ࡱ> 9 7O}^T+0[nX14e^fJTAUTOMERISM AND MASS SPECTRA OF THIOMORPHOLIDES Patricia E. Allegretti1, Facundo Namor1, Eduardo A. Castro2* and Jorge J. P. Furlong1 1 Laboratorio de Estudio de Compuestos Orgnicos (LADECOR), Divisin Qumica Orgnica, Departamento de Qumica, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, (1900) La Plata, Buenos Aires, Argentina. 2 INIFTA (UNLP-CONICET-CIC), Departamento de Qumica, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, Diagonal 113 y 64, Suc. 4, C. C. 16, (1900) La Plata, Buenos Aires, Argentina. SUMMARY The mass spectra of N,N-disubstituted thioamides can provide valuable information about keto-enol equilibria occurring in gas phase. Mass spectra of selected thiomorpholides have been analysed and specific fragmentation assignments have been done to characterised and weigh co-existing keto and enol tautomers. The predictive value of this methodology is not only supported by the influence of substitution nature and size of these compounds on these equilibria but also by the good correlation found between the selected fragments abundances ratio and semi-empirical calculation (AM1) of the corresponding heats of tautomerization. The results show that the thioketo-thioenol equilibrium can be studied by mass spectrometry and ionization in the ion source has a negligible effect on the position of that equilibrium. KEYWORDS: Tautomerization, Thiomorpholides, Mass Spectrometry, Theoretical Calculations, AM1 Semiempirical Molecular Orbital Method * Corresponding autor ( HYPERLINK "mailto:castro@quimica.unlp.edu.ar" castro@quimica.unlp.edu.ar / direccin@inifta.unlp.edu.ar) INTRODUCTION Thioamides are compounds of interest in several applicative areas, not only as intermediates of synthesis (1,2) but also in the field of the chemistry of peptides (3). Among the members of this family of compounds, the thiomorpholides are particularly interesting since they not only exhibit diverse biological activity (4-6) but also they are synthesis precursors of organic compounds such as substituted thiophenes which are present in natural products and can adequately replace the phenyl group in medical chemistry (7). In this work mass spectrometry and semi-empirical calculations are employed to study the tautomeric thioketo-thioenol equilibria for a group of selected thiomorpholides.  In order to know the effect of the morpholide group on the tautomers distribution the corresponding behavior was compared with that of the N,N-dimethylsubstituted thioamide. The mass spectrometry seems to be very informative for studying and identifying tautomers, because in this case external factors like solvents, intermolecular interactions, etc., can be excluded by transferring the tautomeric system into gas phase, where the process becomes truly unimolecular (8). As it has been proved in the case of keto-enol tautomerism of a series of 1- and 3-substituted acetylacetones (9) and a variety of carbonylic and thiocarbonilic compounds (10-17), there is no significant interconversion of the tautomeric forms in the gas phase following electron impact ionization. Thus, the mass spectrometry provides a moment picture of the tautomeric gas phase mixture and normally the M+. do not undergo tautomerization following evaporation and ionization in the ion source. This is not the case if gas chromatography is used as the sample introduction system into the mass spectrometer since tautomerism takes place in the gas phase after sample injection. Notwithstanding, fast tautomerism precludes tautomers separation in the analytical column. Consequently, the different pathways of fragmentation of the tautomeric