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

solvation is not as clear as in the network encountered in protic solvents. It is well known112,114,145,146,157 that amines may undergo auto-association in aprotic media giving rise to aggregates of various stoichiometry. The dominating aggregate is a dimer with typ-

ical formation constant K ¾ 0.1 M 1 (the value for cyclohexylamine in cyclohexane)145.

D

The structure of the aggregates has been studied in some cases and found to be non-cyclic oligomers146.

Amine aggregates are known145,157 to be affected inversely by temperature, hence in SNAr rates, then, overall negative energies of activation can be observed in reactions where

a pre-equilibrium, such as 2B !K B:B , exists. It has been proved in many reactions in

solution that aggregates can react without previous dissociation. One of the earlier reports is on the butylaminolysis of p-nitrophenyl acetate in chlorobenzene158, more recent ones are about the butylaminolysis of 2-hydroxy-5-nitro-˛-toluene sulphonic acid sultone in acetonitrile and toluene159, the butylaminolysis of several nitro-substituted 4-nitrophenyl benzoates and cinamates114 and on the rearrangement of the Z-p-nitrophenylhydrazone of 3-benzoyl-5-phenyl-1,2,4-oxadiazole into 4-benzoylamino-2-p-nitrophenyl-5-phenyl- 1,2,3-triazole in benzene152. Curiously, in this last reaction, the authors ‘have excluded the possibility that the amine behaves as a dimer because in other reactions catalysed by aliphatic secondary amines (e.g. SNAr) this kind of dependence on amine concentration is not usually observed’152,160. They described the effect as ‘catalysis of catalysis’, a term that was also used in the observed effect by two molecules of piperidine in the reaction of 1,2-dinitrobenzene in n-hexane115. Notwithstanding, it has been recently shown that for SNAr reactions in non-polar solvents, auto-association of amines is very important because of the low permittivity of the media and the consequent range of electrostatic forces and the importance of hydrogen bonding. These types of interactions form the basis

of the so-called ‘dimer nucleophile’ mechanism10,143,144.

It had been previously suggested114a,163,164 that amine dimers should be more nucleophilic than the free amine, since the formation of the hydrogen bond would increase the electronic density on the nitrogen atom which partially donates its hydrogen. In fact, theoretical calculations by the PCILO method165 showed that the dimers of aliphatic amines are linear, stabilized with respect to the monomer Eca, 4 5 kcal mol 1 and the examination of the electron density shows a 0.022 electron transfer. Ab initio theoretical calculations166 carried out on ammonia dimers indicate a 0.0136 electron density increase. NMR studies169 of butylamine in benzene show also that aggregation increases the amine nitrogen electron density167,168.

Besides self-association, the nucleophile can also aggregate to any other hydrogenbond acceptor present in the media, forming mixed aggregate; this effect is particularly important in solvents of low permittivity10. Tertiary non-nucleophilic amines added as catalysts are prone to form these mixed aggregates, and various authors have recently shown their formation in SNAr reactions with amines in non-polar solvents. Thus, Hirst and coworkers162 have recognized the importance of these interactions to stabilize the protonated amine in the reactions of 1-chloro- and 1-fluoro-2,4-dinitrobenzenes with morpholine in benzene, forming what they called the hetero-conjugates of the conjugate acid of the nucleophile. (See Section III.I.) Frena and coworkers152,160 described as ‘catalysis of catalysis’ the effect that requires association of a pair of amines, and this term was also used in the observed effect of pyridine in the reaction of piperidine with 1,2- dinitrobenzene in n-hexane115. In this reaction, taking into account that there are no significant changes of kA with [Py] when the constant concentration of piperidine is high, the authors concluded that piperidine is a better catalyst than the mixed aggregate [piperidine-pyridine].

Aggregation with the co-solvent may also be very important in SNAr reactions with amines in binary solvents, when the non-polar solvent is mixed with small amounts of a co-solvent that has hydrogen-bond donor or hydrogen-bond acceptor capabilities. Thus, aggregation of amines with protic solvents is very well known, and aggregation with DMSO144,161 and with other hydrogen-bond acceptor additives162 has also been shown.

Ab initio theoretical calculations show a three times stronger interaction for the solvated nucleophile CH3OH Ð Ð Ð NH3 than for the ammonia dimer167. Ab initio calculations168 on the hydrogen-bonding ability of pyridine bases with water showed a 0.03 charge transfer from the pyridine to the water molecule and the dimers are again linear, the stabilization energy being 4.7 kcal mol 1. The operation of all these mixed aggregates will be discussed below in connection with the ‘dimer nucleophile’ mechanism169.

