Investigations into the Mechanism of Solvolysis of 3-aryloxybenzisothiazoles †

The solvolysis of selected 3-aryloxybenzisothiazoles (6a−c; Figure 1) in alcohols has been theoretically investigated. The geometries of ethers 6a−c were fully optimized at the DFT(O3LYP) level, with the 6-31++G(d,p) and 6-311++G(3df,3pd) basis sets. Calculations including solvation effects were performed with the 6-31++G(d,p) basis set. Overall, theoretical values for bond lengths and angles around the central ether linkage in ethers 6a−c are very close, for the isolated molecule and in methanol, and are also very close to those obtained by X-ray crystallography, revealing that the nature of the substituent on the aryl system has a negligible effect on geometric parameters around the ether linkage. The same applies to charge distributions, predicted using the NPA approach. However, measured rate constants for the solvolysis of the same compounds in alcohols show that the rate is affected by the electron-withdrawing/donating characteristics of the substituent on the aryl ring and by the polarity of solvent. Two general pathways were considered for the solvolysis of ethers 6: associative (addition-elimination) or dissociative (fragmentation-recombination) mechanisms. Molecular orbital calculations by means of polarized continuum model (PCM) reaction field predicted that solvolysis of ethers 6 prefers an addition-elimination mechanism. Calculations show also that a dissociative mechanism for the solvolysis of ethers 6a−c is energetically much more demanding than its addition-elimination counterpart and is therefore a highly improbable pathway for the solvolysis. In addition, it was found that the putative cation intermediate formed during a dissociative process should easily convert into its 2-cyanobenzenesulfone cation isomer, via cleavage of the S−N bond.


