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

a[DNA] D 20 ð 10 4 mol dm 3.

G. Catalysis by Hydrogen-bond Acceptor (HBA) Additives

If the ‘dimer mechanism’ interpretation is correct, addition of a HBA co-solvent, e.g. dimethyl sulphoxide (DMSO) ˇ value D 0.76 178, in catalytic amounts should increase the reaction rate by forming a mixed aggregate RNH2 Ð Ð Ð OS(CH3)2 (B:DMSO), equation 35, where the amine acts now as a HBD, and therefore this mixed aggregation should increase its nucleophilicity. DMSO has been shown to increase the nitrogen electron density of primary and secondary amines161.

The reaction rate of 2,6-dinitroanisole with cyclohexylamine in toluene increases rapidly with small additions of DMSO up to 0.5%; then the increase with [DMSO] is slower108.

Studies of the amine concentration rate dependence show that the reactions are strictly third-order in amine for DMSO <2%. For DMSO constants >10% the reactions show the classical behaviour usually found in base-catalysed SNAr180. The specific solvent effects observed for small additions of the HBD co-solvent are consistent with the formation of the mixed aggregate, and a linear correlation was found between kA and [DMSO], shown by equation 36, which expresses that the third-order term is more affected by the small additions of DMSO than the fourth-order term. Equation 36 is valid for [DMSO] <2% (0.282 M).

Although the catalytic effect of the aggregation of the nucleophile with DMSO could also operate in the second step, the above interpretation is preferred since it also explains the early reported ‘anomalous’ catalytic effect of small additions of DMSO (<0.2 M) observed when the first step is rate-determining (i.e. reaction of 2,4-dinitrochlorobenzene with piperidine in benzene)181.

Similar rate accelerations due to the addition of small amounts of DMSO were found in the reactions of 1,2-dinitrobenzene with butylamine in benzene. While the reaction is almost insensitive to other additives, the accelerations observed upon addition of DMSO to benzene exceed expectations based only on considerations of the polarity of the medium9. Catalysis by other HBA additives was recently studied by Hirst and coworkers162 in connection with the ‘homo-/hetero-conjugate mechanism’.

H. The Homoand Hetero-conjugate Mechanisms

Hirst and coworkers proposed in 1977182 that in the reactions of 2,4,6-trinitrophenyl phenyl ether with aniline in benzene, aggregates can be formed between the nucleophile and its conjugate acid, which can be formulated as NuHNuC, and the reaction would take place within aggregates by SB-GA. They explained148 the upward curving plots as being due to electrophilic catalysis of the expulsion of the leaving group by homoand hetero-conjugates of the conjugate acid, as shown in Scheme 14, where I and II refer to the intermediates in equation 1 and Scheme 1, and Nu is the nucleophile.

I C Nu II C NuHC

NuHC C Nu NuHC Nu

II C NuHC Nu products

SCHEME 14

Accelerations of the rates due to an additive P are explained as electrophilic catalysis by the heteroconjugate NuHCP, while a second-order term in the concentration of P can be obtained if the relative basicities of Nu and P are such that P can compete with Nu for removal of the proton from I followed by electrophilic catalysis by the homoconjugate PHC P.

Support for this mechanism has been obtained from the study of the effect of twelve hydrogen-bond acceptors on the reactions of 1-chloro- and 1-fluoro-2,4-dinitrobenzenes with morpholine in benzene162. The reaction of 1-chloro-2,4-dinitrobenzene is not catalysed by either morpholine or DABCO, i.e. kA D k1; the first stage of the reaction is rate-determining and the various additives have no effect on the rate constant. On the other hand, Table 22 shows that the reaction of the fluoro-substrate is highly sensitive to the presence of the various additives and it is base-catalysed while for ten additives there was a linear dependence of kA on either their concentration, [P], or on the square

of their concentration, [P]2. An approximately linear correlation was found between the logarithms of the factors which measure the dependence on [P] and the hydrogen-bonding parameter, ˇ179. The authors correlate the slopes with the former pKHB ‘Taft parameter’, which is now called the hydrogen-bonding parameter, ˇ179. The acceptors, P, consisted of a variety of substances ranging from acetonitrile through nitrobenzene and pyridine N-oxide to hexamethylphosphoric triamide, and covered a range of pKHB values from 0.90 to 3.56. Anisole and dimethylaniline with very low pKHB values of 0.02 and 0.45 did not produce accelerations.

