ANALYST, SEPTEMBER 1991, VOL. 116 901 Thermal Degradation of Some Benzyltrialkylammonium Salts Using Pyrolysis-Gas Chromatography-Mass Spectrometry Neville J. Haskins and Robert Mitchell* SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, Hertfordshire AL6 9A R, UK A number of benzyl quaternary ammonium salts have been examined by pyrolysis-gas chromatography-mass spectrometry using various temperatures for the pyrolysis. The products show that simple substitution reactions dominate at low temperatures with slight evidence for classical Hofmann degradation. Raising the temperature gave increasing concentrations of Ir2-diphenylethane and stil bene which must be produced by intermolecular reactions. There appeared to be a linear relationship between the amount of Ir2-diphenylethane produced and the temperature of the pyrolysis.Keywords: Benzyltrialkylammonium salts; pyrolysis-gas chromatograph y-mass spectrometry Quaternary ammonium salts such as choline (an endogenous component) are important in medical research, or as drugs (dequalinium bromide or propantheline bromide for ex- ample). However, the stability of such compounds at elevated temperatures is poor. The elimination of alkyl substituents from quaternary salts by either the Hofmann or Saytzeff reaction is well known. It was decided to examine the stability of benzyl quaternary ammonium salts at high temperature. This work describes the products formed by Curie-Point pyrolysis using support wires of various Curie-Point tempera- tures. Experimental All samples were obtained from Aldrich (Gillingham, Dorset, UK) and were used without further purification. Each of the salts was prepared for spectral analysis by dissolving it in methanol (100 mg per 10 ml) and adding 5 pl of the solution to a wire pre-washed in methanol.The wires were loaded into a glass carrier. The carriers were loaded into a Curie-Point pyrolyser (Horizon Instruments, Heathfield, Sussex, UK) and the radiofrequency field was applied for 4 s. Wires giving Curie-Points of 385, 510, 610 and 770 "C were used. Helium was passed over the wire at a flow rate of 1 ml min-1. The pyrolysate was trapped on a fused silica column (15 m x 0.25 mm i.d.) coated with BP-5 (SGE, Milton Keynes, Buckinghamshire, UK) at ambient temperature. The column was heated from ambient temperature to 300 "C at a rate of 10 "C min-1.The helium passing through the pyrolyser was used as the carrier gas at a flow rate of 1 ml min-1. The column was passed directly into the electron ionization source of a VG Analytical 7070F double focusing mass spectrometer linked to a VG 2050 data system (VG Analytical, Wythenshawe, Manchester, UK). The mass spec- trometer was continually scanned from 600 to 20 u at a rate of 1.5 s decade-' giving a total cycle time of about 3 s. Ionization was effected at 70 eV. After acquisition, spectra were transferred to a VG Analytical 11-2505 data system for processing. Results and Discussion The benzyltrialkylammonium salts examined were benzyl- trimethylammonium chloride (I), benzyltriethylammonium chloride (11), benzyldimethyldodecylammonium chloride (111) , benzyldimethyltetradecylammonium chloride (IV), benzyldimethylhexadecylammonium chloride (V) and benzyl- dimethylstearylammonium chloride (VI). * Present address: The Sheffield Polytechnic, Sheffield S1 lWB, UK.Fig. 1 shows a typical reconstructed gas chromatogram obtained after the pyrolysis of benzyldimethylhexadecylam- monium chloride (V). The major components are mainly those that might be expected from simple nucleophilic substitution reactions between the chloride anion and the quaternary cation (Scheme 1). This type of reaction in most instances should give rise to three pairs of compounds, consisting of the halide and the tertiary amine. This is observed in the pyrolysis of compound (V): the observed pairs are benzyl chloride and dimethylhexadecylamine; chloro- methane and benzylhexadecylmethylamine; and l-chloro- hexadecane and benzyldimethylamine.The proportion of each pair varies, with the least abundant being benzyldi- methylamine/chloroalkane. This order of abundance was observed for all the salts examined (Fig. 1). The products from the substitution reactions are observed at all wire temperatures. The most studied reaction of quaternary ammonium salts is the Hofmann degradation1 which should give rise to benzyldimethylamine, hydrogen chloride and the corresponding alkene (Scheme 2). Benzyl- dimethylamine can also arise from a substitution reaction, whereas hydrogen chloride is unlikely to be detected through a gas chromatograph. Accordingly, the evidence for Hofmann elimination depends on the detection of the alkene.Trace amounts of alkene were found but at a low concentration and only at the higher wire temperatures, implying that under the Time --c Fig. 1 Reconstructed gas chromatogram for the pyrolysate from the pyrolysis of benzyldimethylhexadecylammonium chloride at 385 "C. A, Benzyl chloride [relative molecular mass (M,) = 1261 and chloromethane (M, = 50); B, dimethylbenzylamine (M, = 135); C, 1,2-diphenylethane (M, = 182); D, 1-chlorhexadecane (M, = 260); E, dimethylhexadecylamine (M, = 269); F, hexadecanoic acid (M, = 256); G, dimethylheptadecylamine (M, = 283); H, benzylhexadecyl- methylamine (M, = 345); I, unknown, but containing a CI6 alkyl group?; J, unknown, but containing a Ci6 alkyl group?; and *, expected elution position of stilbene (observed with higher Curie- Point temperatures)902 ANALYST, SEPTEMBER 1991, VOL.116 f t H3C\ ,CH3 N I H &r3 'CH3 + Scheme 1 anion and the quaternary cation Nucleophilic substitution reactions between the chloride r C I - Scheme 2 nium salt 100 90 80 s < 70 E 60 A c .