On the ionizing properties of supercritical carbon dioxide: uncatalyzed electrophilic bromination of aromatics

Abstract

Supercritical carbon dioxide (scCO₂), a solvent with a zero dipole moment, low dielectric constant, and no hydrogen bonding behavior, is a suitable medium to perform the uncatalyzed electrophilic bromination of weakly activated aromatics with no interference of radical pathways. The ability of scCO₂ to promote these reactions matches those of strongly ionizing solvents such as aqueous acetic and trifluoroacetic acids. Conversely, carbon tetrachloride, with similar polarity parameters to scCO₂, leads exclusively to side chain functionalization. The strong quadrupole moment, and the acidic, but non basic, Lewis character of carbon dioxide, are proposed as key factors for the singular performance of scCO₂ in reactions involving highly polar and ionic intermediates.

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Introduction

Supercritical carbon dioxide (scCO₂) is a unique solvent for chemical reactions¹ described as non polar, non nucleophilic and non basic, with low dielectric constant and no hydrogen-bonding behavior,^2,3 which nevertheless exhibits ionizing and dissociating properties.⁴ This reveals the importance of the strong quadrupole moment and the acidic, but non basic, Lewis character of carbon dioxide for the specific solvation of polar and ionic solutes,⁵ as well as its potential to influence the course of chemical reactions in ways that are unfeasible for conventional solvents.⁶ Hence, understanding solvation in scCO₂ is crucial for devising competitive applications of this medium in green chemistry,¹ and the study of strongly solvent-dependent reactions in scCO₂ is a useful approach to this goal.⁷

The reaction of molecular bromine with alkyl aromatics⁸ is a suitable probe for solvation in scCO₂ since it follows polar or radical pathways depending on the reaction conditions. In the presence of Lewis acid catalysts,^8,9 or in strongly ionizing solvents,¹⁰ the reaction proceeds through the electrophilic aromatic substitution mechanism,^8–11 which involves the rapid formation of a charge transfer π-complex [ArH·Br₂], followed by the rate-determining ionization of the Br–Br bond with σ-adduct formation [ArHBr⁺, Br⁻], and then loss of a proton to restore aromaticity (Scheme 1). Lewis acids facilitate the reaction⁹ by coordinating bromine atoms, which enhances both the electrophilicity of the brominating species (Step 1, Scheme 1) and the ability of bromide as a leaving group (Step 2, Scheme 1). Strongly ionizing solvents promote the ionization of the polarized π-complex [ArH·Br₂] by solvating the leaving bromide anion (Step 2, Scheme 1).^8,11 Conversely, reactions in apolar solvents under thermal conditions provide mainly side-chain functionalization at benzylic positions.¹²

Scheme 1 Mechanism of the electrophilic bromination of aromatics.^10,11

Predicting the course of these reactions in scCO₂ is not obvious. Actually, scCO₂ is an excellent solvent for radical reactions¹³ which has been found suitable for side-chain photobromination of alkyl aromatics¹⁴ with minor interference of polar side processes. Therefore, the reaction of bromine with aromatics in scCO₂ represents an interesting test for solvation in this medium, as well as an alternative approach to a major transformation in synthesis which continues to raise interest from mechanistic,¹¹ preparative, and environmental¹⁵ points of view.

We herein report a comparative study of the reaction of bromine with weakly activated aromatics in different solvents under thermal conditions. The results show that scCO₂ is a suitable solvent to perform the selective electrophilic bromination of weakly activated aromatics in the absence of added catalysts (eqn (1)). The ability of scCO₂ to promote the uncatalyzed bromination of benzene is matched only by 85% aqueous trifluoroacetic acid, a strongly ionizing polar protic solvent. The results disclose the role of the Lewis acid character,⁵ the quadrupole moment,¹⁶ and the low basicity¹⁷ of carbon dioxide in the solvation of the different species involved in the reaction.

Results

The experimental setup for the bromine reactions with aromatic substrates 1 in scCO₂ was designed to rigorously prevent catalysis by the stainless steel reactor walls. So reactions were run by placing a 2 mL amber glass ampule containing bromine capped with a pierced (1/32′) polypropylene top inside a 12 mL glass vial containing the aromatic substrate ([1] = 0.6 M, molar ratio 1 : bromine 3 : 1). Then the glass vial was fitted with a drilled (1/32′) polypropylene cap and inserted into a 33 mL stainless steel reactor. The system was carefully pressurized with CO₂ to 250 bar at 40 °C and was allowed to stand unstirred for 2 h at the same temperature.¹⁸ Next the reactor was cooled to 0 °C and allowed to slowly depressurize into a trap at −78 °C.