D. The ‘Dimer Nucleophile’ Mechanism

Taking into account the self-aggregation of the amine that prevails in non-polar aprotic solvents, Nudelman and Palleros144 proposed that the observed third-order in amine could be due to a mechanism involving attack of the dimer of the nucleophile superimposed on the classical reaction with the monomer, as shown in Scheme 12 A cyclic intermediate, 36, similar to 9 proposed by Capon and Rees126, is formed straightforwardly in the addition step through the dimer of the amine. The proposed mechanism does not preclude attack by the monomer which directly would form intermediate 37, as reported for the two-step mechanism shown by equation 1. The intermediate 36 formed in the first step is in mobile equilibrium with the second classical intermediate 37, and either of them can react to form ultimate products, by spontaneous or base-catalysed decomposition. The whole reacting system is depicted in Scheme 12. A cyclic transition state was also proposed by Banjoko and Otiono170 but for the second step (decomposition of the intermediate complex, 37).

Application of the steady-state treatment to the whole mechanism gives an expression involving the seven specific rate constants for each step, the association equilibrium constant for the nucleophile, K1, and the constant for the equilibrium between intermediates 36 and 37, K2. The complete expression and the different limit situations that were evaluated are derived in Reference 144. A simplified reacting scheme, where only attack for the dimer is considered, is shown by equations 26 and 27. The dimer of the nucleophile (B:B), equation 26, attacks the substrate, S, forming the intermediate, SB2, and a third molecule of amine assists the decomposition step (equation 27). Both transition states in Scheme 12 are highly zwitterionic and the extra amine molecule should help to stabilize the developing charges in these non-polar solvents and to assist the departure of the nucleofuge (probably as suggested by Hirst, see below). The derived expression for kA in this simplified reacting scheme is equation 28.

Here K D [B:B]/[B]02 stands for the amine auto-association constant. Usually, in the reactions with amines with poor nucleofuges the second step is rate-determining, the inequality

which is responsible for the plateau observed in some cases in the plot of kA/[B] vs [B]

(e.g. the reaction of 2,4-dinitroanisole with butylamine in benzene at 60 °C, Figure 11)143a. The first report of this mechanism was published in 1980143b for the reactions of 2,4- and 2,6-dinitroanisole with butylamine in benzene, and afterwards several other systems were studied some of which are shown in Table 19. That association of the nucleophile, at relatively high [B], in SNAr reactions should increase its nucleophilicity was suggested earlier163a,171; the original proposal here is the operation of the dimer of the amine as an entity, according to the experimental evidence.

The reactions shown in Table 19 exhibit a very small overall energy of activation, and in some cases [e.g. the reaction of 2,4-dinitroanisole with butylamine in benzene (Figure 11), and with cyclohexylamine in cyclohexane and in benzene (not shown)144] negative activation energies are observed. Since the equilibrium association constant, K1,

diminishes with increasing temperature, this is a reasonable explanation for the apparently surprising ‘inverse’ temperature effect. The rate-determining step is preceded by a fast equilibrium, whereby the expected increase in rate for the slow step with increasing temperature would be compensated by a shift of the preceding equilibrium towards the monomer. Similar small or even negative overall energies of activation were observed by Banjoko and Ezeani150 for the reactions of dinitrophenyl phenyl ethers with aniline and substituted anilines in benzene.

In the cyclic intermediate proposed in Scheme 12, the second molecule of amine acts as a proton donor to the leaving group as well as a proton acceptor from the positively charged nitrogen of the zwitterion, thus stabilizing the dipolar transition state that otherwise should be quite unstable in benzene. The third molecule of amine would assist the decomposition of the zwitterionic intermediate to the products, forming the acid conjugate of the dimer through concerted detachment of the proton from the intermediate. This ‘protonated dimer’ catalyses the nucleofuge departure in the non-polar solvents10.

If this interpretation is correct, catalysis by mixed aggregates should be also observed since, as was mentioned above, amines form such aggregates in non-polar aprotic media. Overwhelming evidence of the participation of these aggregates in the kinetic law has been accumulated in recent years. One of the first systems where this effect was considered is the reaction of 2,4-dinitrofluorobenzene with o-anisidine in benzene172. A quadratic dependence of kA with [B] was observed and interpreted as due to a hydrogen-bonded dimer operating as the main nucleophile in a mechanism similar to that shown in Scheme 12. When the reaction is run in the presence of a hydrogen-bond acceptor (HBA) such as pyridine, a new mixed associated nucleophile, B:P, is present in the system as depicted in Scheme 13. Three competing nucleophilic reactions are shown: attack by the dimer (measured by k1), by the monomer (determined by k4) and by the B:P complex (measured by k7). An equilibrium between the three possible tetrahedral intermediates (36,37,38) is established (measured by the equilibrium constants K2, K3 and K4), k 4 being greater than k0 1 and k0 7 as discussed earlier. The whole kinetic expression for kA as well as the simplification that can apply to limit situations are fully discussed in Reference 172; the general expression for kA can be reduced to equation 31, which can be written in the condensed form of equation 32.