- c .- a 50 .- 40 30 20 10 0 - a CK CH=CHR + + HCI Classical Hofmann degradation of a quaternary ammo- m/z Fig. 2 of benzyltrialkylammonium salts Mass spectrum of 1,2-diphenyIethane obtained after pyrolysis conditions used for the pyrolysis, Hofmann elimination is not a major degradation pathway. One product observed (peak F, Fig. 1) was identified as hexadecanoic acid. This probably arises from oxidation of the hexadecyl moiety. Homologous acids were observed in the other long-chain alkyl quaternary salts.The amount was variable, suggesting that oxidation was caused by residual air after loading the pyrolyser. 100 90 80 70 '5 60 .E 50 .z 40 30 20 10 0 1 % c a 4- a - 20 1 51 89 152 I I 1 I, II 60 100 140 m/z Fig. 3 Mass spectrum of stilbene obtained after pyrolysis of benzyltrialkylammonium salts 0.36 $ 0.32 m 0.28 0.24 Y al al g 0.20 z 0.12 $ 0.16 - 5 0.08 0.04 ". - 0 340 420 500 580 660 740 Wire temperaturePC Fig. 4 Plot of p (%) versus T ("C), where p (%) = proportion of 1,2-diphenylethane formed on pyrolysis. A, Benzyltrimethylammo- nium chloride: y = 0.00103~ -0.340; B, benzyltriethylammonium chloride: y = 0.00049~ -0.174; C, benzyldimethyltetradecylammo- nium chloride: y = 0.00014~ -0.043; and D, benzyldimethylstearyl- ammonium chloride: y = 0.00010~ -0.028 -1.0 -2.0 -3.0 - 4.0 s -- - -5.0 I -7.0 -8.0 1 -9.0 \ -10.0 I I I I I I '.0.95 1.05 1.15 1.25 1.35 1.45 1.55 1/T x K-' Fig. 5 Arrhenius plot of log [p (%)I versus 1/T (K), wherep (%) = proportion of 1,2-diphenylethane formed on pyrolysis. A, Benzyl- trimethylammonium chloride; B, benzyltriethylammonium chloride; C, benzyldimethyldodecylammonium chloride; and D, benzyl- dimethyltetradecylammonium chloride At the highest wire temperatures additional products were observed. Examination of the spectra (Fig. 2) indicated that these were 172-diphenylethane and smaller amounts of stil- bene (Fig. 3). Such products would require some type of reaction between two molecules of the quaternary cation o r perhaps between benzyl chloride and the quaternary salt.ANALYST, SEPTEMBER 1991, VOL.116 903 N CH( ‘CH, R 1 O C H : + HCI Scheme 4 on pyrolysis Possible formation of stilbene via a carbene intermediate Scheme 3 explain the formation of 1,2-diphenyIethane Possible modification of the Stevens’ rearrangement to Further examination of the proportion of 1,2-diphenylethane formed showed that it was linearly dependent on the wire temperature and appeared to be less abundant as the size of the alkyl substituents increased (Fig. 4). The classical Arrhe- nius plot showed a similar trend (Fig. 5 ) . The formation of 1,2-diphenylethane might arise from a combination of benzyl free radicals themselves, or generated from an ylide formed by abstraction of the a-proton (Scheme 3). Such reactions have been observed in the study of the Stevens’ rearrangement carried out by Ollis et al.1 However, the ylide in the Stevens’ rearrangement is normally stabilized by the presence of a fl-keto group. It must be stressed that in the present situation considerably higher temperatures are used and the concentrations are not equivalent. Hence the formation of 1,2-diphenylethane in the hot melt after pyrolysis is occurring under far more rigorous conditions than the normal Stevens’ rearrangement. The presence of stilbene could arise from a combination of carbenes formed by simple disproportionation of the inter- mediate ylide formed by elimination of a benzyl methylene proton (Scheme 4). The presence of such reactive species might account for trace amounts of higher relative molecular mass material seen after some reactions, but too weak to identify conclusively. Conclusions The analysis of quaternary salts has often generated problems owing to their non-volatility as intact species, and the formation of decomposition products if heat is used. This paper shows that the decomposition reactions are more complex than might be expected. Pyrolysis of benzyl quaternary ammonium salts proceeds by several competing mechanisms. The products formed depend on the temperature of pyrolysis and the bulkiness of the alkyl substituents about the quaternary ammonium centre. At lower temperatures simple displacement reactions appear to predominate. At higher temperatures more complex multi- centre reactions, probably involving free radicals, take place giving rise to 1,2-diphenylethane and trace amounts of stilbene. Reference 1 Ollis, W. D., Rey, M., and Sutherland, I . O., J. Chem. SOC., Perkin Trans. I, 1983, 1009. Paper 1 I01 2486 Received March 15th, 1991 Accepted April 30th, 1991