Org. Chem. 1986,51, 2676

More documents

Recommendations

Info

Distorted Amides as Models J. Org. Chem., Vol. 51, No. 14, 1986 2683 Table VI. Second-Order Rate Constants (koa) for OH--Catalyzed Hydrolyses of Some Amides at 25 OC in H20a kOH-, compound M-1 s-l ref 3Imethyl-l-acetylbenzimidazolium 2 X los 6e 3-methyl-l-acetyltetrahydrobenz- 1.0 X los 6e imidazolium 3-methyl-l-acetylimidazolium 1.5 X lo5 6f l-acetylbenzimidazole 4.67 X lo2 6e l-acetylimidazole 3.17 X lo2 6c 3d 3.65 X lo2 this work 3a 2.62 X lo2 this work 3b 1.75 X lo2 this work 3c 1.68 X lo2 this work 5 6.0 X 10 this work p-nitrophenyl acetate 1.49 X 10 b N- acetylpyrrole 8.5' 3f N- benzoylpyrrole 2.7 3f a,a,a-trichloro-N-methylacetanilide 4.9 x lo-' 3a p-nitroacetanilide 2.2 X 3b l-phenylazetidin-2-one 1.27 X 9b l-phenyl-2-piperidone 2.0 X 9b p-methoxyacetanilide 8.19 X 10" 3c p-chloroacetanilide 8.47 X 10" 3c acetanilide 7.55 x 10" 3c p-methylacetanilide 6.84 X lo4 3c aEntries 1, 2, and 4 in 31.6% ethanol/H20. bMenger, F. M.; Portnoy, C. E. J. Am. Chem. SOC. 1968,90,1875-1878. CRefers to kl[OH-] term in eq 1. no more than and we expect a reduced deformation for the C=O unit in 3 because it resides in a more symmetric environment. Depending upon structure, amide resonance energy generally lies between 16 and 22 k~al/mol.~~ Values of 0 and 4 in excess of Oo will diminish the amide resonance since both motions tend to decrease the N:, C=O orbital overlap. The major difference between 3 and 5 stems not from changes in the tilt angle but in the torsion4 or twist angle. Assuming a cosine 4 relationship for the N-C=O overlap% one can conclude that 5 is less torsionally strained than 3. This is consistent with the lower vC-o for 5 than 3a, 1705 cm-l vs. 1755 cm-l, respectively, both values exceeding vcE0 for unstrained N-methylacetanilide (1665 ~m-l).~' At first glance, the most unusual aspect of the hydrolyses of 3 and 5 is the great reactivity in both acid and base (24) Mock, (Mock, W. L. Bioorg. Chem. 1975, 4, 270-278) has discussed torsional strain considerations and heavy atom rehybridization as it pertains to enzymecatalyzed hydrolysis of peptides. In effect, torsional distortion of an amide must produce a C=O unit with disymmetric *-faces irrespective of any special structural features attributable to the bicyclic nature of 5. Rehybridization of the C=O unit has the consequence of returning the axes of the (predominantly) p orbital on C and N lone pair into conjunction, thereby compensating to some extent the distortion energy. (25) Winkler, F. K.; Dunitz, J. D. J. Mol. Biol. 1971, 59, 169-182. (26) Streitweiser, A. Molecular Orbital Theory for Organic Chemists; Wiley: New York, 1961; pp 11-20. (27) (a) The idea that ucd is a measure of amide or ester hydrolytic reacticity is not new. For example Indelicato et aLnb have established a linear correlation between u- and log rate constant for base hydrolysis of a limited series of j3-lactams. Also, for eaters such as para-substituted phenyl acetatesnc or methylbenzoates,27c, good correlations of Y C and ~ various Hammett a-values are observed. Since correlations between eater hydrolysis (log rate constants) and U-values also exist,ne apparently u- and hydrolytic reactivity are correlated. It should be mentioned, however, that structural effecta that influence Y C will ~ be predominantly ground state in nature, while the hydrolytic reactivity depends upon both the ground- and transition-state energies. Hence, correlations are to be expected only when the structural modifications in a series of compounds produces a regular change in both the ground and transition states. (b) Indelicato, J. M.; NoMlas, T. T.; Pfeiffer, R. R.; Wheeler, W. J.; Wilham, W. L. J. Med. Chem. 1974,17,523-527. (c) Cohen, L. A.; Takahashi, S. J. Am. Chem. SOC. 1973,95,443-448. (d) Laurence, C.; Berthelot, M. J. Chem. Soc., Perkin Trans. 2 1979,9&102. (e) Exner, 0. In Advances in Linear Free Energy Relationships; Chapman, N. B., Shorter, J., Eds.; Plenum: London, 1972. z K W z W 7 - - - :,-, REACTION COORDINATE Figure 5. A stylized reaction coordinate/energy profile for OHattack on N-phenyl-2-piperidone (solid line, L ~G'~), 3a (--, AGt3) and 5 (- - -, AG*5). AG'A - AG15 9 kcal/mol; AG'A - AGt3 N 10 kcal/mol. relative to "normal" anilides3 and amides. Second-order rate constants for OH--catalyzed hydrolysis for some se- lected amides and p-nitrophenyl acetate are given in Table VI. It may be concluded that 3 and 5 are among the most reactive neutral amides reported, comparing favorably with l-acetylimidazole. Several factors allow one to postulate with certainty the mechanism of base-induced hydrolysis of 3 and 5 as being akin to that given in eq 6. First, since