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

1236

TABLE 7. Experimental and literature kinetic constants for SNAr reactions of BunNH2 and But NH2 with several substrates9

aT 37 °C. bT 27 °C. c T 25 °C.

mild acceleration observed conforms to the mathematical form of equation 12; k0 and k00 become the terms k1k2/k 1 and k1k3/k 1, respectively, when the effect is due to authentic base catalysis, as is the case of the reactions with p-fluoronitrobenzene.

Examining the results of the reactions of o- and p-fluoronitrobenzene with n- propylamine and isopropylamine in toluene and in DMSO, the observed very low k00 :k0 ratio for the reactions of o-fluoronitrobenzene clearly shows that decomposition of the intermediate -complex is not a slow step. Efficient activation in this reaction requires coplanarity of the o-nitro group (the nitro-oxygen atoms support a strong negative charge as shown by theoretical calculations)83a,b and the result is interpreted as due to the strong hydrogen bond formed between the ammonium hydrogen and the oxygen atoms, which loosens the N H bond (calculations show that a real hydrogen transfer occurs in the vacuum)83a. It was observed that branching in the amine does not produce a highly significant decrease in the rate (see also Table 28).

The reaction of p-fluoronitrobenzene with n-propylamine, on the contrary, proceeds almost exclusively by the base-catalysed step. Very interestingly, this reaction exhibits a 100-fold decrease in rate when compared with the reaction with n-propylamine in toluene. It is obvious that primary steric effects cannot be greater than those in o- fluoronitrobenzene: interestingly, it was found that the large diminution in the rate is due to the great slowness of the base-catalysed step82. Therefore, when comparing reactivities in reactions with fluorine substrates, steric effects of the nucleophile must be examined at different amine concentrations; it is almost certain that primary steric effects should be low, but stereoelectronic effects on the hydrogen abstraction in the intermediate complex are expected to be important: the o:p ratio for isopropylamine in toluene is ca 104. Although it may be argued that branching in the amine reduces the k3/k 1 values not only by reducing the rate of proton transfer (k3) but also by increasing the rate of decomposition of the zwitterionic intermediate to reactants (k 1) because of steric congestion, this effect was shown to be not very important with the reactions of o-fluoronitrobenzene (see Table 28) and also with the reactions of p-fluoronitrobenzene in DMSO82. It was observed that kn propylamine/kiso propylamine changes from 100 in toluene to almost 1 in DMSO where the first step is rate-determining.

Consistently with these arguments, analysis of the data in Table 7 indicates that stronger influence of steric effects is exerted on k00 (related to k3) than on k0 (related to k2). It is also observed that the ratios of k0 seem to depend on the substrate, while the ratios of k00 for the same reactions are higher (stronger retardation effects) and similar, despite the nucleofuge9. There is evidence21 for unfavourable stereoelectronic conformational effects when the transition step contains piperidine groups and it has been also recently reported that a change from primary amines to piperidine results in a reduction in the rate of proton transfer24.

Section III will show the importance of amine aggregates in SNAr reactions in aprotic solvents when the second step is rate-determining: it is obvious that branching of the amine will diminish the formation of the aggregates that help the proton transfer and the nucleofuge departure from the -complex.

4. Gas-phase basicity scales

The advent of techniques that enable the study of fast reactions in the gas phase, such as ion cyclotron resonance (ICR) spectrometry, Fourier-transform ion cyclotron resonance spectrometry (FT-ICR) and high pressure mass spectrometry (HPMS), allowed the measurement of the gas-phase proton affinities for strong bases84 86 as well as for

low-basicity compounds87 91. These data are useful as a reference for further estimations of the specific solute solvent interactions when the compounds are used in solution, especially in solvents of low permittivity (i.e. low dielectric constant).

Recent measurements for the following gas-phase proton transfer equilibria:

BiHC C B0 ! Bi C B0HC , υ G° D RT ln K

where B0 is the reference base, have been made by ICR, FT-ICR87,88 and HPMS91,92, covering a wide interval between 41 kcal mol 1 and 318.2 kcal mol 187 .

