Electrofugality of Some Ferrocenylphenylmethyl Cations

The electrofugality scale has been extended with new substituted ferrocenylphenylmethyl cations 1–4. Ef values were determined by applying the linear free energy relationship (LFER): log k = sf (Ef + Nf). Due to ability of the ferrocene moiety to efficiently stabilize the positive charge, ferrocenylphenylmethyl cations constitute a group of very powerful electrofuges (Ef > 1). Impact of the phenyl group in ferrocenylphenylmethyl derivatives on stabilization of the positive charge is considerably leveled by the ferrocenyl group, so the rate effect of the alkyl substituents (methyl, ethyl and tert-butyl) on the phenyl ring is suppressed, causing narrow range of Ef parameters. Lack of breakdown of Hammett-Brown plot if the rates for the complete set of substrates 1–5 have been correlated, indicates that the ferrocenyl group in α-position diminishes the stabilizing effects of electron-donating substituents as well.


INTRODUCTION
THE first step in solvolytic SN1 reactions involves the heterolytic cleavage of the carbon-leaving group bond and formation of the carbocation intermediate (electrofuge) and the free leaving group (nucleofuge). [1] The reactivity of a substrate is determined with both abilities the leaving group and the carbocation to depart from the substrate, i.e., with their electrofugality and nucleofugality. A comprehensive electrofugality and nucleofugality scales have been constructed based on solvolytic reactivity of benzhydryl derivatives in various solvents. Accordingly, the heterolysis rate constant of any substrate in a given solvent can be predicted by using the following three-parameter LFER (Equation 1): [2,3] log k = sf (Nf + Ef) (1) in which k is first-order rate constant at 25 °C, sf is the nucleofuge-specific slope parameter, Nf is the nucleofugality in a given solvent, and Ef is the independent variable referring to electrofugality. According to above equation, the nucleofuge specific parameters can be derived from log k vs. Ef plots, [4] while the electrofugalities can be derived from log k/sf vs. Nf plots, taking the known sf and Nf parameters. The Ef values obtained are justified if the linear plots obtained have a slopes of unity. [5] In our previous work we determined the electrofugality of some ferrocenylphenylmethyl cations, mostly those with electron-accepting groups on the phenyl ring (5 in Scheme 1). [6] In this work we chose to extend the spectrum of Ef parameters for ferrocenylphenylmethyl substrates by investigating some more reactive ferrocenylphenylmethyl electrofuges (1)(2)(3)(4)Scheme 1). The aim was to (a) collect additional Ef parameters that can be used for estimation of the absolute first-order heterolysis rates in a given solvent for variety of substrates that are combination of ferrocenylphenylmethyl moiety and any nucleofuge of known sf and Nf parameters, by applying Equation (1), (b) to determine if the stabilizing effect of the ferrocenyl group is similar to that in less reactive substrates, and (c) to make feasible comparison of reactivities of the series of ferrocenylphenylmethyl cations with numerous electrofuges with known Ef values.
To enable measurements using conventional kinetic methods available for us, such a reactive electrofuges should be combined with poor nucleofuges. Up to now the least reactive nucleofuge on the scale is acetate anion (Nf from -3.55 to -4.8 in various solvents). [6,7] It turned out that acetates of ferrocenylphenylmethyl cations 1-4 solvolyze too fast, so electrofuges 1-4 should be combined with less reactive nucleofuges. Having in mind that according a qualitative rule of thumb, the abilities of leaving groups are arranged in the same order as the acidities of their conjugate Brönsted acids, we assumed that carboxylates with longer alkyl chain, as are butyrate, isobutyrate, valerate, and isovalerate (a-d, Scheme 1), would be appropriate. Hence, the first step was determining their nucleofugalities.
To get Nf and sf values, according to well established procedure, the series of benzhydryl butyrate, isobutyrate, valerate, and isovalerate should have been subjected to kinetic measurement in a given solvent, and the corresponding nucleofuge-specific parameters would have been be derived from log k vs. Ef plots (Equation 1). However, except dianysylmethyl isobutyrate, the synthesis of other substrates failed. Therefore, instead using reactive benzhydryl substrates (Ef > 0) to get the nucleofugality parameters from log k vs. Ef plots, we used ferrocenylphenylmethyl derivates whose Ef values have already been detemined. [6]