intermediates can be used to identify the individual tautomers (10). The results obtained by mass spectrometry when correlated with those from molecular orbitals for amides, ureas, hydantoins, isoquinolinones, ketones, diketones, lactones, demonstrate that mass spectrometry constitute an adequate tool for predicting tautomeric equilibrium shifts within a family of organic compounds (10-17). As mentioned above, tautomerism for some thiomorpholides is studied by resorting to gas chromatography-mass spectrometry and semi-empirical calculations. EXPERIMENTAL Preparation of Thiomorpholides Thiomorpholides are prepared by the Willgerdt-Kindler reaction, modified to improved the yields and the reaction times by microwave irradiation (18). The reaction was carried out in a household microwave oven by mixing 2 mmoles of acetophenone, 6 mmoles of morpholine and 4 mmoles of sulphur in an open pyrex recipient for 4 minutes at 900W. Once the reaction mixture is cooled down to ambient temperature 10 ml of dichloromethane were added, the excess sulphur filtered and reduced pressure distillation carried out. The resulting product was eluted in a silica gel column with hexane : ethylacetate 8:2. Gas Chromatography-Mass Spectrometry Determinations These determinations were done by injection of methanol solutions (1 (l) in an HP 5890 Series II Plus chromatograph coupled to an HP 5972 A mass spectrometric detector under the following conditions: Column : HP5-MS, 30m x 0.25 mm x 5 m. Carrier gas: Helium. Injector temperature: 200C. Oven temperature: 80C, 10C/min, 200C. Interface temperature: 300C. Ion source temperature: 185C. The pressure in the mass spectrometer, 10-5 torr, precludes ion-molecule reactions. Electron energy: 70 eV. Computational Procedure AM1 calculations were performed using the standard Hyperchem package [19]. Since we resorted to heat of formation values in order to rationalize experimental findings and the AM1 technique has been specially parameterized to reproduce this sort of experimental data, we deem this choice is a sensible one for the molecular set under study. RESULTS AND DISCUSSION Mass spectra of 2-phenylethanethiomorpholide; 2-(3-bromophenyl)ethanethiomorpholide, 2-(2,4-dimethylphenyl)ethanethiomorpholide and 2-(b-naphtyl)ethanethiomorpholide were analyzed. Additionally the mass spectrum of the N,N-dimethylethanethioamide was studied to compare its tendency to form the enol tautomer with that of the thiomorpholides. Table 1 depicts mass spectral data which is relevant to the study of tautomerism of these compounds. Since coexisting tautomers are not separated by chromatography in the working conditions, the mass spectra are the result of mass spectra superposition, so that adequate fragments should be selected for proper comparison. (M-SH)+ and (CSNC4H4O)+ were selected and assigned to the thioimidol and thioamide forms respectively. The ion abundances in Table 1 were calculated as follows: (1000 x ion abundance / total ion abundance). Table 1. Ion Abundances of Selected Data of Some N,N-Disubstituted Thioamides Mass Spectra. CompoundM+.(M-SH)+(CSNC4H8O)+(M-SH)+/ (CSNC4H8O)+2-Phenylethanethiomorpholide32.41.371.91.8x10-22-(3-Bromophenyl)ethanethiomorpholide32.00.4187.32.1x10-32-(2,4-Dimethylphenyl)ethanethiomorpholide38.075.143.31.72-(b-Naphtyl)ethanethiomorpholide20.89.541.42.3x10-1N,N-Dimethylethanethioamide418.562.631.0*2.0* *The structures of this fragment ion is (CSN(CH3)2)+. As it can be observed the equilibrium position depends on the substituent nature taking into account electronic and steric effects. In related studies (7,8) it was concluded that bulky substituents in the