The structure in the solid state and in solution of 3(5)-trifluoromethyl-4,5(3)-polymethylenepyrazoles

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1 The structure in the solid state and in solution of ()-trifluoromethyl-,()-polymethylenepyrazoles Marcos A. P. Martins, a ilo Zanatta, a elio G. Bonacorso, a Fernanda A. Rosa, a Rosa M. Claramunt, b Mª Ángeles García, b M. Dolores Santa María, b and José Elguero c * a úcleo de Química de eterociclos (UQUIME ), Departamento de Química, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil b Departamento de Química Orgánica y Bio-Orgánica, Facultad de Ciencias, UED, Senda del Rey, 9, E-2800 Madrid, Spain c Instituto de Química Médica, CSIC, Juan de la Cierva, E-2800 Madrid, Spain iqmbe@iqm.csic.es Dedicated to Professor Armand Lattes for his 0 years of professorship Abstract The tautomerism of three polymethylenepyrazoles bearing at position () a trifluoromethyl group has been studied by MR in solution (, C,, 9 F) and in the solid state ( C, ). The conclusion is that in all cases they are - tautomers. DFT calculations have been carried out to compare these compounds to the analogous - derivatives and to assess the Mills- ixon effect in the case of trimethylene derivatives as well as the effect of replacing a by a group on the tautomerism. Keywords: Tautomerism, pyrazoles, trifluoromethyl, MR, CPMAS, DFT calculations Introduction In this paper we present a comparative study of three pairs of methyl/trifluoromethyl pyrazoles concerning tautomerism and MR properties, determined both in solution and in the solid state. The experimental data of the methyl derivatives,, and, are from the literature [,2]. Theoretical calculations, at different levels, have been carried out on pairs of tautomers, a and 2 b, of pyrazoles -. ISS 2- Page 29

2 C a a C b b b a 2a 2 C a a 2 8 8a a 2 a 2 C a 2 8 8a 2 2b b b Scheme. The six pairs of ()-methyl/trifluoromethylpyrazoles The aim of this work is to determine if the structural information can be transferred from the well-known methyl pyrazoles,,,, to the less studied trifluoromethylpyrazoles, 2,, [- ]. Regarding (),-polymethylenepyrazoles (the IUPAC name of tetramethylene-pyrazoles is tetrahydroindazoles and pentamethylenepyrazoles are also named hexahydrocyclohepta[c] pyrazoles), they are known but not with perfluorinated substituents [-9]. Results and Discussion MR studies in solution The MR results in solution of compounds 2, and have been gathered in Tables ( MR) and 2 ( C, and 9 F MR). ISS 2- Page 0

3 Table. MR results (δ in ppm, J in z). Solvent: DMSO-d Pyrazole (t)*.-. (m).8-. (m) 2.9(t)* (s) 2. (eq) (m).22 (eq ).89 (eq) (m). (eq) (m) ---. (s) 2.0 (ax) (m) 2.82 (ax) (q). (ax) (m).8 (ax) (m) (t)*.-.2 (m).-.80 (m).-.2 (m) 2. (t)*.0 (s) * Sum of -2 z corresponding to two J (in this kind of symmetrical spin-system, observation of a triplet for a methylene group does not imply necessarily that the coupling constants are equal). Table 2. C and MR results (δ in ppm, J in z). Solvent: DMSO-d Pyrazole J CF = J CF = J CF =. 8 or - a or 8a (a) J CF =2. J = ( ) J CF =28. J = (C8) J CF =29.0 J =0.8 (a) In 9 F MR, the group appears at 9.8 ppm (2); 9.8 ppm (); 9. ppm (). The assignments are based on literature results on compounds, and and their - methyl derivatives [,8], on MR studies of trifluoromethylpyrazoles [] as well as on 2D MR experiments. The signal is that of the, the other one is not observed. It is worth mentioning that the C and signals (both C and 9 F) are almost identical. This indicates a very similar a/b tautomer composition for pyrazoles 2, and to the point that the determination of the predominant tautomer for any of them results in determining it for all three pyrazoles. ISS 2- Page

