Evaluation of Electronic Effects in the Solvolyses of p-Methylphenyl and p-Chlorophenyl Chlorothionoformate Esters

e solvolyses of p-tolyl chlorothionoformate and p-chlorophenyl chlorothionoformate are studied in a variety of organic mixtures of widely varying nucleophilicity and ionizing power values. is solvolytic data is accumulated at 25.0C using the titration method. An analysis of the rate data using the extended (two-term) Grunwald-Winstein equation and the concept of similarity of substrates based on their l/m ratios shows the occurrence of simultaneous side-by-side addition-elimination and unimolecular SNN1 mechanisms.


Introduction
Chlorothionoformate esters are useful as derivatizing agents [1] and common organic building blocks in the synthesis of commercial thiocarbonate esters, nitriles, and isonitriles [2,3].High fungicidal activity was demonstrated [4] for the p-substituted aryl thiocarbamate analogs which are also cytotoxic [5].
Lee at al. [7][8][9] expanded on Queen's MeOCSCl and PhOCSCl mechanistic work to include in their study the substrates ethanolyses, methanolyses, and solvolyses in water, aqueous ethanol, and aqueous acetone.ey then proposed that MeSCOCl [7,8] had   1 character in the water-rich solvents and a greater   2 character in the more organic mixtures.For PhOCSCl, Koo and others [9] also suggested a general base catalyzed   2 mechanism in the aqueous binary mixtures of ethanol (EtOH), methanol (MeOH), and acetone.
On the basis of large negative cross-interaction coef-�cients obtained for the aminolysis of substituted aryl chlorothionoformates with substituted anilines in acetonitrile, Oh et al. [10] proposed a concerted mechanism with a four-membered hydrogen-bonded cyclic transition state.On the other hand, Castro and coworkers [11][12][13][14][15][16] proposed that the aminolysis of chlorothionoformates using pyridine, alicyclic, and bicyclic amines is a stepwise process with the formation of a zwitterionic tetrahedral intermediate while their phenolysis [17] is concerted.
In a recently summarized [18] and ongoing solvolytic mechanistic study of nucleophilic substitution in chloroformate (ROCOCl), chlorothioformate (RSCOCl), chlorothionoformate (ROCSCl), and chlorodithioformate (RSCSCl) esters, we have successfully correlated their solvolytic rate coefficients in a series of binary aqueous organic mixtures of varying solvent nucleophilicity (  ) [19,20]  power ( Cl ) [21][22][23] values using the extended (two-term) Grunwald-Winstein (G-W) equation ( 1) [24]: In ( 1),  and   are the speci�c rates of solvolysis of a substrate in a given solvent and the standard solvent (80% ethanol), respectively, l is the sensitivity to changes in solvent nucleophilicity (N), m represents the sensitivity that controls the importance of the solvent ionizing power value (Y), and c is a constant (residual) term.
A thorough Grunwald-Winstein analysis in 49 solvents yielded an l value of 1.66, and an m value of 0.56 for phenyl chloroformate (PhOCOCl, 2) [25,26].e l/m ratio of 2.96 obtained was advanced as being characteristic for a stepwise addition-elimination (A-E) process that is associated with the formation of a rate-determining tetrahedral intermediate [26].For phenyl chlorodithionoformate (PhSCSCl, 3), we obtained  = ,  = , and  =  and proposed a unimolecular   1 ionization with strong rearside nucleophilic solvation of the developing dithioacylium cation [26,27].We further recommended [18] that the l and m values for 2 and 3 can be taken as typical values for bimolecular addition-elimination (A-E) and unimolecular ionization (S  1) mechanisms occurring in alkyl and aryl ROCOCl substrates, including those where sulfur is substituted for one or both oxygens.
Drawing upon extensive literature data and using (1) for benzoyl chloride (PhCOCl), we obtained [44]  = ,  = , and  =  in the less ionizing solvents, and  = ,  = , and  =  in the highly ionizing aqueousorganic mixtures.Recently, Bentley and Koo, Bentley and Harris [45,46] provided convincing evidence that concurrent interchange mechanisms involving one dissociative and one an associative pathway do indeed occur in the solvolyses of p-substituted benzoyl chlorides.
Like many other ROCOCl substrates, benzyl chloroformate (PhCH  OCOCl) proceeds through a stepwise A-E process in all of the typical aqueous organic solvents except in the aqueous �uoroalcohols where a solvolysis-decomposition type mechanism with loss carbon dioxide is dominant [48].
Choi et al. [49] showed that phenyl �uorothionoformate (5) solvolyses by a bimolecular pathway in all solvents (including the �uoroalcohols) studied with the addition step of the addition-elimination reaction being rate-determining.ey obtained an l value of 1.32, an m value of 0.39, an l/m ratio of 3.38, a solvent deuterium isotope effect value for methanolysis ( MeOH / MeOD ) of 2.11, and entropies of activation in the range of −26.2 to −21.0 cal mol − K − .
An analysis of the solvolytic data for p-�uorophenyl chlorothionoformate (8) using (1) recently con�rmed dual mechanistic channels (Schemes 1 and 2) occurring in the ��een binary aqueous organic solvents studied at 35.0 ∘ C and these pathways were shown to be highly dependent on the solvents ionizing ability [40].

