The properties and the use of substituted benzofuroxans in pharmaceutical and medicinal chemistry: a comprehensive review.

Since the synthesis of 4,6-dinitrobenzofuroxan in 1899 by Drost, benzofuroxans have attracted particular attention. This peculiar series of compounds exhibit a broad spectrum of biological activity including antibacterial, antifungal, antileukemic, acaricide and immunodepressive properties. These works embrace a period of more than 50 years since the pioneering paper of Gosh and Whitehouse and papers in this major field of the heterocyclic chemistry are still published in 2013. The review has been built in two independent parts. The first one is directly dedicated to the structure of substituted benzofuroxans and will show many medicinal applications of these compounds such as nitric oxide-releasing abilities, induction of oxidative stress, potent anti-cancer agents, anti-chagas agent, target for antiamoebic agent, Ca2+ channel blockers or cytotoxic, mutagenic and genotoxic agent… The second part of this review will be in close connection with the use of benzofuroxans as synthetic precursors in the preparation of new biological compounds such as quinoxaline dioxide, benzimidazole and phenazine derivatives. The interaction of substituted benzofuroxans with electron rich heterocycles or carbanions is the key step in the synthesis of these new biological active compounds. These derivatives can be used as cytotoxic drugs, antimycobacterial agent and display anti-malarial, antileishmanial and antituberculosis activity. The nature of the substituent linked to the carbocyclic ring of benzofuroxan is of primary importance to understand the medicinal properties of this family of compounds. For example, when benzofuroxans are substituted by electron-releasing substituents, the chemical reactivity is transferred from the carbocyclic ring to the furoxan ring.

The stepwise Diels-Alder reaction of 4-nitrobenzodifuroxan with Danishefsky's diene.

The Diels-Alder reaction of 4-nitrobenzodifuroxan (NBDF) with 1-methoxy-3-trimethylsilyloxy-1,3-butadiene has been investigated experimentally and theoretically. Treatment of NBDF with excess diene in chloroform at room temperature was found to afford a single product that contained a carbonyl functionality. Based on an X-ray structure and NMR spectroscopic data, the product appeared to be a result of the hydrolysis of the OSiMe(3) moiety of the thermodynamically more stable endo [2+4] cycloadduct, characterized by a cis arrangement of the MeO and NO(2) functionalities. In situ NMR investigations of the interaction were carried out at room temperature in CDCl(3) and at -40 °C in deuterated acetonitrile. Calculations at the B3LYP/6-31G* level in the gas phase and in acetonitrile were carried out under the assumption that the most stable cis conformation of the diene is also the most reactive in the interaction. The analysis revealed the NBDF/cis diene interaction involves the formation of a zwitterionic intermediate. Importantly, this intermediate is formed in two preferred conformations, which correspond to the endo and exo modes of approach of the reagents. Cyclization of these two identified conformations afforded the experimentally characterized endo and exo [2+4] cycloadducts. According to the calculations, the interconversion of the two conformers can either take place through a return to the pre-reaction complexes or it can occur by rotation through an intermediate conformation of lesser stability. In view of the stepwise character of the interaction, the possibility that the intermediate zwitterion is the result of the interaction between NBDF and the trans diene could not be excluded. Calculations carried out with the most stable and more populated s-trans conformer confirmed this idea and supported the role of the zwitterion in the overall interaction.

Synthesis and reactivity of highly nucleophilic pyridines.

3,4,5-Triamino-substituted pyridines are avid for electrophiles but are still willing to give them back. In these compounds three amino groups conjoin their forces into the heterocyclic nitrogen, making it a powerful Lewis base. A short and efficient synthesis is described, and the origin of its unique activity in nucleophilic organocatalysis is rationalized by kinetics and thermodynamic quantifications.

Electrochemical and spectrophotometrical investigation of the electron-accepting strength of organic superelectrophiles: X-ray structure of their charge transfer complexes with tetrathiafulvalene.