4 From a large collection of C chemical shifts of pyrazoles [0] it is possible to estimate the chemical shifts of 2a and 2b from those of -methyl- and 2-methyl-tetrahydroindazoles unsubstituted at position and from the effects of a trifluoromethyl group at positions and of pyrazoles: 2a ppm 2b ppm ppm ppm The experimental data (Table ),. (C) and 0. (Ca) correspond to tautomer 2a, thus all are - tautomers 2a, a and a. ote that the signal of the Ca(C8a) carbon atom is much more dependent on the saturated ring than C. In general and by analogy with literature results [,,8], the signals of b tautomers, 2b, b and b, are expected at different positions. MR studies in the solid state The MR results obtained in the solid state using the CPMAS technique are reported in Table. The results of Table are of the utmost importance for the present work. They must be commented in detail: i) Although in the three cases it appears that two molecules are present, by comparison with MR data in solution, it is clear that both families of signals belong to tautomer a: 2a, a and a. ii) By deconvolution we have estimated the proportion of the two molecules always being 0% of the major component and 0% of the minor one and this for 2a, a and a. The estimated error is ±%. The two molecules should correspond to two independent molecules in the crystal that probably differ in their conformation. iii) Most signals of pyrazole a (both molecules) are broad. This broadening is not due to tautomerism since b is absent. Therefore, we assigned it to conformational motions involving the polymethylene chain. This is probably related to the fact that in the DSC experiments (see experimental part) only shows a phase transition. ISS 2- Page 2

5 Table. C and CPMAS MR results (δ in ppm) Pyrazole 2 major minor major 8.2. broad broad broad broad minor broad broad broad broad major minor or - a or 8a (bs) (bs) broad ( ) (bs) broad ( ) (bs) (C8) (bs) (C8) (bs) Gas phase values (theoretical calculations) The tautomerism of polymethylenepyrazoles has been the subject of many calculations in relation with the Mills-ixon effect. We have been the first to extend the Mills-ixon effect from its original definition concerning resonance forms [] to the equilibrium present in tautomerism, first to pyrazoles [8,2] and then to enols of β-diketones []. These studies reported that small rings favor the tautomers b with an endo single bond. Since the -methyl group of the and series should produce a negligible effect on the tautomerism, we have decided to study pyrazoles and (previously reported [8]) and 2 and. To these four pyrazoles we have added the corresponding five-membered derivatives (trimethylene pyrazoles) and 8. a b 8a 8b We have reported in Table the results of the calculations of the twelve pyrazoles in what energy aspects are concerned. ISS 2- Page

6 Table. Energy of the most stable tautomer (in hartree), the difference in energy between both tautomers (in kj mol ) and the dipole moment (in D). BLYP/-G** calculations Ring o. R Most stable Difference in +ZPE Dipole moment size tautomer energy correction b: b a:.0 b a:. a: 2.9; b: b: b 8a: 2. 8b 8a: 2.8 8a:.0; 8b:.2 a: 2.9 b a: 2.22 b a: 2. a: 2.; b: a: 9.0 2b 2a:. 2b 2a:.8 2a:.08; 2b:.0 a: 0.9 b a: 0.29 b a: 0.8 a: 2.; b: 2. a: 8.2 b a:. b a:.2 a:.0; b:.00 The results of Table correspond to the balance between two factors: The preference for the -position (i.e. -tautomers a) increases in average 0.8 kj mol from to being slightly dependent on the ring size. The a/b tautomerism changes from Mills-ixon in the case of /8 (. kj mol ), to neutral in the case of / (+.0 kj mol ), to "anti-mills-ixon" in the case of /2 (+. kj mol ) The variation with the ring size is not linear as can be seen in Fig.. 2 Anti-Mills-ixon zone Average (kj/mol-) Mills-ixon zone Ring size Figure. Differences in energy (ZPE corrected) of the average values (methyl and trifluoromethyl substituents) derivatives against the ring size: (, 8), (,2) and (,). ISS 2- Page

