N,N-dimethyl-3-phenylpropylamine

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Preparation of a salt of N,N-dimethyl-3-phenylpropylamine from (R,S)-N,N-dimethyl-3- phenyl-3-hydroxypropylamine

1. Abstract:

N,N-dimethyl-3-phenylpropylamine (DMPPA) was prepared from a mixture of N,N-dimethyl-3-phenyl-3-hydroxypropylamine (DMPHPA) with hydrogen iodide (HI) and red phosphorous (P_red) via the Nagai method. The final product was characterised by gas chromatography/mass spectrometry (GC/MS), Fourier transform infrared (FTIR) spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy. An unlikely percentage yield of 146.4% was obtained, most probably due to extraction solvent that had not been completely evaporated due to time constraints, as well as drying agent that had not been removed from the final product. The GC/MS results showed N,N-dimethyl-3-phenylpropylamine with a retention time of 7.696 minutes, however they also showed, along with the IR and NMR results, that an impure final product of N,N-dimethyl-3-phenylpropylamine was obtained. Other compounds in the final product included tolpropamine, 1-cyclohexyltrimethylamine, and doxepin.

2. Introduction:

This experiment was performed to introduce a method commonly used in clandestine laboratories for the illicit manufacture of methamphetamine. Ephedrine or pseudoephedrine are commonly used in conjunction with HI and P_red in a catalytic reaction to produce methamphetamine. This method came about when Japanese chemist, Nagai Nagayoshi, was researching the structure of the naturally occurring alkaloid, ephedrine, in 1893 [1].

A cognate synthesis, as performed in this experiment, uses DMPHPA together with HI and P_red to form DMPPA. It works the same way as the Nagai method in that the hydroxyl group on DMPHPA is protonated, forming a hydronium ion leaving group. A nucleophilic substitution reaction then occurs with an iodide anion, and an intermediate is formed with the loss of water. The intermediate undergoes reductive de-halogenation, as the P_red consumes the iodine to form phosphorous triiodide [2], and the desired product, DMPPA, is generated [3]. The reaction mechanism for this procedure is shown in Figure 1.

The presence of red phosphorous allows recycling of HI and enhances its reducing efficiency. It intervenes in the catalytic cycle of the reaction by an oxido-reductive disproportionation with the liberated iodine, affording hypophosphorous acid (H₃PO₄) with associated regeneration of HI [4].

Figure 1 Reaction mechanism for the formation of DMPPA from DMPHPA using HI and red phosphorous. The box in the bottom left hand corner shows the reaction mechanism for the red phosphorus’ involvement in the catalytic cycle for the regeneration of HI [4].

3. Method:

A mixture of 0.96 g DMPHPA, 1.2 g P_red, and 5 mL of HI solution were heated under reflux for 2 hours and monitored by TLC. The mixture was diluted with 150 mL water and the excess P_red was filtered off. Sodium bisulfite was added for decolourisation, followed by NaOH to basify the mixture to pH 12. An extraction was performed using 3 x 20 mL of dichloromethane (DCM), and the combined organic layers were washed with 2 x 10 mL dilute NaOH, then dried with sodium carbonate (Na₂CO₃), and evaporated using a rotary evaporator. The yield was determined, and the product was characterised by GC/MS, FTIR and NMR.

Refer to the ‘Chemistry and Pharmacology of Recreational Drugs Practical Manual 2014’ for a detailed method [5].

4. Results and Discussion:

A final mass of 1.28 g of DMPPA was obtained from 0.96 g of DMPHPA, giving an unlikely percentage yield of 146%. The most probable reason for a percentage yield greater than 100% is the fact that some of the drying agent, Na₂CO₃, had accidentally been transferred into the final round bottom flask before evaporation. Also, due to a lack of time, the final product had to be removed from the rotary evaporator before all of the extraction solvent had been evaporated.

The GC/MS results show that there are at least four compounds in the final mixture (see Figure 2), meaning an impure product was obtained. The library search results do not show that there is DMPPA in the final mixture, however it is likely that the peak at 7.696 minutes belongs to DMPPA because it has the largest area percentage of 83.08%, and the mass spectrum of the compound at this peak shows a molecular ion of mass-to-charge ratio (m/z) of 163 (the molecular mass of DMPPA is 163.26 g mol^-1). The library search results show that the peak represents another compound however, and although there are some similarities, there are many differences between its mass spectrum and the experimental mass spectrum. Interestingly, the mass spectra for the peaks at 13.410, 13.717 and 14.114 minutes do not exactly match the mass spectra of the compounds from the library searches. This could mean that there may have been an issue with the program, or the compounds of interest may not have been in the library search system. Nonetheless, these other peaks have been labeled as representing the compounds tolpropamine (3.01%), 1-cyclohexyltrimethylamine (1.63%), and doxepin (12.28%), respectively.