Several experiments were carried out to test equation 32 and the four constants could be evaluated; the determined values are shown in equation 33172. It can be observed that catalysis by a HBA-nucleophile complex is more important than for the nucleophile itself, as expected on the basis of the ‘dimer nucleophile’.

Experiments carried out in the range [B] D 0.025 0.1 M, in the presence of pyridine, [P] D 0.037 and 0.062 M, showed that equation 31 holds in the whole range of [B] studied, i.e. 0.02 0.8 M. At low [B] the points for kA vs [B] approach a straight line of slope 5.0 ð 10 5 s 1 M 2 and intercept 3.8 ð 10 5 s 1 M 1 (for [P] D 0.037 M). If equation 32 holds, the slope of kA vs [B] at the origin is a measure of k˛ C k [P]. This term was measured and found to be 4.4 ð 10 5 s 1 M 1, which agrees fairly well with

the value of 5.9 ð 10 5 s 1 M 1 found for the runs at low [B], showing that equation 32 holds in the whole range of [B] studied172.

SCHEME 13

From the magnitude of the calculated constants it is possible to estimate a higher limit for the value of the uncatalysed term in equation 31; since k [P] is between 2 and

8ð10 5 s 1 M 1, the uncatalysed term should be <6ð10 7 s 1 M 1. For measurements of this term it would be necessary to work at very low [B] and also at very low [P], but then the reactions would become too slow to be measured.

In terms of the ‘dimer mechanism’ a term in [P]2 would also be expected in special systems according to the reacting scheme shown in Scheme 13. Actually, one molecule of pyridine would act forming the mixed associate nucleophile, and the second molecule

Linearization of the amine profiles (kA/[B] vs [B]) shows decreasing slopes for 0 25% methanol, consistently what would be expected on the basis of the mechanism depicted in Scheme 12. The continuous diminution of the slope with increasing methanol percentage shows the continuous diminution in the auto-association constant of the amine, K, to be practically nil at 25% methanol175. For higher methanol content in the mixed solvent, the classical mechanism is observed.

F. Catalysis by Methanol

The above interpretation of specific solvent effects on the ‘dimer nucleophile mechanism’ has been recently criticised, however, by Banjoko and Bayeroju155 in a paper which they called “strong evidence against the ‘dimer’ mechanism”. Their contention was that the observed decrease in rate is due to a special feature in the reaction of 2,6-dinitroanisole (2,6-DNA) with cyclohexylamine in benzene175. Since they did not observe similar behaviour in the reaction of phenyl 2,4,6-trinitrophenyl ether with aniline in benzene-methanol155 they proposed that the retarding effect observed in the reaction of 2,6-DNA with cyclohexylamine is the result of the reaction being reversible. According to their suggestions, since methanol is formed as a product arising from the nucleofuge departure, additions of small amounts of methanol to the solvent would result in a decrease in rate as expected by Le Chatelier’s principle. This argument, obviously, does not take into account the rising portion of the curve, and the fact that the reaction produces quantitatively N-(2,6-dinitrophenyl) cyclohexylamine even in pure methanol. Moreover, the authours even suggest that all reactions of amines with substrates having methoxy nucleofuges are likely to be reversible.

Although this argument could be refuted by the observation of the ‘dimer nucleophile’ in other systems10, it was of interest to examine the effect of addition of a hydrogenbond donor(HBD) co-solvent different from methanol, to the reaction of a substrate where the nucleofuge is methoxide, such as the reaction of 2,6-DNA with cyclohexylamine in

In the reactions of 2,6-DNA with cyclohexylamine [B] D 0.264 M in toluene and in octanol at 35, 45 and 60 °C, it was observed that at 35 °C the reaction is slightly faster in toluene than in octanol, whereas at 45 and 60 °C the inverse is observed177. These results show, once more, the difficulties of studying related reaction rates at a single temperature. A very low enthalpy of activation is observed for the reactions in toluene consistently with the operation of the ‘dimer’ nucleophile mechanism. The reaction in octanol shows a higher enthalpy of activation and also a slightly higher entropy of activation177.

To add new experimental evidence to the argument of competition between selfand mixed aggregates, the reaction was studied in toluene octanol mixtures at the same base concentration that was used in studies in toluene methanol, i.e. [B] D 0.4 M. A continuous increase in rate on addition of increasing amounts of octanol to toluene would be expected on the basis of Banjoko and Bayeroju’s arguments155. On the contrary, a decrease in rate is observed on small additions of octanol (Figure 13b), up to nearly 30% of octanol where the valley of the curve is reached; then it begins to increase up to the value in pure octanol. As expected, on the basis of a special effect of a medium hydrogen-bond donor co-solvent that competes with the amine itself for aggregation, the reaction in the toluene octanol system exhibits a similar, albeit smaller, dependence on the protic solvent content than that observed in the toluene methanol system104.