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A Study of the Precursors, Intermediates and Reaction Byproducts in the Synthesis of MDMA

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A Study of the Precursors, Intermediates and
Reaction Byproducts in the Synthesis of MDMA

R.J. Renton, J.S. Cowie and M.C.H. Oon
Forens. Sci. Int. 60, 189-202 (1993)

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Abstract

3,4-Methylenedioxymethylamphetamine (MDMA) was prepared by three synthetic routes. Analytical data from thin-layer chromatography, gas chromatography and gas chromatography-mass spectrometry of the precursors (safrole and isosafrole), intermediates (isosafrole glycol, piperonylmethylketone, N-formyl-3,4-methylenedioxymethylamphetamine, N-formyl-3,4-methylenedioxyamphetamine and 1-(3,4-methylenedioxyphenyl)-2-bromopropane), reaction by-products and the product MDMA were obtained. Further analyses of MDMA using other techniques including ¹H- and ¹³C-nuclear magnetic resonance spectroscopy, X-ray diffraction, infrared spectroscopy, ultraviolet spectroscopy and high performance liquid chromatography were also carried out. The results were then used as reference data for the identification of MDMA in case samples and also to establish the route of synthesis of illicitly prepared MDMA by the study of trace impurities.

Introduction

Fig. 1.
Diagram of the synthetic routes investigated.
Route I: PMK → N-formyl-MDMA → MDMA
Route II: PMK → N-formyl-MDA → MDMA
Route III: safrole → MDPBP → MDMA.

Although patented in 1914 as an appetite suppressant¹, 1-(3,4-methylenedioxyphenyl)-2-(N-methylamino)- propane, more commonly known as 3,4-methylenedioxymethylamphetamine (MDMA or Ecstasy), is a relatively new drug of abuse in the UK. Over the last 4 years, the number of seizures of the drug has increased and already, illicit laboratories for the production of MDMA have been uncovered. There is no current therapeutic use for MDMA in the UK and under British legislation, it is controlled as a class 'A' drug by the Misuse of Drugs Act, 1971, as amended by the Misuse of Drugs Act, 1971 (Modification) Order, 1977.
MDMA in illicit preparations was first observed in 1972 (Gaston, T.R. and Rasmussen, G.T. pers. commun.) and various aspects of this drug have been reviewed^2,3. However, there is only limited information on the forensic examination of the various methods of illicit manufacture. Verweij⁴ examined the reaction mixtures of MDMA prepared by low pressure reductive amination. A number of impurities were identified by gas chromatography-mass spectrometry (GC-MS). The analyses by GC-MS of samples from a clandestine laboratory involved in the synthesis of MDMA from sassafras oil was carried out by Noggle et al.⁵. Lukaszeweski⁶ made a study of the various syntheses of 3,4-methylenedioxyamphetamine (MDA) where the precursors, intermediates and reaction by-products were characterised by chromatographic and spectroscopic techniques.
This study was designed to obtain analytical data pertaining to the identification of precursors, intermediates and reaction by-products encountered in certain synthetic routes as well as obtaining further analytical information to assist in the laboratory identification of MDMA.

Experimental

Materials

Safrole (97%), N-methylformamide (NMF, 99%) and trifluoroacetic anhydride (TFAA) were purchased from Aldrich Chemical Co. (Gillingham, Dorset, UK); isosafrole (cis and trans, 95%) and methylamine (33% in ethanol) were obtained from Fluka Chemical Co. (Glossop, UK); formamide and lithium aluminium hydride (LAH) were from Cambrian Gases (Croydon, UK). Other reagents, solvents (general purpose reagent grade) and methanol (Analar grade) for high-performance liquid chromatography (HPLC) were obtained from BDH Ltd (Poole, UK).

Syntheses

Fig. 1 shows a summary of the syntheses of which Routes I and II involve the Leuckart reaction^7,8. The original synthesis of MDMA¹ was carried out by Route III. Piperonylmethylketone (PMK) was synthesized from isosafrole through the intermediate isosafrole glycol⁶.
Route I.
Formic acid (3.66 g), NMF (7.6 g) and PMK (9.0 g) were refluxed at 150—170°C for 7 h with additional formic acid (7.32 g) added periodically. On cooling, a clear yellow solution of N-formyl-3,4-methylenedioxymethylamphetamine (N-formyl-MDMA) was obtained. Concentrated hydrochloric acid (30 ml) was added to this solution which was refluxed for a further 3 h. The reaction mixture was made basic with sodium hydroxide and the crude MDMA extracted into diethyl ether. After the volume of the organic solvent was decreased, the remaining residue was treated with hydrogen chloride gas to yield a gelatinous brown precipitate of impure MDMA hydrochloride. The crude salt, dissolved in boiling methanol, was added to chilled acetone to form a crystalline product. This was recrystallized to yield fawn crystals with a melting point of 147—148°C⁹.
Route II.
Formamide (65 g) and PMK (23 g) were refluxed at 190°C for 5 h. The solution was made basic and extracted with diethyl ether. The ethereal solution was first washed with dilute sulphuric acid, rinsed with water and finally dried over anhydrous sodium sulphate. The diethyl ether volume was reduced to yield a clear yellow solution of N-formyl-3,4-methylenedioxyamphetamine (N-formyl-MDA). This was added drop-wise to LAH (2.5 g in 100 ml of sodium-dried diethyl ether) and refluxed for 3 h. The excess LAH was decomposed by the addition of water and the resulting mixture was filtered and the precipitate washed with diethyl ether. The washings and the filtrate were combined and extracted with dilute sulphuric acid. The aqueous solution was made alkaline with dilute sodium hydroxide and extracted with diethyl ether. The solvent was evaporated leaving an amber oil of crude MDMA.
Route III.
The reactions described in the Merck patent¹ involve the formation of 1-(3,4-methylenedioxyphenyl)-2-bromopropane (MDPBP) from safrole followed by reaction with methylamine. This was the method followed.
Extraction of intermediates and reaction by-products
Route I. An aliquot of the acidic N-formyl-MDMA reaction mixture was washed with diethyl ether, made basic with dilute sodium hydroxide and extracted with diethyl ether. This sample was analysed by thin-layer chromatography (TLC), gas chromatography (GC) and GC-MS.
Route II. A sample of the N-formyl-MDA reaction mixture was made acidic with tartaric acid¹⁰ and extracted with diethyl ether. The organic layer was separated and extracted with dilute hydrochloric acid. The acidic extract was then made basic with dilute sodium hydroxide and extracted with chloroform. This sample was analysed by the above-mentioned methods.
Route III. A sample of the chloroform used to extract the brominated intermediate from the safrole/hydrobromic acid reaction mixture was analysed by the techniques described above.
Preparation of the trifluoroacetyl (TFA) derivative
Ethyl acetate (1.0 ml) and TFAA (0.1 ml) were added to a 10-ml screw-topped tube containing the dried extract. The reaction mixture was heated at 60°C for 20 min, evaporated to dryness and methanol (0.1 ml) was added to the tube prior to GC-MS analysis.
Extraction of impurities from case samples
Powder or crushed tablet (5 mg), known to contain the MDMA salt, was vortex-mixed with redistilled diethyl ether (1 ml) and centrifuged. The supernatant was taken off, evaporated to dryness and methanol (0.1 ml) was added prior to GC-MS analysis.

