Régis Goumont

Super acidifiers: the origin of the exceptional electron transmission capability of the SO2CF3 group in carbanion stabilization

As part of studies aimed at clarifying conflicting reports concerning the acidifying effects exerted by the SO2CF3 vs. NO2 moieties with respect to carbanion stabilities, we have investigated the ionization equilibria of an extended set of benzyltriflones and have determined both pKa values of the carbon acids and 1H and 13C NMR parameters of the resulting carbanions. Acidities determined in H2O-Me2SO mixtures and in pure Me2SO show a contrasting behaviour between 4-X-substituted benzyl triflones and related arylnitromethanes. While the latter exhibit a decreasing acidity on going from H2O to Me2SO media, the benzyltriflone analogues show in fact increasing acidity in Me2SO. This opposing trend suggests that the exocyclic alpha-SO2CF3 moiety is strongly stabilizing the negative charge of the carbanions through polarizability effects favored by the dipolar aprotic Me2SO solvent. As a result, inversions in the acidity sequences of alpha-NO2 and alpha-SO2CF3 activated carbon acids are observed on going from H2O to Me2SO. 1H and 13C NMR data are in full accord with the conclusion that only little negative charge is transferred to the 4-X-substituted phenyl ring upon ionization. Increasing further the ring substitution by electronegative groups to 2,4- and 2,4,6- patterns, enhances the charge transfer but this nevertheless remains moderate even with the most activated 2,4,6- trinitro or 2,6-dinitro-4-SO2CF3 sequences. Altogether, our results provide convincing evidence of the unusual electron transmission ability of the very strongly acidifying SO2CF3 group.

High Brønsted βnuc values in SNAr displacement. An indicator of the SET pathway

Nucleophilic substitutions of 4-chloro-7-nitrobenzofurazan (NBD-Cl) and 3-methyl-1-(4-nitrobenzofurazanyl)imidazolium ions (NBD-Im+) with a series of 4-X-substituted anilines have been kinetically investigated in 70–30 (v/v) and 20–80 (v/v) H2O–Me2SO mixtures. The rate-limiting step in these reactions is nucleophilic addition with formation of Meisenheimer-type σ-adducts followed by fast expulsion of the leaving group (Cl− or Im). The reactions are characterized by a notable sensitivity to basicity of the aniline nucleophiles, with Hammett ρ values of −2.68 and −3.82 in 30% and 80% Me2SO, respectively, for NBD-Cl and even more negative values, −3.43 and −5.27, respectively, for NBD-Im+. This is consistent with significant development of positive charge at the nitrogen atom of the zwitterionic σ-adduct. Unexpectedly, the Bronsted-type plots reveal abnormally high βnuc values, ca. 1.0 and 1.3–1.4, respectively. Satisfactory correlations between the rates of the reactions and the oxidation potentials of the respective anilines support a SET mechanism for this process, i.e. initial (fast) electron-transfer from the aniline donor to the nitrobenzofurazan acceptor moiety and subsequent (slow) coupling of the resulting cation and anion radicals within the solvent cage with formation of the σ-adduct. An alternative possible explanation of the high βnuc values being related to the strong −I effect exerted by the negatively charged 4-nitrobenzofurazanyl structure, which would induce a greater positive charge at the developing anilinium nitrogen atom in the σ-adduct-like transition state as compared with the situation in the reference protonation equilibria of anilines, is considered less probable. It is thus proposed that obtention of abnormal βnuc values may be an indicator of electron-transfer in nucleophilic aromatic substitution and highlights the transition from the polar (SNAr) to the single electron-transfer (SET) mechanism.

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.

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.

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.

Electrochemical Oxidation ofσ-Complex-Type Intermediates in Aromatic Nucleophilic Substitutions

A series of sigma-adducts (1H-...7H-) derived from the addition of 2-nitropropenide ion to various nitrobenzofuroxans and nitrobenzofurazans have been oxidized electrochemically. The results show that the rearomatization of the carbocyclic ring of these adducts as well as that of a few additional 4,6-dinitrobenzofuroxan adducts (8 H- a-c) is associated with much higher oxidation potentials than found for the same process in the dinitro- and trinitrobenzene series. Especially high Eo values are measured for the oxidation of the 2-nitropropenide 4,6-dinitro- and 4-nitro-6-trifluoromethylsulfonylbenzofuroxan adducts 1H- and 4H- in acetonitrile: E (1H-)= 1.15 V versus SCE; Eo(4H-)=1.33V versus SCE. These values fit well with the available evidence that the chemical oxidation of these adducts requires the use of very strong oxidizing agents to proceed efficiently. The mechanism for the oxidation process has been established. It is shown to involve transfer of two electrons and liberation of one proton per sigma-complex precursor with no evidence whatsoever for the intermediacy of radical anionic species.

Carbon Nucleophilicities of Indoles in SNAr 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.