The effect is interpreted as evidence of the operation of the homo-/hetero-conjugate mechanism. The authors presume that for the mechanism given by equation 1, for additives P which are much less basic than the nucleophile N, electrophilic catalysis also occurs both with the hetero-conjugate NC HP formed between the conjugate acid of the nucleophile, N, and P, as well as with the homo-conjugate NuC HNu. For more basic additives, electrophilic catalysis is possible by the species PHC and its homo-conjugate

PHPC153,162,182 .

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 intermediate153. For a given nucleophile, dimer formation increases with increase of concentration, hence the relative importance that reaction via a dimer should increase with increasing nucleophile concentration.

I. The Substrate Catalyst Molecular Complex

That the formation of molecular complexes (especially EDA complexes) can catalyse the decomposition of the -adduct has been discussed in Section II.E. Another possibility is that the substrate and catalyst (nucleophile or added base) form a complex which is then attacked by a new molecule of the nucleophile: in this context catalysis need no longer be associated with proton removal. Thus, Ryzhakov and collaborators183 have recently shown that the N-oxides of 4-chloropyridine and 4-chloroquinoline act as - donors toward tetracyanoethylene and that the reactions of these substrates with pyridine and quinoline are strongly catalysed by the -acceptor. Similarly, the formation of a Meisenheimer complex between 1,3,5-trinitrobenzene and 1,8-diazabicyclo[5,4,0]undec- 7-ene in toluene has been assumed to take place via an association complex to explain the observed second-order in tertiary amine184.

A new assumption to be discussed in this section is that the fourth-order kinetics in SNAr by amines in aprotic solvents is due to the formation of the substrate-catalyst molecular complex. Since 1982, Forlani and coworkers149 have advocated a model in which the third order in amine is an effect of the substrate nucleophile interaction on a rapidly established equilibrium preceding the substitution process, as is shown in Scheme 15 for the reaction of 4-fluoro-2,4-dinitrobenzene (FDNB) with aniline (An), where K measures the equilibrium constant for:

K

FDNB C An ! FDNB Ð An

If, for the sake of simplicity, it is assumed that the reaction proceeds only via the molecular complex, according to Scheme 15 the relation between kA and [An] is shown by equation 37.

k′′2

Products (I) . ArNH2 k′′3 (A rNH2 )

SCHEME 15

Scheme 15 could be a reaction pathway parallel to the classical reaction (equation 1), and it was postulated to explain the third order in amine observed in the reactions of FDNB and aromatic amines in benzene and in chloroform184. The K values were calculated from the absorbances of the reaction mixture extrapolated to zero reaction time, in a wavelength range in which the starting materials do not show an appreciable absorbance value. Good agreement was observed between the values of K for the FDNB/aniline complex in chloroform by U.V. and 1H-NMR spectroscopy, as well as for the K obtained kinetically (based on Scheme 15) and spectroscopically.

Catalysis by DABCO in the reactions of FDNB with piperidine, t-butylamine, aniline, p-anisidine and m-anisidine (usually interpreted as base catalysis as in Section II) was also assumed to occur by the formation of a complex between DABCO and the substrate149b. The high (negative) -value of 4.88 was deemed inappropriate for the usually accepted mechanism of the base-catalysed step (reaction 1). For the reactions with p-chloroaniline, m- and p-anisidines and toluidines in benzene in the presence of DABCO a -value of2.86 was found for the observed catalysis by DABCO (k3DABCO). The results were taken to imply that the transition state of the step catalysed by DABCO and that of the step catalysed by the nucleophile have similar requirements, and in both the nucleophilic (or basicity) power of the nucleophile is involved. This conclusion is in disagreement with the usual interpretation of the base-catalysed step.