Analytical techniques

HPLC

The two HPLC systems used 12.5 cm by 4.9 mm (i.d.) stainless steel columns with slurry packed 5 µm Spherisorb silica (Phase Separations, Queensferry, UK) and an eluent flow rate of 2 ml/min.
System I. A reciprocating pump, type HM (Metering Pumps, London, UK), delivered the eluent of methanol/30% hydrochloric acid/ammonium hydroxide (d. 0.880) 2000:5.8:18.4. The sample in 0.02 M methanolic hydrochloric acid was introduced to a Rheodyne model 7125 injection valve (Berkeley, CA, USA) fitted with a 5-µl loop. A Cecil CE212 UV detector (Cecil Instruments, Cam-bridge, UK) monitored the eluant by absorption at 284 nm.
System II. An Applied Chromatography Systems model 400 pump (ACS Ltd., Macclesfield, UK) delivered the eluent of 0.01 M ammonium perchlorate in methanol adjusted to pH 6.7 by the addition of 1 ml/l of 0.1 M sodium hydroxide in methanol. The sample in methanol was introduced to a Rheodyne injection valve, model 7125, fitted with a 20-µl loop. A LDC spectromonitor III (LDC Analytical Ltd., Stone, UK) monitored the eluant by UV absorption at 284 nm.

GC-MS

A VG 12-12F quadrupole mass spectrometer (VG Biotech, Altrincham, UK) was used in combination with a Carlo Erba model 4160 gas chromatograph (Fisons Instruments, Crawley, UK). The inlet of a fused-silica capillary column of bonded dimethyl silicone (15 m by 0.22 mm i.d., 0.25 µm film thickness; Thames Chromatography, Maidenhead, UK) was connected to a split/splitless injector. The column outlet was inserted directly into the ion source of the mass spectrometer. A splitless injection was made with the GC oven temperature held at 100°C for 1 min. The temperature was ramped at 30°C/min to 280°C where it was maintained for 5 min. The temperature of the injection port and the transfer line was 270°C. The inlet pressure for the helium carrier gas was 1.0 kg/cm-2. The mass spectrometer was used in the EI mode, the source temperature was 200°C and electron energy was 70 eV. Mass spectra were obtained by scanning from 35 to 535 amu at 1 s/scan and the data was processed on a VG DS2050 Data System (VG Analytical, Manchester, UK). Isobutane was the reagent gas in the chemical ionization (CI) mode and the source temperature was 200°C. The vacuum in the source housing was 10-4 Torr and the mass spectrometer scanned from 100 to 400 amu at 1 s/scan.

Other techniques

Ultraviolet (UV) spectra were recorded on a Uvikon UV/visible spectrophotometer, model 810 (Kontron Scientific Instruments Ltd., St Albans, UK). Infrared (IR) spectra were obtained as potassium bromide discs on a Perkin Elmer IR spectrophotometer, model 298, used in conjunction with a Perkin Elmer IR data station 3600 (Perkin Elmer Instruments, Beaconsfield, UK). The other techniques are detailed with their tabulated data.

Results and Discussion

MDMA and intermediate compounds

There is a large number of potential synthetic routes to MDMA² but the choice of this study was restricted to three. From the information available, it appears that the Leuckart reaction (Routes I and II) is the most commonly used reaction in the illicit production of amphetamine type drugs. This reaction can be easily adapted to the manufacture of methylenedioxy-substituted analogues. The reactions (Route III) described in the Merck patent¹ could be used for those in search of a published method.
The IR, UV and ¹H-MMR spectra were all consistent with those published previously^9,13. The ¹³C-NMR spectra (both broad-band proton decoupled (BBPD) and single frequency off-resonance decoupled (SFORD) spectra) and the XRD pattern of MDMA·HCl are presented in Fig. 2 and Tables 1 and 2 respectively. Fig. 3 and 4 show the mass spectra of N-formyl-MDMA and MDPBP. The mass spectra of safrole, isosafrole, isosafrole glycol, PMK, N-formyl-MDA and MDMA have been reported previously^6,9. The mass spectrum of MDMA is not highly characteristic. It has a base peak of mass 58 with minor ions of mass 135 and 136¹⁴. A highly characteristic mass spectrum can be obtained with the TFA derivative. Fig. 5 shows the mass spectrum and proposed fragmentation route. The chromatographic data for MDMA and related compounds by TLC, GC and HPLC are shown in Tables 3, 4 and 5, respectively.

Reaction by-products

Route I.

A reaction by-product N,N-dimethyl-3,4-methylenedioxyamphetamine (DMMDA) was identified. This assignation was based on the mass spectrum shown in Fig. 6 together with a molecular weight of 207 (from the CI mass spectrum) and by analogy with the corresponding amphetamine synthesis^11,12. However, DMMDA (a tertiary amine) has the same mass spectrum as its isomer N-ethyl-3,4-methylenedioxyamphetamine (a secondary amine)^13,14. The compound did not, however, form a derivative with TFAA, showing it to be a tertiary amine and not a secondary amine. This compound could be the product of the reaction of dimethylformamide (DMF) and PMK where DMF is an impurity of NMF¹². Verweij⁴ has identified DMMDA as an impurity in illicit MDMA manufactured by low pressure reductive amination.

Route II.