Substrate conversion and product distribution were determined exclusively from the organic material collected from the internal walls of the glass vial and the ampule, which were washed with specific volumes of dichloromethane solutions of acetone or cyclohexene as quenchers for bromine, and adamantane as an external standard. The resulting solutions were treated with sodium bicarbonate and sodium sulphate, and then analyzed by gas chromatography and mass spectrometry (see the results in Table 1). The external walls of the glass vial, the stainless steel reactor, the outlet valve and the cold trap were washed separately and analyzed following the same procedure. Only trace amounts of starting materials or reaction products were found in these regions. Mass balances were >95% in all cases, indicating that the diffusion of reagents from the glass vial to the stainless steel external reactor walls was negligible in the experimental process. The control experiments performed by pressurizing the reactor to 250 bar at 40 °C, cooling the system to 0 °C and maintaining it at this temperature for 2 h, followed by depressurization and analysis of the reaction mixture as described above, showed no significant conversion of substrates. Comparative experiments in conventional solvents (neat and 85% v/v aqueous acetic and trifluoroacetic acids, and carbon tetrachloride) were done using the same concentrations, molar Br₂ : 1 ratios, temperature and reaction time, and protected from light (Table 1). The resulting mixtures were quenched and analyzed as described above. Detailed experimental procedures are described in the Experimental part and the ESI.‡

Table 1 Uncatalyzed bromination of aromatics 1 in scCO₂ and conventional solvents^a

1/Run	Solvent^b	Conv.^c (%)	Product distribution (%)
a Reactions in scCO2 (250 bar) and conventional solvents performed at 40 °C for 2 h, with a molar ratio 1 : Br2 3 : 1 and [Br2] = 0.2 M. The results are the average of at least three independent runs.b AA: acetic acid, TFA: trifluoroacetic acid, aq. AA and aq. TFA: 85% v/v aqueous acids.c Substrate conversion relative to bromine.d 3,5-Dibromo-1,2-dimethylbenzene was obtained in a 2% yield.e ortho-α,α′-Dibromoxylene (2fαα′) was obtained in a 2% yield.
1	scCO2	10	100
2	aq. AA	—	—
3	TFA	3	100
4	aq. TFA	4	100
5	CCl4	—	—
6	scCO2	38	38	62	—	—
7	aq. AA	20	39	61	—	—
8	TFA	68	36	64	—	—
9	aq. TFA	90	25	75	—	—
10	CCl4	74	—	—	98	2
11	scCO2	66	36	64	—
12	AA	19	—	—	100
13	CCl4	100	—	—	100
14	scCO2	43	14	86	—	—
15	AA	33	10	32	23	35
16	TFA	100	17	83	—	—
17	CCl4	91	—	—	98	2
18	scCO2	77	100
19	AA	5	100
20	CCl4	—	—
21	scCO2	>99	—	95	3^d	—
22	AA	41	18	82	—	—
23	CCl4	>99	—	—	—	98^e
24	scCO2	66	92	8	—
25	AA	28	77	10	13
26	CCl4	83	—	—	100
27	scCO2	32	88	12
28	AA	—	—	—
29	CCl4	—	—	—
30	scCO2	27	100
31	aq. AA	—	—
32	CCl4	—	—

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Bromine reacted with benzene (1a) in scCO₂ to give bromobenzene with 10% substrate conversion relative to bromine after 2 h under our reaction conditions (Entry 1, Table 1). Prolonging the reaction time up to 5 h did not improve the result. Conversely, bromine did not react with benzene in carbon tetrachloride, benzene, acetic acid or aqueous acetic acid, under similar reaction conditions. The reactions in neat and aqueous trifluoroacetic acid gave, respectively, 3% and 4% substrate conversions after 2 h at 40 °C.¹⁹

Toluene (1b) reacted with bromine in scCO₂ to give exclusively ortho- and para-monosubstituted products, with 38%substrate conversion vs. bromine (Entry 6, Table 1). meta-Bromotoluene was not found as a reaction product, which evidenced a high positional selectivity and absence of acid-catalyzed isomerization of the products.²⁰ Benzylic functionalization was never detected under our reaction conditions. The reactions of bromine with toluene in neat trifluoroacetic acid, aqueous acetic and trifluoroacetic acids gave, respectively, 68%, 20%, and 90% substrate conversions (Entries 7–9, Table 1).²¹ The same results were obtained when the reactions were performed by slowly adding a bromine solution to the substrate solution under the same conditions.