Superbases. Measurements of the basicity of very strong bases have been carried out in the gas phase, extending the gas-phase basicity scale for organic compounds

up to PA D 1050 kJ mol 184 86 , and a basicity scale for these superbases has been recently proposed86,87,93. Raczynska and coworkers, studied a series of amidines84,85 and guanidines86 using the gas-phase values for Pr3nN and Bu3nN85 as the starting points in the basicity scale. A quantitative comparison based on the Taft and Topsom analysis94 was conducted for alkyl substituents, for which the relative basicities (υRGB) obey equation 13:

where a is the reaction constant for the polarizability effect and a is the directional polarizability parameter of Taft and coworkers94,95. An interesting intramolecular stabilization has been observed with the amidinium and guanidinium ions, that will be discussed in Section III. M, because of its connection with the ‘dimer’ mechanism.

Weak bases. Several basicity scales have been suggested, such as the HPMS91 and the FT-ICR87,88 basicity scales. Most of the investigations have been centred on compounds which are usually more basic than water, but Table 8 shows the recently measured relative basicities υ G0 and the basicity relative to ammonia, υ G0(NH3) of very low-basicity compounds, determined by FT-ICR87.

The FT-ICR gas-phase basicity scale for the weak bases87,93 can be compared with the results obtained by McMahon and coworkers91,92 using ICR and HPMS spectrometric techniques. Satisfactory agreement was found with the existing ICR data, but some variances were observed with the HMPS results.

5. Solvation effects on relative basicities

The overall importance of the medium on the reaction rates has been shown previously, but the nature and extent of solute solvent interactions can alter tremendously various properties of the nucleophile; the variations are usually satisfactorily correlated by some of the several quantitative structure activity relationships (QSAR) that have been discussed37,38,51,96. The term quantitative structure property relationship (QSPR) has been recently proposed for cases where a specific property, such as the basicity, is examined97.

The QSAR technique, widely developed by Kamlet, Taft and coworkers38,98 for the prediction of specific solute solvent interactions, has been used to predict the different solute solvent contributions to property variations of compounds. The influence of solvent on the relative basicity of dipolar trimethylamines has been recently studied: a descriptor was developed to describe a unique solute solvent interaction involving dipolar amines99.

υ G°(NH3)a,b,87a . Reprinted with permission from Reference 87a. Copyright (1994) American Chemical Society

aAll quantities are given in kcal mol 1.

bυ G° NH3 D G° NH3 G (base).

c See also S. G. Lias, J. E. Bartmess, J. F. Liebman, J. L. Holmes, R. D. Levin and G. W. Mallard, J. Phys. Chem. Ref. Data, 17, Suppl. 1 (1988).

It was found that a better representation of non-specific interactions between solvents and the monosubstituted dipolar trimethylammonium ions is gained from the product of Ł and the solvent dipole moment ( ). The obtained results were compared with the gas-phase basicity and the solvent attenuation factors (SAF) were calculated99.

The multiparametric equation 14 has been also applied to estimate solvent effects on the relative basicities υ G of propylamines97:

where the intercept, i.e. υ G0, represents the relative basicity in the absence of solvents.

TABLE 9. Solvent solvatochromic parametersa and the relative basicities (υ G) of propylamines in the gas phase and various solvents (values are in kcal mol 1 at 298 K and relative to diethylamine)97. Reprinted with permission from Reference 97. Copyright (1995) American Chemical Society

aFrom Reference 101.

b(Gas), gas phase; AQ, water; MeOH, methanol; EtOH, ethanol; 2-PrOH, propan-2-ol; EG, ethylene glycol; DMSO, dimethyl sulphoxide; AN, acetonitrile; NB, nitrobenzene; NM, nitromethane.

c Gas-phase basicity values are taken from D. H. Aue and M. T. Bowers, in Gas Phase Ion Chemistry (Ed. M. T. Bowers), Vol. 2, Academic Press, London, 1979.

Table 9 shows the basicity variations of propylamines in the gas phase and in different solvents, relative to diethylamine; the equilibrium is given by equation 15.