Nitro Benzoxadiazoles (benzofurazans), benzoxadiazoles-N-oxide (benzofuroxans) and benzothiadiazoles are ranked amongst the strongest electrophiles known to date. In the past twenty years, their propensity to act as electron organic acceptors has been less studied. In this paper, we report on the study of their electrochemical behavior and on the structural characterization of charge transfer complexes (CTC) deriving from their interaction with tetrathiafulvalene (TTF) derivatives, both in solution and in the solid state. The first half wave reduction potentials (E(1/2)(I)) associated with a reversible monoelectronic transfer process of a large set of nitro substituted benzoxadiazoles (benzofurazans), benzoxadiazoles-N-oxide (benzofuroxans) and benzothiadiazoles have been determined through a detailed electrochemical approach in acetonitrile with a microelectrode network using the ferrocene as an internal reference potential in this electrochemical study. Determination of the electron affinity (EA(CT)) of this series of substituted electrodeficient heteroaromatics as well as their LUMO energy was performed using the Charge Transfer Spectroscopic (CTS) method in solution and by DFT calculations, respectively. The use of the correlation EA(CT) versus the reversible half wave potential (E(1/2)(I)) appears to be a useful tool to estimate readily the E(1/2)(I) or EA(CT) values when they cannot be experimentally determined. The diffusion coefficient of these electrophiles has, for the first time, been determined in acetonitrile. These air stable electrodeficient heteroaromatics have been explored as potential new organic acceptors in the formation of charge transfer (CT) complexes with TTF derivatives. Crystallographic data of two CT complexes with TTF (especially the C-C and C-S bond lengths of the TTF moieties) indicate that these complexes exhibit weak electron delocalization and that both molecules remain neutral. Their resulting levels of charge transfer were probed using UV-visible, IR spectroscopy and by DFT calculations.

The Diels-Alder reaction of 4,6-dinitrobenzofuroxan with 1-trimethylsilyloxybuta-1,3-diene: a case example of a stepwise cycloaddition.

The reaction of 4,6-dinitrobenzofuroxan (DNBF) with 1-trimethylsilyloxybuta-1,3-diene (8) is shown to afford a mixture of [2+4] diastereomeric cycloadducts (10, 11) through stepwise addition-cyclization pathways. Zwitterionic intermediate sigma-adduct 9, which is involved in the processes, has been successfully characterized by (1)H and (13)C NMR spectroscopy and UV/visible spectrophotometry in acetonitrile. A kinetic study has been carried out in this solvent that revealed that the rate of formation of 9 nicely fits the three-parameter equation log k=s(E+N) developed by Mayr to describe the feasibility of nucleophile-electrophile combinations. This significantly adds to the NMR spectroscopic evidence that the overall cycloadditions take place through a stepwise mechanism. The reaction has also been studied in dichloromethane and toluene. In these less polar solvents, the stability of 9 is not sufficient to allow direct characterization by spectroscopic methods, but a kinetic investigation supports the view that stepwise processes are still operating. An informative comparison of our reaction with previous interactions firmly identified as prototype stepwise cycloadditions is made on the basis of the global electrophilicity index, omega, defined by Parr within the density functional theory, and highlighted by Domingo et al. as a powerful tool for understanding Diels-Alder reactions.

Theoretical and experimental 1H, 13C and 15N NMR studies of N-alkylation of substituted tetrazolo[1,5-a]pyridines.

The (15)N as well as (1)H and (13)C chemical shifts of nine substituted tetrazolopyridines and their corresponding tetrazolopyridinium salts have been determined by using NMR spectroscopy at the natural abundance level of all nuclei in CD(3)CN. In this paper, we report, for the first time, the N-alkylation reaction of electron deficient tetrazolopyridines. The treatment of tetrazolopyridines 5-13 with one equivalent of trialkyloxonium tetrafluoroborate leads to a mixture of two isomers, i.e. N3- and N2-alkyl tetrazolo[1,5-a]pyridinium salts. It has been observed that the N3-isomer is always the major isomer, except in the case of the CF(3) substituent, where the two isomers are obtained in the same amount. The quaternary tetrazolopyridinium nitrogen N3 is shielded by around 100 ppm (parts per million) with respect to the parent tetrazolopyridine. Experimental data are interpreted by means of density functional theory (DFT) calculations, including solvent-induced effects, within the conductor-like polarizable continuum model (CPCM). Good agreements between theoretical and experimental (1)H, (13)C and (15)N NMR were found. The combination of multinuclear magnetic resonance spectroscopy with gauge including atomic orbital (GIAO) DFT calculations is a powerful tool in the structural elucidation for both neutral and cationic heterocycles and in the determination of the orientation of N-alkylation of tetrazolopyridines.