RESULTS AND DISCUSSION
A series of X-substituted ferrocenylphenylmethyl butyrates, isobutyrates, valerates, and isovalerates (5a-5d) which were prepared according to the procedure presented in the Supporting Information, were subjected to solvolysis in various solvents. The solvolysis rates were measured titrimetrically (details are given in Kinetic Methods in the Experimental) at 25 °C or at least three different temperatures and the rate constants were extrapolated to 25 °C by using Eyring plot. The first-order rate constants at 25 °C (measured and extrapolated) are presented in Table S1 (Supporting Information).
The trends observed from the kinetic data can be summarized as follows. Carboxylates with straight side chains are slightly more reactive than the corresponding carboxylates with branched side chains (Tables S1). Also, the solvolytic reactivities of substrates with non-branched carboxylates (butyrates and valerates) are similar ( Figure  S1a), whereas those with branched chain somewhat differ, i.e., isovalerate is slightly more reactive that isobutyrate ( Figure S1b).
To extract the nucleofugality parameters (N f and sf) for carboxylates a-d, the logarithms of the first-order solvolysis rate constants in the given solvents were plotted against published Ef, values of ferrocenylphenylmethyl cations 5. [6] The correlation lines are presented in Figure  S1a and S1b in the Supporting Information. The nucleofugespecific parameters (Nf and sf) are presented in Table 1.
Once the nucleofuge specific parameters for the four carboxylates a-d in various solvents have been determined, the electrofugality of ferrocenylphenylmethyl cations 1-4 could be assessed. The substrates prepared were the combination of electrofuges 1-4 and the carboxylates a-d (preparation is presented in Experimental). Solvolysis rates were measured in various aqueous solvents (Table 2).
To extract the electrofugalities, log k/sf vs. Nf were plotted for the series of ferrocenylphenylmethyl Scheme 1. The heterolytic step in the solvolysis of some X-substituted ferrocenylphenylmethyl carboxylates.
carboxylates 1-4 ( Figure 1). The weighted average of the slopes of correlation lines in Figure 1 is 0.9969 ± 0.004. The electrofugalities obtained from the correlations are shown in Table 3 in which, for sake of comparison, the electrofugality of some less reactive ferrocenylphenylmethyl cations as well as benzhydryl cations are presented. By comparing the Ef values of ferrocenylphenylmethyl cations and benzhydryl cations it is obvious that the effect of the substituent on the phenyl ring is much more pronounced in benzhydryl derivatives. Thus, switching from 4-methyl to 3-chloro substituent in benzhydryl substrates cause decrease of Ef values for about three units, which roughly corresponds to difference in reactivity of three orders of magnitude. On the other hand, the difference of Ef parameters between 3-chloroferrocenylphenylmethyl cation and 4-methylferrocenylphenylmethyl cation is about one unit, i.e., 4-methyl derivative is only about ten times more reactive than 3-chloro derivative. Table 2. Solvolysis rate constants of some 1-4 ferrocenylphenylmethyl butyrates (a), isobutyrates (b), valerates (c), and isovalerates (d) in various solvents at 25 °C

Substrate
Electrofuge (a) LG (b) -5,3 -5,1 -4,9 -4,7 -4,5 -4, Kinetic results obtained earlier with the series of ferrocenylphenylmethyl derivatives 5 as well as quantum chemical calculations showed that the effect of the substituents on the phenyl ring is suppressed due to very strong electron donating ability of the α-ferrocenyl group, i.e., leveling occurs. [6] The question arose if this applied to all X substituents (1)(2)(3)(4)(5), or electron-donating substituents on the phenyl in substrates 1-3 had somewhat more pronounced effect than in 5. This assumption was tested with Hammett-Brown correlation. If the effects of electrondonating substituents in 1-3 were stronger than those in the series of 5 examined earlier, breakdown of the σ + , ρ + correlation line would occur. However, as presented in Figure 2, linear correlation has been obtained if all data for substrates 1-5 are included. In the limits of experimental error, essentially the same slope has been obtained in e.g. 90 % aq. ethanol for the complete set of ferrocenylphenylmethyl isoburtyrates 1-5 (ρ + = -1.60) and that for the series of 5 determined earlier (ρ + = -1.46), due to very strong electron-donating ability of the ferrocenyl group (Figure 2).

General Procedure for the Synthesis of Ferrocenylphenylmethyl Butyrates, Isobutyrates, Valerates, and
Isovalerates: A solution of butyryl, isobutyryl, valeroyl, and isovaleryl chloride (≈ 2 eq) in anhydrous benzene (10 mL) was added dropwise to a previously prepared stirred solution of the appropiate phenylferrocenemethanol (1 eq) and pyridine (0.5 g, 6.32 mmol) in anhydrous benzene (10 mL). The reaction mixture was stirred under argon at ambient temperature for from 1-2 h to overnight Precipitated pyridinium chloride was removed by filtration, and excess of pyridine was removed with hydrochloride acid (15 mL, 5 %). The benzene layer was separated and washed with concentrated solution of sodium hydroxide and water. After drying over anhydrous sodium sulfate, benzene was evaporated in vacuum. Butyrates, isobutyrates, valerates, and isovalerates were obtained as dark red crystals or oils (yield 44.2-85.9 %).

4-Fluorophenylferrocenylmethyl Isovalerate (4d):
This compound was obtained from 4-fluorophenylferrocenemethanol (0.5 g, 1.61 mmol), pyridine (0.5 g, 6.32 mmol), and isovaleryl chloride (0.29 g, 2.41 mmol); yield 0.37 g, 58.4 %. 1  Kinetic Methods: Solvolysis rate constants were measured titrimetrically by means of TIM 856 titration manager (Radiometer Analytical SAS Villeurbanne Cedex, France), using a Red Rod Ag/AgCl combined pH electrode. Typically, 20-50 mg of the carboxylates were dissolved in 0.10-0.20 mL of dichloromethane, and injected into the solvent that was thermostated at the required temperature (± 0.01 °C). The liberated acid was continuously titrated at pH = 7.00-7.80 by using a 0.016 M or 0.032 M solution of sodium hydroxide in appropriate solvent. Individual rate constants were obtained by the least-squares fitting of data to the firstorder kinetic equation for three to four half-lives. The rate constants were averaged from at least three measurements.