Isolation of Methamphetamine from 1-(1',4'-Cyclohexadienyl)-2-methylaminopropane (CMP) Using Potassium Permanganate

Fracia S. Martinez,* Daniel M. Roesch, and James L. Jacobs

U.S. Department of Justice
Drug Enforcement Administration
Southwest Laboratory
2815 Scott St.
Vista, CA 92081
[email: fracia.s.martinez -at- usdoj.gov]
[Reprinted with Permission from the Journal of the Clandestine Laboratory Investigating
Chemists Association 2008;18(1):18-22. Reformatted to Microgram Journal standards;
Abstract and Keywords Added (and Slight Changes Made) by the Microgram Editor.]

ABSTRACT: Methamphetamine illicitly prepared via active metal/ammonia (Birch) reduction of ephedrine or
pseudoephedrine is commonly contaminated with 1-(1',4'-cyclohexadienyl)-2-methylaminopropane (CMP), often
in significant amounts. Large percentages of CMP in methamphetamine samples result in poor quality (mixed)
FTIR spectra. Preliminary treatment/cleanup of CMP-contaminated samples with potassium permanganate gives
clean methamphetamine for FTIR analysis.
KEYWORDS: Methamphetamine, 1-(1',4'-Cyclohexadienyl)-2-methylaminopropane, Ephedrine,
Pseudoephedrine, Birch Reduction, Potassium Permanganate, Forensic Chemistry

Introduction
One of the primary methods of clandestine methamphetamine synthesis is the reduction of ephedrine or
pseudoephedrine utilizing an alkali metal such as lithium or sodium, and liquefied ammonia. During a typical
reduction of (pseudo)ephedrine, only the hydroxyl group is reduced, producing methamphetamine. With excess
alkali metal, and in the presence of an additional proton source [1-8], the aromatic ring is additionally reduced to
form a cyclohexadiene (Figure 1). This product is readily generated and is consistent with Birch (Na, EtOH,
NH3) type reactions. The product produced in this reaction is known as 1-(1',4'-cyclohexadienyl)-2-methylaminopropane (CMP), or more simply, the Birch reduction product. On occasion, the CMP to methamphetamine ratio
is very high in the final product of this synthesis, which can yield an undesirable, mixed infra-red spectrum
(Figure 2 - second pane). Separation and identification of methamphetamine and CMP is easily accomplished by
gas chromatography/mass spectroscopy, but some scientists prefer infrared spectroscopy, as it provides easy
differentiation of the various phenethylamines. This paper will describe a quick, qualitative method for the
elimination of CMP commonly found with methamphetamine manufactured from (pseudo)ephedrine using the
lithium - ammonia reduction method [9-11].

Experimental
Reagents and Solutions:
*
A 2% solution of potassium permanganate was prepared by dissolving 0.5 grams KMnO4 in 25 mL water
(use caution, potassium permanganate is a moderately strong oxidizing corrosive).
*
Aqueous base (sodium hydroxide, sodium bicarbonate, etc.).
46

Microgram Journal, Volume 6, Numbers 1-2 (January - June, 2008)

*
*
*

Organic solvent (hexane, diethyl ether, or similar).

Hydrogen chloride (HCl).
Mixture of Methamphetamine - CMP (60:40).

Instrumentation:
*
Nicolet Avatar 370 DTGS-Thermo Electron Corporation. Smart Golden Gate Diamond ATR with KRS-5
Lenses. Number of scans 16, resolution 4 cm-1, and range 400 - 4000 cm-1.
*
Agilent 5973 GC-MSD quadrupole electron impact mass spectrometer system with a 30 m HP-5 MS,
0.25 mm, 0.25 :m column. Carrier gas is ultra pure Helium. Instrument parameters: Temperature 90OC
to 300OC at 30OC/minute, initial time 1 minute, final hold time 6 minutes, injection port temperature
260OC, transfer line 280OC.
*
LCQ Advantage Max ThermoFinnigan quadrupole ion-trap mass spectrometer equipped with an
electrospray ionization source (ESI) and interfaced to a Surveyor HPLC system. Phenomenex Luna
column C18 - 2.0 x 30 mm x 3 :m. Gradient flow of 95:5 to 5:95 Solvent A/Solvent B over a 10 minutes
run. Solvent A is H2O with 0.1% (v/v) formic acid, while Solvent B is acetonitrile with 0.1% (v/v) formic
acid. The flow rate was 200 :L/minute. Samples were prepared using Solvent A. Mass spectrometry
data were collected in the positive ion mode using the full-scan mode in order to provide molecular
weight information.
Procedure:
1.
Place 25 mg of the sample (methamphetamine/CMP) in a test tube.
2.
Dissolve the sample in 3 mL of water and add 0.5 mL of 2% KMnO4 solution, then agitate with vortex.
3.
Add aqueous base (e.g., sodium hydroxide, sodium bicarbonate, or similar) to the test tube to make a
basic solution (pH > 12).
4.
Add organic solvent (3 mL hexane) to the test tube, shake, and isolate the organic layer in a new, clean
vessel.
5.
Bubble HCl gas through the organic extract.
6.
Isolate the precipitate (filtration, evaporation, or similar), dry, and obtain an IR spectrum.

