Assessing the superelectrophilic dimension through σ-complexation, SNAr and Diels–Alder reactivity

Abstract

In the domain of organic chemistry, S(N)Ar substitutions represent a class of reactions of overwhelming importance, both in synthesis and in the understanding of structure-reactivity relationships, especially the role of sigma-complex intermediates. The primary factor necessary for achievement of S(N)Ar reactions is the presence of a good leaving group, which allows facile rearomatization of the ring undergoing nucleophilic attack. Consistent is the finding that the superelectrophilic chloronitrobenzofuroxans--or furazans--exhibit a very high S(N)Ar reactivity, allowing a number of C-C, C-N, C-O couplings to be achieved that are not accessible with the classical series of nitro-substituted aromatics. Of particular interest is the synthesis of a number of indoles, indolizines, pyrroles and extended pi-excessive aromatic structures like azulene substituted by superelectrophilic moieties. The remarkable driving force for the facile completion of these reactions is the 10 orders of magnitude greater reactivity of 10pi-electron-deficient heteroaromatics such as 4,6-dinitrobenzofuroxan (DNBF) than of the most reactive trinitrobenzene derivatives in sigma-adduct complexation. Among the factors that have been recognized as governing superelectrophilicity, there is the poor aromaticity of 6-membered 10pi-electron structures investigated, with a common origin for sigma-complexation and pericyclic processes. A remarkable capacity of these structures is actually to contribute to a variety of Diels-Alder reactions. As an example, the DNBF molecule formally behaves as a nitroalkene, being susceptible to act as a dienophile as well as a heterodiene. Another remarkable Diels-Alder pathway is the capacity of the 6-membered carbocyclic ring of DNBF to act as a carbodiene. Also noteworthy is the successful Diels-Alder trapping of the dinitroso intermediate associated with 1-oxide/3-oxide tautomerism of the furoxan moiety of 4-aza-6-nitrobenzofuroxan. A point of fundamental importance in taking advantage of the reactivity of superelectrophilic structures at hand has been a successful calibration of their reactivity within the electrophilicity E scale developed by Mayr to describe nucleophile-electrophile combinations in general. It has thus been established that the E parameters measuring the electrophilicity of neutral heteroaromatics lie in the same region of the E scale as a number of highly reactive cationic reagents. Besides a reactivity rather similar to that of the 4-nitrobenzenediazonium cation (vide supra), the most electrophilic neutral molecules (DNBF, DNTP, DNBZ) are as electrophilic as tropylium cations or a number of metal-coordinated carbenium ions. Furthermore, there is a remarkable link between the pK(a)(H(2)O) and E scales, as evidenced by the existence of a unique linear relationship spanning more than 20 orders of reactivity. This relationship appears as being a nice probe to predict the feasibility of S(N)Ar substitutions and related sigma-complexation processes. Also revealing in terms of feasibility of the rea...

Nucleophilic Substitution Reactions of 2‐Methoxy‐3‐X‐5‐nitrothiophenes: Effect of Substituents and Structure–Reactivity Correlations

“…, the E parameters of the thiophene series 1a–d cover a domain of electrophilic reactivity of 4 orders magnitude from the weakest electrophile 1d ( E = −21.33) to the strongest ones 1a ( E = −17.18). Figure also reveals that the thiophenes 1a–d used in this study display an electrophilicity that compares well with that of 4‐(2,2‐bis‐(phenylsulphonyl)vinyl)‐ N , N ‐dimethylaniline 9 ( E = −16.53) , the substituted pyridinium salt 10 ( E = −17.90) , the 3‐methoxybenzaldehyde 11 ( E = −19.32) , and the diethyl 4‐methyl‐benzylidenemalonate 12 ( E = −21.11) , respectively, but lower than that of 1,3,5‐trinitrobenzene 8 ( E = −13.19) , the conventional aromatic electrophile in S N Ar processes and the 3,5‐difluoro‐substituted benzhydrylium ion 5 ( E = 8.02), the most electrophilic species known to date . Within the E scale developed by Mayr and co‐workers, the electrophilicity of the most reactive thiophene, i.e., 1a ( E = −17.18) appears to be higher than that of some benzylidenemalonate such as the substituted diethyl benzylidenemalonate 4 ( E = −23.80), but have an E value lower by 11 units than that of 7‐chloro‐4,6‐dinitrobenzofuroxan 6 and 7‐chloro‐4,6‐dinitrobenzofurazan 7 ( E = −6.11) .…”

The Stepwise Diels–Alder Reaction of 4‐Nitrobenzodifuroxan with Danishefsky’s Diene

“…In an attempt to characterize 13, the reaction was also studied by 1 H NMR spectroscopy at À40 8C in deuterated acetonitrile, a solvent that should contribute to increase the stability of this dipolar intermediate because of its greater polarity relative to CDClA C H T U N G T R E N N U N G 3 . Apart from a slower conversion of 15 into 14, as well as a slower hydrolysis of the OSiMe 3 group of this latter adduct into 16, the NMR experiments at À40 8C provided the same picture of the overall interaction as those carried out at room temperature.…”

“…The propensity of 4,6-dinitrobenzofuroxan (DNBF), a prototype compound in this family, to undergo facile carbon-carbon coupling with weak nucleophiles such as benzenoid aromatics (anilines, phenols) or pexcessive heterocycles (indoles, pyrroles, thiophenes, furans, aminothiazoles) illustrates this behavior and has led to many synthetic, analytical, and biological applications. [1][2][3][4][5][6][7][8][9][10][11][12] Of equal interest is the exceptional electrophilic reactivity of DNBF, which is largely a reflection of the low aromatic character of the benzofuroxan structure.…”

“…This situation is totally different from the one encountered in the investigation of the DNBF/6 interaction (Scheme 2). In this instance, the zwitterionic intermediate 7 is so stable that it has been successfully characterized by 1 H and 13 C NMR spectroscopy, as well as by UV-Vis spectrophotometry and stopped-flow kinetics. [17] A possible explanation of this contrasting behavior is that the negative charge of the adduct 7 is delocalized through a large cyclohexadienyl moiety, as depicted in resonance structures 7 ac.…”

N-Alkoxy-3,5-dinitro-4-aminobenzoic acid derivatives with controlled physico-chemical properties

“…Starting from these results, we now present a continuation of our investigation in the synthesis of new compounds with such pre-established properties, starting only from one of the above isomers, namely 4-chloro-3,5-dinitrobenzoic acid 1 and following classical S N Ar [30][31][32] and/or S N 2 [33] reactions, we obtained nine compounds (2)(3)(4)(5)(6)(7)(8)(9)(10), as shown in Fig. 3.…”