a-carbon to the carbonyl group, shift the equilibrium towards the enol form, and it is observed when comparing in Table 1 the data for 2-phenylethanethiomorpholide and 2-(b-naphtyl)ethane thiomorpholide, particularly the ion abundances ratio (M-SH)+/(CSNC4H8O)+(1.8x10-2 vs. 0.23). Besides, it is also observed that electron-donor substituents favor the occurrence of the thioimidol structure which is adequately illustrated by the ion abundances ratio for 2-phenylethane thiomorpholide and 2-(2,4-dimethylphenyl)ethanethiomorpholide) (1.8x10-2 vs. 1.7). Electron-acceptor substituents exert the opposite effect: 2-phenylethanethiomorpholide vs. 2-(3-bromo phenyl)ethanethiomorpholide (1.8x10-2 vs. 2.1x10-3). Out of the comparison with the N,N-dimethyl ethanethioamide it could be inferred that the thiomorpholide group makes the enol tautomer less stable than the corresponding thioketo, probably due to steric and electronic effects (the bigger thiomorpholide group would interact sterically with the thiol group more strongly than with the thiocarbonyl group and besides, the morpholide oxygen electron-acceptor effect would be less detrimental on the zwitterionic canonical form describing the thioketo structure (with the positive charge on the nitrogen atom and the negative charge comfortably located on the sulphur atom) respect to the analogue thioenol. It is well known that reactivities of neutral molecules and their corresponding molecular ions can be quite different so that it is very important to analyze the possibility of tautomerism occurrence between ionic species. In this sense, diverse families of compounds have been studied (10-17) and negligible influence on the tautomeric equilibrium position could be detected after ionization in the ion source of the mass selective detector used to generate the experimental data. Notwithstanding, to support that the observed tautomeric equilibria distributions come from the molecular species with negligible contribution from tautomerism of molecular ions, theoretical calculations of heats of formation were carried out for both species. Table 2 shows the enol-keto heats of formation differences for the selected molecules and corresponding molecular ions and their correlation with the experimental data. Table 2. Heats of Formation Differences for Enol-Keto Tautomerization of Selected N,N- Disubstituted Thioamides and Correlation with Mass Spectral Data.* CompoundDH enol-keto (Neutral molecules)DH enol-keto (Molecular ions)Ion abund. ratio2-Phenylethanethiomorpholide-9.05.11.8x10-22-(3-Bromophenyl)ethanethiomorpholide-4.10.12.1x10-32-(2,4-Dimethylphenyl)ethanethiomorpholide-12.420.51.72-(b-Naphtyl)ethanethiomorpholide-9.802.3x10-1N,N-Dimethylethanethioamide-13.802.0 *The heats of formation units are kJ mol-1 and the mass spectral data are extracted from Table 1. The semi-empirical AM1 results are used to determine the heats of formation differences which follow the same tendency observed by mass spectrometric results only in the case of the neutral molecules. For molecular ions no tendency is observed; for example the DH for tautomerization of the 2-(2,4-dimethylphenyl)ethanethiomorpholide should be lower than that for the 2-phenylethane thiomorpholide which is not the case (5.1 vs. 20.5 kJ mol-1). CONCLUSIONS As shown in several previous papers (10-17) the usefulness of mass spectrometry to predict tautomeric behavior is demonstrated here along with the additional support provided by suitable theoretical calculations performed at the semi-empirical level via AM1 method. The mass spectra of N,N-disubstituted thioamides can provide valuable information regarding