Patai S., Rappoport Z. 1996 The chemistry of functional groups. The chemistry of amino, nitroso, nitro and related groups. Part 2 / 1215 1300

3. Mixed solvents

The study of solute solvent and solvent solvent interactions in mixed solvents has been gaining significance in recent years61 64, because of the increasing application of these solvents. Casassas and collaborators67 have used the Kamlet Taft multiparametric equation for the correlation of dissociation constants of acids in 1, 4-dioxane water mixtures. They found that when the main solvent is retained the property does not involve significant changes in the cavity volumes and, in those cases, the pK in binary solvents can be described by equation 8:

Bosch, Roses and coworkers62,65,66 have used the dissociation of electrolytes in binary solvents of low permittivity using 2-methylpropanol or propan-2-ol as the main solvent

of solutes between blood and brain73. It was shown in a recent publication74 that for a series of alcohols, the a coefficient is effectively zero, so that all the alcohol phases have the same basicity as bulk water, no matter what their water content is. This would indicate that the alcohols have similar hydrogen-bond basicity to water, contrary to results of solvatochromic measurements; the anomaly is assumed to be due to the strong dependence of the ˇ values on the indicator used in the solvatochromic determinations75. It is suggested that the partition equations are more useful to represent the real interactions with the solvatochromic method74.

C. The Influence of the Nucleophile

The basicity, nucleophilicity, polarizability and steric requirements of the nucleophile have been recently shown to affect the SNAr reactions with amines.

1. Basicity

The effect of basicity is clearly shown by the dependence of the rates of reactions of structurally related nucleophiles76,77. Bordwell76 has pointed out that Brønsted plots reported in the literature for reactions in which bond formation to the nucleophile is rate-limiting have slopes ˇNu that range for the most part between 0.5 0.7, as shown in Table 5; ˇNu measures the sensitivity of the rates to changes in the basicity of the nucleophile. Its size appears to be associated with the extent of charge transfer in the transition state for the rate-limiting step, and it can be used to describe the position of the transition state along the reaction coordinate.

In single-electron-transfer reactions from carbanions where charge transfer is essentially complete, ˇNu is near-unity, while for SN2 reactions ˇNu ranges from 0.2 to 0.5. In SNAr processes, where the size of ˇNu is determined by the bonding between the

TABLE 5. Brønsted ˇNu values for SNAr reactions with thianion, amine, and oxanion families in hydroxylic solvents76. Reprinted with permission from Reference 76. Copyright (1986) American Chemical Society

O2 N

NO2

NO2

NO2

NO2

aG. Bartoli, L. DiNunno, L. Forlani, and P. E. Todesco, Int. J. Sulphur Chem., Part C 6 77 (1971). bG. D. Leahy, M. Liveris, J. Miller and A.J. Parker, Aust. J. Chem., 9, 382 (1956).

c J. E. Dixon and T.C. Bruice, J. Am. Chem. Soc., 94, 2052 (1972).

dP. A. Nadar and C. Gnanasekaran, J. Chem. Soc., Perkin Trans. 2, 671 (1978). eJ. J. Ryan and A. A. Hummfray, J. Chem. Soc. (B), 1300 (1967).

nucleophile and a partially positively charged sp2 carbon atom, ˇNu is large but not near-unity. The observation that it increases when more nitro groups are added to the electrophile (e.g. ˇNu for amines reacting with picryl chloride is 0.12 unit larger than for 1-chloro-2,4-dinitrobenzene) is consistent with the expected extent of charge transfer in the transition state.

Connected with the determination of Brønsted plots, some mathematical treatments have been recently developed attempting to yield structural information on the transition state.

These treatments have been also applied to SNAr. For example, for a neutral nucleophile, all the classical pathways identified at present are represented by the general reaction mechanism shown by Scheme 2. A concerted mechanism, indicated by the diagonal path in Scheme 2, had not been discussed until lately, but was observed, among other systems, in the hydrolysis of 1-chloro-2,4,6-trinitrobenzene and 1-picrylimidazole. The study was then extended to other related substrates and structure reactivity relationships could be obtained78.

X

X NuH

SCHEME 2

The Brønsted ˇ values for substituted phenyl ethers, 0.39 to 0.52, are in the range expected for concerted reactions, but indicate a transition state with less proton transfer than in the case of 3-methylimidazolium chloride derivatives, (ˇ D 0.60 0.65). The structure reactivity parameters were interpreted on the basis of the mathematical method developed by Jencks and More O’Ferral. The tridimensional energy maps are shown in Figure 2, where proton transfer is represented along the x-axis and C O bond formation along the y-axis. The position of the transition state along the reaction coordinate is shown in Figure 3 (the third dimension is omitted for clarity). The reaction coordinate shows more degree of proton transfer than C O bond formation. The change in the nucleofugue from imidazole to OPh produces some stabilization in state II and a greater decrease in the energy of state IV. This produces a shift along the reaction coordinate toward I (arrow 1) and a little shift to II (arrow 2) by a perpendicular Thornton effect. The result of the two changes (arrow 3) indicates a lower degree of proton transfer and a small increase in the C O bond formation78.

Recently, the same group79 have reported the kinetic study of the reaction of 1-pyrrolidino-2,4-dinitrobenzene, 1-piperidino-2,4-dinitrobenzene and 1-morpholino-2,4- dinitrobenzene with NaOH in the presence of the amine leaving group and proposed the formation of -complexes, which were found to react faster than the original substrates.