The diffusion rate of bromine from the glass vial into the substrate solution had a significant impact on the reaction efficiency. Thus, increasing the contact area between the substrate and bromine solutions through the ampule cap generally improved the substrate conversion. However, no reaction took place when benzene (1a) and bromine were placed in the same glass vial at 250 bar and 40 °C for 2 h without stirring. This indicates that high bromine concentrations in the reaction mixture inhibits the reaction rate.¹⁰ In the case of toluene (1b), the reactions performed by placing bromine in an open ampule inside the glass vial led to 29% substrate conversion. Control experiments performed by slowly adding (0.0196 mmol min⁻¹) a bromine solution in aqueous acetic and trifluoroacetic acid to a benzene solution (1a) in the same solvents at 40 °C showed no differences in relation to our standard conditions.

The relative reaction rates of benzene (1a) and toluene (1b) with bromine in scCO₂ were estimated in competitive experiments performed with initial molar ratios 1a : 1b : Br₂ 1.5 : 1.5 : 1 for 15 min under our standard conditions. A gas chromatography analysis of the reaction products, performed as described above, showed an average relative conversion 1b : 1a of 5 : 1. The competitive reactions performed at 40 °C for 15 min in aqueous acetic or trifluoroacetic acids led to an exclusive reaction of 1b, and relative conversions 1b : 1a of 350 : 1, respectively.²² Therefore, the uncatalyzed bromination of aromatics in scCO₂ exhibited poorer substrate selectivity than the reactions in aqueous acetic or trifluoroacetic acids, but displayed similar positional selectivity.²³ By way of comparison, the substrate selectivity reported^9a for the reaction of toluene (1b) and benzene (1a) with bromine in nitromethane at 25 °C in the presence of FeCl₃ was 1b : 1a 3.6 : 1. The ortho:meta:para regioselectivity of the bromination of 1b under the same conditions was 68.7 : 1.8 : 29.5.

The bromine reactions with a series of aromatics 1 in scCO₂ exclusively gave the corresponding electrophilic substitution products in all cases (Table 1). Remarkably, the selectivity in the reaction of cumene (1d) (Entries 14–17, Table 1) was similar for scCO₂ and trifluoroacetic acid, while the reaction in acetic led mainly to the products derived from benzylic functionalization, followed by solvent-promoted ionization. Ethylbenzene (1c) also led to bromination at the benzylic position in acetic acid (Runs 11 and 13, Table 1). For ethylbenzene (1c), cumene (1d), tert-butylbenzene (1e), ortho-xylene (1f), biphenyl (1h), and fluorobenzene (1i), the electrophilic aromatic substitution reactions in scCO₂ took place preferentially at the less sterically hindered para positions (Table 1). ortho-Xylene (1f) reacted faster than para-xylene (1g), probably due to the less hindered reactive positions in the former. No acid-catalyzed rearrangement of the isomeric xylenes was observed under our reaction conditions.²⁰ The reactions of toluene (1b), ethylbenzene (1c), and tert-butylbenzene (1e) with bromine in scCO₂ at 100 bar and 40 °C led to the same results reported in Table 1, indicating that the electrophilic bromination or aromatics 1 is no pressure-sensitive.⁴

The reactions proved less efficient in glacial or aqueous acetic acid (Table 1). For instance, biphenyl (1h), and fluorobenzene (1i) failed to give any substitution product in acetic acid and aqueous acetic acid, respectively (Entries 28 and 31, Table 1), while they reacted with 32% and 27% substrate conversions in scCO₂ (Runs 27 and 30, Table 1). Remarkably, fluorobenzene (1i) reacted with bromine in scCO₂ to give para-bromofluorobenzene (2i_p) exclusively, while the regioselectivity reported^9b for the reaction in nitromethane in the presence of FeCl₃ was ortho:meta:para 10.5 : <0.2 : 89.5. Chlorobenzene and bromobenzene were unreactive in both scCO₂ and conventional ionizing solvents.