Propylamines with positive basicity values are less basic than diethylamines, and propylamines with negative values are more basic than diethylamines. The expected order Pr3N > Pr2NH > PrNH2 is observed in the gas phase, while in solution the basicity trend shown in Table 9 indicates that dipropylamine is the most basic amine in all the solvents used, except in DMSO, where propylamine is the most basic amine. Analysis of the different solute solvent interactions carried out by the correlation coefficients found for equation 14 shows that the dipolarity polarizability term ( Ł ) has an important contribution (the coefficient changes from 2.4 for PrNH2 to C3.9 for Pr3N), possibly due to the different interactions in the ammonium ions. It has been shown that alkyl substituents which are polarizable98 do contribute to the reduction of the positive character of the ammonium ions, although this contribution is highly attenuated in solution100. The solvent basicity (ˇ) is also important because the number of acidic sites differs for the different types of ammonium ions. Propylammonium ion has three acidic hydrogens at which individual specific solute solvent interactions take place. On the other hand, tripropylammonium ions depend strongly on this specific interaction for the dispersal of the charge into the solvent. This is shown by the b values, that change from 2.3 to C4.3. Thus, for the basicity of propylamines in solution, solute solvent interactions of the ammonium ions with the dipolar basic solvents seem to play the greatest role in the determination of the relative basicities. This observation is consistent with that made for the basicity of substituted ethylamines, in which it was shown that their basicities are very sensitive to the polar, acidic and basic nature of the medium101.

D. The Influence of the Substrate

1. Steric and conformational effects

The relative importance of steric effects in the substrate on the rates of SNAr reactions with amines in aprotic solvents was studied earlier and it was shown that the rates

of reaction of 2-nitro-6-alkyl chlorobenzenes with piperidine in benzene could be satisfactorily correlated with the -Hammett substituents102. Correlations including steric parameters did not significantly improve the linear regression coefficient. This means that substitution in both sites of the reaction centre does not produce severe steric congestion that would affect the rates unless very bulky substituents were present. Thus, in the case of the reactions of 2-nitro-6-alkyl chlorobenzenes with piperidine in benzene only the bulkiest substituent, the 6-methyl group, was out of the straight line102.

Similar results were then found for piperidino-debromination of various nitro-activated five-membered ring heterocycles103. The existence of such linear Hammett plots for ortho-substituted substrates was interpreted as a peculiar feature of five-membered ring heterocycles, where steric effects of substituents ortho to the site of the nucleophilic attack are minimized1a.

It was recently shown that also the reactions of 2-nitro-6-alkyl anisoles with amines in aprotic solvents are not strongly influenced by steric effects104. On the contrary, it was observed that even the 6-methyl-2-nitroanisole reacts with cyclohexylamine about 15-fold faster than the 4-methyl-2-nitroanisole. The absence of primary steric effects and even the increase in rate can be understood by considering some substrate conformational features. When one of the ortho positions is not substituted, the methoxy group may be coplanar with the ring, but when both ortho positions are substituted, rotation of the methoxy group was predicted. The loss of coplanarity would result in a decrease of resonance stabilization, as can be seen in Figure 6; this was proposed as the reason that makes the 6-substituted compound more reactive104. Further crystallographic studies of related anisoles and phenetoles confirmed that the alkoxide group is almost perpendicular to the aromatic ring105. Thus, an X-ray determination of the structures of both 2,6- and 2,4-dinitroanisole revealed that when methoxy is ortho-substituted on one side alone, the methoxy group makes only a very small angle (5°) with the ring, whereas when there are two nitro groups adjacent to methoxy, the methoxy group makes a large angle with the ring (79°), as shown in Figure 7105.

Taft and coworkers106a, have recently reviewed the substituent and structural effects in a comprehensive analysis of substituents constants106a, followed by a survey of structural effects in organic chemistry106b.