INTRODUCTION
Benzisothiazoles, also known as saccharins, are heterocyclic compounds with many relevant applications.The parent compound, saccharin (1,2-benzisothiazol-3(2H)-one1,1-dioxide), 1 is a commonly known substance and the oldest artificial sweetener. 2Moreover, saccharin and its anion, saccharinate, act as ligands in coordination chemistry 3,4 and have recently been considered for the formulation of amide-based ionic liquids. 5−8 Some saccharyl derivatives show biological activity, such as herbicidal, 9,10 antimicrobial and antifungal, 11−14 potential in enzymatic inhibition 15 or anti-HIV-1 activity. 16enzisothiazoles are also relevant in organic and bioorganic synthesis.−19 Addi- tionally, benzisothiazoles are structurally very challenging and belong to a group of heterocycles that play a major role in the design of synthetic methods.−25 Reduction of the C−OH bond in the alcohol is achieved after etherification of the hydroxyl group (3a,b; Scheme 1).Derivatization weakens the C−O bond of the original alcohol, so that addition during catalytic transfer hydrogenolysis occurs selectively across this longer bond.−28 The side products, tetrazolone 29 5a or saccharin 1 5b, are watersoluble and the catalyst is easily filtered off and may be re-used.
Ground state structural features are often used for predicting and interpreting the outcome of reactions. 30,31he effect of the heterocyclic part on the C−O bond strength in aryl, 32 naphthyl, 32 allyl, 33,34 benzyl 24,35 and naphthylmethyl ethers 25 has been assessed through structural analysis obtained by X-ray crystallography.Reported crystal structures for aryloxy-and naphthoxy-tetrazoles and benzisothiazoles 32 reveal that the central ether linkage (3; Scheme 1) is much shorter on the saccharyl or tetrazolyl ether side (C−O b around 132 pm) than on the aryl or naphthyl side (O−C a around 143 pm), with C−O−C bond angles around 117º.As may be deduced from crystallographic analysis, in these heteroaromatic ethers the ether oxygen appears to show an sp 2 hybridization 32 and is strongly conjugated with the saccharyl or tetrazolyl ring system but not with that of phenyl or naphthyl substituents.The X-ray analyses also show that the plane of the naphthyl or aryl ring is at right angles to that of the saccharyl system.If O conjugates with the carbon atom of the heteroaromatic system through an sp 2 hybrid, then it cannot also conjugate with the aromatic carbon.Indeed, in these molecules the O−Ca bond is much closer in strength to an aliphatic C−O bond than in the original phenols or naphthols.This change in structure upon derivatization, instrumental for success in transfer ipso-replacement reactions, 32 can be ascribed to the saccharyl and the tetrazolyl systems which, together with oxygen, act as excellent leaving groups.
In view of the structural features described, it appeared important to assess the stability of saccharyl ethers in solution, especially when the solvent can act as a nucleophile.For nucleophilic attack on the same aryl ethers, the carbon atom of the C−O−C moiety that lies in the heteroaromatic system (C 3 , Scheme 2) is expected to be more susceptible than the other C-atom in the ether linkage (C 5 , Scheme 2), because it is more positively charged.In previous work 35 3-(4-nitrophenoxy) 1,2-benzisothiazole1,1-dioxide and 3-(4-methoxyphenoxy) 1,2-benzisothiazole 1,1-dioxide (6, Z = 4-NO 2 and 4-CH 3 O, respectively) were refluxed with ethanol.The aryl saccharyl ether bearing the electronwithdrawing nitro group was readily converted into ethyl saccharyl ether 7, but the ether with the electrondonating methoxy group was found to be unreactive towards solvolysis, even when refluxed for extended periods of time.It may be argued that, for the 4nitrophenoxy derivative, the ether bond is labile because it suffers the influence of the electron withdrawing 4-nitrophenyl and of the electron deficient heteroaromatic saccharyl ring.Similar behaviour was observed for 2,6-dinitrophenyltriflate 36 and 2,6dinitrophenyltosylate. 37Likewise, for 3-(4-methoxyphenoxy) 1,2-benzisothiazole 1,1-dioxide, the electron-donating 4-methoxyphenyl would offset partly the electron-withdrawing effect of the saccharyl ring.It could be hypothesized that the charge density at C 3 would be higher in this ether than in 3-(4-nitrophenoxy) 1,2-benzisothiazole 1,1-dioxide, making the nucleophilic substitution much more difficult for the former than for the latter.
The preliminary results described by Johnstone 35 prompted us to further investigate the mechanism of solvolysis of aryloxybenzisothiazoles 6. Kinetic studies were conducted for a library of ethers 6 in different alcohols (Scheme 2). 36Results of these studies have consistently shown that the rate of solvolysis is highly dependent on the substitution pattern and nature of the substituent on the aryl ring.Electron-withdrawing groups Z were found to increase the rate while electrondonating groups were found to decrease it.The rate of solvolysis was also found to increase substantially with increasing dielectric constant of the solvent. 36onsidering that bond lengths are related to reactivity and electronegativity, 30,31 differences in the relative ether bond lengths for ethers 6 (R = 4-NO 2 and R = 4-CH 3 O) could also be hypothesized.However, analysis of reported bond lengths and angles for these ethers, obtained by X-ray crystallography, shows that the ether bond lengths C 3 −O 4 and O 4 −C 5 are 133.5 and 141.7, and 133.1 and 142.4 pm respectively, revealing no significant difference with the electronic nature of the substituent on the aryl ring, in the crystal. 35Thus, the opposite electronic effects of nitro and methoxy substituents have no opposed effect on the C 3 −O 4 −C 5 bond lengths, and the explanation for different chemical behaviour in solvolysis of these ethers cannot be found in groundstate electronic features in the crystal.However, electronic features for the same compounds in solution or in the gas-phase can vary substantially from those ob-served in solid state and the changes may translate in different reactivity.
We now describe results of a theoretical study on the solvolysis of ethers 6 in alcohols, aimed at complementing our data from kinetic studies and Linear Free Energy Relationship analysis.An addition/elimination mechanism is proposed.

