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

TABLE 10. Rate constants of reactions between 1,2-DNB and BA in aprotic solvents at various temperaturesa,110. Reprinted with permission from Reference 110. Copyright (1989) American Chemical Society

In non-polar solvents such as benzene, toluene, chlorobenzene and diisopropyl ether (called solvent set B), a mild acceleration is observed, and the reactions are slower than in hexane. A molecular complex (see below) is proposed to explain the results for the reactions in solvent set B.

E. Molecular Complexes

It is now well established that molecular complexes may play a catalytic role in chemical transformations112,113, and their influence in the SNAr reactions with amines is the subject of intense research activity at present8,10,110,113 117. Although there is no total acceptance that these complexes are real intermediates on the reaction path, increasing evidence is being accumulated regarding their role in the substitution reactions. The curve-crossing (configuration mixing) model118 120 has proved very useful in providing a

For Ks [Am] × 1 and k2 Ck3 [Am] − k 1, a linear response to the nucleophile concentration, such as that depicted in equation 8, is obtained. This behaviour is characteristic of most base-catalysed reactions. On the other hand, whereas all the studied reactions were base-catalysed in n-hexane, only mild acceleration was observed in benzene9. Also, the reactions seem to be inhibited in benzene and other electron-donor solvents, and Silber and coworkers attributed this effect to a preferential solvation exerted through EDA complex formation with the aromatic substrate, as shown in Scheme 49.

Products

KD kc

PIP

[1,2-DNB.D]

SCHEME 4

These studies have been recently extended to the reaction of n-butylamine (n-BA) and piperidine (PIP) with other aromatic substrates, such as 1-chloro-2,4-dinitrobenzene (CDNB) and 4-chloro-3-nitrotrifluoromethylbenzene (CNTFB) in hexane, benzene, mesitylene and binary mixtures of hexane with the aromatic solvents, and the results are consistent with Scheme 4 which includes the proposal of a preferential solvation with the donor solvent, D115. As expected, a decrease in rate was observed in the reactions with butylamine with increasing amounts of the donor solvent, which was attributed to the formation of the EDA complex with the solvent. The result is expressed by equation 18 which, in the limiting case where Ks − KD, reduces to equation 19.

By fitting equation 19 with the experimental data, the values of KD were obtained for the following systems: CDNB benzene D 0.76 š 0.02, CNTFB benzene D 0.26 š 0.02, CDNB mesitylene D 0.96 š 0.02 and CNTFB mesitylene D 0.48 š 0.02 mol 1. It can be observed that KD increases with increasing donor strength of the aromatic solvents115. For the reactions with piperidine, on the contrary, an increase in rate was observed with increased molar fractions of the donor solvent. This result was interpreted

as a conventional solvent effect since, in this case, K ¾ K .

S D D

The SNAr reactions with amines in chloroform show a peculiar behaviour and the rates cannot usually be correlated with reactions in other solvents. It has been observed in the reaction of 2,4-dinitrochlorobenzene with piperidine48c and in the reaction of 1,2- DNB with butylamine115 that chloroform exerts a special solvent effect due to its known hydrogen-bond donor ability. Thus, an association between the solvent and the nucleophile can be postulated as a side-reaction to the SNAr115. Associations of chloroform with amines are known122 and the assumption of a partial association between piperidine or butylamine and chloroform as the cause of the downward curvature in the plots of kA vs [amine] seems plausible.

Forlani and coworkers123 studied the reactions of 1-halogeno-2,4,6-trinitrobenzene with 2-hydroxypiridine in aprotic solvents: the reaction provides two isomeric products as

1248 Norma S. Nudelman

shown in Scheme 5. For X D Cl, in THF at 45 °C the reaction afforded compound 8a in 68% relative yield, and 32% of compound 8b. In the presence of 2-hydroxypyridine compound 7 is quantitatively converted into compound 8b. The authors studied the kinetics of the reaction of 2,4-dinitrofluorobenzene in THF, toluene and chlorobenzene in excess of 2-hydroxypyridine, and the data are gathered in Table 11, which also includes data of the reaction of 2,4-dinitrochlorobenzene in chlorobenzene.

SCHEME 5

It can be observed that kobs increases with increasing initial concentration of 2- hydroxypyridine. The authors interpret the increase in rate as due to the formation of a molecular complex as shown in Scheme 6; the equilibrium constant K for the formation of the complex was estimated in each case and the values are shown in Table 12. Some observations on these results are discussed in Section III.

