The super-electrophilic reactivity of 4-nitro-6-trifluoromethanesulfonyl-benzofuroxan in aqueous solution

A kinetic and thermodynamic study of the covalent hydration of 4-nitro-6-trifluoromethanesulfonylbenzofuroxan, 4 , to give the corresponding hydroxy σ -adduct, C-4 , in aqueous solution is reported. Analysis of the data obtained in the pH range 0.8–13 has allowed dissection of the observed rates into forward ( , k O H1 2 k − OH2 ) - and reverse ( k + − H 1 , k -2 ) - rate constants as well as the obtention of pK a values for water addition to the carbocyclic ring. The results reveal that C-4 is the most stable hydroxy σ -adduct known to date (pK a = 2.95) and that its formation arises exclusively from the attack of water molecules between pH 2.5 and 8.5. The related rate constant O

) -and reverse ( k -rate constants as well as the obtention of pK a values for water addition to the carbocyclic ring.The results reveal that C-4 is the most stable hydroxy σ-adduct known to date (pK a = 2.95) and that its formation arises exclusively from the attack of water molecules between pH 2.5 and 8. 5

Introduction
−8 The high capability of 4,6-dinitrobenzofuroxan (DNBF, 1) to form the hydroxy σ-adduct, C-1, in aqueous solution is illustrative of this behavior. 1The pK a value for formation of C-1 according to eqn. ( 1) is equal to 3.75 at 25°C, as compared with a pK a value of 13.37 for formation of the analogous adduct C-2 of 1,3,5trinitrobenzene (TNB, 2), the conventional reference aromatic electrophile in σ-complex chemistry. 1,9The use of dilute alkali hydroxide solutions is, in fact, necessary to achieve the formation of C-2 in aqueous solution (eqn.( 2)). 9

C-2 2
(2) Extensive studies have revealed that DNBF is a stronger electrophile than the positively charged 4-nitrobenzenediazonium cation. 10This has led to many analytical applications with the use of DNBF as a suitable probe to assess the reactivity of extremely weak carbon nucleophiles such as benzenoid aromatics or π-excessive heteroaromatics with large negative pK a values, e.g., 1,3-dimethoxybenzene (pK a = -9) or aniline (pK a = -6). 4,11Another important electrophile is 4chloro-7-nitrobenzofurazan which is largely used for biological processes. 12,135][16] This new facet of the reactivity of DNBF is very promising for the synthesis of highly functionalized heterocyclic structures. 17bviously, the above results called for the recognition of other heteroaromatic compounds that might behave similarly to, or even surpass, the DNBF structure in terms of electrophilicity and Diels-Alder reactivity.In this regard, two different strategies could be reasonably envisioned where the expected variation in reactivity will arise either from a change in the nature of the annelated five-membered ring or a modification of the electrophilic character of the carbocyclic ring by the introduction of more powerful electron-withdrawing substituents-including by azasubstitution.Considering the first approach, a recent study has been made 18a of the series of 2aryl-4,6-dinitrobenzotriazole 1-oxides, 3a-e (eqn.(3)), leading to evidence that the electrophilicity of the carbocyclic ring of all compounds of this family ranks somewhat lower than that of DNBF.Concomitantly, the potentiality of this ring to be involved in Diels-Alder processes is reduced and only 3a, i.e., the most activated benzotriazole in the series, was found to exhibit some dienophilic or heterodienic reactivity.18b Regarding the second strategy, promising results have been recently obtained through azaand diaza-substitution of the carbocyclic ring, 19,20 but another approach was to look at the effect of the introduction of very strong electron-withdrawing substituents in this ring.In particular, the available literature data indicate that the SO 2 CF 3 group is generally more activating than a NO 2 group, especially in σ-complexationand related S N Ar reactions. 21

C-3a-e
In this context, we report here the results of a kinetic and thermodynamic study of the covalent hydration of 4-nitro-6-trifluoromethanesulfonylbenzofuroxan, 4, in aqueous solution, to give the adduct C-4, according to Scheme 1.Our results reveal that 4 is the most electrophilic neutral heterocycle known to date.Various features emphasizing this behavior will be discussed.These include a high rate of water attack at the 7-carbon of 4, as well as the occurrence of nucleophilic catalysis of this process by carbonate ions and the formation of the dianion D-4 in dilute alkali solution [eqn.(6)].