EXPERIMENTAL
All the calculations were performed with the Gaussian 09 program package.Functionals and basis sets were applied as defined in Gaussian. 38The quantum chemical calculations were performed at the DFT level of theory using either the valence double-ζ polarized 6-31++G(d,p) or the extended valence triple-ζ polarized 6-311++G(3df,3pd) basis set 39−43 and the O3LYP 44 functional.−47 This requirement results essentially from the presence in the molecules of hypervalent S atoms, as indicated by the strong improvement of the calculated vibrational data for the >SO 2 stretching and bending modes (compared to other vibrations) upon inclusion in the basis set of diffusion and polarization functions. 47,48−49 In the present study, geometries were optimized using the Direct Inversion in the Iterative Subspace (DIIS) method. 50Vibrational frequencies were calculated at the same level of theory and the nature of the stationary points on the potential energy surface (PES) resulting from optimization was determined by inspection of the corresponding calculated Hessian matrix.Absence of imaginary frequencies indicated that they correspond to true minima.This also enabled the determination of thermodynamic quantities such as zeropoint-corrected vibrational energy and free energy at 298.15 K.The charge distribution has been analyzed using the Natural Population Analysis (NPA) performed at the optimized geometries obtained at the DFT/O3LYP level. 51Solvation effects were included through the use of the polarizable continuum model (PCM), using the integral formalism variant (IEFPCM), as implemented in Gaussian 09, and the internal parameters defined for the used solvents. 52,53Geometry optimization calculations with solvation effects included were done at the O3LYP/6-31++G(d,p) level, using the optimized gas-phase geometries obtained at this level as starting geometries.

RESULTS AND DISCUSSION
The solvolysis of ethers 6 in alcohols was investigated theoretically.Because X-ray data are available for ethers 6 (Z = NO 2 , OCH 3 ), 35 these were chosen for our study, allowing for results of the calculations to be compared with those obtained for the condensed state.