Results and Discussion
e �rst-order speci�c rates of solvolysis of 6 and 7 at 25.0 ∘ C in pure and aqueous organic mixtures of widely varying nucleophilicity (  ) and ionizing power values ( Cl ) are reported in Table 1.In 6 and 7, there is a gradual rate increase that coincides with the increase of water content in the aqueous-organic mixtures (with increasing  Cl values).On the other hand, in the strongly hydrogen-bonding aqueous-HFIP mixtures, the �rst-order speci�c rates for 6 and 7 decrease with increasing water content (and increasing   and decreasing  Cl values).One can also observe that 7 is approximately 10-fold faster than 6 in the aqueous ethanol solvents and 2-to 3-fold faster in the aqueous methanol and acetone mixtures, but this situation is reversed with 6 being the faster in the aqueous �uoroalcohol (TFE and HFIP) mixtures.
A comparison of just the p-substituted aryl chlorothionoformate ethanolysis rate exhibits a rate order of  7 >  8 >  1 >  6 .ese observations are consistent with the Hammett   values of +0.23, +0.06, and −0.17 [52] for para-Cl, para-F, and para-CH 3 , respectively, with increased electronwithdrawing ability for the substituent favoring the ratedetermining addition of a solvent molecule at the carbonyl carbon.
An addition-elimination mechanism with the addition step rate-determining is favored for phenyl �uorothionoformate (5) in all of the solvents studied at 10.0 ∘ C [49].Using the similarity model concept [29,53], we �rst compared the log (k/ o ) values for p-tolyl chlorothionoformate (6) to those obtained for 5. is plot is shown in Figure 2 for the seventeen common binary solvents studied.is xy-graph results in an abominable correlation coefficient (R) of 0.169, slope of 0.10 ± 0.16, intercept (c) of −0.08 ± 0.21, and F-test of 0.4.A review of the plot shows signi�cant deviation for the 90 HFIP, 70HFIP, and 90 TFE values and a noticeable divergence from the line-of-best �t for the four TFE-EtOH mixtures, especially for the 80T-20E point.Removal of these seven data points does indeed improve the correlation signi�cantly resulting in a R value of 0.973, slope of 1.32±0.11,and   0.22±0.06.is illustrates that, like 5, the A-E mechanism is the dominant pathway for 6 in the ten remaining ethanol, methanol, and binary mixtures of aqueous ethanol, methanol, and acetone.e slope of 1.32 + 0.11 indicates that in these ten solvents there is a much later transition state for addition to 6 when compared to that seen for the solvolyses of 5.
Using the extended Grunwald-Winstein equation ( 1) for all of the twenty speci�c rates of solvolysis of 6 listed in Table 1 leads to a very inferior correlation coefficient (R) of 0.505,   0.33 ± 0.22,   0.34 ± 0.16,   −0.03 ± 0.20, and a very low F-test value of 2.9.For the two-term G-W analyses, these  are unacceptable correlation and F-test values and this could re�ect the presence of concurrent mechanisms.
In Table 2, we report the relevant G-W analyses for substrates 1-8. Figure 2 clearly shows that the highly ionizing common solvents (90 HFIP, 70HFIP, 90 TFE, and 80T-20E) deviate the most in the plot that is presented for log (  ) 6 versus log (  ) 5 .Removal of the three HFIP (97, 90, and 70) values, the three TFE (97, 90, and 80) values, and the 80T-20E rate value, in the G-W analyses of 6, results in a marginal   1,   16 ± 1,   6 ± 1,    ± 12, and a F-test of 17.However, deletion of any additional TFE-EtOH points does not improve the correlation coefficient but the P value (probability value indicating that the results are statistically insigni�cant) for the l term rises and the F-test value decreases substantially.e resulting l/m ratio of 3.54 observed is in line with values observed in the aryl chlorothionoformate substrates 1 (  6) and 8 (  26) for solvents governed by a dissociative A-E mechanism shown in Scheme 1.
For 6, in the seven strongly hydrogen-bonding solvents of 80T-20E, aqueous TFE, and aqueous HFIP, we get an l value of 5 + 1, an m value of 17 + 1, a c value of −225 + 2, an R value of 0.986, and a F-test value of 69, all derived from a G-W analyses using (1) (and listed in Table 2).e l value has an associated P value of 0.03, indicating that the result is statistically signi�cant [54].A large negative c value is observed because the experimental  o value is the one applying to the other reaction channel.For 6 in the ionizing �uoroalchohol mixtures, the l and the m values and the l/m ratio of 0.42 are in the range previously observed for ionization reactions (Scheme 2) for 1 (  7) and 8 (  6).
A plot of log (  ) 6 against 1.63   + 0.46  Cl in the twenty pure and binary solvents studied is shown in Figure 3. e seven �uoroalcohol-containing mixtures (80T-20E; 97, 90, 70, HFIP; 97, 90, 80 TFE) were excluded in the correlation analysis but are added on the plot to show their extent of deviation from the correlation line.In Figure 3, if one carefully scrutinizes the positioning of the 80T-20E data point, one can discern that there may well be some contribution from the A-E pathway in this solvent mixture.Using the equation log (  ) 6 = 1.63   + 0.46  Cl + 0.30, one can estimate the addition-elimination pathway speci�c rate for 6 in 80T-20E to be 6 × 1 −7 s −1 .is would suggest that in 80T-20E there is a 22% contribution from the addition-elimination pathway.
In Figure 4, we show a plot of log (  ) for 4chlorophenyl chlorothionoformate (7) against log (  ) for phenyl �uorothionoformate (5) in the seventeen common pure and binary solvents studied.is linear regression results in an inadequate correlation coefficient on 0.812, slope of 61 + 11, intercept of − ± 16, and an F-test value of 29.It is apparent from Figure 4 that the 90 HFIP and 90 TFE values digress considerably from the correlation line.Excluding these two values leads to a signi�cantly improved   62, slope of 11 ± , intercept of −12 ± , T 2: Correlations of the speci�c rates of solvolysis of 1-8 using the extended Grunwald-  and an F-test value of 160.is analysis promotes the possibility that for 7 in the remaining ��een solvents a similar bimolecular addition-elimination pathway is operative.For 7 using (1) for all of the nineteen solvents listed in Table 1 results in a low correlation coefficient of 0.679 to values with high standard errors associated of    ± ,    ± ,   − ± , and a dismal F-test value of 7. Observing that the 90 HFIP and 90 TFE values deviated signi�cantly in Figure 4, it would be expected that if speci�c rates for solvolysis of 5 had been available the deviations for 97 HFIP and 97 TFE would have been even greater.
Excluding the 97, and 90 HFIP, and 97, and 90 TFE data points in the G-W analyses using (1), we obtain improved   We have used the l/m ratio to suggest earlier and later transition states within otherwise very similar mechanisms and as a useful indicator for the presence of general base catalysis [55,56] in solvolytic reactions of this type [29].e l/m ratios for p-chlorobenzoyl chloride, p-nitrobenzoyl chloride, p-nitrophenyl chloroformate, and p-nitrobenzyl chloroformate of 3.19, 3.29, 3.67, and 3.50 [29,44] are of similar values to those obtained for the aryl chlorothionoformate 1 and 6-8 when they are reacting by the addition-elimination channel.
A plot of log (  ) for 4-chlorophenyl chlorothionoformate (7) against 1.79   + 0.45  Cl in the nineteen pure and binary solvents studied is shown in Figure 5. e six data points for 97, 90, and 50 HFIP and 97, 90, and 50 TFE were excluded from the G-W analyses using (1) but were added to the plot to show their positive deviations from the correlation line.
Aer subtracting out the A-E component in the rates of reaction of 7 that were indicated to be occurring in the seven �uoroalcohol mixtures (97-50 HFIP, 97-50 TFE, and 80T-20E), we can then carry out a correlation of the estimated speci�c rates remaining to get   091,   0  017,   0800,   −00 (large negative value because   is for the A-E pathway), and a F-test value of 10. e l/m ratio of 0.52 is typical for   1 mechanisms seen in acyl halides and of the type shown in Scheme 2.
For the aryl chlorothionoformate esters 1, 6, 7, and 8, the evidence for a change in mechanism from a bimolecular A-E pathway to an ionization (  1) mechanism in the highly ionizing �uoroalcohol mixtures is compelling and occurs even in substrates (7 and 8) that contain electron-withdrawing halogen substituents in the para position.ese observations are consistent with Bentley's G3 calculations that a C=S bond strongly stabilizes the developing carbocation [47].is formation of a cationic transition-state, favored in the highly ionizing solvent mixtures, is in all probability due to sulfur's ability to modify its electron cloud and therefore to be highly polarizable.

