Perkin communications. Change of rate determining step induced by the gem-dimethyl effect

摘要

J. CHEM. SOC. PERKIN TRANS. I 1989 Perkin Com m unications Change of Rate Determining Step Induced by the gem-Dimethyl Effect Iva 6. Blagoeva and Denis T. Tashev Institute of Organic Chemistry, Bulgarian Academy of Sciences, 1 113 Sofia, Bulgaria Anthony J. Kirby University Chemical Laboratory, Cambridge CB2 1EW The base-catalysed cyclisation to the hydantoin of 2,2,3-trimethyl-5-phenylhydantoate (2; R1 = R2 = Me) is slower than that of the 2,3-dimethyl compound, even though the acceleration expected from the gem-dimethyl effect is observed for the acid-catalysed reaction. We have used the introduction of a pair of methyl groups to drive the remarkable cyclisation of 2,2,3,5-tetramethyl hydanto- ate* (l),which involves general acid catalysed attack on the C0,-group by the ureido anion.' This is an example of the gem-dialkyl or Thorpe-Ingold effect,2 known to favour cyclisation processes both kinetically and thermodynamically.2' 0 0KMelj NHMe Meamp; NMe We report a striking exception to this rule.Figure 1 shows pH-rate profiles for the cyclisation of three hydantoate esters (2; R' = R2 = H; R' = H, R2 = Me; R' = R2 = Me), with one or two methyl groups at the 2-position. In the acid-catalysed region below pH 2 the introduction of one and two methyl groups increases k,+ by factors of 30 and 1 100. But the picture is quite different for the base-catalysed reaction. koH For (2; R' = H, R2 = Me) isonly 13 times faster than for (2;R' = R2 = H), and the introduction of the second methyl group actually slows the reaction: koH for the gem-dimethyl compound is six times smaller than for (2; R' = H, R2 = Me).0 0 MeN NHPh Ph MeNK, (2) (3) Since the thermodynamic gem-dimethyl effect on cyclisation should be the same for both acid and base-catalysed reactions, this is evidence for a specific retardation of the base-catalysed reaction of (2; R' = R2 = Me). The mechanism of the base- catalysed cyclisation of N-phenylhydantoate esters is generally agreed3-5 to involve rate determining spontaneous breakdown of the tetrahedral intermediate T-(Scheme). In contrast to the reaction at low pH, no buffer catalysis is observed for the base- * 2-( 1,3-Dimethylureid0)-2-methylpropionate. f PH Figure 1. pH-rate profiles for the cyclisation of (2; R' = R2 = H) (squares), (2; R' = H, R2 = Me) (triangles) and (2; R' = RZ = Me) (circles), at 25 "C and ionic strength 1.0~.t 4--'v) U- 3-n k0 2-m m-m-'1 0 0.1 0.2 0.3 0.4 0.5 Total buffer Figure 2. Buffer catalysis (50 free base acetate at 25 "C and ionic strength 1.0~)for the cyclisation of (2; R' = RZ = Me) (circles), and its absence for the reactions of (2R' = RZ = H) (squares) and (2; R' = H, R2 = Me) (triangles). catalysed cyclisation of N-phenylhydantoate ester~,~ or of the hydrolysis of the hydantoins prod~ced.~,~ We have confirmed this result for (2; R' = R2 = H); and (2; R' = H, R2 = Me); but the cyclisation of (2; R' = RZ= Me) shows strong buffer catalysis over the whole pH-range. These results are illustrated in Figure 2 for reactions in acetate buffer. The clear conclusion is that the rate determining transition state is different for the cyclisation of (2; R' = R2 = Me).The only reasonable alternative transition state (Scheme) is that for the base-catalysed formation of T-, so we conclude that this step is rate determining for the cyclisation of (2; R' = R2 = Me) In principle, the breakdown of T-(Scheme) should become cleanly rate determining for the cyclisation of (2; R' = R2 = Me) also at sufficiently high buffer concentration, but this is not achievable under our experimental conditions. 0 0 T' Evidently the loss of EtO- from T-is now faster than ring opening. One reason could be an accelerated elimination of EtO-from the fully substituted T- (R' = R2 = Me, R3 = Ph), but steric acceleration of this sort will act to some extent on both modes of decomposition of T-.It seems certain that a major factor is a reduction in the rate of C-N cleavage, caused J. CHEM. SOC. PERKIN TRANS. I 1989 by the gem-dimethyl effect, working in reverse to disfavour the ring-opening. (Similar effects have been identified recently for the ring-opening reactions of dihydrouracils' and cyclo-pro pane^,^ and seem likely to be general.) However, a change of rate determining step is not in itself sufficient to explain why the base-catalysed cyclisation of (2; R' = R2 = Me) is actually slower than that of (2; R' = H, R2 = Me), and this problem is under active investigation, Acknowledgements We are grateful to the Bulgarian Academy of Sciences, and to the Royal Society, London, for travel funds.References 1 I. B. Blagoeva, I. G. Pojarlieff, and A. J. Kirby, J. Chem. Soc.. Perkin Trans. 2, 1984, 745. 2 (a)C. K. Ingold, S. Sako, and J. F. Thorpe, J. Chem. Soc., 1922, 11 17; (h)N. L. Allinger and V. Zalkow, J. Org. Chem., 1960,25,701;(c) A. J. Kirby, Ah. Phys. Org. Clzem., 1980, 17, 183; (d)I. B. Blagoeva, B. J. Kurtev, and I. G. Pojarlieff, J. Chem. Soc., Perkin Trans. 2, 1979, 11 15. 3 J. Mingl and V. Sterba, COIL Czech. Chem. Commun., 1987,52, 156. 4 M. Bergon and J.-P. Calmon, J. Chem. Soc.,Perkin Trans.2,1978,493. 5 I. B. Blagoeva and I. G. Pojarlieff, Compt. Rend. Acad. Bulg. Sci., 1977, 30, 1043. 6 I. B. Blagoeva, I. G. Pojarlieff, and V. I. Rachina, J. Chem. Soc., Chem. Commun., 1986, 946. 7 P. P. Piras and C. J. M. Stirling, J. Clzem. SOC.,Perkin Trans. 2, 1987, 1265. Received 9th December 1988; Paper 8j04863K