Molecular Geometry and Charge Density Analysis of the Studied Aryl Saccharyl Ethers
The ethers investigated (6;Z = H, NO 2 , OCH 3 ) have two (Z = H) and three (Z = NO 2 , OCH 3 ) intramolecular rotational degrees of freedom, represented by arrows in Figure 1, that may result in different conformers.These are related with: (i) the relative orientation of the saccharyl and aryl rings (dihedral angles A and B; for dihedral A, only the zusammen (Z) orientation was considered, since conformations where the aryl ring is directed to the phenyl group of the saccharin moiety are expected to correspond to structures of high energy, due to hindrance); (ii) the relative orientation of the substituent and the aryl ring (dihedral angle C).
The O3LYP/6-311++G(3df,3pd) fully optimized geometries of the global minimum of the studied molecules are presented in Figure 2. In all these structures, the C−O−C ether linkage was found to stay nearly in the plane of the saccharyl moiety.For the unsubstituted phenoxysaccharin (6a; Z = H), the potential energy profile for internal rotation around the dihedral angle B calculated at the O3LYP/6-31++G(d,p) level revealed that in the global minimum conformation the B dihedral is −92º, i.e., the phenyl substituent is nearly perpendicular to the plane of the heterocycle.In case of the two phenyl-substituted compounds (6b and 6c), the calculations also predicted the phenyl and saccharyl planes as being nearly perpendicular to each other, while the phenyl substituents (4-OCH 3 and 4-NO 2 ) stay approximately aligned with the plane of the aromatic ring.For 4-methoxyphenoxysaccharin (6b; Z = 4-OCH 3 ), the potential energy surface has its global minimum for the conformation where dihedral B is −95º and dihedral C is −179º.For 4-nitrophenoxysaccharin (6c; Z = 4-NO 2 ), the global minimum conformation was predicted to correspond to the structure where dihedral B is 119º and dihedral C is −180º.
Table 1 shows selected bond lengths and angles around the central ether linkage and dihedral angles for aryloxysaccharins 6 investigated, obtained from calculations with the 6-311++G(3df,3pd) and 6-31++G(d,p) basis sets.Structure calculations were also performed in methanol, at the O3LYP/6-31++G(d,p)level, using a Polarizable Continuum Model (PCM).The corresponding parameters determined by X-ray crystallography, available for 4-methoxyphenylsaccharin 6b and 4nitrophenylsaccharin 6c, are also included in the Table 1.For both aryloxysaccharins 6b and 6c, the calculated lengths for O , also similar to those obtained in the crystals, and are indicative of a significant degree of sp 2 character on oxygen.The values obtained theoretically for the geometric parameters of the central ether linkage in the 3 studied molecules are also very similar for the isolated molecule (for both basis sets) and in methanol (see Table 1).Overall, the results reveal that the electronic nature of the substituent on the aryl system has very little or no effect on geometric parameters of the ether linkage, even in methanol.Nevertheless, the calculations show that for the nitro-substituted phenoxysaccharin 6c the relative orientation of the aryl ring to the saccharyl system changes somewhat in methanol, with the dihedral angle B varying from around 120º (as found theoretically for the isolated molecule and in the crystalline phase) to about 95º, a value more similar to those calculated for the isolated molecule or observed in the crystalline phase in compounds 6a and 6b.Thus, for the most polar ether, the polar solvent induces a significant change in the relative orientation of the two rings, while keeping the structure of the C−O−C linkage practically unaltered.
The charge distribution for aryloxysaccharins 6a−c, has been analyzed using the Natural Population Analysis (NPA).Atomic charges for sulfur S 1 , nitrogen  S3 (Supporting Information).
N 2 , carbons C 3 , C 5 and oxygen O 4 , and the dipole moments for the molecules, are included in Table 2 (see Figure 1 for atom numbering).The most electronegative natural charges are accumulated on the nitrogen N 2 from the saccharin moiety (−0.7e) and on the oxygen O 4 from the ether bridge (−0.4e).As expected, the most electropositive atom is carbon C 3 , suffering from the electronwithdrawing effect of both the saccharyl ring and the ether oxygen.Comparing relative charges in those atoms for compounds 6a, 6b and 6c, we can see that the electronic nature of the substituent has little or no effect on charge at carbon C 3 .However, as expected, substituent effects are significant on carbon C 5 of the aryl ring.The electron donating 4-methoxyphenyl group on 6b raises the charge density in carbon C 5 , compared to the unsubstituted ether 6a, while the electron withdrawing 4-nitrophenyl group in 6c lowers the charge density of the same carbon C 5 .
In order to gather more information regarding the effect of solvent in the solvolysis mechanisms for each compound, quantum chemical calculations were performed for the compound in methanol, using the PCM method, at the DFT(O3LYP)/6-31++G(d,p) level of theory.The atomic charges calculated in methanol follow the trends observed for the isolated molecules, but a higher dipole moment is predicted, induced by the polar solvent (Table 2).The relative energies obtained in methanol are presented in Table 3.The values of ∆Hº, relative to the heat of dissolution, are relatively constant for all three compounds.The average value is 50.58 kJ a See Figure 1 for schematic drawings and atom numbering.Atomic charges (q) are in units of electron; Dipole moment |µ| in Debye.
mol −1 , with a standard deviation of 5.60 kJ mol −1 .In general, the trends observed in the thermodynamic data for the compounds in methanol are very similar to those calculated for the gas-phase even though, in reactions involving protic solvents, hydrogen bonds are expected to play an important role in thermodynamic parameters and mechanisms involved, but akin in all three molecules investigated.