Reaction by-products such as [1-(3,4-methylenedioxyphenyl)-2-propyl]amine and [1-(3,4-methylenedioxyphenyl)-2-propyl]methylamine which have been identified in the synthesis of MDA⁶ using the Leuckart reaction were not observed in this study. However, GC-MS provides some evidence to suggest the presence of methylenedioxy substituted pyrimidines and pyridines analogous to those observed in the cognate synthesis of amphetamine^10,15. The mass spectrum of the tentatively substituted pyrimidine (Fig. 7a) is characterized by its two major ions of mass 213 and 214. The molecular ion of mass 214 exhibits a mass shift of 44 from that observed in the mass spectrum of the cognate amphetamine impurity¹⁵, suggesting a methylenedioxy substituted analogue. Similarly, the molecular ion of mass 348 (Fig. 7b) of the tentatively identified substituted pyridine impurity¹⁰ exhibits a mass shift of 88 with respect to similar compounds observed in amphetamine synthesis. This suggests a methylenedioxy doubly substituted pyridine analogue which is consistent with the structure of the known impurity.
No significant reaction by-products were identified in Route III which involves the formation of the intermediate MDPBP.

Applications

Impurities are often observed in illicitly prepared drugs samples as they are not usually purified to any great degree after manufacture. In the case of illicitly prepared amphetamine, the presence of 'route specific' impurities is used to establish the manufacturing process¹¹. Applying this analogy to MDMA, the identification of the reaction intermediates in the illicit sample can be used to establish the synthetic route used. Figure 8 shows the chromatogram of an extract of a typical sample. The reaction intermediates isosafrole glycol, PMK and N-formyl-MDMA were observed together with the reaction by-product DMMDA. This demonstrates that route I was used in the manufacture.

Conclusion

In addition to providing reference data for the identification of MDMA in case samples, the analytical data from this study can be used to determine the synthetic route used in the illicit manufacture of MDMA, and may also help in the discrimination of sources of origin in the comparison of illicit samples.

Table 4
GC Data for MDMA and Related Compds.

Compound	Relative retention time
(MDMA = 1.0)
Safrole	0.35
trans-Isosafrole	0.44
cis-Isosafrole	0.53
PMK	0.97
DMMDA	1.21
MDPBP	1.44
Isosafrole glycol	2.24
N-formyl-MDA	5.77
N-formyl-MDMA	6.45

GC was performed using a glass column
(2 m x 6 mm o.d.) packed with 3% OV17
coated on GasChromQ (Phase Sep.,
Queensferry, UK) with a N₂ carrier gas
flow rate of 30 ml/min. The Philips
PU4500 gas chromatograph was fitted
with a flame ionization detector. The
oven temp was 200°C isothermal,
injector temp was 200°C and the
detector temp was 280°C.

Table 1
Data From ¹³C-NMR Spectra of MDMA·HCl

Chemical shift (BBPD, Fig. 2a)	Multiplicity (SFORD, Fig. 2b)	Assignment
15.4	quartet	C-2
30.2	quartet	C-1
39.1	triplet	C-4
57.3	doublet	C-3
101.2	triplet	C-9
108.7	doublet	C-11
109.6	doublet	C-7
122.6	doublet	C-6
129.8	singlet	C-5
146.9	singlet	C-8
148.1	singlet	C-10

Table 3
TLC Data for MDMA and Related Compounds

Compound	Relative Retention Value
MDMA	0.27
DMMDA	0.38
N-formyl-MDA	0.75
N-formyl-MDMA	0.78

TLC was carried out on glass plates coated
with Kieselguhr 60 F254 (Merck TLC plates,
BDH Ltd., Poole, UK) that had been dipped
in a methanolic solution of 0.01 M sodium
hydroxide¹⁶. The plates were developed
in a methanol/acetone (3:1) solvent system,
visualised in ultraviolet light (254 nm) and
sprayed with acidified iodoplatinate solution.

Table 2

XRD Pattern of MDMA·HCl

• Fig. 2. The ¹³C NMR spectra of MDMA.HCl. (a) BBPD and (b) SFORD.
• Fig. 3. The mass spectrum of N-formyl-MDMA.
• Fig. 4. The mass spectrum of MDPBP.
• Fig. 5. The mass spectrum of the MDMA·TFA derivative and the proposed fragmentation pathway.
• Fig. 6. The mass spectrum of DMMDA.
• Fig. 7. Mass spectra of (a) substituted pyrimidine and (b) substituted pyridine.
• Fig. 8. Total ion chromatogram of illicitly prepared MDMA and impurities. A: PMK; B: MDMA; C: DMMDA; D: isosafrole glycol; E: N-formyl-MDMA. A VG 15—250 quadrupole mass spectrometer, fitted with a Hewlett Packard 5980 gas chromatograph (Hewlett Packard Analytical, Winnersh, UK), was used in the analysis of extracts of case samples. The operating conditions were in the EI mode as described earlier.

