Distorted Amides as Models rates similar to those for N-protonated 3 since the pK, values of the aniline leaving groups are similar and, once N-protonated, the electronic effects in the ground states are equal. The dihedral angle changes should also reduce the pK, for 0-protonated 5 from values of -1.2 to -2.59 which are commonly seen for substituted acetanilidesm since resonance forms such as >N+=C!
2686 J. <strong>Org</strong>. <strong>Chem</strong>., Vol. <strong>51</strong>, No. 14, <strong>1986</strong> In spite of the "loading" to favor C-N cleavage and disfavor C-O cleavage, the tetrahedral intermediates do not undergo an unusually preferential breakdown to products, even when the nitrogen is protonated. This is clearly contrary to the Deslongchamps' theory since the tetrahedral intermediates are never expected to revert back to (exchanged) starting materials.% Recently Perrin and Arrhenius have critically examined much of the evidence upon which the stereoelectronic theory is based and found it to be ambiguous.36 At least two examples, one in acetal hydrolysisNa and another amide hemiacetal cleavage,36b have been reported which must proceed without stereoelectronic control. Rationalizing the exchange observed in the acidic range requires due consideration of both the bicyclic structure and the relative leaving group abilities of a CN+(H)< group with two 0 antiperiplanar lone pairs, or a C-O+H2 unit with one 0 antiperiplanar lone pair to assist departure. The OH of 16, though leas basic (pKa ~ -4~") which makes it less likely to protonate than N (pK, ~4~'), becomes a much better leaving group when protonated or partially and hence C-0 cleavage can compete with C-N cleavage in acid. In a given situation, whether both modes of cleavage compete is difficult to predict since there is a subtle balance of effects. For example, in 17 (Ar = C,H$ the (C-O/C-N)ad cleavage ratio is nearly unity while in 18 C-N cleavage is exclusively Presumably the reduction in pK, of the anilinium group in 18 (which in principle would disfavor C-N cleavage since less N- protonated material is present) is more than compensated for by the increased leaving group ability of an anilinium vs. ammonium group. OCHs OCH3 I I +,CH3 Ar-C-N-H Ar-C-N-H I ' CH3 I 'Ar OCH3 OCHf 1734e 1 8340 Conclusions and Speculations An attractive hypothesis for enzyme catalysis is that the introduction of strain in the substrate, enzyme, or both on formation of the E'S complex plays an important part in bringing about the observed rate accelerations.2 In several instances, better substrates for a specific enzyme lead to larger k, terms, but within certain limits, this occurs with little change in the Michaelis constant. For example, Hofstee has shown that the hydrolysis rate of substituted phenyl esters (CH3(CH2),C02 ArC02-) catalyzed by liver esterase or chymotrypsin increases with increasing values of n, which apparently leads to a larger number of prod- uctive E'S contacts with a concomitant induction of strain.38 Similarly, pepsin-catalyzed hydrolyses of some tri- and tetrapeptides show a variation of lo3 in k, but KM varies randomly by only a factor of 4.39 Analogous findings with elastase catalysis of peptide hydrolysis were interpreted in terms of distortion of the scissile amide (35) Perrin, C. L.; Arrhenius, G. M. L. J. Am. <strong>Chem</strong>. SOC. 1982,104, 2839-2842. (36) (a) Chandrasekhar, S.; Kirby, A. J. J. <strong>Chem</strong>. SOC., <strong>Chem</strong>. Commun. 1978, 171-172. (b) Deslongchamps, P.; Dub€, S.; Lebreux, C.; Pattersen, D. R.; Taillefer, R. J. Con. J. <strong>Chem</strong>. 1976, 53, 2791-2807. (37) An estimate of the pK, of 16-H+ can be made by utilizing a drop of -3.7 pK units in passing from RCH2N+H(CH3)2 (i.e., 9.86 to 6.10) according to the procedure of G~thrie.'