X-ray structure of a CT complex relevant to Diels-Alder reactivity of anthracenes.

Combining the results of thermodynamic and kinetic investigations with an X-ray characterization of a transient CT complex sheds more light on the Diels-Alder reactivity of a strongly electron-deficient olefin, namely the 4-nitrobenzodifuroxan.

The ambident reactivity of 2,4,6-tris(trifluoromethanesulfonyl)anisole in methanol: using the SO2CF3 group as a tool to reach the superelectrophilic dimension in sigma-complexation processes.

The kinetics of sigma complexation of 2,4,6-tris(trifluoromethanesulfonyl)anisole (7 d) have been investigated over a large pH range of 2-13.70 at T = 20 degrees C in methanol. Two competitive processes associated with the initial addition of MeO(-) at the unsubstituted 3-position of 7 d to give a 1,3-dimethoxy adduct (9 d-Me) and a subsequent and slow conversion of this species into a 1,1-dimethoxy isomer (8 d-Me) have been identified. Both adducts 8 d-Me and 9 d-Me are 10(5)-10(6) times more stable than the related adducts 8 a-Me and 9 a-Me of 2,4,6-trinitroanisole (7 a), a conventional reference aromatic electrophile in Meisenheimer complex chemistry. The high stability of 8 d-Me and 9 d-Me is shown to derive from greater rates of formation and lower rates of decomposition than previously determined for 8 a-Me and 9 a-Me, thereby emphasising the especially high activation of a benzene ring by SO(2)CF(3) group(s). Analysis of the collected rate and equilibrium data for sigma complexation in the anisole series 2,4,6-tris(SO(2)CF(3))-, 2,6-bis(SO(2)CF(3))-4-nitro-, 4-SO(2)CF(3)-2,6-dinitro- and 2,4,6-trinitro- supports the idea that the especially high capacity of resonance stabilisation of the negative charge of the adducts through an F(pi)-type (as defined in ref. 49) polarisation effect is a major factor that accounts for the strong activation provided by SO(2)CF(3) groups. A most significant result is the finding that the 1,1-dimethoxy adduct 8 d-Me is by far the most stable benzene sigma adduct so far reported. With a pK(a)(MeOH) value of 7.32, this adduct is formed exclusively through methanol addition up to pH approximately 10. This is consistent with the location of 7 d in the superelectrophilic region defined by pK(a)(MeOH) < or = 9.5-10.5. For comparison, the solvent contribution is negligible in the formation of the 1,3-isomer 9 d-Me, the pK(a)(MeOH) (10.59) of which is situated on the upper limit of the boundary. Taking advantage of the simple relationship linking pK(a) values for sigma complexation in methanol and water, a ranking of the triflone 7 d on the general thermodynamic scale constructed for Meisenheimer electrophiles in water is informative. An approximate calibration on the electrophilicity scale kinetically derived by Mayr et al. has also been made.

Carbon nucleophilicities of indoles in S(N)Ar substitutions of superelectrophilic 7-chloro-4,6-dinitrobenzofuroxan and -benzofurazan.