Effect of solvents with different dielectic constant
The geometry of phenoxysaccharin 6a was optimized in 5 different alcohols.Table 4 presents the effects of solvent polarity on the energy of 6a in the ground state.As it can be seen in Table 4, the energy of compound 6a in alcohols decreases consistently as the dielectric constant of the solvent increases.This stabilizing effect of the solvent polarity is in fact expected to be even stronger for compound 6c, due the higher relative polarity of this compound.Results from kinetic studies have shown that the rate of solvolysis for these ethers increases consistently with increasing the dielectric constant of the solvent. 36

Mechanism of Solvolysis
Two general mechanistic pathways for the solvolysis of aryloxybenzisothiazoles 6 were considered, paths a (i), and b (ii), involving associative or dissociative mechanisms.The two possibilities are schematically represented in Figure 3, using a diagram adapted from the More O'Ferrall-Jencks representation.tained through O3LYP/6-31++G(d,p) molecular orbital calculations (Tables 1 and 2) show a C 3 −O 4 bond length of around 133 pm and an electronic density at the heteroaromatic carbon C 3 of about (0.59e).Cleavage of this bond is expected to require a very high energy of activation and would also be thermochemically disfavored, since it would lead to the formation of a formal positive charge on a carbon that already exhibits a high partially positive charge in the original ether.To obtain information regarding the energy profiles for both pathways, the energies of the major species involved were calculated.For simplicity and atom economy, we considered methanol as the nucleophile.For pathway a, calculations were carried out for ethers 6a−c.For pathway b, only compound 6a was considered.Results obtained are presented in Figures 4 and 5.As described below, the performed molecular orbital calculations by means of polarized continuum model reaction field predicted that the solvolysis prefers an addition-elimination mechanism.
As proposed in Figure 3 pathway a proceeds through a zwitterionic (ZW) structure that may develop to a neutral intermediate.Both the performed calculations in vacuo and in methanol showed that the ZW intermediate is unstable, with no minimum found for this species in the calculated PES, while the neutral intermediate, which results from nucleophilic addition and proton transfer, was found to be a minimum (in solution, the protic solvent molecules participate in the   5.In all calculations, the relative zero level of energy was chosen to be the energy of each aryoxysaccharin 6a-c plus the nucleophile (methanol) in gas phase.Solvent stabilization effects were evaluated by using the PCM approach with the Integral Formalism variant (IEFPCM).
Croat.Chem.Acta 87 (2014) 363.proton exchange).−60 This type of calculations for the present systems is, however, beyond pratical limitations.Thus, in the following discussion, we explored mechanism a considering the neutral intermediate.
In order to examine the effect of substituent on ground state energies of reagents, products and the intermediate formed upon addition of nucleophile, calculations on the gas-phase and in methanol were per-formed on the different systems under study.Table 5 presents the relative energies of species corresponding to the most stable stationary points for the additionelimination mechanism (pathway a) and the dissociative-associative mechanism (pathway b) of the aryloxysaccharins 6a−c, with the formation of methoxysaccharin 7, in gas-phase and in methanol, calculated at the DFT(O3LYP)/6-31++G(d,p) level of theory.For a schematic representation, Figure 4 presents a diagram of the relative energies of species corresponding to the most stable stationary points for the additionelimination mechanism, pathway a.
Aryloxysaccharins 6a−c and the nucleophile methanol, in gas-phase or methanol, were chosen to be the relative zero level of energy.The relative energies of the structures corresponding to the most stable stationary points for the addition-elimination mechanism (pathway a) show that the energy for the neutral intermediates from the 3 ethers in the gas phase, is very close, ranging from 71 kJ mol −1 in 6c to 77 kJ mol −1 in 6a.Thus, the nature of the substituent has a negligible effect on the relative energy of said intermediates, in the gas phase.However, substituent effects appear to be more pronounced for the products, where calculated energies vary from −46 kJ mol −1 , for products resulting from 6c, to −28 kJ mol −1 , for products resulting from 6b.Thus, the products from the nitro derivative 6c are calculated to be more stable (by 18 kJ mol −1 ) than those from the methoxy derivative 6b (Table 5).
As shown in Table 5, relative energies in methanol are consistently smaller than in the gas-phase, by ca.60 kJmol −1 , for reagents and products, and by ca.45 kJ mol −1 for the neutral intermediates (see also Figure 4).Additionally, data presented in Table 5 shows that the effect of solvent polarity is more pronounced on the  31++G(d,p) level of theory.Solvent stabilization effects were evaluated by using the PCM approach with the Integral Formalism Variant (IEFPCM).
Table 5.Relative energies (∆Gº; kJ mol −1 ) of the structures corresponding to the most stable stationary points for the additionelimination mechanism (pathway a) and the dissociative-associative mechanism (pathway b) of the aryloxysaccharins 6a-c, with the formation of methoxysaccharin 7, in gas-phase and in methanol as solvent, calculated at the DFT (O3LYP)/ 6 a Schematic representation of reagents, intermediates and products for each pathway mechanism are presented in a More O'Ferral-Jencks-type diagram shown in Figure 3.For the dissociative-associative mechanism only compound 6a was considered.The relative zero level of energy was chosen to be the energy of each aryloxysaccharin 6a-c plus the nucleophile (methanol) in gasphase or methanol respectively.Values in parenthesis correspond to the relative energy in methanol calculated with respect to the corresponding aryloxysaccharin 6a-c plus the nucleophile in the gas-phase.Solvent stabilization effects were evaluated by using the PCM approach with the Integral Formalism variant (IEFPCM).
reactants than on corresponding intermediates.Regarding substituent effects in methanol, the relative energy of intermediates ranges from 86 kJ mol −1 , for 6c, to 95 kJ mol −1 , for 6a, showing a stabilizing effect of the nitro substituent corresponding to about 9 kJ mol −1 .The relative energy of products from ethers 6a−c in methanol ranges from −49 kJ mol −1 , for 6c, to −29 kJ mol −1 , for 6b, showing that the products from the nitro derivative 6c are calculated to be more stable (by 20 kJ mol −1 ) than those from the methoxy derivative 6b.Thus, the substituents induce similar effects on the energy of intermediates and products, in the gas phase and in methanol.
For pathway b, only compound 6a was considered for the theoretical investigation.It is established that the energetic demand of the two processes is determined by the reaction barrier for each process. 61,62Many efforts were made to determine reaction barriers.Theoretical calculations of the TS were found to be a true challenge.Unfortunately, the calculated activation barriers in vacuum were too high, and no convergence was achieved.However, considering the large energy difference of the intermediates in pathways a, and b, it appears reasonable to assume that the energy barriers in processes a and b must indeed be quite different, with the energy barrier associated to process b being much larger (see Figures 4  and 5 and Table 5 for values).The energies calculated for the intermediates associated to pathway b, in gasphase and in methanol, are 642.03kJ mol −1 and 202.59 kJ mol −1 , respectively, much higher than those associated to pathway a, thus making pathway b a highly im-probable route for the solvolysis.Also, the calculations showed that the putative saccharyl iminium cation 10 formed from the dissociative process leads to a product resulting from cleavage of the S−N bond, the 2cyanobenzene sulfone cation 12 (see Figure 6), in a barrierless process.A similar ring-opening reaction has been predicted for deprotonated isosaccharin. 1Isosaccharin is formed from saccharin, through light-induced isomerisation. 1

