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

‘internal solvation’, favoured by the alkylamino chain separated by three carbon atoms from the imidazole nitrogen.

In the gas phase, the imidazole ‘sp2’ nitrogen atom is the preferred site of protonation. (GB for histamine is 949 kJ mol 1, for 4-methylimidazole 915 kJ mol 1 and for PhCH2CH2NH2 895 kJ mol 1.) In aqueous solution PhCH2CH2NH2 is more basic than 4-methylimidazole by 2.3 pKa units (13 kJ mol 1). This reversal is due to a better solvation of NH3C compared with DNHC, but in the gas phase, and likely in aprotic solvents, the energetically preferred imidazole nitrogen protonation is further favoured by ‘internal solvation’. This change in histamine cation structure on going from aqueous media to gas phase has recently been considered in theoretical calculations195,196. Similarly for the case of the ˛-amino acid histidine, a recent semi-empirical calculation197 gives the structure with an intramolecular H-bond CDOÐ Ð ÐH N(Im) as the most stable conformation of protonated histidine.

Arginine is another example of an ˛-amino acid in which guanidine and amine functions are separated by a chain of four carbon atoms. Raczynska and coworkers86 suggested that the strong gas-phase basicity of arginine (comparable to the GB of DBN) may be due to the ‘internal solvation’ of the guanidinium cation, 48.

These authors conclude that ‘the problem of internal solvation is still an experimental and theoretical challenge’; GB measurements for this type of molecules of low volatility are not always in good agreement194. Molecular orbital calculations may help to solve the difficult experimental problems, but they have to take into account conformational isomerisms and the prototropic tautomerisms of the amidine and guanidine moieties. In light of the above discussion, the proton affinities deduced from the experimental GB values should be based on accurate estimations of the ‘entropy of cyclization’86.

The accurate determination of gas-phase basicities and gas-phase acidities opened the way to analyses of the effect of solvation on proton acidities, and on hydrogen-bond acidities and basicities, as well as on substituents effects.

L. Isotope Effects

Forlani and coworkers184 determined that the magnitude of kA was found to increase linearly with nucleophile concentration for the reaction of picryl fluoride with 2-hydroxypyridine in chlorobenzene, and kAH/kAD D 1.5 for mono-deutero-2- hydroxypiridine was observed184. Since isotope effects are usually small in SNAr in apolar solvents1 the authors attributed the isotope effect to the formation of a substratecatalyst molecular complex. They obtained a value of kAH/kAD D 1.75 for the ratio of the association constants, kH/kD. When the substrate was picryl chloride, the slight increase of kA with nucleophile concentration was interpreted in terms of Scheme 6 giving a value of K D 2.9 š 1 identical with that for the fluoro-substrate 3.0 š 1 .

Taking into account, for instance, the slight differences in K observed for 1-fluoro-2,4,6- trinitrobenzene and 1-chloro-2,4,6-trinitrobenzene in Table 13, it is difficult to explain such a difference in KH/KD. Nevertheless, a H/D isotopic effect of 1.5 could be easily explained

on the basis of the auto-association of 2-hydroxypyridine, involving hydrogen bonding, since the tendency of 2-hydroxypyridine to form dimeric species is very well known124. Another alternative explanation for the observed H/D isotopic effect is the ability of 2-hydroxypyridine to act as a ‘bifunctional’ catalyst: as mentioned in Section II.F, 2- hydroxypyridine is able to both base-catalyse proton abstraction and acid-catalyse the nucleofuge departure. Either of these two explanations seems to be more satisfactory to account for the observed H/D isotopic effect than the weak rationale based on the molecular complexes.

Clearly, these isotope effects could also be explained on the basis of the ‘dimer nucleophile’ or ‘homo/heteroconjugate’ mechanisms.

M. Further Treatment of Kinetic Results

1. ‘Inversion Plots’

Several alternative mechanisms have been described here that have been reported to explain the ‘anomalous’ kinetic results, such as the observed fourth-order kinetics. Further treatment of the different equations may help to understand the scope of the different proposals. In a simplified form for the dimer mechanism, only attack by the dimer nucleophile can be considered, as shown by equation 41.

responsible for the plateau observed in some cases [e.g. the reactions of 2,4-dinitroanisole with cyclohexylamine in benzene (Figure 11) and in cyclohexane (not shown)]143,144 and it was also observed in the reactions with n-butylamine in benzene at 60 °C (the reactions at 80 °C show a slight curvature, tending to a farther asymptotic behaviour). In all the SNAr systems studied by other authors, in which fourth-order kinetics were found, the observation of a similar plateau in the plots of kA/[B] vs [B] was not reported.