Conclusions
e p-tolyl chlorothionoformate (6) and the p-chlorophenyl chlorothionoformate (7) are shown to solvolyze by the generation of concurrent bimolecular stepwise additionelimination and unimolecular ionization (  1) mechanisms.e exact delineation of the change in mechanism is identi-�ed utilizing the concept of substrate similarity based on l/m ratios, and statistical results obtained through the application of the two-term extended Grunwald-Winstein equation (1).
For 6 in the more nucleophilic solvents, we obtain an l value of 1.63, an m value of 0.46, and an l/m ratio of 3.54.For 7 in a similar set of solvents, we obtain an l value of 1.79, an m value of 0.45, and an l/m ratio of 3.98.It is now proposed that in such nucleophilic solvents 6 and 7 undergo an addition-elimination (association-dissociation) process with the addition-step being rate determining.
In the strongly hydrogen-bonding aqueous HFIP, aqueous TFE, and 80T-20E mixtures, we obtain an l value of 0.45, an m value of 1.07, and an l/m ratio of 0.42 for 6, and an l value of 0.43, an m value of 0.82, and an l/m ratio of 0.52 for 7. e sensitivities for l and m obtained (for 6 and 7) are be�tting the proposal of an ionization component with an appreciable nucleophilic solvation of the developing cationic transition state.