Figure 2 Annotated gas chromatogram (left) with mass spectral results for peak at 7.696 minutes (left). The experimental mass spectrum is on top, and the mass spectrum from the library search is on the bottom to highlight their differences.

Since the peak at 7.696 minutes appears to be the compound of interest, this is the one that will be focused on. The base peak is at m/z 58, and other major fragments have m/z of 163, 155, 146, 132, 117, 103, 91, 77, 66, 65, 50 and 42. The mass spectrum of the compound shown in the library search also has a base peak at m/z 58, molecular ion at m/z 163, and major fragment ions at m/z of 136, 119, 91, 71, 42 and 30.

The major similarities are the base peak and the molecular ion, which is why this compound would have been selected in the library search, however there are more differences than similarities. Hence it can be concluded that the compound representative of this peak is not 2-dimethylaminoethylester-4-methylbenzoic acid as the library search had suggested.

The fragment ions in the experimental mass spectrum do however support the chemical structure of DMPPA (see Table 1). The fragment at m/z 117 would mean a loss of m/z 46 from the molecular ion at m/z 163. A possible explanation would be the loss of C₂H₈N⁺ from DMPPA, leaving C₉H₉⁺. A further loss of m/z 14, equating to CH₂, would represent the peak at m/z 103, and the loss of another carbon off the chain would represent the peak at m/z 91 – this generally rearranges into the tropylium cation (C₇H₇⁺). The fragment ion at m/z 77 represents a benzene ring (C₆H₅⁺), and the small peak at m/z 65 represents a 5-membered cyclic carbon ring that commonly results from the rearrangement of benzene when it looses a carbon atom. Finally, the base peak at m/z 58 also supports the structure of DMPPA because it represents a loss of the benzene ring and part of the carbon chain coming off the benzene ring, equating to m/z 105, leaving behind C₃H₈N⁺. A further loss of m/z 16 (CH₄) from this fragment would result in the peak at m/z 42, which makes sense as this leaves C₂H₄N⁺, which forms as an imine i.e. a double bond between one of the carbon atoms and the nitrogen atom.

Table 1 Proposed structures of the major fragment ions from the experiment mass spectrum of GC peak at 7.696 minutes.

Molecular ion – m/z 163	m/z 117	m/z 103	m/z 91
m/z 77	m/z 65	Base peak – m/z 58	m/z 42

Although the molecular ion and fragment ions support the proposed product, it is not confirmed that the final product is DMPPA because of the perplexing library search results, and the fact that there is a lack of literature to compare the results with. It is therefore important to analyse the experimental FTIR spectrum of the final product.

The FTIR spectrum, shown in Figure 3, exhibits peaks at 3024 cm^-1 and 2950 cm^-1 that are most commonly representative of a C-H aromatic stretch, and an sp³ C-H stretch, respectively, which are both present functional groups in DMPPA. Also visible in the spectrum, as well as being present in the structure of DMPPA, are C=C aromatic stretches at 1602 and 1471 cm^-1, C-H out-of-plane bending at 698 cm^-1, C-H bending at 1452 and ~1375 cm^-1, C-C-N bending at 1228 cm^-1, and a C-N stretch at 1029 cm^-1. The structure of DMPPA is quite simple and so all the major stretches and bends have been accounted for in the FTIR spectrum. A number of large peaks from 2564 – 2468 cm^-1 are also visible in the spectrum however these cannot be accounted for as they do not represent any functional groups present in DMPPA. It is generally not common to have peaks in this region for any compound, as there are not many functional groups that have a frequency in this region, so it is assumed that this peak represents an impurity in the product. This is confirmed by the GC/MS results that also showed impurities in the final product. It is also important to analyse the NMR spectrum to confirm that it too supports the FTIR and GC/MS results.

Figure 3 Annotated FTIR spectrum of final product.

The ¹H NMR spectrum is shown in Figure 4 and the NMR results are summarised in Table 2 on the following page. Just like the FTIR results, these too support the chemical structure of DMPPA. In the DMPPA molecule, there are seven different proton environments. Three of these environments have been grouped together as ‘A’ in Figure 4 because their chemical shifts are very similar and it is difficult to determine their multiplicity. It was evident that these peaks were from the protons on a mono-substituted benzene ring because they are generally de-shielded and hence further downfield. Also, the integral was close to five for these peaks, and the only five protons that would have similar chemicals shifts to one another in the structure of DMPPA are the ones on the benzene ring.