2. o- vs p-Activation

For SN Ar reactions with amines, the presence of a nitro group in a position ortho to the nucleofuge plays an important role. In spite of the steric effects which will tend to decrease the reactivity of o-nitroaromatics, and the fact that the rate-enhancing effect of the resonance stabilization of the transition state will be more important from the para position, a ko/kp ratio greater than unity is usually found in the reactions of

H R

Me

R O O

Me

N O N O

O O

FIGURE 6. Orbital interactions in 4-R- and 6-R-2-nitroanisoles104

FIGURE 7. ORTEP plot of 2,6-dinitroanisole105. Reproduced by permission of the International Union of Crystallography

with amines. This ratio is always greater for reactions carried out in aprotic solvents than those in protic solvents1b,2c,107.

This inversion in reactivity has received considerable attention, and recent studies have contributed to a better understanding of the transition states and intermediates in the SNAr reactions with amines. Several explanations have been proposed for the greater reactivity of the o-nitro derivatives with amines. The first, which is applicable to most of the systems, is an enhanced stabilization of the zwitterionic intermediate through intramolecular hydrogen bonding between the ammonio proton and the ortho-nitro group (a phenomenum visualized in structure 6a and earlier called ‘built-in solvation’)2c. Although this proposal has been criticized, independent evidence that such intramolecular hydrogen bonding indeed occurs has been obtained from a proton transfer study, that suggests a hydrogen bond of about 9.6 kJ mol 1 for a 2,4,6-trinitrobenzene derivative in aqueous solution108. No doubt that in a less polar solvent, and with a smaller number of nitro groups sharing the negative charge, this hydrogen bond will be appreciable stronger.

Besides the increased reactivity, formation of species like 6a may also produce a change in the rate-determing step in substitutions of ortho-derivatives when compared with the para-isomers. For example, it has been recently demonstrated that the formation of 1L D F; R1 D n-C3H7, i-C3H7; R2 D H is rate-limiting in the reaction of n-propylamine and isopropylamine with o-fluoronitrobenzene in toluene, while it is the decomposition of the corresponding zwitterionic intermediate that is rate-determining in the same reactions

with p-fluoronitrobenzene82. Such differences in the mechanisms of the reactions must be kept in mind in the analysis of the activation of SNAr reactions with ortho- and para-nitro groups1a.

3. The field effect

For dinitro-substituted substrates, it has been recently shown that activation in 2,4- dinitrophenyl substrates is mainly due to the mesomeric effect of the 4-nitro group, thus reducing the electron density at the reaction site83. However, another important feature of highly polarizable groups, such as a nitro group in the ortho position, has been considered to be the field effect107.

This effect has been reported in the reactions of 2,4- and 2,6-dinitroanisole (DNA) with cyclohexylamine in benzene107. Both substrates have an ortho-nitro group and the stabilization of the zwitterionic intermediate through hydrogen bonding with the ammonio proton will be similar in both cases. Nevertheless, in spite of increased steric hindrance in the di-ortho-derivative and of the expected greater resonance stabilization of the intermediate by a para- than by an ortho-nitro group, and hence an overall higher energy of the transition states of the substitution of 2,6-DNA when compared with its 2,4-isomer, the inverse effect is observed. The accepted mechanism for the uncatalysed step involves a transfer from an ammonium proton to the nucleofuge in concert with the departure of the leaving group, as shown by complex 7. When there are two o-nitro groups, the quaternary ammonium proton can be hydrogen-bonded to one or the other; formation of this intermediate is favoured by the twisting of the methoxy group, giving a more favourable ‘looser’ transition state.

In the reactions of the same substrates with piperidine, SN2 reactions are observed together with SNAr. The SNAr reaction of 2,6- is 10 times faster than that of the 2,4-, while the SN2 reaction is 103 times faster107. The spectacular inversion in reactivity was interpreted as due to a favourable field effect by the ortho-nitro group. It was proposed that the methoxy group in 2,6-DNA would adopt a conformation perpendicular to the ring plane and the greater reactivity of 2,6- over 2,4-DNA would be due to a favourable field effect, as in the previous reaction with cyclohexylamine107. To confirm this assumption, the SN2 reaction with N-methylpiperidine in benzene was also studied. As expected on the grounds of the favourable field effect, the 2,6-DNA was nearly 300 faster than the 2,4-DNA107.

