of detec-
amine synthesis from the Internet without tion of the clandestine laboratory will
knowledge of the risks associated with the increase as well.
handling of anhydrous ammonia.
2.2 The Nazi Synthetic Method
The small-scale clandestine laboratories are
often considered to be more dangerous than The key reagent in the Nazi methamphet-
the larger scale labs [4]. Smaller scale labo- amine synthesis is the solvated electron.
ratories suffer from amateur chemists inex- The solvated electron is a potent reducing
perienced in the handling of hazardous agent [10] and is sufficiently long-lived in
chemicals and the consequences of potential liquid ammonia that it is useful for synthetic
accidents. This point is evident from the purposes [11]. Dissolving lithium (or
large number of children present at clandes- sodium) metal in anhydrous ammonia gen-
tine laboratories [4]. Of the reported 7,200 erates the solvated electron, Scheme 1. The
clandestine laboratories seized in 1999, proposed mechanism of the Nazi reaction
nearly 870 children were reported to be at involves the two-electron reduction of
the sites with 180 exposed to toxic chemi- ephedrine or pseudoephedrine to give the
cals and 12 found injured by the chemicals
[8].
The small size of the clandestine metham- Scheme 1. Dissolution of
phetamine labs and the brief time required lithium metal in anhydrous
ammonia results in the
for the methamphetamine synthesis provide formation of solvated lithium
stealth for the laboratories [9]. The required ions and electrons. The
electron is the key reagent
unreactive form. Compounds of this class
will be referred to as catalytic compounds.
The distinct advantage of catalytic com-
pounds is that it is not feasible to overcome
the catalyst by the addition of excess
lithium. The catalyst will simply regenerate
itself and consume the excess electrons.
Metal compounds typically fall under this
category.
2.4 Program Goals
In this paper we will provide an overview of
our investigations to date. There are four
Scheme 2. Proposed mechanism for important goals that we are interested in ad-
the two electron, two-proton dressing. The first is to maximize the ability
reduction of ephedrine or of the additive to prevent the illicit manu-
pseudoephedrine to facture of methamphetamine, i.e., counter-
methamphetamine product, Scheme 2. The production. The second is to minimize the
synthesis of methamphetamine can be pre- ease with which the additive is defeated, i.e.,
vented if a reagent already present in the counter-action. The third is to minimize or
anhydrous ammonia scavenges the electron. make transparent the impact of the additive
on the legitimate use of anhydrous ammonia
2.3 Chemical Approaches to Electron by the farmer. Lastly, we desire to limit the
Scavenging impact of the additive on the environment.
In this paper we will focus on the first two
The principle strategy in this study is to goals, counter-production and counter-
scavenge solvated electrons. In the absence action. The other two goals will be reported
of a suitable reducing agent, the reduction of on separately.
ephedrine/pseudoephedrine can not take
place, Scheme 2. This strategy can be fur-
ther broken down into two distinct catego-
ries. The first is a stoichiometric approach
that uses a compound capable of undergoing
a finite number of one-electron reduction
processes. Compounds that exhibit reac-
tivity of this type will be referred to as stoi-
chiometric compounds. Organic chemical
compounds typically fall under this cate-
gory. The disadvantage of this approach is
that, in principle, the inhibitor can be over-
come by the addition of excess lithium
metal. Another approach is the use of a
compound that is capable of catalyzing the
conversion of the solvated electrons into an