Superelectrophilic 7-chloro-4,6-dinitrobenzofuroxan (DNBF-Cl) and 7-chloro-4,6-dinitrobenzofurazan (DNBZ-Cl) are shown to undergo facile carbon-carbon couplings with a series of weak carbon nucleophiles consisting of a number of differently substituted indoles, 1,2,5-trimethylpyrrole and azulene, in acetonitrile. Despite the fact that steric effects preclude a coplanarity of the donor and acceptor moieties, the resulting substitution products are subject to an intense intramolecular charge transfer. A kinetic study of the various substitutions has been carried out. The absence of a significant dependence of the rates of coupling on the hydrogen or deuterium labeling at the reactive center of the nucleophiles indicates that the reactions take place through an SEAr-SNAr mechanism with the initial nucleophilic addition step being rate-limiting. A vicarious-type substitution is shown to be unreasonable. Referring to Mayr nucleophilicity parameters (N), which have become recently available for a large set of indoles, the electrophilicity of DNBF-Cl and DNBZ-Cl, could be ranked on the general electrophilicity scale E developed by this author (Acc. Chem. Res. 2003, 36, 66). With essentially similar E values of -6.1, these two compounds have an electrophilicity which approaches that of cationic stuctures such as 4-nitrobenzenediazonium cation or tropylium cations. Most important in the context of SNAr substitutions, DNBF-Cl and DNBZ-Cl are 7 orders of magnitude more electrophilic than picryl chloride, the conventional reference electrophile in this field. It is this so far unique behavior which allows the facile coupling of DNBF-Cl and DNBZ-Cl with such weak carbon nucleophiles as indoles. Based on a nice Brönsted-type correlation for 5-X-substituted indoles, the unknown pKaCH values measuring the Brönsted C-basicity of several N-benzylindoles could be readily estimated. The influence of some steric effects in 2-methylindole systems is pointed out.

The versatile electrophilic reactivity of 4,6-dinitrobenzo[d]isoxazole-3-carbonitrile.

The interaction of 4,6-dinitrobenzo[d]isoxazole-3-carbonitrile (5a) with methoxide ion has been kinetically investigated in methanol and a 20:80 (v/v) MeOH-Me2SO mixture. In methanol, stopped-flow experiments have revealed that a monomethoxyl sigma-adduct (5a-Me) is first formed, resulting from a fast MeO- addition at the unsubstituted 7-carbon. Rate and equilibrium constants for this sigma-complexation process could be determined, allowing a ranking of 5a within the pKa scale established for Meisenheimer electrophiles in methanol. With a pKa value of 13.50, the electrophilicity of 5a falls in the range of 1,3,6,8-tetranitronaphthalene, 2,4-dinitrothiophene or 4-nitrobenzofuroxan. This corresponds to a two-pKa units increase in electrophilicity from that of TNB, the common reference in sigma-complex chemistry but it is notably below that of so-called superelectrophilic molecules like 4,6-dinitrobenzofuroxan. In addition to its ease of sigma-complexation, 5a is found to undergo a slow but thermodynamically favourable addition of MeO- to the cyano group bonded to the isoxazole ring, leading to a complete conversion of the adduct 5a-Me into a dinitroimidate 6. The reactivity of 6 could be kinetically assessed. Going to 80% Me2SO still afforded initially the adduct 5a-Me but this anionic species undergoes addition of a second molecule of MeO- to the CN group, giving a dianion whose structure is unprecedented in the literature. Combining the above results with synthetic observations showing that 5a can readily contribute to S(N)Ar reactions under appropriate experimental conditions emphasizes the multifaceted electrophilic reactivity of this electron-deficient heterocycle.

Electrophilicity of aromatic triflones in sigma-complexation processes.

