J . Org. Chem., Vol. 43, No. 6, 1978
Hydrolysis of Sulfonamide Isoxazole Derivatives Chile. (4) (a) A. G. Anderson and G. Berkelhammer, J. Am. Chem. SOC., 80, 992 (1958); (b) C. G. Johnston, J. L. Gardner, C. H. Suelter, and D. E. Metzler, Biochemistry, 2, 689 (1963); (c) S. G. A. Alivisatos, F. Ungar, and G. J. Abraham, ibid., 4, 2616 (1965). (5) C. S.Y. Kim and S. Chaykin, Biochemistry, 7, 2339 (1968). (6) S. L. Johnson and P. T. Tuazon, Biochemistry, 16, 1175 (1977). (7) For discussions of micellar catalysis and inhibition see ref 8-1 1. (8) E. H. Cordes and C. Gitler, Prog. Bioorg, Chem., 2, 1 (1973). (9) "Reaction Kinetics in Micelles", E. H. Cordes. Ed., Plenum Press, New York, N.Y. 1973. (IO) E. J. Fendler and J. H. Fendler, "Catalysis in Micellar and Macromolecular Systems", Academic Press, New York. N.Y., 1975. (11) C. A. Bunton, Prog. Solid State Chem., 8, 239 (1973); C. A. Bunton, "Micellar Reactions", Chapter 4 in "Applications of Biomedical Systems in Chemistry", Part It. J. H. Jones, Ed., Wiley, New York, N.Y., 1976. (12) S. Shinkai. R Ando, and T. Kunitake. Bull. Chem. SOC.,Jpn., 48, 1914 (1975). (13) For discussioi of micellar effects on the dissociation of weak acids, see ref 8-11 and 14. (14) C. F. Hiskey arid T. A. Downey, J. Phys. Chem., 58, 835 (1954); C. A. Bunton and M. J. Minch, b i d . . 78, 1490 (1974); L. K. J. Tong and M. C. Glessman, J. Am. Chem SOC.,79, 4305 (1957). (15) C. A. Bunton and B. Woife, J. Am. Chem. SOC.,95, 3742 (1973). (16) C. A. Bunton, K. Ohmenzetter,and L. Sepulveda, J. Phys. Chem., 61,2000 (1977). (17) A. K. Yatsimirski, K. Martinek, and I. V. Berezin, Tetrahedron, 27, 2855 (1971); K. Martinek. A . I G t of 1111make compound I1 less reactive than I. Values of AS* for I and I1 are 4.3 and -6.9 eu, respectively, but a t the acid concentration used in the activation parameter determinations, I is practically completely in its protonated
I
I
-1
0
as
Figure 3.
form, then k+ N k and AS* has a maximum value for this reaction, whereas I1 exists mainly in its unprotonated form, therefore 12, < k and consequently the AS* obtained must increase when reaction conditions reach those of I. These values are consistent with those typically reported for hydrolysis reactions that proceed by the A-1 mechanism,20 whereas A-2 hydrolysis has considerable more negative values.20 Experimental Section Materials and Apparatus. Sulfuric acid analytical reagent grade Carlo Erba G.R. was used; H3P04, NaH2P04, and NaOH were all analytical reagent grade; I was a commercial NF product purified according to ref 1;and I1 was prepared in the same way as it has been previously reported.21 Spectrophotometricreadings and UV absorption spectra were taken in a Beckman DB-G spectrophotometer.NMR spectra were recorded on a Varian T-60, and chemical shifts are quoted in ppm downfield from tetramethylsilane. Reactions. The hydrolysis reactions were carried out in sealed ampules of 5-mL capacity containing approximately 3 mL of solution which was prepared quantitatively by transferring 0.250 g of I or I1 to a volumetric flask of 100 mL capacity and adding the appropriate sulfuric acid solution until the volume was completed. The same procedure was followed with each acid solution. The ampules were immersed in a constant temperature oil bath at 100.0 f 0.2 "C for I and at 135.0 f 0.2 " C for 11;they were then withdrawn at appropriate intervals and quickly cooled in an ice bath for analysis at a later time. Identification of Hydrolysis Products. Both I and I1 give a unique product with aromatic amino group, which was identified