Table 1. Summary of Inhibition Results
Additive Methamphetamine
a
Yield Amount of Additive
b
c
No additive 89 9 % 0.0 %
Water 86 % 0.6 %
Urea d 37 % 23 %
Ammonium carbonate 54 % 246 %
Boron trifluoride etherate 95 % 1 %
Citric acid 99 % 14 %
e
Ascorbic acid 99 % 14 %
f
-Tocopherol 1 % 14 %
g
Butylated hydroxytoluene 99 % 14 %
h
Trolox 99 % 14 %
i
Pentamethylchromanol 50 % 14 %
1-Chloromethyl naphthalene 1 % 14 %
Trichloroethylene 1 % 14 %
2-Chloro-6-(tri- 31 % 10 %
j
chloromethyl)-pyridine k
1,1-Difluoroethane l
100 % 322 %
1,1,1,2-Tetrafluoroethane 5 % 10 %
FeCl 3 m 19 % 1.0 %
FeCl3 + H2O 3 % 1.0 %
FeCl 2 m 0 % 1.0 %
FeCl2 + H2O 87 % 1.0 %
FeSO 4 n 94 % 1.0 %
FeSO4 + H2O o
95 % 1.0 %
Fe(III) Citrate
p 0 % 1.2 %
Fe(acac)3 0 % 0.1 %
Fe(F3-acac)3 p 0 % 0.1 %
Fe(F6-acac)3 p 31 % 0.1 %
Fe(CO) 5 p 76 % 1.0 %
Fe(CHD)(CO)3 100 % 0.1 %
Ferrocene 0 % 0.1 %
MoOCl
m 4
99 % 0.5 %
MoOCl4 + H2 O 55 % 10 %
WF6 92 % 273 %
Figure 1. Structures of Vitamin E and
derivatives.
a
Methamphetamine synthetic yield as a percentage of the
methamphetamine/ephedrine ratio. Unless otherwise indicated, the es-
b
timated error is 10 %. As a mol % relative to the amount of
c
lithium, i.e., amount of solvated electrons, used. Average of ten
d
observations. A variable
e
mixture
f
of ammoniumg bicarbonate
h
and am-
monium carbamate. Vitamin C. Vitamin E. BHT. 6-hydroxy-
2,5,7,8-tetramethylchroman-2-carboxylic
i
acid,
j
a water soluble vitamin
E derivative. A vitamin E derivative. The active ingredient in
k l m
the anhydrous ammonia additive N-Serve. HFC-152a. HFC-134a.
n o
0.6 mol % water
p
relative to lithium. As the heptahydrate. As the
dihydrate. Abbreviations: acac = acetylacetonate, F3 -acac = 1,1,1-
trifluoroacetylacetonate, F6-acac = 1,1,1,5,5,5-hexafluoroacetonate,
CHD = cyclohexadiene.
3 Results and Discussion lithium and 0.61 mmol ephedrine to a 10 mL
solution of liquid anhydrous ammonia con-
Our investigations have been carried out taining 0.025 mmol of water. Under these
predominantly by evaluating the yield of conditions, the synthesis of methamphet-
methamphetamine produced as a function of amine was not inhibited within our margin
the nature of the additive. The results from of error. Only low concentrations of water
these studies are summarized in Table 1. were investigated in order to assess the con-
tribution of waters of hydration and atmos-
3.1 Water pheric contamination. The lack of signifi-
cant methamphetamine synthesis inhibition
Water quenches the solvated electron by the at these concentrations is due to the use of
reduction of ammonium, excess lithium.
H2O + NH3 OH- + NH4+ 3.2 Organic Compounds
NH4+ + e- ½ H2 + NH3
Of the non-metallic, non-halogenated com-
to yield hydrogen gas and hydroxide. We pounds studied, -tocopherol (Vitamin E,
investigated the addition of 4.2 mmol see Figure 1 for structure), was by far the
most active inhibitor that we have identified. inhibition activity observed with Vitamin E,
The reaction was carried out using 0.61 but not all. At concentrations equivalent to
mmol of Vitamin E in 10 mL anhydrous those used in the Vitamin E investigation,
ammonia to which 4.2 mmol lithium and the methamphetamine yield was reduced to
0.61 mmol ephedrine was added. These re- 50 %. Remarkably, when the concentration
sults indicate that each Vitamin E molecule of the pentamethylchromanol was reduced
is capable of scavenging greater than 6.9 to 0.059 mmol, the methamphetamine yield
electrons. The limit of reactivity of this remained at 50 %. The reason for this ap-
compound has not yet been evaluated. parent independence of methamphetamine
yield on the concentration of the
Substitution of the long hydrocarbon chain pentamethylchromanol additive remains un-
of Vitamin E with a carboxyl group, i.e., clear.