Results and Discussion

The potassium permanganate reaction was performed on a mixed (60:40) sample of methamphetamine and CMP.
Prior to performing the potassium permanganate reaction, this sample was analyzed by mass spectrometry for
confirmation of sample components (Figures 3, 4A, and 4B). Potassium permanganate was then reacted with the
mixture. When CMP is reacted with potassium permanganate, the double bonds on CMP are hydroxylated. By
applying this technique with an aqueous base/organic solvent extraction, the CMP sodium salt formed remained
in the aqueous phase while methamphetamine passed into the organic phase, where it was isolated by
precipitation as the hydrochloride salt form. The final product was then sufficiently pure to be identified by
infrared spectroscopy (Figure 2). Again a mass spectrometer was used to determine the effectiveness of the
reaction, and the analysis confirmed that methamphetamine had been fully isolated from CMP (Figure 5 and 6).
To verify the hydroxylation of CMP and to show that no methamphetamine is produced by this reaction, a pure
sample of CMP was reacted with potassium permanganate using the described technique and then analyzed by
LC/MS (Figure 7). The presence of the 186 and 220 fragments in the mass spectrum obtained indicate that a
mixture of dihydroxylated and tetrahydroxylated derivatives of CMP are produced by reaction with aqueous
potassium permanganate (pH > 8) [12]. There is no indication in the mass spectrum that CMP is converted to
methamphetamine (no significant molecular ion at m/z 150). Methamphetamine is left unaffected when reacted
with potassium permanganate (Figure 8).

Microgram Journal, Volume 6, Numbers 1-2 (January - June, 2008)

47

Conclusions
In mixtures where the ratio of CMP to methamphetamine is high, the isolation of methamphetamine can be
achieved by reacting CMP with potassium permanganate and an aqueous base. The procedure facilitates the
isolation of methamphetamine from its primary by-product associated with the lithium - ammonia method of
methamphetamine synthesis. It is rapid and straightforward, with few steps, and allows for convenient
identification of methamphetamine using infrared spectroscopy.

Acknowledgments
The authors acknowledge the contributions and assistance of Supervisory Chemist David W. Love; Senior
Forensic Chemist Sandra E. Rodriguez-Cruz, Ph.D.; and Laboratory Worker Donald G. Smith (all at this
laboratory).

References
1.

Smith M. Dissolving Metal Reactions; In: Reduction, Robert L. Augustine, ed., Marcel Dekker, New
York, NY:1968, pp. 95-108, 118, 121-122, 12-127, 131-132, and 162-170.

2.

Watt GW. Reactions of organic and organometallic compounds with solutions of metals in liquid
ammonia. Chemical Reviews 1950;46:317-322; 328-329; 335-338; and 371-379.

3.

Kaiser EM. A comparison of methods using lithium/amine and Birch reduction systems. Synthesis
1972(8):391-415.

4.

Birch AJ, Smith H. Reductions by metal-amine solutions: Applications in synthesis and determination of
structure. Quarterly Reviews (The Chemical Society, London) 1958;12:17-33.

5.

Birch AJ. The reductions of organic compounds by metal-ammonia solutions. Quarterly Reviews (The
Chemical Society, London) 1950;4:69-93.

6.

March J. Hydrogenation of Aromatic Rings; In: Advanced Organic Chemistry, 3rd Ed., John Wiley and
Sons, New York, NY:1985; pp. 700-702.

7.

Vogel AI. Reduction of Aromatic Compounds; In: Vogels Textbook of Practical Organic Chemistry,
5th Ed., Brian S. Furniss, et al., eds, 1989, John Wiley and Sons (Co-publisher), New York, NY:1989;
pp. 1114-1117.

8.

Fieser LF, Fieser M. Birch Reduction; In: Reagents for Organic Synthesis, John Wiley and Sons, New
York, NY:1967; pp. 54-56.

9.

Person EC, Meyers JA, Vyvyan JR. Structural determination of the principal byproduct of the
lithium-ammonia reduction method of methamphetamine manufacture. Journal of Forensic Sciences
2005;50(1):1-9.

10.

Person EC, Knops LA. Clandestine ammonia generation. Journal of the Clandestine Laboratory
Investigating Chemists Association 2004;14(1):20-25.*

11.

Anonymous. Methamphetamine byproduct from birch reduction tentatively identified. Journal of the
Clandestine Laboratory Investigating Chemists Association 1997;7(2):7-10.*

48

Microgram Journal, Volume 6, Numbers 1-2 (January - June, 2008)

12.

Internet Website (Author Not Listed). Hydroxylation. Dihydroxylated products (glycols) are obtained by
reaction with aqueous potassium permanganate (pH > 8) or osmium tetroxide in pyridine.
www.cem.msu.edu/~reusch/VirtTxtJml/addene2.htm (Last Accessed February, 2008).

13.

Solomons TWG. Organic Chemistry, 4th Ed., John Wiley and Sons, New York, NY:1988; pp. 320-325.

* Law Enforcement Restricted Publication.