The kinetics of sigma-complexation of 2,6-bis(trifluoromethanesulfonyl)-4-nitroanisole (4) have been investigated over a large pH range of 2-15.68 in methanol. Two competitive processes have been identified with the initial addition of MeO(-) at the unsubstituted 3-position of 4 to give a 1,3-dimethoxy adduct (4b-Me) and a subsequent and slow conversion of this species into the 1,1-dimethoxy isomer (4a-Me). Both 4a-Me and 4b-Me are more stable than the related adducts of 2,6-dinitro-4-trifluromethanesulfonylanisole, i.e.5a-Me and 5b-Me, and 2,4,6-trinitroanisole, i.e.6a-Me and 6b-Me, the latter compound being a conventional reference aromatic electrophile in Meisenheimer complex chemistry. The high thermodynamic stability of 4a-Me (pK(a) = 10.48) and 4b-Me (pK(a) = 12.23) relative to 5a-Me (pK(a) = 10.68) and 6a-Me (pK(a) = 12.56) or 5b-Me (pK(a) = 15.38) and 6b-Me (pK(a) = 16.46), is shown to derive from an especially high capacity of a para or an ortho SO(2)CF(3) group to stabilize a negative charge through Fpi-type polarization effects. From the kinetic data, it appears that the contribution of a methanol pathway to the formation of 4a-Me is much weaker than that found to operate in the formation of the 1,1-complex 5a-Me of 2,6-dinitro-4-trifluromethanesulfonylanisole, the experimental evidence suggesting that the reactivity of 4 and 5 is located just beyond the region defining the boundary between super- and normal-electrophilicity in methanol. Comparison of our results with available literature data show that this boundary corresponds to a pK(MeOH)(a) value of approximately 10, in agreement with our previous finding of a very effective solvent contribution to the sigma-complexation of 1,3,5-tris(trifluoromethanesulfonyl)benzene (13; pK(MeOH)(a) = 9.12) in methanol. Taking advantage of our observation that pK(MeOH)(a) and pK(H(2)O)(a) values for sigma-complexation at unsubstituted ring positions are related by a nice linear correlation, an approximate ranking of the electrophilicity of our aromatic triflones on the E scale developed by Mayr (Acc. Chem. Res. 2003, 36, 66) can be made.

Evidence for the intermediacy of Wheland-Meisenheimer complexes in SEAr reactions of aminothiazoles with 4,6-dinitrobenzofuroxan.

Reactions of DNBF with a series of 2-aminothiazoles (1 a-f) to afford thermodynamically stable C-bonded sigma-adducts have been investigated in acetonitrile. A most significant finding emerged on recording NMR spectra immediately after mixing of equimolar amounts of DNBF and the unsubstituted 2-aminothiazole (1 a) in Me2SO: namely, that the formation of 9 a is preceded by that of a short-lived intermediate species X. From the 1H NMR parameters characterizing this intermediate, as well as the dependence of its lifetime on the experimental conditions-the presence of excess DNBF over 1 a increases the lifetime of X while an excess of base (1 a) accelerates its conversion into 9 a--it is convincingly demonstrated that the structure of X combines the presence of a positively charged Wheland complex moiety (with regard to the thiazole ring) with that of a negatively charged Meisenheimer complex moiety (with regard to the benzofuroxan system). So far, only one intermediate of this type (noted WM) has been successfully characterized, in the reactions of DNBF with 1,3,5-tris(N,N-dialkylamino)benzenes. Among the key features supporting the intermediacy of X along the reaction coordinate leading to 9 a is the fact that the reactions of DNBF with 1 a in the presence of an alcohol (MeOH, EtOH, nPrOH) produce new adducts arising from the addition of an alcohol molecule to the thiazole moiety of WM-1 a. Reflecting the presence of three chiral centres, these species are formed as mixtures of several diastereomers that could all be characterized in their racemic forms in ethanol. These findings generalize the previous report on the formation of Wheland-Meisenheimer carbon-carbon complexes in homocyclic series.

Superelectrophilicity of the nitroolefinic fragment of 4-nitrobenzodifuroxan in Michael-type reactions with indoles: a kinetic study in acetonitrile.

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 (k1NBDF) 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 omega 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.

Mayr electrophilicity predicts the dual Diels-Alder and sigma-adduct formation behaviour of heteroaromatic super-electrophiles.

We report on the dual reactivity, i.e. anionic Meisenheimer sigma adduct formation and Diels-Alder adduct formation, of a series of heteroaromatic super-electrophiles, including 4,6-dinitro-benzofuroxan, -N-arylbenzotriazoles (4), -benzothiadiazole and -benzoselenadiazole. Measured pK(a)(H(2)O) values for sigma adduct formation provide a quantitative measure of super-electrophilic reactivity with a satisfactory correlation between the Mayr E electrophilicity parameter and pK(a)(H(2)O): E = -0.662 pK(a)(H(2)O) (or pK(R+) -3.20 (r(2) = 0.987). The most highly electrophilic, pre-eminent super-electrophile is 4,6-dinitrotetrazolopyridine (E = -4.67, pK(a)(H(2)O) = 0.4), which supercedes the reference Meisenheimer super-electrophile, 4,6-dinitrobenzofuroxan (E = -5.06, pK(a) = 3.75), having itself an E value superior by 8 orders of magnitude compared to 1,3,5-trinitrobenzene as the benchmark normal Meisenheimer electrophile (E = -13.19, pK(a)(H(2)O) = 13.43). (For relevant kinetic parameters as well as E and pK(a) values, see .) In a parallel study we have investigated Diels-Alder (normal and inverse electron demand) reactivity of this series of heteroaromatic electrophiles and have shown that Mayr E values are valid predictors of whether DA adducts will form and how rapidly. The observed order of pericyclic reactivity corresponds to E = -8.5 as the demarcation E value, in close agreement with sigma complexation; thus pointing to a common origin for the two processes, i.e. an inverse relationship between the degree of aromaticity of the carbocyclic ring and ease of sigma complexation, or DA reactivity, respectively.