The reaction of FDNB with aniline, first studied in toluene and in chloroform, was then extended to other solvents: in the reactions with aromatic amines, the order changes from two in solvents of considerably donicity (THF, dioxane) to three in solvents of low donicity (benzene, carbon tetrachloride), and is explained as arising from competition between the solvent and amine for complex formation with the substrate185. (Molecular complexes formed within benzene and 1,2-DNB were discussed in Section II.E.) In the presence of a constant initial concentration of triethylamine (TEA) approximately of the same magnitude as that of the nucleophile, the reactions of FDNB with both aniline and p-chloroaniline in benzene are no longer catalysed by the nucleophile, while catalysis is observed when the reagent is p-anisidine185. This is interpreted as evidence of the substrate-catalyst association. Considering that the K value for FDNB-TEA 0.47š 0.17 is higher than that between FDNB and aniline (0.062) and p-chloroaniline (0.02) the insensitivity to catalysis by the nucleophile is assumed to be due to a ‘saturation’ phenomenon (complete formation of the molecular complex FDNB-TEA) that precedes the attack of the nucleophile. Since the association constant of TEA and p-anisidine (0.67) is of the same order of magnitude than FDNB-TEA, catalysis of the reaction by the nucleophile still takes place in the presence of TEA.

Nevertheless, when other solvents were studied, no total consistency is observed between the magnitude of the equilibrium constants and the experimental order in

amine. Thus, while the reactions in chloroform K D 0.37 š 0.9 and in chlorobenzeneK D 0.27 š 0.1 are third-order in amine, the reaction in 1,4-dioxane K D 0.81 š 0.7 is second-order in amine186. These peculiarities were not explained. The reactions of FDBN with substituted 2-aminothiazoles in benzene are not catalysed by the nucleophile (they do not form molecular complexes), however the reactions are catalysed by DABCO, 2-hydroxypyridine and ˛-valerolactam. Forlani has shown that ˛-valerolactam forms a hydrogen-bonded complex with the substrate and similar complexes are formed between 2-hydroxypyridine and aromatic nitro derivatives187.

The reaction of 1,3,5-trinitrobenzene (TNB) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in toluene184 was also proposed to proceed by the mechanism shown in Scheme 16. The visible spectrum, recorded immediately after mixing appropriate solutions of TNB and DBU in toluene, shows a feeble absorbance maximum at 505 nm, which changes to a stable maximum at 468 nm, after variable reaction times. The first maximum was attributed to a molecular complex between TNB and DBU, and the second maximum at the Meisenheimer complex, 39, although NMR structural determinations were not possible, because of the low solubility of the complex in toluene.

zwitterionic complex

I

SCHEME 16

(CH2 )5 N

+

H N

−

NO2

(39)

Under the experimental conditions [TNT] × [DBU]0, the rate of formation of the second maximum (468 nm) is slow and the authors could make a quantitative evaluation of the first interaction attributed to the formation of a molecular complex (MC). The low reactivity under these conditions was interpreted as due to the fact that the MC has very little tendency to rearrange to the zwitterionic complex, since the amount of DBU complexed by TNB would be unavailable for the nucleophilic attack. Since in this system the basecatalysed step for departure of HL does not exist, the small increase in kobs values with the [DBU] was interpreted as evidence of the mechanism shown in Scheme 16. Similarly, the increase in kA with [amine] observed in the reactions of FDNB with butylamine in

toluene, usually considered base-catalysed, was recently reinvestigated188 and interpreted as produced by the formation of a substrate-amine molecular complex, which with another amine molecule rearranges to the Meisenheimer complex as shown in Scheme 16. Nevertheless, several conceptual problems are associated with this alternative interpretation. One of the major conflicts between this mechanism and that described in Section II.E is the requirement of an additional molecule of amine, associated with the assumption that the molecular complex cannot evolve to the intermediate.