Inversion of equation 28 (Section III.D) gives expression 42, which allows some esti-

Taking into account that the uncatalysed decomposition is slower than the base-catalysed one, equation 42 can be simplified to equation 43:

A plot of [B]/kA vs [B] 1 should be linear, except where the conditions that allow the simplification to equation 43 are not fulfilled. Such a plot is presented as line A in Figure 15 for the reaction of 2,4-dinitroanisole (DNA) with cyclohexylamine (CHA) in cyclohexane, and as line B in Figure 15 for the reactions with n-butylamine (BA) in benzene, both at 80 °C. Each is satisfactorily linear, and they allow evaluation of the different k values. Estimations of the k1k3K/k 1 values for this and other reactions are given in Table 26144. The reactions at 80 °C exhibit useful behaviour for evaluation of the

aFrom Equation 28.

bFrom the inverted slope of Equation 43.

c From the quotient between the slope and the intercept of Equation 28.

dFrom the quotient between the inverted slope of Equation 43 and the intercept of Equation 28. eCyclohexane/benzene ratio of 99:1.

fData from Reference 144.

same expression from the plot of kA/[B] vs [B]. Indeed, at low [B] equation 28 can be simplified to equation 29, and the slope of the plot of kA/[B] vs [B] agrees satisfactorily with the values obtained from the inversion plot. These results can be interpreted as evidence that equation 28 holds and that the simplification to equation 29 is justified10. The intercepts allow an estimation of the order of magnitude of k1k2K/k 1 and, from both quotients, the ratio k3/k2 can be reckoned (Table 26). The quotients increase with decreasing temperature in accord with the increased association constant.

In the reaction of DNA with CHA and with BA in benzene, the slopes of the curves at the origin are not zero. For the last case, the rate of the reaction allows several kinetic measurements at low [B] and exact evaluation of the slope at the origin of kA vs [B] for a range of [B] D 0 0.03 M. At 45 °C a value of 2.2 ð 10 3 M 2 s 1 is obtained which agrees satisfactorily with the value k1k2K/k 1 D 1.9 ð 10 3 M 2 s 1 obtained from the intercept of the plot of kA/[B] vs [B] constructed with the data obtained at higher [B]. The values for the reaction at 35 and 27 °C are 1.6ð10 3 and 1.4ð10 3 s 1 M 2, respectively, which agree satisfactorily with the data obtained at higher [B]. Similar agreement was found for the other systems gathered in Table 16. The satisfactory agreement between the quotients obtained from both sets of data obtained under different conditions indicates that the assumptions made are correct and the whole treatment justified.

Hirst’s proposal for the fourth-order kinetics implies an electrophilic catalysis of the second step by the homoconjugate acid of the nucleophile, BHC B (where B stands for the nucleophile). The simplified equation would be

k4 BH +B

which requires that the catalyst acts in the second step, and the derived expression is given by equation 45:

On the other hand, the eight-membered cyclic transition state mechanism proposes that two molecules of the nucleophile intervene in the decomposition of the zwitterionic intermediate. It can be described in condensed form by equation 46, and the derived kinetic expression is equation 47.

Equation 45 and 47 as well as equation 28 account for the quadratic dependence of kA with [B], with a zero intercept if the uncatalysed decomposition is assumed to be negligible. However, the peculiar kinetic behaviour observed in some systems (which has just been described) can only be explained by equation 28. Hirst148 and Banjoko170

have not reported the observation of a plateau in the plots of kA/[B] vs [B] in the reactions studied, therefore their respective mechanisms can account satisfactorily for their results. However, only the dimer nucleophile mechanism can account for the observation of the ‘inversion plots’, i.e. a linear plot of [B]/kA vs [B] 1, agreement between the several k values evaluated under different reaction conditions and a rather large range of [B].

The other alternative mechanisms discussed here, which are based on the formation of different types of complexes with the substrate, failed to accommodate additional observations, such as the conformational effects. Indeed, if any difference would be expected between the cis- and trans-1,2-diaminocyclohexane in forming complexes with the substrate, that would be in favour of an increase in rate for the reaction with the trans-isomer, contrarily to the experimental observation.

2. Evaluation of the equilibrium constants

One of the major difficulties in Forlani’s proposal of the molecular complex substratecatalyst mechanism, to explain the fourth-order kinetics, is the assumption that this complex needs an additional molecule of amine to decompose to products. The formation of molecular complexes between dinitrohalobenzenes and certain amines (especially aromatic amines) has been widely studied, and their involvement in SNAr reaction has been discussed in Section II.E. The equilibrium constants for the formation of those complexes were calculated in several cases, and they were included in the kinetic expressions when pertinent. But in all cases, the complex was assumed to be in the reaction pathway, and no need of an additional amine molecule was invoked by the several authors who studied those reactions.