SNAr with other 6-R-2-nitroanisoles R D alkyl were also studied and the results compared with the 4-R-2-nitroanisoles83a. It was found in all cases that 6-R reacted faster than the 4-R consistent with the absence of primary steric effects due to the proposed twisting of the di-ortho-substituted anisoles. However, the more striking result was the spectacular reactivity of the 6-bromo- and the 6-nitro-isomer, in spite of the electronic and steric effects; e.g. in the reaction with cyclohexylamine in benzene 6-Br is almost 104 more reactive than the 4-R83a. It was proposed that the methoxy group in the di- ortho-substituted anisoles is twisted out of the plane of the aromatic ring by the presence of substituents on each side, which facilitates the replacement of methoxy by an amine group. When both substituents are electron-withdrawing groups, the favourable field effect exerted through the space is superimposed on the twisting of the nucleofuge, and both are responsible for the spectacular increase in rate of the 2,6-dinitroanisole when compared with the 2,4-dinitro isomer. Thus, in the case of the DNA with piperidine, the SNAr

reaction with 6-NO2 is nearly 10 times that of the 4-, while the SN2 is nearly 104 times faster than the 4-NO283a.

A similar twisting was expected to occur with the phenoxy ether to explain the greater reactivity of the 2,6-isomer in recent studies of the reactions of 2,4-dinitro and 2,6- dinitrophenyl phenyl ethers with n-butylamine109. Nevertheless, in this case, the authors

assume that the twisting of the phenyl moiety in the 2,6-substrate will increase the electron density on the oxygen atoms of ‘at least one of the nitro groups in the -complex, leading to stronger ortho-nitro hydrogen bonding of the ammonio hydrogen atoms and to a greater propensity to a reaction third order in nucleophile concentration’109. When a methyl group is introduced at the 6-position of the 2,4-dinitrophenyl ether, the curvilinear upward kinetic form which is observed was also attributed to the increase in basicity of the ethereal oxygen atom. Notwithstanding, the unexpected increased reactivity of the 6-position in all these systems is well explained in terms of the field effect in all the cases. On the contrary, the changes in the kinetic law, giving rise to a third-order dependence on the nucleophile concentration, require a more comprehensive mechanistic explanation, as will be discussed in Section III.

4. The nitro nucleofuge

When the leaving group is the nitro group, the reactions with amines in aprotic solvents show a behaviour different from SNAr reactions with other nucleofuges, such as halogens or alkoxy groups, since an intramolecular hydrogen bond may be expected between the leaving nitro group and the ammonium H of the nucleophiles. This effect was observed in the reactions of 1,2-dinitrobenzene with butylamine and piperidine, in several aprotic solvents110. In solvents such as ethyl acetate, THF, acetonitrile, DMF and DMSO (called solvent set A), neither reaction is base-catalysed and the formation of the intermediate is rate-determining kA D k1 . The sequence and range of reactivity for butylamine and piperidine are similar in these solvents. This is unexpected, considering that from the overall rate constants observed in SNAr reactions, in which the formation of the - adduct is rate-determining, butylamine is usually an order of magnitude less reactive than piperidine1. Besides the intramolecular hydrogen bond with the o-nitro group, similar to that depicted in complex 6a, another intramolecular hydrogen bond was postulated for 1,2-dinitrobenzene (DNB) (or other substrates where nitro is the nucleofuge) such as that depicted in the intermediate 6b.

(6b)

If this structure makes a major contribution to the stability of the transition state, the usual reactivity and solvent effects found for other nucleofuges with these amines will not be the same in these cases. A structure such as 6b was earlier proposed for rationalizing the unexpected fast expulsion of the nitro group in the reactions of 1,2- DNB and 1,2,4-trinitrobenzene with piperidine in benzene111. This proposal was fully confirmed by the study of the reactions in several aprotic solvents. The reactions of 1,2- DNB with butylamine (BA) (Table 10) and piperidine in the set of solvents A could be correlated with the Kamlet Taft38 solvatochromic equation, when the ˇ parameter, which measures the solvent hydrogen-bond acceptor capability, was included in the correlations. The calculated equations as well as the whole F and partial F1, F2 confidence levels showed the weight of the ˇ parameter110.