+H

FIGURE 2. Tridimensional reaction coordinate diagram for the hydrolysis of 1-X-4-Z-2,6- dinitrobenzene. The x-axis represents the proton transfer reaction and the y-axis, the C O bond formation78. Reproduced by permission of the Indian Journal of Technology

FIGURE 3. Structure reactivity Jencks More O’Ferral diagram for the hydrolysis of 1-X-2,4,6-tri- nitrobenzenes: (a) vertical level line as a consequence of ∂ˇ/∂pKBH D px D 0; (b) level line clockwise rotated from the horizontal as a consequence of ∂ˇXH/ ∂pKXH D py D negative;

(c) reaction coordinate with an angle higher than 45 degrees with the vertical as the line that bisects the two level lines. Effect of change in the X substituent by better withdrawing groups, arrows 1, 2 and 3. Effect of change in the base (B) by other with lower pKBH, arrows 4, 5 and 678. Reproduced by permission of the Indian Journal of Technology

2. Nucleophilicity and polarizability

The nucleophilicity of the amine is another factor affecting reactivity, and changes in it have been sometimes responsible for the observed scattering in the Brønsted plots. The Ritchie equation80 (equation 11) has been applied to a variety of reactions in which nucleophilic addition to, or combination with, an electrophilic center is rate-limiting.

Here k is the rate constant for reaction of an electrophile with a given nucleophile in a given solvent, k0 corresponds to the reaction of the same electrophile with water (in water) and NC is a parameter characteristic of the given nucleophile in the given solvent, but independent of the electrophile80. Ritchie’s ideas imply that the transition states are characterized by rather large separations of the nucleophile and electrophile moieties. For SNAr reactions involving rate-determining nucleophilic addition, this would mean that bond formation and charge transfer have made little progress in the transition states. These conclusions are in disagreement with those reached on the basis of the ˇNu values obtained from Brønsted plots76. A possible explanation of this conflicting situation is in terms of imbalanced transition states, with desolvation of the nucleophile being ahead of bond formation and charge transfer in the transition state1a.

A recent study of the reactions of 2,4-dinitrochlorobenzene and of picryl chloride with a series of nucleophiles that are presented in Table 6 shows that a plot (not shown) of log k against the pKa values of all the nucleophiles is badly scattered77. Differences of up to 108 are observed for bases with similar pKa values. Part of this scatter is due to deviations that result because different families of nucleophiles (with different nucleophilic atoms) give rise to different Brønsted correlation lines. Thus, for the reactions of picryl chloride good correlations are observed for a family of oxyanions (ˇ D 0.38, plot not shown), primary and secondary amines (Figure 4, ˇ D 0.52) and quinuclidines (Figure 4, ˇ D 0.66).

On the other hand, the correlation with the NC parameter shown in Figure 4 for the same

relative nucleophilic reactivities, which the authors attributed mainly to steric effects77. For example, secondary amines such as piperidine and morpholine are relatively more reactive than less hindered primary amines in reactions with 2,4-dinitrochlorobenzene. Notwithstanding, it will be shown below that other effects have been also found to be responsible for these changes. Steric effects cannot account for the slope of less than one observed for the reactions of picryl chloride, because the slope is not significantly different (0.82 š 0.11) when the points for the more hindered secondary amines are omitted from the plot77. The slopes less than one observed for these reactions (Figure 5) mean that picryl chloride shows a lower selectivity toward nucleophilic attack than does 2,4-dinitrochlorobenzene, in accordance with the reactivity selectivity principle and with relative nucleophilic reactivities that are substrate-dependent77. Nevertheless, in other cases, it has been found that nucleophilic additions to halonitroarenes do not follow the reactivity selectivity principle7.

The nitro group is highly polarizable and electrostatic repulsion between this group and the incoming nucleophile should decrease the rate when the nitro group is located in the ortho-position. Nevertheless, polarizability effects of the nucleophile may be rateenhancing because of the operation of London forces, as shown earlier with the reactions with thiophenoxide ions81. Although no studies of these effects have been conducted in

TABLE 6. Second-order rate constants for nucleophilic aromatic substitution

reactions of 2,4-dinitrochlorobenzene and picryl chlorided77 . Reprinted with permission from Reference 77. Copyright (1992) American Chemical Society

aAt 25 °C in aqueous solution.

bFrom C. D. Ritchie, J. Am. Chem. Soc. 97, 1170 (1975) unless noted otherwise. c PC is picryl chloride.

dDNCB is 2,4-dinitrochlorobenzene. eData from Reference 80c.

fR. H. Rossi and E. B. Vargas, J. Org. Chem., 44, 4100 (1979). gIn methanol at 25 °C.

hData from M. R. Crampton and J. A. Stevens, J. Chem. Soc., Perkin Trans. 2, 1097 (1990). iData from J. E. Dixon and T. C. Bruice, J. Am. Chem. Soc., 94, 2052 (1972). Rate constants corrected from 30 to 25 °C using the Arrhenius equation, assuming an activation energy of 10 kcal mol 1.

jlog k D 4.01 from work reported in R. H. Rossi and E. B. Vargas, J. Org. Chem., 44, 4100 (1979).

k Values of NC for morpholine and piperidine in methanol solution were obtained by taking the average value of NC determined by fitting the rate constants for the reactions of these nucleophiles with 2,4-dinitrofluorobenzene, 2,4-dinitrochlorobenzene, 2,4- dinitrobromobenzene and 2,4-dinitroiodobenzene, to plots of log k against NC (using the data reported in Reference 80c). Data for the reactions of these substrates with azide ion were excluded from the correlation lines for the purpose of calculating these NC values. lBased on data from Reference 80c.

m In units of S 1.