Use of CCl₄ as a solvent for the reaction of alkyl-substituted aromatics with bromine always led to the exclusive functionalization of the benzylic position (Table 1). The dramatic change in the reaction course observed upon going from CCl₄ to scCO₂ contrasted with the similar standard polarity parameters tabulated for these solvents:² dipole moment (zero in both cases), relative permittivity (2.24 and 1.1–1.5), E_TN (0.052 and 0.068–0.116), and hydrogen-bond acceptor/donor indexes β/α (0.12/0 and 0/0).

Discussion

scCO₂ is a suitable solvent to perform uncatalyzed bromination of weakly activated aromatics without interference of radical pathways. Such performance is indicative of specific interactions of carbon dioxide with the different intermediate species involved in the reaction (Scheme 1), which can be summarized as follows:

(i) The lower toluene (1b)/benzene (1a) selectivity observed in scCO₂, if compared to that in aqueous acetic and trifluoroacetic acids, evidences a less substrate-selective [ArH·Br₂] π-complexation (Step 1, Scheme 1) and, therefore, a stronger electrophilic brominating species in scCO₂.^11,23 This suggests that the very low Lewis base character of carbon dioxide¹⁷ prevents a strong interaction with bromine and preserves its electrophilic character. Accordingly, the actual brominating species in scCO₂ would be unsolvated bromine molecules.

(ii) At a low bromine concentration, the polarized [ArH·Br₂] π-complex evolves into the σ-adduct [ArHBr⁺, Br⁻] through the solvent-promoted ionization of the Br–Br σ-bond (Step 2, Scheme 1).^10,11 The specific Lewis acid–base, dipole–quadrupole, and ion–quadrupole interactions of carbon dioxide with the leaving bromide anion^5d,24 appear strong enough to activate this process. The preference for the para position observed in the reactions of bromine with toluene (1b) in scCO₂ and conventional ionizing solvents (Table 1), if compared with the ortho-selectivity reported^9b for the FeCl₃-catalyzed reaction, can be attributed to the greater steric hindrance of the solvation shells around the terminal bromine atom in the π-complex if compared to the complexed Lewis acid.^9,10d In this context, the para-selectivity observed in the reaction of bromine with fluorobenzene (1i) in scCO₂ (Entry 30, Table 1) would be indicative of significant interactions of carbon dioxide with the fluorine atom, in agreement with the well-known CO₂-philic character of fluorinated hydrocarbons.¹

(iii) The non basic character of carbon dioxide¹⁷ further contributes to differentiate the reaction course in relation to conventional solvents as it enhances the role of bromide anion as a Bronsted base to remove the proton from the σ-complex in the rearomatization step (Step 3, Scheme 1), and prevents the ionization of HBr. In this way, scCO₂ should minimize the complexation of molecular bromine with bromide anion [Br₂ + Br⁻ ⇆ Br₃⁻],^10,11,25 a side process that actually depletes the electrophile from the solution. Although no data on this complex equilibrium in scCO₂ are presently available, this factor should not be disregarded as a significant contributor to the singular efficiency of this medium to promote the electrophilic aromatic bromination of benzene (1a).

(iv) At a high initial bromine concentration, the electrophile would compete with scCO₂ in the ionization of the polarized π-complex [ArH·Br₂] to give the σ-complex and Br₃⁻ (Step 2, Scheme 1). Since the delocalized Br₃⁻ species is a weaker base than bromide anion, this process actually removes both the reactive electrophilic brominating species and the base required in the last rearomatization step (Step 3, Scheme 1) from the reaction medium. This side process accounts for the low reaction rates and the kinetic orders higher than two observed in conventional solvents,¹⁰ and also the inhibitory effect by the high initial bromine concentrations observed in scCO₂. Indeed, these effects should be greater for reactions in scCO₂ as the solvent cannot participate as a base in the rearomatization step in this case.