Trolox, resulted in a complete loss of
quenching efficiency. We have found that 3.3 Halogenated Organic Compounds
introduction of compounds containing car-
boxylic acids, i.e., citric acid, ascorbic acid, The reduction of halogenated hydrocarbons
and Trolox, did not result in the inhibition of using dissolving metal reductions is well
methamphetamine synthesis. The origin of established [12]. Taking advantage of this
this observation is unclear but it is likely that known reactivity, we have found many
these acids are fully deprotonated in the halogenated organic compounds to be very
basic ammonia solutions to give the conju- efficient methamphetamine synthesis in-
gate base and the ammonium cation. The hibitors. A notable exception to this is a
anionic nature of the conjugate base will lack of reactivity observed for the compound
likely result in a more negative reduction 1,1-difluoroethane. Halogens serve as good
potential for the compound, reducing or leaving groups upon reduction. The reaction
eliminating the thermodynamic driving force is probably driven partly by the solvation of
for electron scavenging. We speculate that the halide product in the polar ammonia sol-
low concentrations of ammonium cations vent.
promote methamphetamine synthesis by as-
sisting in the protonation of the metham- The hydrofluorocarbons (HFC’s) 1,1-di-
phetamine precursor, Figure 2. fluoroethane (HFC-152a) and 1,1,1,2-tetra-
fluoroethane (HFC-134a) are halogenated
organic compounds that possess boiling
points of –25 and –26 oC, respectively. Im-
portantly, these boiling points are very close
to that of ammonia, –33 oC. The close
boiling points increase the likelihood that
Figure 2. Proposed mechanism for the promotion of methamphetamine
the halogenatedsynthesis
organicbycompound
low concentrations
will be of the ammoniu
carried over during a distillation of the am-
monia [13], making it very difficult to re-
move the additive. Additionally, the halo-
genated compounds will remain below their
Replacement of the carboxylic acid group on boiling points in liquid ammonia, minimiz-
Trolox with a methyl group, i.e., ing evaporative loss of the additive during
pentamethylchromanol, restored some of the storage. These two compounds, which pos-
sess ozone depletion potentials of zero, are Further investigations involving this com-
being used as replacements for ozone de- pound are ongoing to better characterize this
pleting CFC-12 in refrigeration, aerosol and system.
open-cell foam blowing applications.
In contrast to the HFC-134a system, HFC-
Our reactivity studies indicated that HFC- 152a was found to not be effective at inhib-
134a is a remarkably efficient scavenger of iting the methamphetamine synthesis, even
solvated electrons in liquid ammonia. The at relatively high concentrations. While
capacity of a halocarbon is expected to be there are fewer fluorine atoms on HFC-
two electrons consumed for every halogen 152a, therefore reducing its capacity to scav-
atom. HFC-134a possesses four fluorine enge solvated electrons, the apparent com-
atoms suggesting that it is capable of scav- plete lack of reactivity was surprising. The
enging eight electrons to produce four fluo- lack of 1,1-difluorethane reactivity is cur-
rides and ethane, Scheme 4. rently under investigation in our laboratory.
Scheme 4. Eight-electron
reduction of 1,1,1,2- tetrafluoroethane (HFC-134a) to ethane.