7 In the case of the methyl derivatives the dipole moments are independent of the tautomerism because a methyl group is electronically similar to the first methylene of the polymethylene chain. Taking into account the considerable increase in dipole moments on going from b to a in the case of the trifluoromethyl derivatives (Table ), the proportion of tautomer a should increase in solution compared to the gas phase; this is consistent with the fact that only 2a and a were found experimentally. Conclusions Replacing a by a results in a very small increase in the stability of the -tautomer a. Although at first glance this seems to correspond to the fact that electron-withdrawing substituents prefer the -position of the pyrazole ring, an analysis of the tautomerism of many pyrazoles bearing different substituents at position (), shows that the () preference cannot be explained by simple electronic considerations [-]. The present work quantifying the effect of the replacement of a methyl by a trifluoromethyl group contributes to the general understanding of substituent effects on the tautomerism of pyrazoles. Experimental Section General Procedures. The compounds were prepared similarly to other trifluoromethylpyrazoles [,8]. To a solution of the corresponding trifluoroacetylcycloalkanone ( mmol) in ethanol (ml) was added rapidly a solution of hydrazine hydrochloride (8 mmol) in ethanol (ml) at room temperature. The mixture was stirred under reflux h. The excess of hydrazine hydrochloride was filtered off and the solvent was removed in a rotatory evaporator. The reaction mixture was extracted with chloroform ( x 20 ml) and dried with sodium carbonate. The solvent was removed in a rotatory evaporator and the product was purified by column chromatography (silica gel mesh, 0 cm column, eluent hexane). Yields > 80%. The purity and the melting points were determined by DSC with a SEIKO DSC connected to a Model SSC200 Disk Station. Thermograms (sample size g) were recorded with a scan rate of.0 ºC min. -. Mass spectra (RMS) at 0 ev using electron impact mode was performed on a VG Autospec spectrometer in the "Laboratorio de Espectrometría de Masas-UAM, Madrid". -(Trifluoromethyl)-,,,-tetrahydro--indazole (2): m.p. 2.9 ºC, RMS: calculated for C 8 9 F 2, 90.08; found Methyl--(trifluoromethyl)-,,,-tetrahydro--indazole (): m.p..9 and 0. ºC (phase transition), RMS: calculated for C 9 F 2, 20.08; found (Trifluoromethyl)-,,,,,8-hexahydrocyclohepta[c]pyrazole (): m.p.. ºC, RMS: calculated for C 9 F 2, 20.08; found ISS 2- Page

8 MR Spectroscopy. Solution. The spectra were recorded on a Bruker DRX 00 (9. Tesla, 00. Mz for,.0 Mz for 9 F, 00.2 Mz for C and 0. Mz for ) spectrometer with a -mm inverse-detection -X probe equipped with a z-gradient coil for, C and ; for 9 F we used a -mm QP direct-detection probe equipped with a z-gradient coil. In all cases the spectra were recorded at 00 K at a concentration of 0.0 M. Chemical shifts (δ in ppm) are given from internal solvent, DMSO-d 2.9 for and 9. for C, and for and 9 F MR, nitromethane (0.00) and one drop of CFCl in CDCl (0.00) were used as external references. Typical parameters for MR spectra were spectral width 00 z and resolution 0.9 z per point. Typical parameters for 9 F MR spectra were spectral width 2900 z, pulse width. µs at an attenuation level of - db and resolution 0.89 z per point. Typical parameters for C MR spectra were spectral width 2000 z, pulse width 0. µs at an attenuation level of - db and resolution 0. z per point; WALTZ- was used for broadband proton decoupling. 2D ( - ) gs-cosy and inverse proton detected heteronuclear shift correlation spectra, ( - C) gs-mqc, ( - C) gs-mbc and ( - ) gs-mbc, were acquired and processed using standard Bruker MR software and in non-phase-sensitive mode. Gradient selection was achieved through a % sine truncated shaped pulse gradient of ms. Solid state. C (00. Mz) and (0.0 Mz) CPMAS MR spectra were obtained on a Bruker WB 00 spectrometer at 00 K using a mm DVT probehead. Samples were carefully packed in a -mm diameter cylindrical zirconia rotors with Kel-F end-caps. Operating conditions involved.2 µs 90 pulses and decoupling field strength of 8. kz by TPPM sequence. C spectra were originally referenced to a glycine sample and then the chemical shifts were recalculated to the Me Si (for the carbonyl atom δ (glycine) =. ppm) and spectra to Cl and then converted to nitromethane scale using the relationship: δ (nitromethane) = δ (ammonium chloride) 8. ppm. The typical acquisition parameters for C CPMAS were: spectral width, 0 kz; recycle delay, s; acquisition time, 0 ms; contact time, 2 ms; and spin rate, 2 kz. And for CPMAS were: spectral width, 0 kz; recycle delay, s; acquisition time, ms; contact time, ms; and spin rate, kz. Computational details. Theoretical calculations were carried out at the BLYP/-G** level [9,20] using the Titan version.0. for Windows 98 package. Particular care has to be taken with the pentamethylene derivatives and because there are several conformations of the seven-member ring that are minima. The absolute minimum corresponds to a pseudo-chair conformation, typical of cycloheptene [2]. Acknowledgements The Spanish authors acknowledge grants from the Ministry of Science and Education (Project nos. BQU and BQU200-02). The Brazilian authors thank the Conselho acional de Desenvolvimento Científico e tecnológico (CPq/PADCT), Fundação de Amparo à pesquisa do Estado do Rio Grande do Sul (FAPERGS) for financial support. The fellowships ISS 2- Page