CONCLUSION
The solvolysis of aryloxybenzisothiazoles 6a−c (Figure 3) has been theoretically investigated in different alcohols.The geometries of the investigated ethers were fully optimized at the DFT(O3LYP) level of theory, with the 6-31++G(d,p) and 6-311++G(3df,3pd) basis sets.Calculations including solvation effects were performed with the 6-31++G(d,p) basis set.Overall, values obtained theoretically for the central ether linkage in all studied aryloxysacharins are very close, for the isolated molecule, in both basis sets, and in methanol.Furthermore, theoretical values are also very close to those obtained by X-ray crystallography, revealing that the electronic nature of the substituent on the aryl system has very little or no effect on geometric parameters of the ether linkage.The charge distributions predicted using the NPA approach for the studied compounds also show that the electronic nature of the substituent has little or no effect on the charge of the carbon atom of the C−O−C moiety that lies in the heteroaromatic system.However, measured rate constants for the solvolysis of compounds 6a−c in methanol, at 40ºC, are 3.84 x 10 −4 s −1 for ether 6a, 0.91 x 10 −4 s −1 for ether 6b and 19.9 x 10 −4 s −1 for ether 6c, 36 showing that the rate of solvolysis is affected by the electron-withdrawing/-donating characteristics of the substituent on the aryl ring.Thus, an explanation for observed differences in rate constants for compounds 6a−c cannot be rationalized by geometric parameters of the ether linkage or by charge distributions in the ground state of reactants.
Two general mechanistic pathways for the solvolysis of aryloxybenzisothiazoles were considered, involving associative or dissociative mechanisms.Molecular orbital calculations by means of polarized continuum model (PCM) reaction field predicted that solvolysis through the addition-elimination mechanism is preferred.We propose a mechanism whereby initial addition of nucleophile to carbon C 3 of the saccharyl system leads to an unstable zwitterionic structure that develops to a neutral intermediate.Comparing the corresponding relative energies for the intermediates and products from the studied compounds, we concluded that the electron donating methoxy substituent induces a minor change in the relative energies, while the electron with-      Color codes: light yellow -C, blue -H, red -O, pink -N, dark yellow -S; Chemcraft software (http://www.chemcraftprog.com)was used to produce structures shown in Table S1 and Table S2.