no second-order qi! H 11 x m n ;:, ' P (6) nil (30-d) n.2 (5) terms in [OH-] are seen in the hydrolysis kinetics and multiple l80 incorporation into the product carboxylates is not observed, the first addition of OH- must be rate limiting and essentially irreversible. This is supported by the FAB-determined composition of the carboxylates formed in 1 N Na180H/Hi80 from 3b, 5 which show single l80 incorporation. Reisolation of l80 labeled 3a from pH 9.8 CHES buffer gives 7.2 f 0.4% l80 exchange per T1,, of hydrolysis. However, at pH 9.8, under the conditions employed (0.02 M CHES, kobsd = 2.05 X s-l) it can be calculated that the OH--dependent term accounts for - 40% of the reaction. Hence, the probable sources of the l80 depletion in reisolated amide 3a at pH 9.8 are the residual H20 and buffer terms. The Hammett plot of the second-order rate constants for OH- attack on 3a-d against u has a p of 0.72, indicative of an initial rate-limiting OH- attack producing a transition state with increased - charge adjacent to the ring. Finally, the observed general base catalysis seen at pH >8 for 3a-d in base is consistent with assistance of H20 attack on the C=O unit, the @-value of 0.8 f 0.1 suggesting that this transition state is quite late with extensive proton transfer to the base. Although curvature in plots of kobd vs. [buffer] is sometimes seen in the base-catalyzed hydrolyses of activated acylacetanilides,3jJJ1 none is seen for 3a-d. Bicyclic 5 shows no general base catalysis of H20 attack at pH >7 (HEPES and TRICENE buffers do show catalysis, but it is nucleophilic and will form the subject of a further Our conclusion about the nature of the buffer catalysis for 3a-d and that OH- attack on 3a-d and 5 is rate limiting and proceeds irreversibly contrasts the interpretation of Blackburn et al.,' who suggested on the basis of admittedly
2684 J. Org. Chem., Vol. 51, No. 14, 1986 limited evidence for 3a, that breakdown of the tetrahedral intermediate (11 in eq 6) is rate limiting. Given the above, it is possible to construct an energy profile for OH--promoted hydrolysis. The lower trace in Figure 5 is a hypothetical reaction profile for OH- attack on acetanilide or N-phenyl-2-piperidone. Since l80 exchange is observed during hydrolysis of the former,3c the second barrier must be equal or slightly greater than that for reversal (i.e., k1 2 k3 + kz [OH-]). Twisting and tilting the N electrons out of conjugation has the net effect of destabilizing the ground state of 3 by removing the amide resonance. In 5 the combination of twisting and tilting distortions must also reduce the amide resonance energy, but it is difficult to quantitate the effect. Based on the observation that vc4 of 5 lies midway between vc-o of 3a and N- methylacetanilide (NMA) it is tempting to place the or- dering of amide resonance energy as NMA > 5 > 3a.27 Relative to N-phenyl-2-piperidone, the kOH- terms for 3a and 5 are (1.3 X 10')- and (3 X 106)-fold larger which correspond the reductions in their respective activation energies to OH- attack of 10 and 9 kcal/mol. The inter- esting speculation to be drawn from the above is that the apparently smaller distortion energy in 5 is more fully manifested in the transition state for base hydrolysis than is the larger distortion energy in 3a. For the same reasons that ground-state destabilization of 3 or 5 leads to a more rapid OH- attack than on a normal anilide, the reverse of this step (k-l in eq 1) must be de- celerated since in that transition state there is no assistance by the N lone pair for ejection of the leaving group. This is schematically shown in Figure 5 as the higher barriers for reversion of 3 and 5. It might be tempting to use Deslongchamps' arguments concerning stereoelectronic controlz8 to speculate that the breakdown of the tetrahedral intermediate (T-, eq 1) to proceed to product is unusually fast and that this is the reason for lack of l80 exchange in base. As can be judged from 12 (N shaded), the two oxygen lone pairs can be ideally disposed anti- periplanar to the departing C-N bond but the N lone pair is oriented 60" relative to either C-0 bond. The lack of 12 double incorporation in the base hydrolysis products of 3 and 5 is certainly consistent with a rapid breakdown of 12, but the data do not require it to be unusually fast since the rate-limiting step is attack and the above arguments indicate that kl is retarded relative to a normal anilide. In actuality there is no reason to contend that the rate constant for breakdown of 12 should be greater than that of T of a normal anilide, since in the latter the lone pairs on oxygen can also attain the comparable configu- ration. [In fact, under acidic and neutral