SCHEME 6

Other interesting data in these reactions concern the H/D isotopic effect of the nucleophile/catalyst, for example when [2-hydroxypyridine] D [2 O2H] D 0.08, kobs H/kobs D D 1.5. Since a very poor H/D effect is usual in SNAr reactions with neutral nucleophiles (amines) in apolar solvents1c, the authors conclude that the unusually high H/D effect should be due to a difference in the KH/KD D 1.75 of the molecular complex. Nevertheless, the same effect could be explained on the basis of an autoassociation of

TABLE 11. Kinetic data for reactions between FTNB (2,4,6-fluorotrinitrobenzene) and Py in chlorobenzene (unless otherwise indicated)123

aErrors are calculated from standard deviations. bNumber of points.

c Correlation coefficient. dIn chlorobenzene.

eMonodeuteropyridone. fIn THF.

gIn toluene.

h1-Chloro-2,4,6-trinitrobenzene.

iIndicative value: error is higher than value. jIndicative value: 1/kcK D 7.4 š 0.2.

1250 Norma S. Nudelman

TABLE 13. Apparent stability constants of molecular complexes between 2-hydroxypyridine and some aromatic nitro derivatives in benzene-d6 at 25 °C125. Reproduced by permission of societa` chimica Italiana from Reference 125

aErrors are standard deviations. bNumber of points.

c Correlation coefficient. d1,3-Dinitrobenzene.

e1-Chloro-4-nitro-benzene.

f1-Chloro-2,4-dinitrobenzene. g1-Chloro-2,4,6-trinitrobenzene. h1-Fluoro-2-nitrobenzene.

i1-Fluoro-4-nitrobenzene.

l1-Fluoro-2,4-dinitrobenzene.

mMonodeutero-2-hydroxypyridine.

the nucleophile, since the tendency of 2-hydroxypyridine to form dimeric species is very well known124.

The study of molecular complexation was then extended to other aromatic nitro derivatives125. Although, as was described before, one of the more frequent methods of studying the formation of molecular complexes is by UV-visible spectrophotometry, the author did not observe detectable differences in the UV-visible absorbance spectra between the 2-hydroxypyridine 1-fluoro-2,4-dinitrobenzene (FDNB) mixtures and the sum of their separate components. The author observed that the signals of the 1H NMR spectra of FDNB in apolar solvents were shifted downward by the addition of 2-hydroxypyridine: from solutions where [2-hydroxypyridine] − [FDNB] he calculated the apparent stability constants, which are shown in Table 13.

F. Electrophilic Catalysis

When expulsion of the nucleofuge is rate-determining, stabilization of the transition state for the leaving group departure is important especially in solvents of low permittivity. Because of the anionic nature of the nucleofuge in the zwitterionic intermediate, acid catalysis has been sought since early times but the results were rather controversial1. Capon and Rees126 suggested that in aprotic solvents the catalysed reaction proceeded via a cyclic intermediate such as shown by 9. On the other hand, Orvick and Bunnett19 were able to measure separately the rates of formation and decomposition to products of the intermediate (the conjugate base corresponding to 2 in Scheme 1) formed in the reaction of 2,4-dinitro-1-naphthyl ethyl ether with butylamine in DMSO. The decomposition of the intermediate was found to be first-order in n-butylammonium ion, but independent of the free amine concentration, and this was an important piece of evidence of the SB-GA.

L NR1R2

NO2

−

NO2

(9)

Recently, Hirst and collaborators127 have carried out a more comprehensive search for electrophilic catalysis in SNAr reactions with primary and secondary amines in dipolar aprotic solvents. Thus, the effects of lithium, trialkylammonium and tetraalkylammonium ions on the reactions of piperidine with 2,4-dinitroanisole and of morpholine with 2,4- dinitrophenyl phenyl ether were investigated in DMSO. Although the reaction between 1-fluoro-4-nitrobenzene and trimethylamine in DMSO had been previously found to be catalysed by trimethylammonium and lithium ions127, no evidence for electrophilic catalysis was found in the present systems. In the case of lithium ions, expulsion of the methoxy or phenoxy groups was not catalysed by this ion. When the putative catalysts are trialkylammonium ions, the lack of catalysis could be due to an unfavourable equilibrium between the ions and piperidine in the case of the methoxide expulsion, as was observed by Nudelman and Palleros104 for the reactions of piperidine with 2,4- and 2,6- dinitroanisole in benzene. But in the phenyl ether morpholine system, this is not the case, and although catalysis of the ejection of the phenoxy group has never been demonstrated experimentally, the premise that it does occur is the basis of the SB-GA mechanism19.

The lack of catalysis could be due to steric effects. Crampton and Routledge24 have shown that steric effects operate in the ejection of the leaving group when the nucleophile is piperidine and the catalyst is its conjugate acid. Similarly, reductions in the rate constants for proton transfers from the zwitterionic intermediates to amines to less than expected for diffusion-controlled reactions have been attributed to steric effects. Additionally, Hirst and coworkers128 have tentatively proposed a contribution of ‘proximity’ effects. In the system studied by Orvick and Bunnett19 the conjugate acid of the base that removes the proton from the intermediate is generated in the immediate vicinity of the nucleofuge and hence has an advantage over other catalysts in solution. Nevertheless, the effect of HBA additives was investigated with regard to the homo heteroconjugate mechanism (see below) and electrophilic catalysis was found.