Nucleophilic reactivities of indoles.

The kinetics of the coupling of indole (1a), N-methylindole (1b), 5-methoxyindole (1c), and 5-cyanoindole (1d) with a set of reference benzhydryl cations have been investigated in acetonitrile and/or dichloromethane. The second-order rate constants for the reactions correlate linearly with the electrophilicity parameter E of the benzhydryl cations. This allows the determination of the reactivity parameters, N and s, characterizing the nucleophilicity of 1a-d according to the linear free enthalpy relationship log k(20 degrees C) = s(N + E) (Acc. Chem. Res. 2003, 36, 66). The nucleophilicity parameters thus defined describe nicely the reactions of 1a-d with 4,6-dinitrobenzofuroxan (2), a neutral superelectrophilic heteroaromatic whose electrophilicity (E) has been recently determined. On this ground, the kinetics of the coupling of 2 with a large variety of indole structures have been studied in acetonitrile, leading to a ranking of this family of pi-excessive carbon nucleophiles over a large domain of the nucleophilicity scale N. Importantly, two linear and parallel correlations are obtained on plotting the measured N values versus the pK(a)(H(2)O) values for protonation at C-3 of 5-X-substituted indoles and 5-X-substituted 2-methylindoles, respectively. This splitting reveals that the presence of the 2-methyl group causes steric hindrance to the approach of 2 from the adjacent C-3 position of an indole structure. The N vs pK(a)(H(2)O) correlation for 5-X-substituted indoles is used for a rapid determination of the C-3 basicity of indoles whose acidity constants cannot be measured through equilibrium studies in strongly acidic aqueous media.

Ring opening and ring closure in an indolizine structure activated through S(N)Ar coupling with superelectrophilic 4,6-dinitrobenzofuroxan, an unusual intramolecular oxygen transfer from a N-oxide functionality.

Coupling of superelectrophilic 4,6-dinitrobenzofuroxan with a pi-excessive indolizine structure affords a strongly dipolar substitution product which undergoes a facile but unusual rearrangement induced by an intramolecular oxygen atom transfer from the N-oxide functionality of the DNBF moiety.

Assessing the nitrogen and carbon nucleophilicities of 2-aminothiazoles through coupling with superelectrophilic 4,6-dinitrobenzofuroxan.

The reactions of 2-aminothiazole (1a), 4-methyl-2-aminothiazole (1b), and 4,5-dimethyl-2-aminothiazole (1c) with superelectrophilic 4,6-dinitrobenzofuroxan (DNBF) have been studied in acetonitrile and a 70/30 (v/v) H2O/Me2SO mixture. While exhibiting a somewhat higher nitrogen basicity than that of anilines, 1a and 1b do not react as nitrogen nucleophiles, affording exclusively anionic C-bonded sigma-adducts (C-1a and C-1b) through electrophilic S(E)Ar substitution of the thiazole ring by DNBF. Only in the case of the 4,5-dimethyl derivative 1c a N-adduct, N-1c, was obtained. On the basis of 1H-15N correlations, it is demonstrated that this adduct, N-1c;1c,H+, is derived from DNBF addition at the exocyclic amino group and not at the endocyclic nitrogen center of 1c. Rate constants have been determined in the two solvents for the formation of the adducts, revealing a reactivity sequence which accounts well for the finding that 1a and 1b behave preferentially as carbon rather than nitrogen nucleophiles. The enaminic character of these thiazoles is assessed through an estimation of the pKa values for their C-protonation in aqueous solution as well as through a positioning of their reactivity on the nucleophilicity scale recently developed by Mayr et al. (Acc. Chem. Res. 2003, 36, 66). With N values of the order of 6.80 and 5.56, 1b and 1a have a carbon nucleophilicity comparable to that of N-methylindole and indole, respectively.