The peaks labeled ‘B’ and ‘C’ both represented triplets with integrals close to 2, meaning the peaks represent the protons on CH₂ groups next to another CH₂ group. This clearly corresponds to the two outer CH₂ groups in the carbon chain in DMPPA. The peak labeled ‘B’ corresponds to the protons on the carbon adjacent to the nitrogen atom, and these peaks are slightly more downfield than ‘C’ because the electronegativity of the nitrogen atom de-shields the ‘B’ protons. The singlet labeled ‘D’ had an integration close to six, which evidently represents the protons on the two CH₃ groups in DMPPA because they both have identical proton environments, and the adjacent atom contained no hydrogen atoms, hence it would be expected to produce a singlet. The final proton environment labeled ‘E’ represents a quintet with an integral of two, indicating protons on a CH₂ group adjacent to four protons i.e. two CH₂ groups. This clearly corresponds to the CH₂ group in between the two CH₂ groups on the carbon chain in DMPPA.

Figure 4 Colour coded NMR spectrum of final product. An expansion is shown for the peaks between 1.9 ppm and 2.8 ppm.

Table 2 Summary of NMR results.

Chemical Shift (ppm)	Peak Integration/No. Of Protons	Multiplicity	Protons (refer to figure)	J-Coupling (Hz)
7.305 – 7.181	4.85 / 5	Difficult to determine	A	–
2.700 – 2.670	2.03 / 2	Triplet	B	7.5
2.607 – 2.576	1.95 / 2	Triplet	C	7.5
2.465	6.01 / 6	Singlet	D	–
1.997 – 1.966	1.99 / 2	Quintet	E	15.5

The ¹H NMR spectrum evidently compares with the proton environments expected for DMPPA, showing that the final product does indeed contain the compound of interest. Three peaks at 5.297, 3.463 and 1.257 ppm however cannot be accounted for in the spectrum. These are most probably due to impurities, given away by the peaks having peculiar integrals of 0.03 and 0.35.

5. Conclusion

In conclusion, the GC/MS, FTIR and NMR results showed that an impure product of DMPPA was obtained, as well as an improbable percentage yield of 146%, most probably due to drying agent and extraction solvent that had not been completely removed from the final product.

To improve the purity of the final product it is strongly suggested to use an alternate extraction method such as solid phase extraction; and to obtain a reasonable percentage yield it would be wise to increase the time of evaporation on the rotary evaporator, and preferably to filter the solution to rid of any unwanted impurities such as drying agent.

6. References:

1. A. Newitz. (2013). That time in 1893 when a Japanese chemist invented crystal meth. Available: http://io9.com/that-time-in-1893-when-a-japanese-chemist-invented-crys-1198461744. Last accessed 1st Nov 2014.

2. G. Preve. (2013). Methamphetamine Synthesis and Effects. Available: http://flipper.diff.org/app/items/info/6027. Last accessed 1st Nov 2014.

3. J. Wallach. (2013). A Comprehensive Guide To Cooking Meth On ‘Breaking Bad’. Available: http://www.vice.com/read/a-comprehensive-guide-to-cooking-meth-on-breaking-bad. Last accessed 1st Nov 2014.

4. D. Albouy, G. Etemad-Moghadam, M. Vinatoru & M. Koenig. (1997). Regenerative role of the red phosphorus in the couple Hydriodic Acid-Red Phosphorus. Journal Of Organometallic Chemistry. 529, p295-299.

5. S. Fu (2014). Chemistry and Pharmacology of Recreational Drugs 65643 Practical Manual 2014. Sydney: UTS. pp 22-25.

7. Appendix:

Appendix 1 – Yield Calculations

m(DMPHPA) = 0.96 g, M(DMPHPA) = 179.26 g mol^-1, M(DMPPA) = 163.26 g mol^-1

n(DMPHPA) = = = 0.0054 mol

m(DMPPA) = = = 0.87 g

% Yield = = 146.4%

Appendix 2 – Supporting GC/MS Results

Appendix 2.1 GC/MS library report.

Appendix 2.2 Experimental mass spectrum of GC peak at 13.410 minutes (top), compared with library search mass spectrum of tolpropamine (bottom).

Appendix 2.3 Experimental mass spectrum of GC peak at 13.717 minutes (top), compared with library search mass spectrum of 1-cyclohexyltrimethylamine (bottom).

Appendix 2.4 Experimental mass spectrum of GC peak at 14.114 minutes (top), compared with library search mass spectrum of doxepin (bottom).

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