J. The ‘Desolvative Encounter Mechanism’

Hayami and Sugiyama189 have recently found that picryl fluoride in acetonitrile follows second-order kinetics with saturation behaviour, while essentially no Brønsted base catalysis was observed, as would be suspected from the ‘rate-limiting nucleophilic’ addition of the nucleophilic amines. Interestingly, picryl chloride was more reactive than picryl fluoride in the presence of a low concentration of the amine nucleophile 2,4- dimethoxyaniline (DMA). The diminished reactivity of picryl fluoride is proposed to stem from the unfavourable encounter complex formation and also from the unfavourable first-order reaction in the complex. The reaction shown in Scheme 17 is proposed as the ‘desolvative encounter mechanism’. It is suggested that in acetonitrile, strongly solvated picryl fluoride, [Pic (Sol)n], is only slightly desolvated on encounter with the first molecule of the nucleophile, so that the solvation is still tight, preventing it from nucleophilic attack by the nucleophilic partner in the complex. However, the participation of a second molecule of the nucleophile would result in a more profound desolvation allowing a productive attack, and would allow the faster reaction in the k2 step for the picryl fluoride (3150, at 298 °C) than picryl chloride (5.2), thus showing a reactivity order parallel to the intrinsic reactivity of these substrates.

PicX.(Sol)n + DMA

k1

K

PicX. (Sol)m . DMA Products

k2 , DMA

SCHEME 17

The calculated equilibrium constants for the ‘encounter complex’ are given in Table 23189. The K value for the complex between 2,4-dimethoxyaniline and picryl chloride is higher than that for picryl fluoride, and this is proposed to be responsible for the higher rate observed for the chloro-substituted compound. The calculated equilibrium constants for the ‘encounter complex’ are different from those for the ‘charge-transfer (or EDA) complex formation’, as shown in Table 23. If the charge-transfer complex were formed through the ‘encounter or association complex’, the equilibrium constant for the charge-transfer complex formation should be larger than that of the encounter complex. Since this is not the case, the authors proposed that the desolvation for the encounter should be much lighter than that required for the charge-transfer peripheral desolvation in the former interaction against the double facile desolvation in the latter (m < n, in complexes 40 and 41). The authors propose that the two interactions constitute different association (reaction) channels and that the charge-transfer complex would not lead to any action of the nucleophile on the substrate189.

K. Conformational Effects

Most of the novel mechanisms hitherto presented were based on the observation of overall fourth-order kinetics (third-order in amine). Nevertheless, this result gives an account only of how many molecules are involved in the rate-determining step. It cannot distinguish, e.g., between three mechanisms that could be depicted as equations 38 40.

To strengthen the point that a dimer nucleophile mechanism could be responsible for the observed third-order dependence on amine and some other peculiar features, some of them already described, a nucleophile was chosen in which intramolecular N HÐ Ð ÐN hydrogen bonding could exist. With such a nucleophile, the reaction with the intramolecularly H-bonded nucleophile should be faster than with the non-H-bonded molecule; and, furthermore, a third-order rate dependence in amine should not be observed for systems (substrate and solvent) where this kinetic behaviour has been found in SNAr reactions with related amines143,144. The plot of the rate of reaction of FDNB with cyclohexylamine in toluene against [B] exhibits a slight upward curvature, typical of a third-order dependence on [B]190. On the contrary, the reactions of trans-1,2-diaminocyclohexane, 42, shows a linear dependence of kA on [B]: it is known that diaxial interactions in this type of amines prevent self-association190 and the kinetic behaviour is that usually found in the classical base-catalysed rate-determining decomposition of the zwitterionic intermediate. However, a more interesting result, expected within the dimer nucleophile mechanism, is the more