σ-Complex formation and oxidative nucleophilic aromatic substitution in 4-nitro-2,1,3-benzoxadiazoles

The feasibility of carrying out nucleophilic displacement of hydrogen from highly electron-deficient heteroaromatics has been addressed through a detailed investigation of the interaction of a series of nitrobenzofuroxans 3a-i and two related heterocycles 5 and 6, with the 2-nitropropenide anion. Although this series corresponds to a large modulation in the electrophilic properties of the six-membered ring, all reactions first lead to the quantitative formation of the sigma-adducts C-3a-i, C-5 and C-6 arising from covalent addition of the nucleophile to the C-7 carbon. With the exception of the 4-aza substituted member C-5, all the adducts have been isolated as pure and very stable alkali salts. Measurements of the oxidation potentials by cyclic voltammetry reveal that the ease of subsequent hydrogen substitution at carbon-7 strongly decreases with increasing electron deficient character of the six-membered ring. The measured E0 values are in the range 0.5-0.6 V (vs. SCE) for the 4-nitro-benzofuroxan and -benzofurazan adducts (C-3e, C-3i) but they go up to 1.20-1.33 V for the 4,6-dinitro- and 4-nitro-6-trifluoromethanesulfonylbenzofuroxan adducts (C-3a,d) in acetonitrile. Consistently with these E0 values, only very powerful oxidants such as the Ce4+/Ce3+ or the MnO4-/Mn2+ couples can successfully oxidize the adducts leading to the expected substitution products in moderate to good yields (35-72%). Interestingly, the rearomatization of the 4-nitro substituted benzofuroxan adducts proceeds with a partial Boulton-Katritzky rearrangement of the resulting products. Another noteworthy result is that the 4-nitrobenzofuroxan and 4-nitrobenzofurazan molecules suffer competitive addition of the (CH3)2C-NO2- anion to the 5- and 7- positions under some experimental conditions. This represents the first well-defined example of isomeric addition of a carbon nucleophile to these heterocycles.

The Diels-Alder reactivity of nitrobenzofuroxans: mono- and di-adducts of isoprene and 2,3-dimethylbutadiene. New convenient precursors to naphtho- and phenanthreno-furoxanic and -furazanic structures

Abstract The reactions of a series of differently substituted nitrobenzofuroxans with isoprene and 2,3-dimethylbutadiene have been investigated. A variety of mono- and di-adducts resulting from normal electron demand Diels–Alder condensations involving the activated C6C7 and/or C4C5 double bonds of the carbocyclic ring as the dienophile contributors have been identified and structurally characterized. The regioselectivity of the reactions is found to be strongly dependent on the substitution pattern of this ring. In the 4-nitro-6-X-series, the diene molecule first adds to the C6C7 double bond if X is a strong electron-withdrawing substituent (X=NO2, SO2CF3) but to the nitroactivated C4C5 double bond if X is a moderately activating substituent (X=CN, CF3). Subsequent addition of a second molecule of diene occurs to give highly stereoselective diadducts in the 6-cyano, 6-trifluoromethyl and 6-nitro systems. Contrasting with this behavior, only monoadducts corresponding to the addition of diene to the nitroactivated C6C7 double bond were obtained in the 4-X-6-nitro-series (X=CN, CF3). 4,6-Dinitrotetrazolo[1,5-a]pyridine reacts similarly to 4,6-dinitrobenzofuroxan, i.e. highly stereoselective diadducts are formed on the reaction with isoprene and 2,3-dimethylbutadiene. A most significant finding is that the treatment of some of the isolated mono- and di-adducts by a strong base like t-BuOK results in a facile β-elimination of nitrous acid. Concomitant oxidative rearomatization of the resulting cyclohexadiene moieties then occurs spontaneously to afford otherwise difficultly available naphtho- or phenanthreno furoxanic or furazanic structures as well as azaphenanthrenotetrazoles.

An extremely highly electrophilic heteroaromatic structure: 4,6-dinitrotetrazolo[1,5-a]pyridine.

A detailed thermodynamic and kinetic investigation of the reactions of 4,6-dinitrotetrazolo[1 ,5-a]pyridine (DNTP) with water and methanol has been made in the corresponding solvents. In aqueous solution, covalent addition of water to DNTP occurs with the exclusive formation of an anionic hydroxy sigma-complex C-4a which is half-formed in a 0.4 M HCl solution (pKa(sigma) = 0.4). This corresponds to a 3 pK-units jump in thermodynamic stability from the most stable hydroxy sigma-complex known so far, i.e. the hydroxy adduct C-3a of 4,6-dinitrobenzofuroxan (DNBF). DNTP forms similarly a very stable methoxy sigma-complex C-4b in methanol (pKa(sigma) = 2.64). Interestingly, the addition of methanol to DNTP also results in the partial formation of a neutral carbinolamine-type adduct (C-5b) at low pH. Rate and equilibrium constants pertaining to most of the reaction pathways involved in the interactions have been determined. In particular, the following rate constants k1(H2O) and k1(MeOH) for formation of C-4a and C-4b have been measured: k1(H2O) = 1.93 s(-1); k1(MeOH) = 3.50 s(-1), to be compared with k1(H20) = 0.035 s(-1); k1(MeOH) = 0.030 s(-1) for sigma-complexation of DNBF under similar experimental conditions. Altogether, the results obtained reveal that DNTP is a considerably more powerful electrophile than DNBF, the common reference as to whether an electron-deficient aromatic or heteroaromatic substrate may be accorded superelectrophilic properties in addition or substitution processes.