References

1. E. Merck, Verfahren zur Darstellung von Alkyloxyaryl-, Dialyloxaryl- und Alkylenedioxy-arylaminopropanen bzw. deren Amstickstoff Monoalkylierten Derivaten. German Patent, No. 274 350, 1914.
2. A.T. Shulgin, The background and chemistry of MDMA. J. Psychoactive Drugs, 18 (1986) 291–304.
3. G.N. Hayner and H. McKinnon, MDMA. The dark side of Ecstasy. J. Psychoactive Drugs, 18 (1986) 341–347.
4. A.M.A. Verweij, Clandestine manufacture of 3,4-methylenedioxy-methylamphetamine (MDMA) by low pressure reductive amination. A mass spectrometric study of some reaction mixtures. Forensic Sci. Int., 45 (1990) 91–96.
5. F.T. Noggle, C.R. Clark and J. DeRuiter, Gas chromatographic and mass spectrometric analysis of samples from a clandestine laboratory involved in the synthesis of Ecstasy from Sassafras oil. J. Chromatogr. Sci., 29 (1991) 168–173.
6. T. Lukaszeweski, Spectroscopic and chromatographic identification of precursors, intermediates and impurities of 3,4-methylenedioxyamphetamine synthesis. J. Assoc. Off. Anal. Chem., 61, 951–967 (1978).
7. M.L. Moore, The Leuckart reaction. Organic Reactions, 5 (1949) 301–330.
8. E. Merck, Verfahren zur Gewinnung von Formylderivaten sekundarer Basen. German Patent 334,555 (1920)
9. K. Bailey, A.W. By, D. Legault and D. Verner, Identification of the N-methylated analogs of the hallucinogenic amphetamines and some isomers. J. Assoc. Off. Anal. Chem., 58 (1975) 62–69.
10. A.M. van der Ark, A.M.A. Verweij and A. Sinnema, Weakly basic impurities in illicit amphetamine. J. Forensic Sci., 23 (1978) 693–700.
11. A.M.A. Verweij, Impurities in illicit drug preparations: amphetamine and methamphetamine. Forensic Sci. Rev., 1 (1989) 1–14.
12. T.C. Kram and A.V. Kruegel, The identification of impurities in illicit methamphetamine exhibits by gas chromatography/mass spectrometry and nuclear magnetic resonance spectroscopy. J. Forensic Sci., 22 (1977) 40-52.
13. T.A. Dal Cason, The characterization of some 3,4-methylenedioxyphenylisopropylamine (MDA) analogs. J. Forensic Sci., 34 (1989) 928–961.
14. F.T. Noggle, C.R. Clark, A.K. Valaer and J. DeRuiter, Liquid chromatographic and mass spectral analysis of N-substituted analogues of 3,4-methylenedioxyamphetamines. J. Chromatogr. Sci., 26 (1988) 410–415.
15. A.M. van der Ark, A.B.E. Theeuwen and A.M.A. Verweij, Impurities in illicit amphetamine; isolation and identification of some pyrimidines. Pharm. Weekbl., 112 (1977) 977–982.
16. J.V. Jackson and A.J. Clatworthy, Toxicological applications of chromatography. In I. Smith and J.W.T. Seakins (eds.), Chromatography and Electrophoretic Techniques, Vol. 1, Paper and Thin Layer Chromatography, William Heinemann Medical Books Ltd, 1976, pp. 380–455.

Impurities in Commercially Available MDP2P

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A Note about some Impurities in Commercially Available Piperonylmethylketone

By AMA Verweij and AGA Sprong
Microgram 26(9), 209 (1993)

ASCII by GC_MS, HTML by Rhodium

Introduction

Diketone compounds are known impurities present in the ketones that are used as starting materials in the different syntheses of 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA)¹. No further studies have been reported in the literature on impurities present in piperonylmethylketone (PMK) (also known as 3,4-methylenedioxyphenyl-2-propanone, MDP2P), used in the illicit production of MDA. Some of these impurities, and their structures, have been determined in commercially available PMK.

Experimental

Analyses were done on a 1:40 dilution of PMK with chloroform. Gas chromatographic-mass spectral analyses were performed on 1 uL injections using a HP 5971A MSD interfaced with a HP 5890 GC. The MSD was operated in the EI mode. The samples were introduced into the GC via a split injector equipped with a 12.5 m x 0.2 mm id HP Ultra-1 fused silica capillary column with a 0.33 um film thickness. The column temperature was programmed from 100 to 280°C at a rate of 10°C per minute. The injection port was 275°C and the transfer line temperature was 280°C. He was used as the carrier gas with a flow rate of about 1 mL/minute.

Results and discussion

Table 1

Peak	Compound Name	MW.	Formula
A	Safrole	162	C10H10O2
A	Isosafrole	162	C10H10O2
B	Piperonal	150	C8H6O3
C	4-Allyl-1,2-dimethoxybenzene	178	C11H14O2
D	Piperonylmethylketone (PMK, MDP2P - Main Component)	178	C10H10O3
E	3,4-Methylenedioxyphenyl- 2-propanone-(3-ol)	194	C10H10O4
F	3,4-Methylenedioxyphenyl- 1-propanone	178	C10H10O3
G	3,4-Methylenedioxyphenyl- 1-butanone	172 (sic)	C11H12O3
H	4-Isopropyl-1,6-dimethyl- 1,2,3,4-tetrahydronaphtalene	202	C15H22
I	3,4-Methylenedioxyphenyl- propionic acid-2-one	208	C10H8O5

The total ion chromatogram (TIC) of a solution of PMK in chloroform is shown in Fig 1 (not included). From the abundance values for the peaks in the TIC shown in Fig 1, the purity of the PMK was estimated to be greater than 95 percent. In the same way, the impurities were found to range from about 0.1 to 1.0 percent. The structure elucidation of the different compounds in the TIC was done by comparing the mass spectral data with different databases^1-3 and applying known fragmentation rules^4,5. In Table 1, the proposed structures of the impurities together with the mass spectral data are given. All the detected impurities except compounds C and H, have the methylenedioxy group, whereas the other structural differences of the impurities are in the substituents attached to the other side chain of the phenyl group. A trace quantity of safrole, as well as isosafrole, was found, giving rise to the assumption that at least the oxidation of safrole in formic acid by hydrogen peroxide was part of the process of manufacturing PMK. The presence of the oxidation products of PMK, the alcohol and the acid (compounds E and I in Table 1), also points to an oxidative process.

 

References

1. AMA Verweij. Impurities in illicit drugs preparations: 3,4-(methylenedioxy)amphetamine and 3,4-(methylenedioxy)methamphetamine. Forensic Science Review 4, 138-146 (1992)
2. Eight Peak Index of Mass Spectra, The Mass Spectra Data Center, The Royal Society of Chemistry. 1983
3. FW McLafferty, DB Stauffer. The Wiley/NBS Registry of Mass Spectral Data. John Wiley and Sons. 1989
4. JR Chapman. Practical Organic Mass Spectrometry. John Wiley and Sons. 1985
5. FW McLafferty, Interpretation of Mass Spectra, University Science Books. 1980

MDP2P by 2-Nitropropene Alkylation of 1,3-Benzodioxole

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Synthesis of MDP2P From 1,3-Benzodioxole
by Friedel-Crafts Alkylation with 2-Nitropropene

