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

The above equations could be further simplified by limiting conditions and the authors

found that, in the reactions with pyrrolidine, the values for kfast showed that in the formation of the 3-adduct 10, the proton transfer is partially rate-limiting, whereas the kslow

relating to the displacement of the phenylthio group showed a squared dependence on the pyrrolidine concentration: this is compatible with the proton transfer being the ratedetermining step in the substitution. On the other hand, the values of kfast and kslow increase linearly with the amine concentration for the reactions with butylamine, indicating that nucleophilic attack is rate-determining.

A Hammett plot of the values of Kc,3 for these reactions has a slope, , of 1.2: the authors133 recognize that in view of the remoteness of the substituents from the reaction centre, this value is surprisingly large and indicates that the phenylthio groups play a significant role in delocalizing the negative charge in the adduct. For comparison, Crampton and coworkers134 have previously determined the for the related process of hydroxide addition at the 3-position and found a value of 0.98

Phenyl 2,4-dinitronaphthyl sulphide, 14. Chamberlain and Crampton130 showed by UVVIS determinations of the reactions of phenyl 2,4-dinitronaphthyl sulphide 14 with amines in DMSO that the reactions proceed through the formation of a single intermediate (Scheme 8) resulting in the quantitative formation of the product, 15. In the reactions with

k4

NR1R2

NO2

PhSH + NHR1R2 +

NO2

(15)

SCHEME 8

n-butylamine kobs increases linearly with [butylamine], whereas in the reactions with pyrrolidine the plot of kobs/[pyrrolidine] versus [pyrrolidine] passes through the origin, and curves with decreasing slope as [pyrrolidine] is increased. That the plot passes through the origin indicates that the uncatalysed pathway, k2, is unimportant, while the curvature indicates that the proton transfer step, kAm, is partially rate-limiting.

Phenyl 2,6-dinitro-4-trifluoromethylphenyl sulphide. Chamberlain and Crampton130 studied also the reaction of phenyl 2,6-dinitro-4-trifluoromethylphenyl sulphide with amines in DMSO. They observed a single rate process with butylamine giving the expected substituted product; again, the observed rate constant increased with [butylamine]. In the reaction with pyrrolidine a rapid reaction giving the 3-pyrrolidino adduct was observed, which could be suppressed by addition of pyrrolidinium perchlorate. Under these conditions the expected 1-substituted product was formed.

It can be concluded that in the reactions of amines with activated substrates derived from substituted arylthio-derivatives in DMSO, the reactions with pyrrolidine are faster than with butylamine. The rate-determining step in the formation of 3-adducts changes from nucleophilic attack with n-butylamine to proton transfer, partially rate-limiting with pyrrolidine and fully rate-determining with piperidine. Crampton and coworkers found that the major factor is the change in kAm with the changing nature of the amine. Although the proton transfer step leading to adducts 10 is thermodynamically favoured, values of the rate constants are very much lower than those expected for diffussion-controlled reactions. This reflects steric hindrance to the approach of the reagents, which becomes increasingly severe as the amine is changed from n-butylamine to pyrrolidine to piperidine.

For reactions at the 1-position, with butylamine as the nucleophile, nucleophilic attack is rate-determining, whereas when pyrrolidine is the nucleophile the reactions are basecatalysed, and the values of K1kAm show a small dependence on the nature of the 40-substituent. The relatively small decrease on changing the 1-substituent from SPh to SEt is compatible with the interpretation that, in the reactions with pyrrolidine, proton transfer from the zwitterionic intermediate to amine is rate-limiting. The authors also discussed why the alternative explanation of base catalysis in terms of the SB-GA mechanism is less preferred; a greater sensitivity on the nature of the leaving group should be expected if this mechanism were operating. Acid-catalysed expulsion of the nucleofuge is also unlikely in view of the pKa values of the group involved.

H. Aromatic Nucleophilic Substitution with Amines under High Pressure

Several studies have recently appeared on the acceleration of SNAr reactions by high pressure135 139. Ibata and coworkers135,136 studied the SNAr reaction of mono-, di-, triand pentachloronitrobenzenes with various amines under high pressure.

In particular, when pentachloronitrobenzene (16) is heated at 50 °C for 20 h with 6.0 molar equivalent of morpholine at 0.60 GPa in tetrahydrofuran (THF) solution in the presence of 5.0 molar equivalent of triethylamine, several products were isolated and are shown in Scheme 9.

Table 16 shows the results of the same reaction under different pressures between atmospheric pressure (10 4 GPa) to 0.78 GPa. At atmospheric pressure, nitro-group- substitution product, 18a, and o-mono- and p-monosubstitution products 19a and 20a were obtained in a total yield of 7.4% recovering 92% of the starting pentachloride 16. When the pressure was raised, the yields of these monosubstitution products increased; at higher pressures diand trisubstitution products appeared and this trend continued in the reactions under pressures above 0.60 GPa, affording higher yields of the trisubstitution product 23a. These results indicate that the second substitution occurred at the pressure

aThe reactions were carried out under the following conditions using 1.0 mmol of 16 and 6.0 mmol of 17; 50 ° C, 20 h, in THF.

bDetermined by HPLC.

over 0.20 GPa and that the third substitution does not proceed below 0.60 GPa, according to what is expected on the basis of the reduced activation of the corresponding reaction centre. By comparing the results observed on changing the amount of morpholine from 1.0 to 15.0 molar equivalent relative to 16, it is again confirmed that the diand trisubstitution reactions are slower than the mono substitution.