Experimental Section
e p-tolyl chlorothionoformate (97%, Sigma-Aldrich), and the p-chlorophenyl chlorothionoformate (98%, Sigma-Aldrich) were used as received.Solvents were puri�ed and the kinetic runs carried out as described previously [19].A substrate concentration of approximately 0.005 M in a variety of solvents was employed.For some of the runs, calculation of the speci�c rates of solvolysis (�rst-order rate coefficients) was carried out by a process [57] in which the conventional Guggenheim treatment was modi�ed so as to give an estimate of the in�nity titer, which was then used to calculate for each run a series of integrated rate coefficients.e speci�c rates and associated standard deviations, as presented in Table 1, were obtained by averaging all of the values from, at least, duplicate runs.
Multiple regression analyses were carried out using the Excel 2010 package from the Microso Corporation, and the SigmaPlot 9.0 soware version from Systat Soware, Inc., San Jose, CA, was used for the Guggenheim treatments.

1 F 3 :
e plot of log (  ) for 4-tolylphenyl chlorothionoformate (6) against 1.63   + 0.46  Cl in the twenty pure and binary solvents studied.e points for TFE-H  O and HFIP-H  O are not included in the correlation.ey are added to show the extent of their deviation from the correlation.values of   ,    ± ,    ± ,   − ± , and an F-test value of 41.Further omission of the three aqueous HFIP (97, 90, and 50) and the three aqueous TFE (97, 90, and 50) values leads to a much improved R=0.966,    ± ,    ± ,   − ± , and F-test value = 69 (reported in

1 F 5 :
e plot of log (  ) for 4-chlorophenyl chlorothionoformate (7) against 1.79   + 0.45  Cl in the nineteen pure and binary solvents studied.e points for TFE-H  O and HFIP-H  O are not included in the correlation.ey are added to show the extent of their deviation from the correlation.

Table 2 )
. e sensitivities l and m obtained are typical for substrates undergoing overall nucleophilic substitution (A-E mechanism) involving rate-determining formation of a tetrahedral intermediate (shown in Scheme 1).e l/m ratio of 3.98 observed is a little higher than those observed for