Written by Scooby Doo

HTML by Rhodium

To a 3-necked 500 ml flask under a nitrogen atmosphere was added 300 mL of dry DCM, 0.1 mole of 2-Nitropropene (8.7g) and 0.5 moles of 1,3-Benzodioxole (61 g). The flask was then secured within a dewar flask sitting on top of a magnetic stirplate. Dry ice was added to the dewar flask which was filled with acetone until a temperature of approx -78ºC was acquired. Once the internal flask temperature of -70ºC was reached, 0.1 mole (19 g) of TiCl₄ was dripped slowly into the stirred solution. The temp started to rise so the addition was controlled to keep the internal flask temp around -60°C to -70ºC. The flask was then stirred for 30 mins at -70ºC, by which time the precipitate which formed from the addition had dissipated. The dewar flask was removed and the stirring solution was allowed to warm up to room temperature, during which time the black solution will change viscosity and colour.
To hydrolyze the formed nitro-titanium complex, 100 mls of water was added to the solution which was then refluxed for 2 hours. During the reflux a brown gas (probably NO₂) is evolved. The flask was cooled and vacuum filtered (cleans it up a lot) the water layer seperated and discarded. The organic layer was then washed with 3x200 mL of 10% NaOH and 1x200 mL of a brine solution. It was then dried with magnesium sulfate, the DCM evaporated and resulting orange-yellow oil vacuum distilled. The 1,3-Benzodioxole came over at 40-45ºC at 10 mbar then a yellow-green fluorescent oil (MDP2P) began distilling at 135ºC at 3 mbar.

8 grams of MDP2P was collected, corresponding to 45% yield from 2-Nitropropene or 23.5% from 1,3-Benzodioxole (calculated on the amount of 1,3-Benzodioxole not recovered during workup).
Reference: Tetrahedron Letters, Vol 29, No 24, pp. 2977-2978 (1988)

Pseudonitrosite FAQ

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Pseudonitrosite FAQ

by Rhodium

Related info: Pseudonitrosite Synthesis, as Performed by Pugsley

Introduction

The hitherto pretty unknown pseudonitrosites are nitrogenous compounds which are formed by the action of N₂O₃ (an equimolar mixture of NO and NO₂) upon etheral solutions of some unsaturated compounds, for example propenylbenzenes and styrenes. They were popular in the late 1800s and early 1900s, but has since then been forgotten(?). After around WWII, there is not a single mention of them in the literature, not even in such a reference work on the subject as Nitroalkenes - Conjugated Nitro Compounds¹.
The pseudonitrosites were discovered by Toennies around 1880, when he made the pseudonitrosite of anethol, but he failed to recognize the constitution of the compound, and mistakenly assigned it the structure of a vicinal ketoxime/nitrite. In the early 1890s, the Italian chemist Angelo Angeli experimented with different allyl- and propenylbenzenes, and again encountered the pseudonitrosites, but he couldn't either determine their exact structure, and with the methods used in analytical chemistry back then, this is understandable. In the early 1900s, the puzzle was solved by studies on styrene pseudonitrosite, and around this time Wallach and Wieland published reviews of pseudonitrosite chemistry^2-3. Very little about pseudonitrosites can be found in Chemical Abstracts, so most pointers to earlier work must be retrieved from the references cited in those articles.
In the 1930's, Victor Bruckner began to explore the possibility of using pseudonitrosites as an intermediate in the synthesis of substituted 1-phenyl-2-amino-propanols, and in his articles he also included improved syntheses of several pseudonitrosites from propenylbenzenes, as well as studies on the pseudonitrosites themselves. One of the most useful reactions he investigated was the basic hydrolysis of propenylbenzene pseudonitrosites, yielding the corresponding beta-nitro derivatives of the propenylbenzenes. This route offered several advantages over the known nitration of alkenes with tetranitromethane, which is expensive, toxic and explosive. In his papers on pseudonitrosites, Bruckner described several experiments with asarone⁴, methylisoeugenol and isosafrole⁵, isoeugenol⁶ and anethole⁷. In the experimental part below, some freely translated parts of his work is included.

Fig 1. Formation of Asarone Pseudonitrosite

Theory

Several methods for the synthesis of pseudonitrosites have been used, such as bubbling N₂O₃ through a solution of the propenylbenzenes in ether, slow addition of a NaNO₂ solution to a solution of the propenylbenzene in glacial acetic acid (Toennies' method), as well as dripping a dilute solution of sulfuric acid into a two-phase solution of NaNO₂ in water and a propenylbenzene in ether (Bruckner's method).

Fig 2. N₂O₃ from NaNO₂ and H₂SO₄

The action of a strong acid (such as sulfuric acid) on sodium nitrite gives the sodium salt of the strong acid, as well as free nitrous acid (HNO₂), which in turn breaks down to an equimolar mixture of NO and NO₂ gas (see Fig. 2). This gas mixture is in equilibrium with dinitrogen trioxide: N₂O₃ ←→ NO + NO₂
At 25°C and normal pressure, only about 10% of the gas is in the form of N₂O₃, and the equilibrium mixture behaves just like as if it was a mixture of NO and NO₂. But, for the sake of simplicity, the equilibrium mixture is commonly called N₂O₃, or dinitrogen trioxide.

Fig 3. N₂O₃ from HNO₃ and iron

N₂O₃ can also be formed by the action of nitric acid (which in turn can be made by dissolving NaNO₃ or KNO₃ in conc H₂SO₄) on certain metals, for example iron (see Fig. 3). The more finely divided the metal, the faster generation of gas. But there is a downside to this method. In the beginning the nitric acid is concentrated, but as N₂O₃ is evolved, the solution becomes more and more dilute. There is a problem associated with this, the ratio of NO to NO₂ isn't constant if the concentration of the acid changes. Concentrated acid gives excess NO₂, and a dilute acid solution gives excess NO. To get maximum yields out of the treated propenylbenzene, the proportions between NO and NO₂ should always be as close to 1:1 as possible, and only the sodium nitrite method will constantly produce a gas mixture with just those proportions. Producing dinitrogen trioxide with the nitrate method is therefore discouraged. This method does not work at all with asarone (only with other propenylbenzenes, such as isosafrole or anethole) according to Bruckner⁴.