In some of Forlani’s works, such as the reactions of 1-halogeno-2,4,6-trinitrobenzene with 2-hydroxypyridine123,125, a substrate-catalyst molecular complex was assumed, but the kinetic law showed the regular second order in amine. Rather interestingly in this scheme, the authors assume that the molecular complex can lead to the formation of products following a second order in nucleophile kinetics, while in the reactions with amines it was presumed that the complex was not on the reaction coordinate, and that an additional molecule of amine was required (the authors needed to include this additional molecule to account for the third order in amine rate law).

In the mechanisms involving molecular complexes discussed in Section II.E, several authors were able to calculate the equilibrium association constants, in reactions showing classical kinetics. On the other hand, Forlani and coworkers, in the reactions discussed in Section III.I, assume that the complexes intervene in determining the third order in amine kinetic law, and make calculations of some K; some results were presented in Table 13. Several features arise from this Table:

(a)The effect of adding a nitro group at the ortho-position diminishes the association constant when compared with p-chloronitrobenzene, but adding another nitro group at the other ortho-position increases K, comparatively to CDNB. The author concludes that this probably arises from a balance of the interaction of the additional nitro group and the steric hindrance of the nitro group in the ortho-position to the halogen atom, but the steric hindrance should be more noticeable in CTNB and the observed effect is the inverse.

(b)The data for the monodeutero-2-hydroxypyridine (KH/KD D 1.7 for FDNB and 3.4 for 1-fluoro-4-nitrobenzene) is interpreted as a clear indication that a major interaction is the hydrogen bond involving the halogen atom (or the nitro group), but it is not so clear, then, why the KH/KD for the 1-fluoro-4-nitrobenzene is twice the value for FDNB.

(c) The large differences between K values for FDNB in THF (17 dm3 mol 1) and in chlorobenzene (3.5 dm3 mol 1) or toluene (0.34), shown in Table 12, are also unexplained.

Taking into account these apparent inconsistencies between the values, which are rather higher than the stated errors given as standard deviations, results in suspicions us regarding the whole way of calculating of the stability constants.

3. The dichotomy of amine effects in aromatic nucleophilic substitution (ANS) in aprotic solvents

In the preceding sections throughout this chapter, several aspects of the influence of the nucleophile on the rates of the different reaction steps and/or mechanisms involved in ANS with amines have been discussed. One of the most outstanding features and most widely studied phenomena is the observation or the absence of base catalysis and, somewhat related with this subject, is the occurrence of a first, second or third order in amine kinetic law.

Hirst and coworkers198 have recently examined the dichotomy of primary and secondary amine effects in ANS in the reactions of 2-trifluoromethyl- and 2-cyano- 4-nitrofluorobenzenes with piperidine, n-butylamine, morpholine and benzylamine in acetonitrile and benzene (see Table 27). The substituents in the 2-position were chosen on the basis of their different steric requirements: the cyano group is linear and much smaller than either the nitro or the trifluoromethyl groups. For the reaction of 2-cyano-4- nitro-fluorobenzene with benzylamine the k3/k2 value is 1.9, and for the trifluoromethyl substrate the values of the ratio are: 6.0 (n-butylamine), 14.9 (piperidine) and 1.2 (benzylamine)198, According to Bunnett’s criteria these low values do not represent true base catalysis, and the authors take the measured kA values as being those for the formation

of the intermediate. The ratio of the rate constants for piperidine and butylamine kAPip/kABu are 15.5 and 4.5 for the ortho-nitro and -cyano substrates, respectively, whereas when the ortho group is the trifluoromethyl the ratio is 0.2, i.e. the secondary amine is less reactive than the primary one. This is interpreted as evidence of the operation of a primary steric effect: as we have demonstrated in an early study on the effect of 2-R substituents in ANS reactions with piperidine in benzene102, this kind of effect should only be observed with an ortho-substituent of steric requirements similar to or greater than a methyl group.