Results
All rate-and equilibrium measurements pertaining to Scheme 1 and eqn.(6) were made at 25°C and constant ionic strength of 0.2 M maintained with KCl.Dilute hydrochloric acid solutions, various buffer solutions and dilute sodium hydroxide solutions were used to cover a pH range of 0.8-13.All pH values were measured relative to the standard state in pure water.Accordingly, the relation [H + ] = 10 -pH / γ ± holds with γ ± being the mean activity coefficient in 0.2 M KCl (γ ± = 0.75 at 25°C). 23 (K a ) Using dilute HCl solutions, as well as formic acid buffers, the pK a value associated with the σ-complexation of 4 (λ max = 412 nm, ε = 7,670 M -1 cm -1 ) according to eqn.(4) was determined from the observed absorbance variations at λ max of the resulting adduct C-4 (λ max = 395 nm, ε = 31,700 M -1 cm -1 ) obtained at equilibrium as a function of pH. 24These actually describe a clear acid-base type of equilibration, as evidenced by the observation of a good straight line with unit slope, fitting eqn.(7).From this plot (not shown), we readily obtained: pK a = 2.95±0.05 at (7)   Going to dilute sodium hydroxide solution (pH ≥ 11) resulted in a new set of absorption spectra characterized by the existence of two clear isosbestic points at λ = 360 and 417 nm (Figure 1).As will be considered in the discussion, there is no doubt that these reversible spectral variations are consistent with a fast conversion of the adduct C-4 into the dianion D-4 (λ max = 395 nm, ε = 26,000 M -1 cm -1 ) according to eqn.(6).From the analysis of the pH dependence of the absorbance changes at equilibrium, the interconversion of the two species was found to obey eqn.(8), leading to pK a = 12.03±0.05at I = 0.The kinetics of formation and decomposition of the adduct C-4 according to the two pathways of equations ( 4) and ( 5) were studied in the pH range 0.8-13 by stopped-flow spectrophotometry.All rate measurements were carried out under pseudo-first-order conditions with a substrate or adduct concentration of 2-3×10 -5 M. In agreement with the competitive but direct kinetic approaches described by equations ( 4) and ( 5), only one relaxation time corresponding to the formation (pH > pK a ) -or decomposition (pH < pK a ) -of the adduct C-4 was observed.The variations in the first-order rate constant, k obsd , for the combined processes at 25°C are plotted in Figure 2 as a function of pH.In the experiments where buffer catalysis was observed (vide infra), the k obsd values used to draw the pH -rate profile were those extrapolated to zero buffer concentration.As shown previously in related studies of the covalent hydration of DNBF or various heterocyclic cations, 1a,25 the observed rate constants may be expressed at each pH as the sum of the individual first-order rate constants for formation (k f ) and decomposition (k d ) of C-4 (eqn.( 9)).Thus, values of k f and k d can be readily derived from k obsd through equations ( 10) and ( 11).4) and (5).Least-square fitting of k f and k d to equations ( 12) and ( 13) gave the parameters which are collected together with those for relevant systems, in Table 1.Assuming, as proposed above, that the OH group of C-4 behaves as a normal oxygen acid and ionizes instantaneously in the most basic media, the observed rate constant k obsd is then given by eqn.( 14) at pH ≥ 11.In view of the measured values of k − OH 2 and k -2 , it turns out that the second term of eqn.(14) does not appreciably affect the pH-dependence of k obsd in the pH range 11-13, which is in agreement with the experimental observation.