Fig 4. Dimerization of Asarone Pseudonitrosite

The pseudonitrosites always dimerizes to the bis-pseudonitrosites, all of which are practically insoluble in water, alcohols and most common organic solvents, with the exception of warm chloroform or ethyl acetate, in which a blue-green solution is produced, consisting of the dissociated pseudonitrosite monomer. During the treatment of a propenylbenzene with N₂O₃, the intensely colored free monomer can be observed for a while before it dimerizes to its crystalline form. The colors of the crystalline pseudonitrosites varies, from the snow-white isosafrole or anethole derivatives to the canary-yellow one obtained from asarone. Upon storage, pseudonitrosites soon decompose with discoloration, releasing nitrogen oxides and hydrogen cyanide. At around 40°C decomposition takes place in less than one day.

Fig 5. Hydrolysis of Asarone Pseudonitrosite Dimer

Treatment of the pseudonitrosite dimer with four moles of an inorganic base (such as KOH in alcohol), produces two moles of potassium hyponitrite (K₂N₂O₂) and two moles of the water-soluble potassium salt of the corresponding nitroalkene. Acidification of the potassium salt solution with dilute acid precipitates the water-insoluble phenyl-2-nitropropene as fine crystals, and the liberated hyponitrous acid breaks down into water and nitrous oxide (N₂O), which can be observed as fine bubbles that is being evolved during this step.
The reaction of a pseudonitrosite with acetic anhydride produces the alpha-acetoxy derivative with release of N₂O, and after reduction of the nitro group this could be hydrolyzed to ring substituted phenylpropanolamine derivatives. Basic hydrolysis of the alpha-acetoxy derivative also produces the phenyl-2-nitropropene. Reaction of pseudonitrosites with primary amines yields secondary alpha-amino derivatives.

Experimental

All these procedures are presented for informational purposes only. These procedures should not be carried out without adequate precautions taken. In most of the procedures highly toxic fumes of nitrogen oxides can evolve, which are irritating on mucous membranes and can destroy lung tissue. Use only with good ventilation. The author assumes no responsibility for any damage or legal consequences resulting from misuse of this information.

Pseudonitrosites^4,5,7

A solution of 1 mole (69 grams) of sodium nitrite in 100 ml water was prepared in a 500 ml flask, and a solution of 0.1 moles of a freshly distilled propenylbenzene (20.8g asarone, 16.2g isosafrole or 14.8g anethole) in 150 ml of diethyl ether was added. During a period of 3-4 hours, a 20% solution of H₂SO₄ (prepared by cautiously adding 0.5 moles (49 grams) of conc. sulfuric acid to 200 ml of H₂O) was added dropwise with magnetic stirring, preferably through a pressure- equalized addition funnel. Watch the addition rate so that the temperature of the two-phase solution doesn't rise over room temp, and this solution can preferably be cooled during the addition In the beginning of the addition of acid, monomeric pseudonitrosite can be seen in the etheral layer. The monomer derived from asarone is greenish, anethol blueish and isosafrole yellow. If oxygen gets into the system during the addition, formed NO oxidizes to brown NO₂ gas, which can lower the yield of pseudonitrosite. After the addition, the solution was allowed to stir for an hour or two, whereafter the solution was filtered with suction, and the precipitate washed with 50ml each of water, denatured alcohol and finally ether. After sucked as dry as possible, the pseudonitrosite crystals was allowed to air dry on a filter paper.

Pseudonitrosite	Color	Yield	Melting point
Asarone	Yellow	16.5g, 58% (22.8g/80%)4	130°C(dec)4
Isosafrole	White	77% (18.4g)5	128°C3
Anethole	White	48% (10.8g)7	126°C(dec)7

Pseudonitrosites cannot be stored, as they begin to decompose within hours at room temperature with the evolution of nitrogen oxides, and should be further processed to for example the very useful phenyl-2-nitropropenes, which upon reduction can yield phenylacetones and amphetamine derivatives.

Phenyl-2-nitropropenes^4,5,7

0.1 mole of the corresponding propenylbenzene pseudonitrosites (28.5g asarone, 23.8g isosafrole or 22.4g anethole) was dissolved in 150ml 8% alcoholic KOH with shaking, and possibly light heating (not over 30°C, especially not in the case of asarone pseudonitrosite, or there is a risk of decomposition (to the aldehyde, amongst other things). Caution: Foaming with evolution of N₂O will occur. The cloudy solution was suction filtered, and the filtrate was poured onto 100 grams of crushed ice. The solution was acidified with dilute HCl and was stirred occasionally until the ice had melted. The precipitate of nitropropene was filtered off, washed with a little cold water and air dried.

Nitropropene	Color	Yield	Melting point
Asarone	Yellow/red*	19.7g, 78%	101°C4
Isosafrole	Yellow		98°C5
Anethole	Yellow		47°C7

*) 2-Nitroasarone exists in two modifications, yellow or red prisms, and depending on concentration and precipitation speed, one often gets a mixture of both species. They both melt at 101°C, the red form transforming itself to the yellow form at 90°C.

References

1. V. V. Perekalin, E. S. Lipina, V. M. Berestovitskaya, D. A. Erefmov, Nitroalkenes (Wiley, 1994)
2. H. Wieland, Zur Kenntniss der Pseudonitrosite, Ann. 329, 225-268 (1903)
3. O. Wallach, Ueber die Additionsproducte von N₂O₃ und von NOCl, Ann. 332, 305-336 (1904)
4. V. Bruckner, Ueber das Pseudonitrosit des Asarons, J. Prakt. Chem., 138, 268-274 (1933)
5. V. Bruckner, Ueber die Verwendung der Pseudo-nitrosite , Ann. 518, 226-244 (1935)
6. V. Bruckner, Ueber die Verwendung der Pseudo-nitrosite II, J. Prakt. Chem. 143, 287-297 (1935)
7. V. Bruckner, Ueber die Verwendung der Pseudo-nitrosite III, J. Prakt. Chem. 148, 117-125 (1937)