The reactions of the three substrates with morpholine showed base catalysis, and when the nucleophile is benzylamine, plots of the second-order rate constants against the nucleophile concentration have an upward curvature197. Similar behaviour exhibits the reaction of 2,4-dinitrophenyl phenyl ether with piperidine in acetonitrile182 while the corresponding reaction with n-butylamine is not catalysed182, thus providing further examples of the dichotomy of amine effects198,199. Taking into account that the dichotomy is also observed when the ortho-group is cyano, for which it has been demonstrated that there is little or no hydrogen bonding between it and the ammonio group of the -complex, the authors conclude that the effects must be steric, although these would not arise from differential steric compressions between primary and secondary amines, but from stereoelectronic effects198. The existence of stereoelectronic effects in ANS have been previously proposed by Bunnett20b,c and Hasegawa22 for reactions involving ortho-nitro groups. Bunnett and Cartano20a ascribed the very large difference in rates between piperidine and pyrrolidine to stereoelectronic inhibition of the detachment of the nucleofuge when piperidine is the nucleophile.

Since morpholine and piperidine are stereochemically similar but exhibit different pKa values, the difference between their rates in the reactions of the fluoro-substrates in acetonitrile could be also due to a change in mechanism, whereby proton transfer from the intermediate 1 in equation 1 becomes rate-limiting when the reagent is morpholine. The change from an uncatalysed to a base-catalysed reaction with decrease in basicity of the nucleophile is well known in ANS for both primary and secondary amines1,200.

TABLE 27. Rate constants (dm3 mol 1 s 1) for the reactions of 2-cyano- and 2-trifluoromethyl-4- nitrofluorobenzenes and 2-cyano-4-nitrophenylphenyl ether with some amines in aprotic solvents at 30 °C198

(continued overleaf )

has interpreted similar results as due to steric inhibition to the electrophilic catalysis of the expulsion of the nucleofuge; the authors expect that the k3/k2 values should be lower for secondary than for the corresponding primary amines, except where hydrogen bonding can take place between a group ortho to the reaction site and the ammonio hydrogen of the intermediate.

Nevertheless, the results observed for the reactions of o- and p-fluoronitrobenzenes with propylamines demonstrate that: (a) the dichotomy is not only observed when comparing primary with secondary amines; (b) the origin is not due to primary steric effects; (c) when there is no ortho-nitro group the decrease in rate for the bulky amine is greater; (d) the diminution in rate is due to an inhibition effect in the base-catalysed decomposition.

All these observations, together with the finding that in the reactions of p- fluoronitrobenzene with n-propylamine in toluene the plot of kA against n-propylamine exhibits a negative intercept, typical of a third order in amine kinetic law, are consistent with the operation of amine aggregates (‘dimers’ or ‘mixed aggregates’) in solvents of low permittivity. In the absence of an ortho-nitro group that could assist the reaction through H-bonding, and it being clear that fluorocarbon compounds are very poor hydrogenbond acceptors201, the only effective way for stabilizing the -complex is through hydrogen bonding with the amine, as observed in the intermediate formed with the ‘dimer’ nucleophile, followed by the amine catalysed decomposition. Branching in the amine hinders aggregation in the nucleophile as well as in the intermediate: this interpretation is confirmed by the solvent effects. As discussed in Section DMSO is a good hydrogenbond acceptor, forms ‘mixed aggregates’ with the amines and consistently with the whole mechanism, the reactions in DMSO are very much faster: the reaction rates with n- propylamine and iso-propylamine are of the same order of magnitude, the reaction rate with this amine being almost twice the value of n-propylamine, as expected for a better nucleophile in the absence of steric effects.

IV. CONCLUDING REMARKS

The SNAr reactions with amines in aprotic solvents pose various difficulties, related to the inability of those solvents to stabilize ionic species, as has been discussed. Several alternative mechanisms have been proposed for these reactions, specially connected with the finding of ‘anomalous’ kinetics, some of them controversial. Although we believe the case is not closed, certain features of the reactions in aprotic solvents can be considered well settled. Those are: the existence of aggregates of the nucleophile and their influence on the kinetic expressions, the formation of complexes between the nucleophile and the substrate (although their participation in the kinetic law is not completely clear); the accelerating effect of HBA additives; the formation of ‘mixed aggregates’; and the homoand hetero-conjugate acid complexes. In this respect, we agree with Hirst and coworkers109,162 that the interpretation of formation of homo- (or hetero-) conjugated acid BHC B by proton transfer from the intermediate and the electrophilically catalysed departure of the nucleofuge due to this aggregate is common to this and to the ‘dimer mechanism’ and they can be formulated as essentially the same, and as reflecting different parts of a spectrum of methods for the formation of the second intermediate, the relative importance of which depends not only on the entities employed, but on their concentrations as well. Nevertheless, there are some experimental findings such as the conformational effects and the ‘inversion plots’, that are only explained by the ‘dimer nucleophile’ mechanisms.

V. ACKNOWLEDGEMENTS

The author is deeply indebted to her coworkers in this area, whose names appear in the references. Enlightening discussions with Prof. J. F. Bunnett on many occasions