Buffer catalysis
Regarding our measurements in buffer solutions, no significant catalysis of the interconversion of 4 and C-4 has been observed in buffers of pK a < 7, i.e., the formic acid, acetic acid, cacodylic acid, TES and dihydrogenphosphate buffers-at least at the relatively low total buffer concentrations used in our experiments (< 2.10 -2 M).The situation is exemplified for the acetic acid-acetate buffers in Figure 4.
In contrast, notable base catalysis was observed for formation of the adduct C-4 in 4cyanophenoxide (ArO -), bicarbonate, and carbonate buffers (Table 2).In these three systems, the k obsd data were found to obey eqn.(15) with B = ArO -, HCO 3 -or CO 3

2-
, as illustrated in Figure 5 for the ArO -and HCO 3 -buffers and in Figure 6 for the CO 3 2-buffers.The fact that two parallel linear plots were obtained in plotting k obsd vs. [CO 3 2-] at pH 9.55 and 10.03 revealed that the catalytic contribution of the dianionic species (CO 3

2-
) overcomes that of the monoanionic one (HCO 3 -) in the carbonate buffers.From the slopes of the plots of Figures 5 and 6, the following catalytic rate constants were derived: Table 2. Rate constants for base catalysis of adduct formation.

Discussion
Our study of 4-nitro-6-trifluoromethanesulfonylbenzofuroxan, 4, has revealed a number of interesting features, especially when compared to the known super-electrophile DNBF and the standard electrophile TNB, as well as positively charged structures such as the tropylium cation 5 26 or the isoquinolinium-or naphthyridinium-cations 6 and 7. 25 Salient features can be highlighted under the following headings.Adduct stability: the role of the SO 2 CF 3 group The high susceptibility of an electron-deficient aromatic or heteroaromatic substrate towards covalent addition through water attack has commonly been the major criterion as to whether it may be accorded super-electrophilic properties.In this regard, Table 1 reveals that the pK a value for the conversion of 4 into the C-adduct C-4 is 2.95, as compared with a pK a of 3.75 for the complexation of DNBF.This makes 4 the most neutral electrophilic heteroaromatic known to date, with a considerable increase in electrophilic character of 10.5 pK units from that of the common reference electrophile (TNB) in σ-complex chemistry.Significantly, the thermodynamic susceptibility of 4 to water addition is greater than that of most positively charged activated structures such as 5 (pK a = 4.70), 26 6 (pK a = 5.11) 25c or 7 (pK a = 5.41).25c The fact that substituting the ortho-like 6-NO 2 group for a SO 2 CF 3 group into the carbocyclic ring of DNBF increases the ease of adduct formation is reminiscent of previous findings in the benzene series. 22,27For example, the equilibrium constant for formation of the 1,1-dimethoxy complex C-8 from 2-trifluoromethanesulfonyl-4-nitroanisole is 3 times greater than that for the analogous complex, C-9, from 2,4-dinitroanisole in MeOH-Me 2 SO mixtures having high Me 2 SO content. 28Similar trends have been derived from studies of NO 2 / SO 2 CF 3 exchanges in a para-position. 27This analogy between the benzofuroxan and benzene series contrasts, however, with the situation found to prevail in the σ-complexation of five-membered ring heterocycles.For example, the equilibrium constants for formation of the 1-methoxy adducts C-10 and C-11 are equal to 2.1.10 4M and 6.4.10 4 M, respectively, in methanolic solution.At present, it is difficult to propose a definitive rationale for such a reversal in the relative activating behavior of NO 2 and SO 2 CF 3 groups in σ-complexformation processes.However, it is noteworthy that a similarly contrasting situation has also been reported in the ionization of carbon acids with, in this instance, a clear demonstration that the electron-withdrawing effects of the NO 2 and SO 2 CF 3 substituents are strongly solvent dependent. 29,30It is therefore possible that the primary role is played by the nature of the solvent, rather than the nature of the aromatic ring, in determining the effects of these two substituents on σ-adduct stability, but this explanation needs further support.
The very high electrophilic character of 4 is further demonstrated by the essentially complete formation of the dianion D-4 in a 0.1 M NaOH solution.In fact, the pK a ' value for formation of D-4 from the adduct C-4 (pK a ' = 12.03) is nearly the same as that for formation of the analogous di-adduct from the DNBF complex C-1 (pK a ' = 11.80).1a This makes the situation for these two anionic σ-complexes reminiscent of that observed for the ionization of the OH group of pseudobases derived from the hydration of heterocyclic cations, e.g., pKa' = 11.15 for C-6. 25 Based on the pK a value for ionization of water (pK a = 15.74) the activating inductive -I effect exerted by the negatively charged 4-nitro-6-trifluoromethanesulfonyl-and 4,6-dinitrobenzofuroxan structures of C-4 and C-1 amounts to 5.5-6 pK units.This is considerably more than in the benzene series, where a 2,4,6-trinitrocyclohexadienyl moiety like that of the TNB adduct C-2 is found to exert an activating effect of the order of 1.5-2 pK units on the acidic fragments covalently bonded to the sp 3 carbon. 31,32