by TLC as IV using the procedure described earlier ref 2. V and VI, products from I and 11, respectively,were both separated from reaction mixtures previously alkalinized with 20% NaOH by ether extractions. The ethereal extracts were dried (Na2S04)and evaporation of the solvent yielded the respective amino derivatives, which were purified and identified by its mp and mixture mp with those of known pure samples. Quantitative Determinations and Kinetic Study. One milliliter of each one of the reaction mixtures was put into volumetric flasks of 50-mL capacity and neutralized by addition of an adequate volume of 1 N NaOH solution, and the flask was filled to the mark with 0.1 M phosphate buffer of pH 2.3. Two milliliters of these solutions was again diluted to 10 mL with the same buffer solution. The relative concentrations of the reactants and products were
15N NMR Spectra of Secondary Amides
J. Org. Chem., Vol. 43. No. 6 , 1978
Table IV. Reaction Rates a t Several Temperatures in Sulfuric Acid (70 w t % )
I1
ITemp, "C
k + X IO4, s-l
Temp, "C
k+ X lo4,s-1
79.0 88.5 99.0 109.0
0.802 2.32 6.89 21.6
115.0 124.0 134.0 144.2
0.751 1.77 3.84 10.2
determined by U V spectrophotometricanalysis using for both I and I1 reaction light of 268 nm as the analytical wavelength; this one corresponds to a maximum in the absorption spectra for both reactants.Each kinetic experience was carried out using 10ampules,which were processed as described above, and their absorbances were regarded. From plots of In (At - A,/Ao - A , ) vs. time (sec) were obtained straight lines as habitually are found in first-order kinetics. The slopes obtained from regression lines were considered as pseudo-first-order constants k+. Medium and Temperature Effects on Reaction Rates. Tables I and IV report the results obtained when I and I1 hydrolyses were carried out at several different acid concentrations and at several temperatures, respectively. NMR in Sulfuric Acid. For 11, methyl signals change from 1.98 and 2.05 in HzS04 at 32 wt % to 2.37 and 2.50 in HzS04 at 70 wt %. Registry No.-I, 723-46-6;11, 64682-95-7;sulfuric acid, 766493-9.
1177
References a n d Notes (1) R. H. Manzo and M. M. de Bertorello, J. Pharm. Sci., 62, 154 (1973). (2) R. H. Manzo and M. M. de Bertorello, J. Pharm. Sci., 62,152 (1973). (3) R. H. Manzo, Ph.D. Thesis, Facultad de Ciencias Quimicas, U.N.C.. 1973. (4) L. Zucker and L. P,. Hammett, J. Am. Chem. SOC.,61, 2791 (1939). (5) C. H. Rochester, Acidity Functions", Academic Press, New York, N.Y.. 1970. (6) M. Liler, "Reaction Mechanisms in SulphuricAcid", Academic Press, New York, N.Y., 1971. (7) J. F. Bunnett and F. P. Olsen. Can. J. Chem., 44, 1899. 1917 (1966). (8) J. F. Bunnett. J. Am. Chem. SOC., 83, 4956 (1961). (9) R. A. Cox, J. Am. Chem. SOC.,96, 1059 (1974) (IO) E. Buncel, Acc. Chem. Res., 8, 132 (1975). (11) R . G. Laughlin, J. Am. Chem. SOC.,89, 4268 (1967). (12) T. Birchail and R. J. Gillespie, Can. J. Chem., 41, 2642 (1963). (13) K. N. Bascomeand R. P. Bell, Discuss. Faraday SOC.,24, 158 (1957). (14) P. H. Wyatt, Discuss. Faraday SOC.,24, 162 (1957). (15) E. Hogfeldt, Acta Chem. Scand., 14, 1627 (1960). (16) E. B. Robertson and H. B. Dunford, J. Am. Chem. SOC., 86, 5080 (1964). (17) C . Perrin, J. Am. Chem. SOC., 86, 256 (1964). (18) With respect to -Ho vs. log as correlation, it has been reported by J. C . D. Brand, J. Chem. SOC.,997 (1950), that the equation (Ho bg,(",SO,/ &SO,-) = conqtant)holds between 90 and 99 wt % sulfuric acid. Some similarity with our correlation could be seen bearing in mind that "so,was assumed by him