The mechanisms of hydrolysis of the γ-lactam isatin and its derivatives

Abstract

The pH dependences of the rates of hydrolysis of isatin, its N-carboxymethyl derivative and its 5nitro substituted analogues exhibit a complex behaviour, showing a first-and second-order dependence upon hydroxide ion concentration, as well as a pH-independent pathway. The pH dependence is interpreted in terms of the formation of tetrahedral intermediates in different protonic states which may break down to products via hydroxide ion, hydronium ion and water catalysed pathways. These y-lactams are as reactive, or more reactive, than benzylpenicillin.The antibacterial activity of p-lactam antibiotics arises from a combination of their chemical reactivity and their molecular recognition by target enzymes.' One aspect of their chemical reactivity is their acylating power and although, e.g., penicillins, 1, are not very good acylating agents they are more reactive than simple unsubstituted amides.' Since ring strain and reduced amide resonance within the p-lactam has been shown not to contribute significantly to the chemical reactivity of the antibiotic^,^.^ the possibility of non-p-lactam structures showing antibacterial activity has gained ~redibility.~ y-Lactams are obvious candidates for potentially showing similar antibacterial behaviour to that of the P-lactam antibiotics.6 Two important aspects of the acylating power of amides are the activation of the carbonyl group towards nucleophilic attack and the stabilisation of the amine leaving group to facilitate C-N bond fission. Both these requirements are met in isatin (lH-indole-2,3-dione) 2 with the a-carbonyl group both activating the y-lactam carbonyl carbon and stabilising the expelled amine anion, 3. RCONH ExperimentalN-CurboxymethyZisutin.-Isatin (14.7 g, 0.1 mol) was dissolved, with warming, in 2 mol dm-3 sodium hydroxide solution (45 cm3). Chloroacetic acid (14.1 g, 0.15 mol) dissolved in 0.1 mol dm-3 sodium carbonate solution (50 cm3) was added and the solution refluxed for 4 h. Excess concentrated hydrochloric acid was added to precipitate both product and starting material. The precipitate was filtered and stirred with 0.1 mol dm-3 sodium carbonate solution (50 cm3) to extract the product. The solution was filtered and the filtrate was acidified to pH 2 with concentrated hydrochloric acid. The resultant solid was recrystallised from water to give a bright orange powder.

The chemistry of isatins: a review from 1975 to 1999

“…At pH values between 5 and 6, the rate of hydrolysis is firstorder in hydroxide concentration or inversely proportional to the concentration of the hydronium ion, but from pH 6.5 to 10.5 it is pH independent. This result reveals the existence of a complex behavior for the hydrolysis of isatin, with different rate limiting steps depending upon the pH of the solution 346 . A similar profile has been observed for 1-methylisatin 347 (Scheme 85).…”

Inhibition of monoamine oxidase by selected C5- and C6-substituted isatin analogues

“…This process is reversible and acidification reforms the isatin. 33 Considering that an incubation time of 20 min was chosen for determining the inhibition potencies of the isatin analogues, the recorded IC 50 values ( Table 2) may be an underestimation of the MAO-A and -B inhibition potencies. Since relatively little loss of inhibition potency of the isatin analogues is observed between the 15 min and 30 min time points, the effect of hydrolysis on the measured IC 50 values is expected to be relatively small.…”

Kinetics and mechanism of isatin ring opening in aqueous binary mixtures of methanol and acetonitrile cosolvents

“…This ring opening is reversible and acidification reforms isatin. Changes in the UV spectrum with pH indicated [9] that above pH 6 the ring-opened form predominates. Thus, according to this fact and in the light of all considerations, taking care of in this study, a mechanism for the ring opening of isatin by sodium hydroxide is proposed which would account satisfactorily for both water dependence and effect of solvent on reaction rate.…”

“…The reaction of isatin with sodium hydroxide in water takes place through the cleavage of the amide bond and formation of a ring-opened amino acid [9]. This ring opening is reversible and acidification reforms isatin.…”