TABLE 24. Reaction of 1-fluoro-2,4-dinitrobenzene (FDNB) with cyclohexylamine, and with 1,2- diaminocyclohexane (DACH) in toluene at 5 °Ca190

a[FDNB] 2.05 ð 106 mol dm 3; error in kA < 2%.

than twofold increase in rate with the cis-isomer, in spite of enhanced steric hindrance. Intramolecular hydrogen bonding between both amine groups in the cis-configuration, 43, increases the nucleophilicity of the hydrogen-bonded donor amine, thereby increasing the rate190 (Table 24).

Consistent with this interpretation is the effect of addition of small amounts of a hydrogen-bond donor solvent. The rate behaviour is compared with that found before in the reaction of the same substrate with piperidine in benzene ethanol mixtures. It is shown that the reaction with piperidine is base-catalysed k3/k2 D 1230 , no selfassociation of the nucleophile in benzene is observed and when small amounts of ethanol are added an important increase in rate is observed. On the other hand, an important decrease in the rate of reaction with the cis- and trans-1,2-diaminocyclohexane mixture was observed on addition of small amounts of methanol. The rate decreases up to 50% toluene 50% methanol and then a two-fold increase in rate takes place on going to pure methanol. The sharp decrease in rate is interpreted as partially due to the rupture of the intramolecular hydrogen bonding between both cis-amino groups, by competition with external hydrogen bonding with the good HBD methanol ˛ D 0.93 178.

The data allowed calculation of the rate ratio shown in Table 25190. The k3/k2 quotients for both nucleophiles are almost equal; the more than two-fold increase in rate observed for the cis-isomer should then be due to a similar increase in k1 or a decrease in k 1. It is reasonable to expect that k 1 would be similar for the two amines (or even bigger for the cis-isomer due to the greater steric effects); thus the increase in rate observed with the cis-1,2-diaminocyclohexane should be due to an increase in k1. The k 1 values were calculated in both cases by standard procedures and it was found that the value is five times greater for the cis-isomer (Table 25). This enhanced rate in the first step is

fully consistent with the proposal of an ‘intramolecularly self-associated nucleophile’ in solvents of low permittivity190.

This proposal finds good support in the gas-phase basicities (GB)68 of various polyfunctionalized amines recently determined. An intramolecular stabilization of protonated polyfunctional groups, also called ‘internal solvation’, has been observed in the gas phase with the amidinium and guanidinium cations86,191,192. This effect is due to cyclization by internal hydrogen bonding between the protonated functional group (Y) and a hydrogenbond donor group (X), 44. Studies of substituent effects on the basicity of amidines and guanidines in solution193 have shown that the amino nitrogen is the preferred site of protonation in solution, similarly as in the gas phase. Thus, the pKa values can be directly compared with the GB values: good regression values are obtained for the plots of pKa vs GB; in the alkyl systems the polarizability P effect seems to be the most important parameter, whereas for aromatic systems other terms are also contributing.

H

+Y X

(CH2 )n

(44)

The bicyclic amidines 1,5-diazabicylo[4,3,0]non-5-ene (DBN, 45), 1,5-diazabi- cylo[4,4,0]dec-6-ene (DBD, 46) and 1,5-diazabicylo[5,4,0]undec-7-ene (DBU, 47) are widely used in ANS as base catalysts, because they exhibit high basicity and low nucleophilicity; the GB values are 993.9, 999.6 and 1002.9, respectively86. It is interesting that the proton affinity (PA) of DBN (1025.7)86 derived from the experimental GB measurements is very similar to the recently reported PA of arginine (1025.9)194. Raczynska and coworkers86 suggested that the strong GB of arginine may be due to the ‘internal solvation’ of the guanidinium cation, 48. In histamine, 49, an important biogenic molecule, Raczynska and coworkers86 have demonstrated the existence of