~~ Since the pK, of benzoquinuclidine is 7.79," the pK, of 16-H+ is estimated to be 4.0. (38) (a) Hofstee, B. H. J. Biochem. Biophys. Acta 1957,24,211-213; (b) 1969, 32, 182-188. (39) (a) Inouye, K.; Fmton, J. S., Biochemisty 1967,6, 1765-1777. (b) Sachdev, G. P.; Fruton, J. S. Ibid. 1970,9, 4465-4470. Somayaji and Brown C=O toward the transition-state geometry.40 Although this hypothesis is difficult to test by crystallographic (or other) means, pyramidal distortion of the C=O unit of a reactive peptide has been reported in structures of various forms of trypsin with pancreatic trypsin inhibit~r.~~ However, Read et have found no C=O distortion in the refined structures of streptomycesgriseus protease B inhibited with turkey ovomucoid inhibitor. One would like to have some idea whether an amide with a distorted N-C=O unit can hydrolyze rapidly enough to be considered as a plausible candidate for that same proposal in the enzyme-mediated hydrolysis of a peptide. Also, one would like to know whether the more significant acceleration arises from twisting the N lone pair out of conjugation, the tilting which is achieved on N pyramidalization, or some combination of the two motions. The present study (and the one reported by Blackburn et al.7 for 3a) has shown that these anilides hydrolyze 106-107-fold more rapidly in both acid and base than do their nondistorted counterparts. This is attributable to an acceleration of nucleophilic attack rather than an enhanced rate of breakdown of the tetrahedral intermediates. Anilidea 3a and 5 differ in reactivity toward OH- by only a factor of -5-6 even though the latter is twisted much less (0, = 30-35O vs. e, = No). This may suggest that the major reduction in the transition state barrier is realized after a relatively small twisting distortion. Additionally, it must be recalled in both cases the N is pyramidalized toward sp3. That rehybridization, even in the absence of twisting leads to a significant reduction in the NC=O interaction.23c An important facet of the above study centers around the 180-exchange results observed for 3 and 5. Contrary to what is observed for substituted acetanilide^,^" neither 3 nor 5 undergo l80 exchange when attacked by OH-. Clearly for the latter, the rate-limiting step is attack, and the tetrahedral intermediate is formed irreversibly. In acid, extensive l80 exchange is observed for both 3 and 5, whereas normal acetanilides show no l80 e~change.~ The extent to which this is attributable to the unique bicyclic structures of 3 and 5, the reaction conditions, or the presence of buffers is at present unknown. However, this raises the possibility that oxygen equilibration and reversal from the tetrahedral intermediates formed during acidcatalyzed amide hydrolysis may be a far more prominent occurance than is currently believed. Acknowledgment. We gratefully acknowledge the financial assistance from the Natural Sciences and Engineering Research Council of Canada and the University of Alberta, in particular we acknowledge receipt of a grant from the Central Research Fund of the University of Alberta and discussions with Dr. J. P. Street. In addition, we acknowledge the helpful advice of the referees and Professor Charles L. Perrin (University of California, San Diego). Registry No. 3a, 76059-52-4; 3b, 102586-85-6; 3c, 102586-86-7; 34 102586-87-8; 5, 102586-88-9; 6, 102586-89-0; 7, 102586-91-4; 8, 102586-92-5; 9, 67752-46-9; 10, 102586-93-6; N-(p-toluenesulfonyl)-1,2,3,4-tetrahydroquinoline-4-acetyl chloride, 102586- 90-3; deuterium, 7782-39-0. Supplementary Material Available: Kinetics data and 180-exchange data (mass spectrometric intensities) (6 pages). Ordering information is given on any current masthead page. (40) (a) Thompson, R. C. Biochemistry 1973,12,47-57; (b) 1974,13, 5495-5501. (c) Thompson, R. C.; Blout, E. R. Ibid. 1973, 22, 57-65. (41) Huber, R.; Bode, W. Acc. <strong>Chem</strong>. Res. 1978, 22, 114-122. (42) Read, R. J.; Fujinaga, M.; Sielecki. A. R.: James, M. N. G. Biochemistry 1983,22, 4420-4433
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