Recently, Forlani129 studied the reactions of fluoro dinitrobenzene (FDNB) with several amines in the presence of some compounds that have been found to catalyse the reaction. The plots of kobs vs [catalyst] show a linear dependence at low catalyst concentration and then a downward curvature. This behaviour has been previously observed in several related cases: the usual interpretation is that the kobs increases on increasing the [catalyst] value until it reaches a maximum when k 1 D k1 C k2 [catalyst].

The deviation from linearity was explained by including a third term due to the catalyst in the rate law equation (equation 20) and the results are given in Table 14.

TABLE 14. A, B and C values (see text) for reactions between FDNB and amines in the presence of various catalysts at 25 °C (errors are standard deviations)129. Reproduced by permission of Societa` Chimica italiana from Reference 129

aPip D piperidine; Bu D n-butylamine; t-Bu D t-butylamine. bSolvent: Bz D benzene; Ch D chloroform; D D p-dioxan. c Numbers refer to the original publication.

dIn s 1 M 1.

eIn s 1 M 2.

fIn s 1 M 3.

gNumber of points.

hCorrelation coefficient.

TABLE 15. Dissection of experimental data (k2 and K values, see text) for reactions between FDNB and amines in the presence of various catalysts at 25 °C129. Reproduced by permission of Societa` Chimica Italiana from Reference 129

aPip D piperidine (pKa D 11.06); Bu D n-butylamine (pKa D 10.59); t-Bu D t-butylamine (pKa D 10.8). bSolvent: Bz D benzene; Ch D chloroform; D D p-dioxan.

c Numbers refer to the original publication.

dIn s 1 M 1. eIn M 1.

fCorrelation coefficient.

Nevertheless, it can be observed that the significant values are in B, and these show a strong influence of the amine used. The author129 interpreted the results through a mechanism involving a molecular complex substrate, and calculated the values of k2 and of the equilibrium constant K, shown in Table 15. Again, the significant values depend on the nucleophilic power of the amine. If such a molecular complex between

the substrate and the catalyst would exist (the author suggests an interaction between the amido group and the fluorine atom or the nitro group), it should be possible to detect it since, in this case, it would not react as it occurs with other previously studied catalysts. Nevertheless, the author was unable to detect any interaction between the catalyst and FDNB.

The downward curvature observed in this and other systems could be easily explained in terms of a ‘mixed aggregate’ between the catalyst and the nucleophile. A hydrogen-bond donation to the amide catalyst would render the amine a better nucleophile, up to a value of ‘saturation’, after which increasing amounts of catalysts should have no further effect. The results in Table 15 can be easily explained in the same terms, where K measures the equilibrium of the association between the amine and the catalyst.

G. Aromatic Nucleophilic Substitution with Amines in which the Nucleofuge is a Sulphur Derivative

Ethyl 2,4,6-trinitrophenyl sulphide. Crampton’s group130,131 has recently studied the reaction of amines with activated substrates where the nucleofuge has a sulphur atom attached to the reaction centre. Thus, in the reactions of ethyl 2,4,6-trinitrophenyl sulphide with butylamine and with pyrrolidine in DMSO, substitution occurs without the accumulation of intermediates on the reaction pathway130. With n-butylamine a firstorder dependence on amine was observed indicating that nucleophilic attack, k1, was rate-determining, whereas with pyrrolidine a squared dependence on amine was observed. The authors argued that base catalysis in this reaction was likely to involve rate-limiting proton transfer from the zwitterionic intermediate, based on the failure to observe an intermediate on the lower kinetic barrier expected for loss of an alkylthio relative to an alkoxy group132, and on the unlikelihood of general acid catalysis involving proton transfer to a sulphur atom.

40-Substituted Phenyl 2,4,6-trinitrophenyl sulphides. By UV-VIS measurements of the reactions of 40 -substituted phenyl 2,4,6-trinitrophenyl sulphides with amines in DMSO, Crampton’s group131 showed the presence of two well-separated processes which were interpreted by Scheme 7129. In each case a rapid reversible equilibrium was established leading to the 3-adduct (10). They also observed a second, much slower process resulting in formation of the N-substituted picramide derivatives, 13. The final spectra were identical to those of the independently prepared products, 13. Chamberlain and Crampton133 showed that the reaction products are in rapid equilibrium with anions derived from them by amine addition at the 3-position and/or loss of a side-chain proton, but they did not find evidence for the accumulation of spectroscopically observable concentrations of intermediates such as 12.

By application of the steady-state treatment to Scheme 7, the authors calculate the

general rate expression for reaction at the 3-position to produce adducts 10 kfast , and the rate expression for product formation kslow , respectively (equations 21 and 22).

Am D R1R2NH; AmHC D protonated R1R2NH2C