the keto-enol equilibria taking place at gas phase. The predictive value of this methodology is supported by the influence of of the nature and size of substituents on tautomeric equilibria and the rather good correlation existing between the selected fragments abundances ratio and the heats of tautomerization determined theoretically via the semiempirical AM1 method. Results show that the thioketo-thioenol equilibrium can be studied by mass spectrometry and ionization in the ion source has a negligible effect on the position of that equilibrium. ACKNOWLEDGEMENTS: Financial support is highly acknowledged to CIC, Buenos Aires, Argentina. REFERENCES M. C. Murguia, R. A. Rossi, Terahedron Lett., 1997, 38, 1335. P. Metzner, Synthesis, 1992, 1185. A. F. Spatola, Chemistry and Biochemistry of Aminoacids, Peptides and Proteins, B.,Weintstein Ed., Marcel Dekker, New York, 1983, Vol. 7, 267-357 and references cited therein. K. Koike, Z. Ja, T. Nikaib, Y. Liu, Y. Zhao, D. Guo, Org. Lett., 1999, 1, 97. C- Farina, R. Pillegata, M. Pinza, G. Pifferi, Arch. Pharm., 1981, 314, 108-117. L. P. Ivan, L.J. Richard, T. S. Halina, Tetrahedron Lett., 2000, 41, 1957. R. L. Jarvest, I. L. Pinro, S. M. Ashman, G. E. Dabrowski, A. V. Fernndez, L. J.Jenning, P. Lavery, D. G. Tew, Biorg. Med. Chem. Lett., 1999, 9, 443. P.Petrientt, A. Kalandarishivilli, Mass Spectrometry Rev., 1966, 15, 339. M. Masur, H. F. M. Nooshabadi, K. Aghapoor, H. Reza Darabi, M. M. Mojahedi, Tetrahedron Lett., 1999, 40, 7549. (10) P. E. Allegretti, C. B. Milazzo, E. A.Castro, J. J.P.Furlong, J. Mol. Structure, Theochem, 2002, 589-590, 161. (11) P. E. Allegretti, L. Gavernet, E. A. Castro, J. J. P. Furlong, J. Mol. Structure, Theochem, 2000, 532, 1, 139. (12) P. E. Allegretti, G. R. Labadie, M. Gonzalez Sierra, J. J. P. Furlong, Afinidad, 2000, VII, 485, 41. (13) P. E. Allegretti, L. Gavernet, E. A. Castro, J. J. P. Furlong, Asian J. Spectr., 2001, 5, 63. (14) P. E. Allegretti, E. A.Castro, J. J.P.Furlong, J. Mol. Structure, Theochem, 2000, 499, 121. (15) P. E. Allegretti, A. S. Cnepa, R. D. Bravo, E. A. Castro, J. J. P. Furlong, Asian J. Spectr., 2000, 4, 133. (16) P. E. Allegretti, V. Peroncini, E. A. Castro, J. J. P. Furlong, Int. J. Chem Sci., 2003, 1, 1. (17) P. E. Allegretti, M. S. Cortizo, C. Guzmn, E. A. Castro, J. J. P. Furlong, Arkivoc (in press). (18) N. Nooshabadi, K. Aghapoor, H. Reza Darabi, M. M. Mojahedi, Tetrahedron Lett., 1999, 40, 7549. (19) Hyperchem 6.03 for Windows Molecular Modeling System, Hypercube Inc., Gainesville, FL. 2000. 41,4 0,23 9,5 20,8 2-(b-Naftil)etanotiomorfolida 1,73 43,3 75,1 38,0 2-(2,4-Dimetilfenil) etanotiomorfolida) 2,13x10-3 187,3 0,4 32,0 2-(3-Bromofenil) etanotiomorfolida 0,018 71,9 1,3 32,4 2-Feniletanotiomorfolida (M-SH)+/(C4H8NOCS)+ (C4H8NOCS)+ (M-SH)+ M+. Compuesto 0,23 41,4 9,5 20,8 2-(b-Naftil)etanotiomorfolida 1,73 43,3 75,1 38,0 2-(2,4-Dimetilfenil) etanotiomorfolida) 2,13x10-3 187,3 0,4 32,0 2-(3-Bromofenil) etanotiomorfolida 0,018 71,9 1,3 32,4 2-Feniletanotiomorfolida (M-SH)+/(C4H8NOCS)+ (C4H8NOCS)+ (M-SH)+ M+. Compuesto 0,23 41,4 9,5 20,8 2-(b-Naftil)etanotiomorfolida 1,73 43,3 75,1 38,0 2-(2,4-Dimetilfenil) etanotiomorfolida) 2,13x10-3 187,3 0,4 32,0 2-(3-Bromofenil) etanotiomorfolida 0,018 71,9 1,3 32,4 2-Feniletanotiomorfolida (M-SH)+/(C4H8NOCS)+ (C4H8NOCS)+ (M-SH)+ M+. Compuesto 0,23 41,4 9,5 20,8 2-(b-Naftil)etanotiomorfolida 1,73 43,3 75,1 38,0 2-(2,4-Dimetilfenil) etanotiomorfolida) 2,13x10-3 187,3 0,4 32,0 2-(3-Bromofenil) etanotiomorfolida 0,018 71,9 1,3 32,4 2-Feniletanotiomorfolida (M-SH)+/(C4H8NOCS)+ (C4H8NOCS)+ (M-SH)+ M+. 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