Reactivity of 4
Besides the pK a value, the rate constant k O H 2 1 for attack by water is a parameter which is very revealing of the electrophilicity of an aromatic-or heteroaromatic sp 2 -carbon site. 1,18Thus, no water reaction is operative in the formation of the TNB-hydroxy complex C-2. 9 In fact, the evidence is that such a pathway is negligible in the formation of all hydroxy-σ-adducts of pK a ≥ 9, a category which includes adducts such as those of 1,3,6,8-tetranitronaphthalene (pK a = 9.96), 33 1,2,3,5-tetranitrobenzene (pK a = 9.62) 34 or the adduct C-3c of 2-(4-nitrophenyl)-4,6dinitrobenzotriazole 1-oxide (pK a = 9.00).18a Also in the benzotriazole 1-oxide family, only the = 1.13×10 -3 s -1 ) on the parent molecule in a small pH range (pH 7-8).18a The only remarkable situation is in the formation of the DNBF adduct C-1 which arises exclusively from the addition of water between pH = 3 and 7.5 (k O H 2 1 = 0.035 s -1 ).1a In view of the above results, a remarkable result highlighting the exceptional electrophilic character of 4 is the presence of a long plateau of about 6 pH units in the pH-rate profile shown in Figure 2.This long plateau is really illustrative of the great predominance of the pathway involving water in the formation of the adduct C-4 between pH 3.5 and 8.5.Also, the k O H 2 1 rateconstant associated with this reaction is equal to 0.15 s -1 , as compared with k O H 2 1 = 0.035 s -1 for the hydration of DNBF at T= 25°C.It follows that the former value represents the highest rate ever measured for water addition at a sp 2 carbon of a neutral aromatic or heteroaromatic compound.It also follows that 4 ranks among the most powerful electrophiles known to date.
Interestingly, Table 1 shows that the k O H 2 1 rate constant for hydration of 4 is somewhat lower than the related rate constants for hydration of the aromatic or heteroaromatic cations 5, 6, or 7. 25,26 In these instances, however, the resulting pseudobases C-5, C-6 or C-7 are more prone to decomposition through both uncatalyzed and H + -catalyzed pathways than is the SO 2 CF 3 adduct C-4, or even the DNBF adduct C-1.As a result, these two anionic complexes are thermodynamically more stable than the quoted pseudobases, as discussed above.