*****

Figure 1. Classic Birch Route of Production with Excess Alkali Metal and Additional Proton Source.

[Figures 2 - 8 Follow.]

Microgram Journal, Volume 6, Numbers 1-2 (January - June, 2008)

49

1,4-Cyclohexadienyl-2-Methylaminopropane

%T

80

60

40

60%MethamphetamineHCl
40%CMPHCl
pre KMNO4 Extraction

%T

80

60

40

%T

80

60%MethamphetamineHCl
40%CMPHCl
post KMNO4 Extraction

60

40

100

Methamphetamine HCl

%T

80

60

40

3000

2000

1500

1000

500

cm-1

Figure 2. IR Spectra - Pre and Post Potassium Permanganate Reaction Versus Reference Standards.

----------

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Microgram Journal, Volume 6, Numbers 1-2 (January - June, 2008)

Abundance

TIC: KMnO4-4.D

2.5e+07
2.4e+07
2.3e+07
2.2e+07

1.56

2.1e+07
2e+07
1.9e+07
1.8e+07

1.69

1.7e+07
1.6e+07

CH3

1.5e+07
1.4e+07

CH3

NHCH3

1.3e+07
1.2e+07

NHCH3

CMP

1.1e+07
1e+07

Methamphetamine

9000000
8000000
7000000
6000000
5000000
4000000
3000000
2000000
1000000

1.61
0

0.60

0.80

1.00

1.20

1.40

1.60

1.80

2.00

2.20

Time-->

Figure 3. Mass Spectrometer TIC Post Adding Methamphetamine Standard

to CMP for a 60:40 Mixture.

Abundance
Average of 1.679 to 1.691 min.: product.D (-)
150000

58

140000

CH 3

130000
120000

NHCH 3

110000
100000
90000

91

80000
70000
60000

77

50000
40000
42
30000

65
51

20000
10000

105
71

0
40

50

60

70

119

84
80

90

100

110

120

134
130

140

150
150

m/ z-->

Figure 4A. Mass Spectrum of CMP.

Microgram Journal, Volume 6, Numbers 1-2 (January - June, 2008)

51

Abundance
Average of 1.550 to 1.562 min.: AS76.D (-)
58
450000
CH3

400000

NHCH3

350000
300000
91

250000
200000
150000
100000

65
42
51

50000

77
71

0
40

50

60

70

134

115
85

80

98
90

103

100

148

128
110

120

130

140

150

m/ z-->

Figure 4B. Mass Spectrum of Methamphetamine.

Abundance
TIC: KMnO4-3.D
1.15e+07
1.55

1.1e+07
1.05e+07
1e+07
9500000
9000000
8500000
8000000
7500000
7000000
6500000
6000000

Methamphetamine after aqueous base/organic solvent extraction

5500000
5000000
4500000
4000000
3500000
3000000
2500000
2000000
1500000
1000000
1.35

500000
0
0.60

0.80

1.00

1.20

1.40

1.60

1.80

2.00

2.20

2.40

2.60

2.80

Time-->

Figure 5. TIC Post Potassium Permanganate Reaction.

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Microgram Journal, Volume 6, Numbers 1-2 (January - June, 2008)

Abundance
Average of 1.547 to 1.556 min.: KMnO4-3.D (-)
58
750000
700000
650000
600000
550000
500000
91

450000
400000
350000
300000
250000

65

200000
42
150000
51

100000

77

134

115

50000

103
70

86

0
40

50

60

70

80

98
90

108

100

110

120
120

148
128
130

140

m/ z-->

Figure 6. Mass Spectrum of Methamphetamine Post Potassium Permanganate Reaction.

CMP_01 #58-89 RT: 0.64-0.90 AV: 16 SB: 20 0.27-0.41 , 1.25-1.50 NL: 1.34E7
T: + c ESI Full ms [ 50.00-600.00]
186.1
100
90
80

Relative Abundance

70
60
50
202.1
40
30
20

220.1

10

184.1

232.1

0
50

100

150

200
m/z

250

300

Figure 7. ESI-MS Spectrum Indicating the Presence of both Dihydroxylated

and Tetrahydroxylated Derivatives of CMP.

Microgram Journal, Volume 6, Numbers 1-2 (January - June, 2008)

53

CH3

CH3

+
N HC H3

N HCH3

Methamphetamine

CMP

Birch Mixture

CH3

NH CH 3
KMNO4
H2O

O rg a nic Lay e r

Methamphetamine

OH
OH
C H3

O Na

ON a
C H3

N H CH 3
OH

o rg an ic extra c t
2N NaO H

OH

CH 3

N HC H 3

NH CH3
O Na

and
ONa

Methamphetamine

OH

and

OH
O Na

CH 3

O Na
CH3

N HCH 3
or

A q u eous
L a ye r

N H CH 3
CH 3

or
CH 3

NH CH 3
OH

NHCH3

OH
O Na

Post Hydroxylation
(CMP)

O Na

Sodium Salts

Figure 8. Proposed Potassium Permanganate Reaction.

----------

*****

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Microgram Journal, Volume 6, Numbers 1-2 (January - June, 2008)