conditions, the breakdown of the intermediate to yield product cannot be unusually fast (vide infra).] At neutrality, the mechanism of buffer-independent hydrolysis of 3 changes from OH- attack to an apparent H20 attack on the neutral form. The data at hand do not allow a clear distinction to be made between HzO attack or the kinetically equivalent OH- attack on the protonated ~____~ (28) (a) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry; Pergamon: Oxford, 1983; and references therein. (b) See particularly pp 101-106 of the preceding reference for this point. H Somayaji and Brown form as was discussed by Blackburn et al.' However, the l80-exchange data observed for 3a in pH 9.8 base suggest that the plateau region is best described as a water reaction. If OH- attack on 3a does not lead to l80 exchange, it is difficult to envision how OH- attack on 3a-H+ (which leads directly to an intermediate capable of breaking down to products with no proton transfers) could give l80 exchange. There is no apparent HzO attack on neutral 5 so that the upper limit for that rate constant is -lo-' s-l compared with 2 X and 1.7 X s-l for the apparent attack of HzO on 3a and 3c, respectively. While attack of the strong nucleophile OH- on 3c and 5 differs in rate by only a factor of 3, attack of imidazole, a weaker nucleophile, differs by 400-fold. That the latter process is ascribable to a nucleophilic role on both substrates is supported by the fact that 2-methylimidazole, (with similar basicity but possessing far greater steric hindrance for its nucleophilic attack than imidazole) shows a much reduced propensity to catalyze the decomposition of either 3c or LZ3 No second-order kinetic terms in 2-methylimidazole are detected. The pH-rate constant profiles for 3 show evidence of a kinetic pKa for each substituent in the range of -3.5-3.8. We believe this is ascribable to the N-protonated form,18 the maximum rate constant for HzO attack on it being 3.5-5 s-l, nearly independent of substituent. However, a less straightforward but kinetically indistinguishable route involving HzO attack on a highly reactive 0-protonated form (3-0H+) cannot explicity be ruled out. Given pK;-OH* N -8lS and pKP-NH' = 4 it can be seen that the ratio of 0 to N protonated 3 is - 10-l2, independent of pH. Now if 3-OH+ has a reactivity comparable to that of the most reactive oxocarbonium ions (lifetimes of 10-10-10-13 s in HzO),zl then even though it is produced in miniscule concentration, its high reactivity could yield a net rate constant for HzO attack on protonated 3 of - 10-2-10 s-l. Although the higher value seems appropriate for what is observed (Table I), we believe the rate data are more consistent with the expected H20 reactivity with an N- protonated form. Williams4f has shown that certain N- acetyltrialkylammonium tetrafluoroborates hydrolyze at 25 "C with rate constants for H20 attack on the order of 0.2 to 3.0 X s-l while Fersht and Jen~ks~~ have determined that attack of H20 on N-acetylpyridinium proceeds with a pseudo-first-order rate constant of 6.9 s-'. There is a dependency of the rate constants for hydrolysis of N-acylammonium on the basicity of the leaving group, and a PLG value of -0.5 has been utilized in the above two studies. While it is not clear that compounds 3a-d should follow the same dependency on leaving group as does the acylated quaternary ammonium or pyridinium species,z9b it seems reasonable that the low pK,, of 3a-d is responsible for the lo2 increase in lability relative to the non-anilide materials studied by Williams.4f The log kobsd vs. pH plot for 5 (Figure 1) increases linearly until at least pH 0 (kObsd = 59 s-l; pH 0). Although rotation of the N-C=O dihedral angle from 90" (as in 3) to smaller values is expected to produce a reduction in pKa(NH+) from -3.5, we believe the N-protonated species is not responsible for the much higher activity of 5 at low pH. Assuming that attack on 5 also adheres to a PLG relationship, fully N-protonated 5 suffer H20 attack at (29) (a) Fersht, A. R.; Jencks, W. P. J. Am. Chem. SOC. 1970, 92, 5432-5442. (b) Structurally, the N-acylpyridinium ions are quite unlike the quaternary N-acyl species, since in the former, considerable delo- calization between the aromatic ring and N-acyl group is present. Hence the two series robably cannot be accurately correlated by a single Brmsted plot.4P
Page 1 and 2: 2676 J. Org. Chem. 1986,51, 2676-26
Page 3 and 4: 2678 J. Org. Chem., Vol. 51, No. 14
Page 5 and 6: 2680 J. Org. Chem., Vol. 51, No. 14
Page 7: 2602 J. Org. Chem., Vol. 51, No. 14
Page 11: 2686 J. Org. Chem., Vol. 51, No. 14

Org. Chem. 1986,51, 2676

Create successful ePaper yourself

Delete template?

Save as template?