Buffer catalysis and isotope effects
Owing to the exalted contribution of the water pathway ) to the σ-complexation of 4, the set of base catalysts involved in the formation of C-4 is restricted to HCO 3 -, 4-cyanophenoxide ion, CO 3 2-and OH -with no possibility of drawing a meaningful Brönsted correlation from the available data (Table 2).A most remarkable feature, however, is the finding that carbonate ions are remarkably efficient catalysts, being only 8 times less reactive than the more basic hydroxide ions.This situation is reminiscent of that observed in the covalent hydration of DNBF.In this instance, an interpretation in terms of nucleophilic catalysis (Scheme 2) was in accord with the fact that the DNBF is known to displace CO 2 from carbonate solutions.1a  3).[42][43][44]     1 associated with the H + -catalyzed decomposition of the adduct C-4 is equal to 0.41.This is in the range of values (0.40-0.70) reported for a number of examples of authentic general acid catalysis, e.g., the hydrolysis of orthoesters and some acetals and ketals. 45eturning to the catalytic mode of action of CO 3 2-in the formation of hydroxy σ-adducts, CO measuring the relative reactivities of OH -and CO 3 2suffers a strong increase with decreasing adduct stability.This ratio is of the order of 8-12 for formation of the two most stable complexes C-4 (pK a = 2.95) and C-1 (pK a = 3.75), and then it increases to 24.5 for the N-picryl benzotriazole adduct C-3a (pK a = 6.70) and to 220 for the N-(4-nitrophenyl) analogue (pK a = 9.00).Such a trend seems to be more consistent with a loss in the ability of CO 3 2-to act as a nucleophilic catalyst rather than with a systematic change in the transition-state structure associated with the mechanism of nucleophilic catalysis.In other words, the nucleophilic pathway of Scheme 2 will only contribute importantly in the hydration of the strongest electrophiles, while the general-base mechanism is the predominant route in the case of electrophiles having pK a ≥ 7.
ISSN 1424-6376 Page 183 © ARKAT USA, Inc Experimental Section Materials 4-Nitro-6-trifluoromethanesulfonylbenzofuroxan, (4).was prepared from 1-chloro-2,6dinitro-4-trifluoromethanesulfonylbenzene by the procedure of Yagupolskii et al., m.p. 180°C (lit.181°C). 46The starting chloro derivative was available from a previous study. 47he adduct C-4 was prepared as a sodium salt as follows: 0.9 equivalent of 5M NaOH was added to a stirred solution of 0.313 g (1 mmole) of 4 in 1 ml of Me 2 SO at room temperature.After one hour, 10 ml of CHCl 3 was added and the solution cooled in an ice bath.When crystals began to deposit, further (5 ml) was added and the mixture stirred for 1h further.Yellow-orange crystals were obtained by filtration, washed (CHCl 3 ), and dried under vacuum to give the sodium salt in essentially quantitative yield.
As with a number of alkali salts of DNBF σ-adducts, 3,5,10,11 the crystals of C-4, Na + decomposed before melting (178°C).Attempts to obtain satisfactory elemental analysis have failed.However, dissolution of the salt in Me 2 SO-d 6 gave 1 H-and 13 C-NMR spectra identical to those recorded in the in situ generation of the adduct in this solvent.

Rate and pK a measurements
Stopped-flow determinations were carried out on an Applied Photophysics Spectrophotometer, with the cell compartment maintained at 25 ± 0.2°C.Other kinetic and pK a measurements were made using a Varian-Cary Spectrophotometer.All kinetic experiments were performed in triplicate under pseudo-first-order conditions with a substrate concentration of (2-3)10 -5 M. All rate constants are considered to be accurate to ± 3%.

Figure 2 .
Figure 2. pH dependence of k obsd (s -1 ) for the formation and decomposition of the adduct C-4 in aqueous solution (T = 25°C; I = 0.2 M).

Figure 3 .
Figure 3. pH-rate profiles of the rate constants k f (s -1 ) and k d (s -1 ) for the formation and decomposition of the adduct C-4 in aqueous solution (T = 25°C; I = 0.2 M).

Figure 4 .Figure 5 .Figure 6 .
Figure 4. Plot showing the constancy of k obsd in acetate buffers at various pH 4.40 and 4.70 in aqueous solution (T = 25°C; I = 0.2 M). 22b adduct C-3a is sufficiently stable to form predominantly through attack by water (

Table 1 .
Kinetic and thermodynamic parameters for formation and decomposition of hydroxy σadducts and relevant pseudobases in aqueous solution a

Table 3 .
Deuterium Isotope Effects for Formation and Decomposition of the hydroxy σ-Adducts

Table 3
reveals that the observed solvent isotope effects for water addition to 4 (k O = 1.67) are also very similar.As elaborated in detail earlier,1a,18asuch solvent isotope effects are too large to be consistent with a transition state which would not involve a rate-limiting proton transfer.This in turn favors a transition state structure of type 13 with a second water molecule acting as a base catalyst.In agreement with this proposal, the isotope effect k + − H 1 /k + − D

Table 2
reveals that the ratio k