Nitrobenzoxadiazoles and related heterocycles: a relationship between aromaticity, superelectrophilicity and pericyclic reactivity.

A study of the dual electrophilic and pericyclic reactivity of 4,6-dinitrobenzofurazan (DNBZ, 2), 4,6-dinitro-2,1,3-benzothiadiazole (DNBS, 3), 4,6-dinitro-2,1,3-benzoselenadiazole (DNBSe, 4) is reported. Kinetic and thermodynamic measurements of the ease of covalent hydration of 2-4 to give the corresponding hydroxy sigma-adducts C-2-C-4 have been carried out over a large pH range in aqueous solution. Analysis of the data has allowed a determination of the rate constants k1(H2O) pertaining to the susceptibility of 2-4 to water attack as well as the pKa values for the sigma-complexation processes. With pKa values ranging from 3.92 for DNBZ to 6.34 for DNBSe to 7.86 for DNBS, the electrophilic character of the three heteroaromatics is much closer to that of the superelectrophilic reference, i.e. 4,6-dinitrobenzofuroxan (DNBF, 1; pKa = 3.75), than that of the standard Meisenheimer electrophile 1,3,5-trinitrobenzene (TNB, pKa = 13.43). Most importantly, water is found to be an efficient nucleophile which contributes strongly to the formation of the adducts C-2 and C-4. This confirms a previous observation that a pKa value of ca. 8 is a primary requirement for having H2O competing effectively as a nucleophile with OH- in the formation of hydroxy sigma-adducts. On the other hand, 2-4 are found to exhibit dienophilic and/or heterodienic behaviour on treatment with isoprene, 2,3-dimethylbutadiene, cyclopentadiene or cyclohexadiene, affording Diels-Alder mono- or di-adducts which have all been structurally characterized. A major finding is that the order of Diels-Alder reactivity follows clearly the order of electrophilicity, pointing to a direct relationship between superelectrophilic and pericyclic reactivity. This relationship is discussed.

Ranking the reactivity of superelectrophilic heteroaromatics on the electrophilicity scale.

The kinetics of the reactions of a series of reference carbon nucleophiles, consisting of N-methylpyrrole A, indole B, N-methylindole C, and enamines D-G, with 10 electron-deficient aromatic and heteroaromatic substrates (1-10), resulting in the formation of stable anionic sigma-adducts, have been investigated in acetonitrile at 20 degrees C. It is shown that the second-order rate constants k(1) pertaining to the carbon-carbon coupling step of these processes fit nicely the three-parameter equation log k (20 degrees C) = s(N + E), allowing the determination of the electrophilicity parameters E of 1-10 and therefore the ranking of these neutral electron-deficient compounds on the comprehensive electrophilicity scale defined for cationic electrophiles by Mayr et al. (Mayr, H.; Kempf, B,; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66). The E values of 1-10 are found to cover a range from -13 to -5, going from 1,3,5-trinitrobenzene 1, the least reactive molecule, to 4,6-dinitrotetrazolo[1,5-a]pyridine 8, 4-nitro-6-trifluoromethanesulfonylbenzofuroxan 3, and 4,6-dinitrobenzofuroxan 2, the three most reactive heterocycles. Of major interest is that the E value of 2 is essentially the same as that for 4-nitrobenzenediazonium cation (E = -5.1), approaching that of the tropylium cation family (E approximately -3 to -6) as well as a number of metal-coordinated carbenium ions. Such a ranking holds promise for expanding the range of coupling reactions which can be envisioned with such strongly electron-deficient neutral heteroaromatics as nitrobenzofuroxans and related compounds. Arguments are also given which exclude the possibility for the reactions studied to proceed via an electron-transfer mechanism.