Figure 1 .
Figure 1.Structure of aryloxysaccharins 6 investigated.The atom numbering adopted is shown.Arrows A, B, C relate to conformationally relevant degrees of freedom.A represents the dihedral angle defined as N2C3−O4C5 and B represents the dihedral angle defined as C3O4−C5C6.Dihedral C is not considered for phenoxysaccharin 6a (X=H); for 4-methoxyphenoxysaccharin 6b, C represents the dihedral angle defined as C7C8−O9C10 and for 4-nitrophoenoxysaccharin 6c, C represents the dihedral angle defined as C7C8−N9O10.
4 −C 5 (a) and C 3 −O 4 (b) bonds are around 140 pm and 133 pm, respectively, similar to those observed in the crystalline state (ca.142 and 133 pm).Calculated values for the C−O−C angle are close to 120º

Figure 4 .
Figure 4. Energy diagram with structures corresponding to the most stable stationary points for solvolysis of aryloxysaccharins 6a-c, with the formation of methoxysaccharin 7, considering an addition-elimination mechanism, in gas phase and in methanol, calculated at the DFT(O3LYP)/6-31++G(d,p) level of theory.The relative energies (∆EG298) are presented in Table5.In all calculations, the relative zero level of energy was chosen to be the energy of each aryoxysaccharin 6a-c plus the nucleophile (methanol) in gas phase.Solvent stabilization effects were evaluated by using the PCM approach with the Integral Formalism variant (IEFPCM).

Figure 5 .
Figure 5. Relative energies of the structures corresponding to the most stable stationary points for the dissociativeassociative mechanism of the aryloxysaccharine 6a, with the formation of methoxysaccharin 7 and phenol 8a, in vacuum and in methanol, calculated at the DFT(O3LYP)/6-31++G(d,p) level of theory.Solvent stabilization effects were evaluated by using the PCM approach with the Integral Formalism Variant (IEFPCM).

Figure 6 .
Figure 6.Potential energy profile showing the convergence in energy during optimization of the putative saccharyliminium 10 (formed from cleavage of the C−O bond of 6a, leading to aryloxy group and a putative saccharylcation), that rearranges to 2-cyanobenzene sulfone 12, through a cleavage of the S−N bond.Calculations performed at the DFT(O3LYP)/6-311++G(3df,3pd) level.

Table S1 .
Structure of the aryloxysaccharins investigated, optimized at the O3LYP/6-31++G(d,p) level of theory, with Cartesian coordinates and NPA charges.*

Table S3 .
Calculated Cartesian coordinates (Å) for each of the considered structures