Highly Efficient Intramolecular Nucleophilic Reactions. The Cyclization of p-Nitrophenyl

p-Nitrophenyl N-(2-mercaptophenyl)-N-methylcarbamate cyclizes rapidly at 25' to N-methylbenzothiazolone with release of p-nitrophenol. The pH-rate constant profile is sigmoidal with pK,,, = 8.7. The effective molarity of the neighboring sulfhydryl group is 1.4 X los M in comparison with bimolecular attack of thiols on p-nitrophenyl N-methyl-Nphenylcarbamate. The pH-rate constant profile for cyclization of phenyl N-(2-aminophenyl)-N-methylcarbamate to 1 methyl-2-benzimidazolone is sigmoidal at 50' with pK,,, of 2.7. The solvent isotope effect kH20/kD20 is 1.2 for the pH-independent reaction where participation by the neighboring group is maximal. Bimolecular reaction of cyclohexylamine (pK, = 10.7) with phenyl N-(4-aminophenyl)-N-methylcarbamate was too slow to be accurately measured, but, employing the upper limit of a detectable second-order rate constant and a reasonable value for the Br4nsted coefficient, the effective molarity of a neighboring amine group in reaction with carbamate esters was calculated to be a t least 3 X IO8 M . Thus, large effective molarities of 105-108 M, previously observed only with oxy anion nucleophiles, can also be obtained in intramolecular reactions of neutral amine nucleophiles. The AS* for intramolecular nucleophilic amine attack is -23.8 eu which implies that part of the large rate enhancement is probably due to a relatively favorable AH* value. Cyclohexylamine catalyzed release of p-nitrophenoxide ion from p-nitrophenyl N-methyl-N-phenylcarbamate at 50' is characterized by AS* = -32.5 eu. An intramolecular reaction bears a striking resemblance to an enzymatic reaction proceeding through an enzymesubstrate complex.2 The study of intramolecular reactions has therefore been of great importance in attempts to understand the mechanism of enzyme c a t a l y ~ i s . ~ . ~ Various intramolecular nucleophiles have been studied in the hydrolysis of carbamate ester^.^-^ These reactions occur with great facility. Neighboring hydroxymethyl and phenolic OH groups have effective molarities of 105-108 A4 in comparison with analogous bimolecular reaction^.^.^.' Carbamate esters are especially favorable compounds with which to study intramolecular nucleophilic processes since the acyl group is highly deactivated by resonance interaction with the adjoining nitrogen (eq 1) which reduces the partial positive charge on the carbonyl carbon. Thus, acyl group deactivation will greatly slow the bimolecular reactions. Carbamate esters are normally quite stable under hydrolytic conditions.8 In a nucleophilic reaction at a carbamate carbonyl, considerable bond making with the incoming nucleophile will be required to attain the transition state. A tight transition state9 will thereby result in which maximum translational and rotational entropy of the nucleophile will be lost in the bimolecular comparison. The maximum effectiveness of a properly positioned intramolecular nucleophile might therefore be determined. The intramolecular nucleophiles that have been utilized previously in carbamate ester hydrolysis are all oxy ani o n ~ . ~ ~ To determine whether large effective molarities are general for negatively charged nucleophiles of various type, we have measured rates of cyclization for carbamate ester I having a neighboring thiol group. Reaction of I takes place through the thiol anion. The effect of a neutral amine neighboring group has been ascertained with carbamate ester 11. fyN-c' + ?