The striking difference between the reaction courses observed in scCO₂ and carbon tetrachloride, both solvents with similar polarity parameters, evidences the ability of scCO₂ to solvate highly polar intermediates and transition states through intermolecular interactions which are silent to standard polarity probes.² These interactions strongly favor polar reaction pathways over alternative routes that lead to side-chain functionalization, such as the thermal homolysis of the Br–Br σ-bond, single electron transfer processes, or even molecule-induced homolysis, which are preferred in carbon tetrachloride.^11i,26 Notwithstanding, the solvent-promoted electrophilic aromatic substitution in scCO₂ is not fast enough to compete with the radical-mediated side-chain bromination of the alkyl aromatics performed under photochemical conditions,¹⁴ and this fact makes scCO₂ a unique solvent to perform either polar or radical reactions of alkyl aromatics with bromine through the proper selection of reaction conditions.

Conclusions

Molecular bromine reacts with weakly activated aromatics in scCO₂ in the absence of Lewis acid catalysts to give electrophilic aromatic substitution products exclusively. The results reported herein evidence the singular ability of scCO₂ to promote strongly polar reaction pathways in spite of the non polar character, similar to pentane or carbon tetrachloride, attributed to this medium by standard polarity probes. The performance of scCO₂ in the electrophilic bromination of weakly activated aromatics, which matches that of aqueous acetic or trifluoroacetic acids, can be attributed to the high quadrupole moment, Lewis acid character and low basicity of carbon dioxide.

Acknowledgements

Financial support from the Spanish Ministerio de Economía y Competitividad (CTQ2013-47180-P), Fondos Feder, and Generalitat Valenciana (ACOMP/2012/217) is gratefully acknowledged. TDA and JRL thank the Spanish Ministerio de Educación, Cultura y Deporte for fellowships. We thank the SCSIE (Universidad de Valencia) for access to its instrumental facilities.

Notes and references

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18. The escape of the bromine solution in scCO₂ from the glass vial takes place mainly by diffusion since the static conditions and the low viscosity of scCO₂ prevent efficient convection mass-transfer in the reaction system. This experimental setup was intended for minimizing the damage of the stainless steel reactor wall, valve, tubing, and fittings caused by the strong oxidant.
19. The rate constants reported^10d for the reaction of benzene with bromine in neat and 87% aqueous trifluoroacetic acid at 25 °C were 7.62 × 10⁻⁷ and 144 × 10⁻⁷ M⁻¹ s⁻¹, respectively. The rate constants for the uncatalyzed bromination of toluene in trifluoroacetic acid at 35 °C and in 87% aqueous trifluoroacetic acid were 3.81 × 10⁻³ and 1.97 × 10⁻³ M⁻¹ s⁻¹, respectively.
20. G. A. Olah and M. W. Meyer, J. Org. Chem., 1962, 27, 3464–3469.
21. The time for achieving 10% conversion reported for the reaction of bromine with toluene in glacial acetic acid and trifluoroacetic acid, at 25 °C were 12.9 × 10⁶ and 5.2 × 10³ min, respectively.^10d,10h.
22. The relative rate constants toluene (1b) : benzene (1a) reported for the reactions with bromine in 85% aqueous acetic acid^10h and 87% aqueous trifluoroacetic acid^10d at 25 °C, are 605 : 1 and 2580 : 1.
23. G. A. Olah, Acc. Chem. Res., 1971, 4, 240–248.
24. (a) D. W. Arnold, S. E. Bradford, E. H. Kim and D. M. Neumark, J. Chem. Phys., 1995, 102, 3510–3518; (b) D. W. Arnold, S. E. Bradforth, E. I. Kim and D. M. Neumark, J. Chem. Phys., 1995, 102, 3493–3509.
25. The reaction of strong acids with Br₃⁻ salts in conventional solvents is known to readily release bromine at room temperature: J. Berthelot, C. Guette, P.-L. Desbène, J.-J. Basselier, P. Chaquin and D. Masure, Can. J. Chem., 1990, 68, 464–470.
26. (a) P. R. Schreiner and A. A. Fokin, Chem. Rec., 2004, 3, 247–257; (b) A. A. Fokin, T. E. Shubina, P. A. Gunchenko, S. D. Isaev, A. G. Yurchenko and P. R. Schreiner, J. Am. Chem. Soc., 2002, 124, 10718–10727.

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Footnotes

† This article is dedicated in memoriam to Professor Ruggero Curci.

‡ Electronic supplementary information (ESI) available: Detailed experimental procedures, gas chromatograms and mass spectra of the reaction products. See DOI: 10.1039/c4ra10557e

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