The kinetics of the coupling of 4-nitrobenzodifuroxan (NBDF) with a series of indoles 8 a-e to give the expected Michael-type adducts 9 a-e have been investigated in acetonitrile solution. No significant influence of the nature of the isotopic substitution at C-3 of the indole ring has been found, indicating that the NBDF addition step is the rate limiting step of the SEAr substitution of the indole moiety. This implies that the measured second-order rate constants (k) for the reactions are identical to the second order rate constants (k1 NBDF) associated to the C-C coupling step. By using the known N and s parameters characterizing the nucleophilicity of indoles, the k1NBDF rate constants are found to fit nicely to the three parameters equation logk1 = s (N + E) introduced by Mayr to describe the feasibility of nucleophilic-electrophilic combinations. Based on this, the electrophilicity parameter E of NBDF could be determined as E= -6.15. This corresponds to a positioning of the reactivity of the nitroactivated double bond of NBDF in the domain of superelectrophilicity previously defined for nitrobenzofuroxans, in accord with the finding that the rates of coupling of 8 a-e with NBDF are only one order of magnitude lower than those for the coupling of these indoles with 4,6-dinitrobenzofuroxan (DNBF). The theoretical scale of electrophilicity introduced by Domingo et al. on the basis of the global electrophilicity index ω defined by Parr is also a very useful tool to discuss the relative reactivities of NBDF, DNBF, and a number of differently activated C=C double bonds.
- Michael addition
- Structure-activity relationships