9 from CPq, CAPES and FAPERGS are also acknowledged. Dr. Ibon Alkorta support is greatly acknowledged. References. Elguero, J.; Yranzo, G. I.; Laynez, J.; Jiménez, P., Menéndez, M.; Catalán, J., de Paz, J. L. G.; Anvia, F.; Taft, R. W. J. Org. Chem. 99,, argittai, I.; Brunvoll, J.; Foces-Foces, C.; Llamas-Saiz, A. L.; Elguero, J. J. Mol. Struct. 99, 29, 2.. Elguero, J.; Fruchier, A.; Jagerovic,.; Werner, A. Org. Prep. Proc. Int. 99, 2,.. Martins, M. A. P.; Blanco, R. F.; Pereira, C. M. P.; Beck, P.; Brondani, S.; Cunico, W.; Zimmermann,. E. K.; Bonacorso,. G.; Zanatta,. J. Fluor. Chem. 2002, 8, 9.. Braibante, M. E. F.; Clar, G.; Martins, M. A. P. J. eterocycl. Chem. 99, 0, 9; Bonacorso,. G.; Wastowski, A. D.; Zanatta,.; Martins, M. A. P.; aue, J. A. J. Fluor. Chem. 998, 92, 2; Flores, A. F. C.; Brondani, S.; Zanatta,.; Rosa, A.; Martins, M. A. P. Tetrahedron Lett. 2002,, 80.. Bardou, L.; Elguero, J.; Jacquier, R. Bull. Soc. Chim. Fr. 9, 289 and 29.. López, C.; Claramunt, R. M.; Trofimenko, S.; Elguero, J. Can. J. Chem. 99,, Martínez, A.; Jimeno, M. L.; Elguero, J.; Fruchier, A. ew J. Chem. 99, 8, Foces-Foces, C.; ager, O.; Jagerovic,.; Jimeno, M. L.; Elguero, J. Chem. Eur. J. 99,, Begtrup, M.; Boyer, G.; Cabildo, P.; Cativiela, C.; Claramunt, R. M.; Elguero, J.; García, J. I.; Toiron, C.; Vedsø, P. Magn. Reson. Chem. 99,, 0.. Mills, W..; ixon, I. G. J. Chem. Soc. 90, Alkorta, I.; Elguero, J. Struct. Chem. 99, 8, 89.. Ramos, M.; Alkorta, I.; Elguero, J. Tetrahedron 99,, 0.. Abboud, J. L. M.; Cabildo, P.; Cañada, T.; Catalán, J.; Claramunt, R. M.; de Paz, J. L. G.; Elguero, J.; oman,.; otario, R.; Toiron, C.; Yranzo, G. I. J. Org. Chem. 992,, 98.. El ammadi, A.: El Mouhtadi, A. Theochem 2000, 9, 2.. Jaronczyk, M.; Dobrowolki, J. C.; Mazurek, A. P. Theochem 200,,.. Martins, M. A. P.; Bastos, G. P.; Sinhorin, A. P.; Zimmermann,. E. K.; Rosa, A.; Brondani, S.; Emmerich, D.; Bonacorso,. G.; Zanatta,. J. Fluorine Chem. 200, 2, Martins, M. A. P.; Pereira, C. M. P.; Zimmermann,. E. K.; Cunico, W.; Moura, S.; Beck, P.; Zanatta,.; Bonacorso,. G. J. Fluorine Chem., 200, 2, Becke, A. D. Phys. Rev. A 988, 8, 098; Becke, A. D. J. Chem. Phys. 99, 98, 8; Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 988,, Ditchfield, R.; ehre, W. J.; Pople, J. A. J. Chem. Phys. 9,, Eliel, E. L.; Wilen, S.. Stereochemistry of Organic Compounds, John Wiley, ew York, 99, p.. ISS 2- Page