Consistent with an eight-electron reduction, 3.4 Coordination Compounds
we have observed near zero methamphet-
amine yields, within our experimental error, We have found Fe(III), as FeCl3, to be a
at HFC-134a concentrations of 10 mol % potent methamphetamine synthesis inhibitor.
relative to lithium, Figure 3. In a strongly coordinating solvent like am-
monia, weakly coordinating ligands, like
Importantly, we have found that distillation chloride, are expected to be displaced by
of a mixture of HFC-134a in ammonia re- ammonia to give the hexaamine complex,
sults in a distillate that effectively quenches Fe(NH3)63+. The role of trace water is un-
the synthesis of methamphetamine. HFC- certain but its presence results in a signifi-
134a therefore effectively quenches the cant increase in inhibition activity. Pre-
methamphetamine synthesis reaction and is sumably, the presence of the water is re-
difficult to remove from the ammonia. sulting in a mixed ligand complex of the
type Fe(NH3)n(OH2)m, where n is 4 or 5 and
m is 1 or 2. The resulting mixed ligand
complex appears to be more a efficient cata-
lyst than the hexaamine.
Scheme 3. Presumed mechanism for the Fe(III)
In the presence of the solvated electron, the
Fe(III) complex is expected to be reduced to
Fe(II). Conceptually, two Fe(II) are capable
of promoting the two electron reduction of
the proton to give hydrogen gas, Scheme 3.
Figure 3. Methamphetamine yield
dependence on the amount of 1,1,1,2-
tetrafluoroethane dissolved in anhydrous
ammonia.
In reality, the mechanism is likely to be sig- The organometallic compounds Fe(CO)5 and
nificantly more complex, involving stabili- Fe(CHD)(CO)3 were found to be ineffective
zation of the intermediate oxidation and inhibitors at concentrations of 1.0 mol %
protonation states of the proton during re- and 0.1 mol % relative to lithium, respec-
duction by direct coordination to the iron tively. However, ferrocene has proven to
center [14]. Furthermore, it is not clear if be a potent inhibitor, reducing the metham-
only the Fe(III) and Fe(II) oxidation states phetamine yield to near zero at concentra-
are involved. The solvated electron is a tions as low as 0.1 mol % relative to lithium,
strong reducing agent and Fe(I) is known to Figure 5. This implies that each ferrocene
exist in aqueous solution [15]. Therefore, molecule is scavenging 1,000 electrons.
upon successful demonstration of the reac- Ferrocene was found to be soluble in am-
tivity of Fe(III), we evaluated the reactivity monia at the concentration needed for
of Fe(II). This compound was found to be activity, i.e., 4 104 M. Solubility is
an efficient inhibitor of methamphetamine important to minimize impact on the
synthesis. However, the reactivity trend in ammonia distribution infrastructure.
the presence of trace water was opposite that
observed for Fe(III). The Fe(II) salt was The efficiency of ferrocene as a catalyst for
significantly more efficient in the absence of the inhibition of methamphetamine synthesis
water. Further investigation is required in is remarkable. Ferrocene is in the lowest
order to sort out the details of the chemistry common oxidation state of this compound.
occurring with these compounds. Oxidation to the ferrocenium ion occurs at
mild potentials, but this process is not likely
One of the principle problems encountered to play a role in a reducing environment. To
with the Fe(II) and Fe(III) coordination the best of our knowledge, reduction of
compounds we have studied has been their ferrocene has not been reported in the lit-
insolubility in anhydrous ammonia. Com- erature.
pounds that are insoluble in anhydrous am-
monia are expected to be incompatible with Reduction of ferrocene probably results in a
the ammonia distribution infrastructure. large structural reorganization, for example,
partial or complete cyclopentadienyl disso-
Figure 4. Structures of the organometallic compounds discussed in the text.
ciation. Such a process is likely to be criti-
3.5 Organometallic Compounds cal to the catalytic function of the compound
by opening up accessible coordination sites
necessary for the stabilization of intermedi-
ates in the proton reduction mechanism.
4 Conclusions
At the present extent of our investigation,
we have identified two potentially
viable additives for anhydrous
ammonia, each capable of inhibiting
methamphetamine synthesis. The
first, 1,1,1,2-tetrafluoro- ethane,
cannot be removed by the simple
distillation of the ammonia.
Furthermore,
we have estimated and experimentally veri- funded under Navy Contract N00024-98-D-
fied that each molecule of this compound is 8124.
capable of scavenging ca. eight electrons. A
high electron scavenging capacity is neces- 6 References
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