The reactions of 16 with pyrrolidine and diethylamine were studied at 0.60 GPa in a similar way described above, with or without triethylamine, as shown in Table 17. It can be observed that even with 10.0 molar equivalent of diethylamine only mono-substitution products 18c, 19c and 20c were obtained, whereas pyrrolidine yielded the trisubstitution product 23b in higher yield than did morpholine. The authors explained these results on the basis of the bulkiness of the amines135.

The effect of steric hindrance was further studied by comparing the reactivity of primary and secondary amines of different steric requirements with 2,3,5,6-tetrachloronitro- benzene, 24 (Scheme 10)140. It is shown in Table 18 that open-chain amines give higher yield of the nitro-substitution products.

SCHEME 10

The reactivity and regioselectivity in the first and second substitutions steps were studied by Ibata’s group141 in the reactions of 24 with 6.0 molar equivalent of morpholine and pyrrolidine, monitoring the kinetics of formation of the reaction products by 1H NMR measurements. In the reactions with morpholine (Figure 8), the yields of 25a, 26a and 27a increased monotonously during the initial 20 h, while 1 decreases monotonously to zero recovery. The amount of 26a decreases slowly after 20 h: this indicates that the second attack of morpholine proceeds slowly to give 28a and 29a, in contrast to no attack on 27a.

The reaction of pyrrolidine is faster than that of morpholine142 and almost all 16 was consumed in the first 10 h (Figure 9). An interesting feature in this reaction is that the

dinitroanisole with n-butylamine at 45 °C144. Reprinted with permission from Reference 144. Copyright (1983) American Chemical Society

showing third-order dependence on the amine (equation 23).

To the best of our knowledge, the first report of this fourth-order kinetics was published in 1980, for the reactions of 2,4- and 2,6-dinitroanisole with butylamine in benzene143b, and afterwards several other systems were studied in the same laboratory, some of which are shown in Table 19144. An early observation in these systems was that they frequently exhibited negative energies of activation; it can be observed in Figure 11 that for low [B], the rates at 60 °C are higher than those at 80 and 100 °C. Both results, the thirdorder dependence on [B] added to the observation of negative enthalpies of activation (characteristic of the existence of pre-equilibrium in the reaction coordinate), were considered evidence of the aggregation of the nucleophile, and that the reaction could proceed by attack of a dimer of the amine (B:B) superimposed on the classical mechanism by the monomer144. Amine aggregations are known to be affected by temperature145,146, inversely so that very low and even overall negative enthalpies of activation are observed where a pre-equilibrium, such as 2B!B:B , exists144.

Although these peculiar kinetics had never been observed before, a careful search in the literature revealed that some ‘anomalous’ results ambiguously ascribed by the authors to ‘unspecific solvent effects’103,147, were indeed due to the fact that these SNAr reactions exhibit a fourth-order kinetic law144. Some of them are shown in Table 20. Shortly afterwards, some other authors reported third-order dependence in amine in SNAr reactions in aprotic solvents148 152. Several alternative mechanisms have been suggested to rationalize this kinetic finding and many studies in the last years have attempted to

TABLE 19. Aromatic nucleophilic substitution in non-polar aprotic solvents. Third-order in amine kinetic law144. Reprinted with permission from Reference 144. Copyright (1983) American Chemical Society

[B] (M)

FIGURE 11. Reaction of 2,4-dinitroanisole with butylamine in benzene144. Reprinted with permission from Reference 144. Copyright (1983) American Chemical Society

TABLE 20. Reported ‘anomalous’ aromatic nucleophilic substitutionsn144 . Reprinted with permission from Reference 144. Copyright (1983) American Chemical Society

nTreatment of the reported data shows third-order in amine kinetic laws.

elucidate the factors involved in these reactions. Hirst153 has recently reviewed some of the evidence of the mechanisms proposed in this controversial subject.

B. The Eight-membered Cyclic Transition State

In the reactions of anilines with picryl phenyl ethers in benzene, Banjoko’s group150,154,155 observed that the second-order rate constant, kA, exhibits a linear dependence on the square of the nucleophile concentration (equation 24).

Banjoko has interpreted the third-order term in the amine concentration as due to a reaction proceeding through an eight-membered ring formed through a network of the inter-hydrogen bonding between two aniline molecules and the zwitterionic intermediate as shown in Scheme 11. In these reactions, the authors found that kA showed little change with temperature in the range 5 35 °C, k0 is almost invariant with temperature, and k0 has negative activation energy for anilines containing electron-releasing substituents. The kinetic form also depends on the substitution in the nucleofuge. Thus, for unsubstituted or nitro-substituted leaving groups a third-order dependence is observed, whereas for leaving groups containing 2,4-, 3,4- and 2,5-dinitro groups in amine a second-order, and for the 2,6-dinitrophenoxy groups a first-order, kinetic law was obtained. The results were explained as a change in the transition state: from eightto sixto four-membered rings, containing three, two or one molecules of aniline, respectively. Why an eight-membered transition state would be more effective in removing the nucleofuge than a six-membered one was not explained. Considering that formation of the cyclic intermediate requires the encounter of intermediate 33 with two amine molecules (aggregates are not considered) to form the highly ordered transition state 35, a highly negative entropy of activation would be expected, but the observed values are within the usual ranges.

Addition of methanol to the reaction of aniline with picryl ether in benzene resulted in a continuous curvilinear increase of kA over the entire range of solvent composition from pure benzene to pure methanol155. The order in aniline changes from three in benzene to