Photoamination - One step from isosafrole to MDMA

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Photoamination of Methylstyrenes The Possible One-pot-shot From Isosafrole to MDMA by Drone #342 By far, one of the most fascinating possible methods of making MDMA is the insanely elegant photolytic reaction between isosafrole and methylamine. For years, like many other individuals, I looked at isosafrole and methylamine and dreamed that somewhere there was a method of adding the two together in a single step, rather than having to make MDP-2-P, then reductively aminate it, and go through all the tedious steps involved. As it turns out, such a method exists: photo-induced nucleophilic amination. The general idea is this: an alkoxy-substituted methylstyrenes (in this case, isosafrole), p-dicyanobenzne (DCB), methylamine, and triphenylbenzne (TPB), are disolved in acetonitrile, exposed to light, and the reaction occurs. Here's the mechanism: p-DCB absorbs a photon, gets activated, and abstracts an electron from isosafrole's double bond, leaving the carbon beta to the benzene ring (in the 2-position) positively charged. From there, the nucleophile (in this case methylamine) attacks the aforementioned carbon, and releases a hydrogen. The hydrogen is then scooped up by the cationicly-charge alpha carbon. The basis of this technology is some research done in 1973, involving the addition of MeOH across double bonds. During the early 90's, some Japanese researchers had the ingenuity to apply this to ammonia as a nucleophile, then tried alkylamines as well. Both were greatly successful, and were directly applied to the synthesis of phenethylamines. Fortunately for MDMA enthusiaists, several papers of theirs focused on the synthesis of methoxylated aryl isopropylamines -- which is exactly what MDMA is. Though MDMA was never expressly synthesized by these fellows, one can easily apply the techniques they developed to MDMA production. General method for the production of amphetamines from methyl styrenes, lifted from the literature. "General procedure of Photoamination. Into a Pyrex vessel was introduced an MeCN-H2O (9:1, 70 mL) solution containing 1-4, 6-8 [various styrenes] (3.5 mmol) and DCB (3.5 mmol), and then the solution was bubbled with gaseous ammonia. The solution was irradiated by an eikosha PIH-300 high pressure mercury vapor lamp under cooling with water. The progress of the reaction was followed by GLC analysis..." Proposed experimental method. Proposed procedure of photomethylamination of isosafrole. Into a Pyrex vessel was introduced an MeCN-H2O (9:1, 70 mL) solution containing isosafrole (C10H10O2; 0.567 grams, 3.5 mmol) and DCB (3.5 mmol). The solution was then saturated with methylamine gas. The solution was irradiated by a 300-W high pressure mercury vapor lamp under cooling with water. Upon completion, the solvent was stripped in vacuo, and the residue was washed an aqueous 10% NaOH solution, and extracted with DCM. The DCM was stripped in vacuo, and the oil distilled in vacuo, yielding the free base of MDMA. The base was disolved in dry Et2O, and dry HCl gas was bubbled in. The precipitated crystals then dried, weighed, and tested for biological activity. By definition, this is an oxidative amination. For old MDMA chemhacks, familiar with reductive amination, this should sound a little weird, but hey, it works. Bibliography: a reading list of the good stuff Neunteufel, R. A., Journal of the American Chemical Society, 1973, 95, 4080-4081 This is the original study of photo-induced nucleophilic addition that inspired the later use of ammonia. While its only marginally useful, it's a good place to start to understand some of the theory of this process. Tetrahedron Letters, 1993, 34, 5131-5134 This is a quick, general sneak-preview of the later study of phenethylamine synthesis. Nice, basic, but not too much detail Tetrahedron, 1994, vol. 50, no. 31, 9275-9286 "Photoinduced Nucleophilic Addition of Ammonia and Alkylamines to methoxy-Substituted Styrene Derivatives" This is the Mack-daddy of all the articles, IMHO. Here's where they show what they got, and lay out the procedure and conditions that would be used for making MDMA. Bulletin of the Chemical Society of Japan, 1998, vol 71, no 7, 1655-1660 "Photoamination of Alkenylnaphthalenes with Ammonia via Electron Transfer" A further study, where aryl isopropylamines are made from their corresponding alkenes. This one's good for several reasons: the use of methylamine, and the evidense it has proving the usefulness of both isomers of isosafrole. The Tetrahedron article by the same research group before used only the trans isomer, but not the cis. Links to other selected photochemistry (and otherwise related) web pages. US Pat #4,483,757:Photochemical process for preparing amines US Pat #4,459,191: Light-catalyzed process for preparing amines

MDMA via Tosyl Chloride Intermediate?

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MDMA via Tosyl Chloride Intermediate?

Synthesis of MDMA by Addition of Methylamine to
1-(3,4-Methylenedioxyphenyl)-2-Propanol Tosylate

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Ollie-RSM

Has anyone ever heard of MDMA being produced by a Markonikov hydration of safrole and conversion of the alcohol to an alkyl tosylsulfonate (via rx with tosyl chloride) followed by S_N2 amination with methylamine? This synthetic pathway would be very similar to the bromination/debromination pathway that is recently in vogue, and might be even simpler. Plus tosyl chloride is dirt cheap ($23 for 1kg).

Siegfried

I try this procedure alot and it was much better than normal alkyl-halide process because the tosylate (and brosylate or nosylate) don't give a lot of elimnation contrary to the alkyl-halide. I got the alkohol intermediate with oxymercuration of the allylbenzene and made the tosyaltion with tosylchloride/pyridine, then the SN2 in MeOH with a little THF for solubility purpose and RT . The yield and reaction time are:

• >95%, 20min, RT for oxymercuration
• >95%, 45min, RT for tosylation
• 50-60%, 5d, RT for S_N2 with MeNH₂-MeOH

The RT and polar solvent are very important because increase the temperatur favorise the elimination, decrease the polarity too. Anyway, this family of S_N2 is favorised with polar protic solvent as MeOH (see the March). As I wrote under another topic, the tosylate are very good but there is even better leaving group they don't give any elimination and have better kinetics: the Triflate, but it's an expensive reagent.

---

For the tosylation of alkohol, the base is pyridine, because

• It neutralizes the HCl
• It form a complex with tosyl chloride which significantly facilitates the attack by the alcohol on the sulfur

For the hydratation of the alkene, acid medium is not good because the 1-aryl-2 propanol first formed is rapidly deshydrated to the stabilized isosafrole wich is hydrated to the 1-aryl-1-propanol. The result is:

• Very poor yield in 1-aryl-2-propanol
• Mixture of 1-aryl-2-propanol and 1-aryl-2-propanol which are not easy to separate (must use distillation).

The oxymercuration process give only the 1-aryl-2-propanol intermediate without rearrangement in about 20min with >95% yield but HgCl₂ can not be used, sorry. Hg(OAc)₂ or Hg(NO₃)₂ or Hg(ClO₄)₂ or Hg(CF₃COO)₂ can be used. You must use Hg²⁺ (mercuric) and not Hg⁺ ion (mercurous). You can make Hg(OAc)₂ from HgCl₂ + CH₃COOH but you must purify it. Anyway Hg(OAc)₂ can easily be purchased.