to be equal to sroichometricwater concentration. (19) Von E. H. Reymerdes and J. K. Seydei, Arzneim-Forsch., 11, 1863 (1969). (20) L. L. Schaleger and F. A. Long, Adv. Phys. Org. Chem.. 1, 1 (1963). (21) R. L. Manzo. P. Catania, and M. M. de Bertorello, Anal. Chem., 48, 1141 (1974). (22) L. P. Hammett, "Physical Organic Chemistry",2nd ed, McGraw-Hill,New York, N.Y., 1970, p 271. (23) J. F. Bunnett, "Investigation of Reaction Rates and Mecnanisms of Reactions", 2nd ed, Part I, S. L. Friess, E. S. Lewis, and A. Weissberger, Ed., Interscience, New York, N.Y. 1961, p 201.
+
Nitrogen-15 Magnetic Resonance Spectroscopy. Natural- Abundance Spectra of Secondary Amides' Philip W. Westerman and John D. Roberts* Contribution No. 5673, Gates and Crellin Laboratories of Chemistry, California Znstitute of Technology, Pasadena, California 91125 Received S e p t e m b e r 28, 1977
The 'jN chemical shifts of 17 N-alkyl- and N-arylethanamides have been determined at the natural-abundance level of I5N using Fourier-transform methods. The shift effects produced by several substituent groups are compared with corresponding substituent effects in amino acids, amino acid derivatives, and dipeptides. The results show that N-alkylethanamides are not especially good models for predicting 15Nshifts in dipeptides. The sensitivity of the 15Nshift of N-arylethanamides to electronic effects, as reflected in the Hammett p constant, is less than that of the 15N shift in para-substituted benzenamines. Peptides contain many fewer nitrogen atoms than carbon or hydrogen atoms and it might be expected that 15N NMR spectroscopy would be useful for structural studies of peptides in solution. The well-known difficulties in observing the NMR signals of 15N,with its low natural abundance and often long relaxation times, have been partially overcome by the use of large samples, high magnetic-field strengths, quadrature detection, and Fourier-transform techniques. Assignments of signals in the 15Nspectra of peptides have been aided by chemical shifts of model systems.2-6 Further help may possibly be expected from secondary amides of the type CH3CONHCaH2R, which could provide a measure of the substituent effect of R on the chemical shift of peptide nitrogen. A number of 14Nshifts of secondary amides have been but the generally broad signals obtained with this nucleus can introduce shift uncertainties. The 15N spectra of N-methylethanamidelo and N-methylmethanamidell have been reported, but there appears to be no other systematic
study of substituent effects in secondary amides. As a result, we have determined the 15N chemical shifts a t the naturalabundance level of a series of secondary amides with R groups generally chosen to correspond structurally t o peptide groupings of naturally occurring amino acids. The sensitivity of 15N NMR shifts to electronic factors, as reflected in Hammett p constants, has been determined for several para-substituted N-phenylethanamides and the results have been compared with similar studies on para-substituted benzenamines.12 Experimental Section Primary aliphatic and aromatic amines were obtained commercially and acetylated by standard procedures. The physical properties of the products were consistent with reported values.'" Proton-noise decoupled I5Nspectra were recorded at the naturalabundance level with a Bruker WH-180 NMR spectrometer operating at 18.25 MHz. Measurements were made with 15-22-mL samples in 25-mm 0.d. tubes, using quadrature detection and Fourier-transform
0022-3263/78/1943-1177$01.00/0 0 1978 American Chemical Society