Tr-E-frog

Thank you for the informative post. What originally got me interested in this method was the fortuitous discovery of 'triflate' anhydride in reasonable quantity. Have you used this leaving group in this reaction? Would you mind posting the details of your procedure? Ultimately, I suspect that the cost of this reagent makes it impractical for any scale up but for a small scale high-yield experiment it may be interesting.

Ritter

I believe the only better leaving group than tosyl is methanesulphonate from mesyl chloride, of course. The methanesulphonly group will probably provide yields 10% or so better in S_N2 substitution w/ anhydrous alcoholic methylamine or ethylamine soln. Methanesulphonyl chloride is a little more expensive than tosyl chloride however it is a liquid and therefor much simpler to handle than stinky irritating tosyl chloride.
On a side note safrol-2 mesylate reacted in 80% yield with excess benzylamine to make N-benzyl MDA which was easily hydrogenated at 30 lbs w/ five percent loading of 10%Pd/C catalyst to produce a total yield of 73% MDA from starting alkene. not too shabby! The methylenedioxyphenyl-2-propanol was generated from methylenedioxyphenylacetaldehyde w/ MeMgI grignard.

Siegfried

Ritter: the oxymercuration process is very simple and easy to carry : RT , >95% yield , 25min reaction time ... The mesylate group is about the same than tosylate or nosylate or brosylate but the best known leaving group are triflate and nonaflate , tresylate is not so good it's about 400 time less reactiv than triflate but it is still about 100 time more reactiv than tosylate and analogs ... Conclusion : triflate is 4000 time more reactiv than tosylate and analogs ( mesylate , brosylate , nosylate ) . For a good explanation of the leaving goup see the chemist bible : "Advanced organic chemistry - Jerry March " chapter : nucleophilic substitution.

Siegfried

The tosylation must be conducted in pure pyridine. 11 mmole tosylchlorid is added slowly ( t<30°C ) to a stirred solution of 10 mmole alkohol in 10 ml pyridine. When tosyl chloride is added, the mixture is stirred for 30-40 min RT. Then the mixture is poured in 100ml 2N HCl, then tosyl is purified . Yield over 95%.

Ritter

Just dug up some references for advancement of tosylate/mesylate esters as feasible, HIGH YIELDING synthetic intermediates to our beloved honey in an aqueous environment.

The following is quoted from: Journal of Organic Chemistry 53, 4081-4 (1988)
(R)-Tomoxetine Hydrochloride: A solution of phenyl-3-(2-methylphenoxy)-propyl methane sulfonate [the mesylate group is on the gamma carbon] (450mg, 1.45mmol) and methylamine (10ml, 40% in water) in THF (10ml) was heated to 65'C for 3h. After cooling, the solution was diluted with ether, washed w/ aq. sat. NaHCO₃ soln. and brine, and dried with anhydrous K₂CO₃. After concentration a pale yellow oil was obtained which was dissolved in ether, bubbled w/ dry HCl gas [and you guys certainly know the rest] to produce a white ppt which was recrystallized w/ acetonitrile to yield title compound (400mg, 94%)

Thats amazing! NINETY FOUR freakin percent from an aqueous MeAmine soln!!! Try achieving that with a halogen leaving group on our favorite alkene by cooking the stinky shit up in a pipe bomb w/ alcoholic MeAmine. You can't, if you are lucky 50% will be . Halogens blow as leaving groups compared to sulfonate derivatives as proved by this paper. It is such an advantage to be able to use good 'ol fashioned aqueous MeAmine compared to homebrew anhydrous alcoholic amine solns! The only drawback noticed immediately is the large excess of MeAmine employed by the authors. This shouldn't present a huge problem because the excess amine cooked off during the heating process can be collected by bubbling through HCl. The 65°C rctn temp is the bp of THF so excess amine will be liberated out of the top of the reflux condensor on rctn pot. A slow stream of N2 can be admitted through a bubbler in the second neck of the rctn. flask forcing the methylamine gas to be expelled out the top of the condenser into a beaker of HCl. Simply evap off HCl to obtain your excess amine back as MeAmine hydrochloride.
There is one other procedure for producing alkyl-methylamines from an alkyl mesylate using the exact same protocol listed above with product isolated in 96% yield! This proves the procedures high yields are reproducible, however both examples listed are performed on primary alkyl mesylates. Since we are working with a secondary alkyl mesylate yields may suffer a bit from steric hindrance during the nucleophilic substitution by MeAmine. Well actually, let me restate that.. my chem theory is getting a little weak.. In most if not all nucleophilic substition reactions in the literature compounds with a leaving group always have higher yields in nucleophilic substition rctns than a complementary compnd w/ a secondary leaving group. Therefore the mesylate in our case may not produce the 90+% yields quoted in the literature but it sure will be much higher than that produced by any halogen.
Siegfried: Excellent work in this area. Was wondering if you'd be kind enough to post the physical properties of the tosylate. Simple experience has proved that most tosylates are solids, however you're the only one who knows for sure. A melting pt. would be very useful. Any recrystallization solvent of choice?
Was an attempt ever made at esterifying the propanol produced w/ H₂SO₄? As a side note any tertiary amine can be used in a similar manner as pyridine to scavenge protons in the esterification rctn. Triethylamine was the amine of choice in the quoted article. Yields of 85% were recognized after several wasteful recrystallizations.
On the subject of hydration of alkene to alcohol, oxymercuration is obviously the most simple method considering rctn. time and yield. However soluble mercury salts just plain suck. It sure would be nice if the H₂SO₄ thing worked. Another possible synthesis may be a PTC rctn. between aq. NaOH and halosafrole. This is a well documented rctn. however conditions will probably have to be closely monitored to minimize isoalkene formation.
Finally, to sum everything up this is a major breakthrough because of the reactivity of amines to sulfonic esters in aqueous environment. Similar reactions in the past have usually reacted alkyl halides as leaving groups and fickle-to-make alcoholic amine solns with long rctn times or high temperature pipebomb pressure vessels. Not very desirable when compared w/ a 3hr STP reflux. Reported yields are also very poor w/ halide exchange rctns. Comment?