Oxybromination of phenol and aniline derivatives in H₂O/scCO₂ biphasic media

Abstract

The oxybromination of phenols and anilines was achieved in the benign H₂O/scCO₂ biphasic system using NaBr–H₂O₂ as the bromine source without the need for metal catalysts or acidic additives. The reactivity of the system is associated with the intrinsic acidity of the medium and the in situ generation of percarbonic acid. High conversions of the starting material were achieved together with very good selectivities under optimized conditions.

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Introduction

Brominated aromatic compounds are widely used as building blocks for fine chemicals.¹ They are also present in the structure of many natural compounds of pharmacological interest.² Most of the processes currently operating for the bromination of aryl compounds employ toxic, corrosive, and expensive molecular bromine, resulting in the formation of large amounts of HBr waste (eqn (1)). In view of the wide use of brominated aromatics, it is of interest to develop ecologically benign and economically attractive alternatives to these processes. In this context, oxybromination is safer and greener since it avoids the hazardous Br₂, replacing it in most cases with a bromide salt in the presence of an oxidant agent under acidic conditions (eqn (2)).

Ar-H + Br₂ → Ar-Br + HBr (1)

The systems reported for oxybromination so far require strongly acidic conditions, volatile organic solvents (VOCs) and metal or other catalysts (e.g. vanadium, copper, zeolites).³ The oxidizing equivalents are mostly provided by peroxides in the processes,⁴ although molecular oxygen could be activated in some instances.^5–7 Kulkrani et al. reported a metal free system operating for the oxybromination of aniline and anisole derivatives in acetic acid as solvent.⁸ Liang et al. recently performed the oxybromination of aromatics in CH₃CN–aqueous HBr mixtures, mediated by NaNO₂.⁷

Increasing effort is currently devoted to the replacement of VOCs in modern organic synthesis and scCO₂ is a promising alternative, since it is non-toxic and non-flammable.⁹ Moreover, it is cheap and readily available. In this article we describe an effective approach to the oxybromination of phenol and aniline derivatives performed without any metal catalyst or potential toxic/polluting acid addition in a biphasic system consisting of scCO₂ and H₂O.

Results and discussion

Background

The use of an H₂O/scCO₂ biphasic system holds several potential advantages: in addition to the benign character of both scCO₂ and water, the coexistence of water with scCO₂ results in an intrinsic pH value around 3 of the water phase (Fig. 1). Moreover, the water phase recovers its neutral pH within a few minutes following the depressurization of CO₂. Thus, this solvent system provides “switchable” acidic conditions without the need for external acid.

Fig. 1 Intrinsic acidity of H₂O/scCO₂ biphasic media.

In oxidation processes, the in situ generation of percarbonic acid from H₂O₂ and CO₂ offers an additional possibility to exploit the chemical reactivity of the H₂O/scCO₂ system (eqn (3)). Eckert et al. invoked percarbonic acid to rationalise the rate enhancement observed in the metal free epoxidation of olefins with H₂O₂ in H₂O/scCO₂.¹⁰ Such an activating effect can also be achieved by the addition of NaHCO₃ to an aqueous H₂O₂ solution.¹¹ The formation of the sodium carboxylate of percarbonic acid then allows a higher concentration of the overall percarbonic species (eqn (4)). Such a bicarbonate activated hydrogen peroxide (BAP), in the absence of CO₂, was used by Richardson et al. for the metal free epoxidation of olefins¹² and sulfide oxidation¹³ in water. We therefore decided to investigate the reactivity of aromatic compounds with bromide salts in the presence of H₂O₂ using an H₂O/scCO₂ biphasic reaction medium in order to obtain the corresponding brominated products.

Screening of reaction conditions

The so called “oxybromination” of an electron rich arene leads to a mixture of ortho- and para- brominated species, and polybromination is also possible. The use of an ortho-substituted substrate reduces the possible combinations to three products. Thus, in order to simplify the analytics, o-cresol1a was used as model substrate in a first screening for suitable reaction conditions (Table 1).

Table 1 Oxybromination of o-cresol in H₂O/scCO₂

Entry	MBr : 1a	Equiv. NaHCO3	Solvent system	Conv.^a (%)	Selectivity^b (%)
					2a + 3a^c	4a
					(isolated yield)
a Standard conditions: o-cresol : MBr : H2O2 = 1 : 3 : 3, 40 °C, 4 h; GC conversion using octan-1-ol as standard. b Selectivity is expressed as the ratio of the GC peak areas; the only detected products are those 3 compounds. c Mono-brominated compounds were obtained as a 40 : 60 mixture of ortho- and para- isomers. d Reaction time = 2 h. e Reaction with a glass lined autoclave.
1	NaBr	—	H2O	12	93	7
2	NaBr	—	H2O/scCO2	54	78	22
3	NaBr	0.1	H2O	32	92	8
4	NaBr	0.1	H2O/scCO2	91	89 (78)	11 (8)
5^d	NaBr	0.1	H2O/scCO2	48	95	5
6^e	NaBr	0.1	H2O/scCO2	93	86	14
7	KBr	0.1	H2O/scCO2	86	91	9
8	TBAB	0.1	H2O/scCO2	90	89	11
9	NH4Br	0.1	H2O/scCO2	60	93	7

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Submitting o-cresol1a to NaBr/H₂O₂ in water at 40 °C resulted in a poor conversion of 12% (entry 1). Using the biphasic H₂O/scCO₂ system under otherwise identical conditions, the conversion increased to 54% (entry 2 vs. 1). If the reaction was performed in absence of scCO₂ but with a catalytic amount of NaHCO₃, there was a noticeable enhancement compared to the CO₂-free system, but conversion was still lower than in the H₂O/scCO₂ system (entry 3). This supports the involvement of percarbonic species in a BAP-type mechanism. The actual oxidant in this case would be percarbonic acid sodium salt (eqn (4)).¹¹

The reason for less improvement with NaHCO₃ than that observed in H₂O/scCO₂ is assumed to be the absence of acidic conditions necessary to achieve an efficient oxybromination.³ Indeed, by combining the effects of the biphasic H₂O/scCO₂ system with the addition of a catalytic amount of NaHCO₃ the conversion could be raised to 91% within 4 hours, while the monobromination selectivity remained high (89%, entry 4). A shorter reaction time (entry 5) or a lower NaBr stoichiometry further improved the monobromo adduct selectivity albeit at the expense of a drop in conversion.

Since oxidation reactions in scCO₂ can be initiated by the reactor walls¹⁴ and the conversion of bromide ions into bromine with hydrogen peroxide is known to be iron catalyzed,¹⁵ it was checked whether the iron-containing steel walls of the autoclave had an influence on the rate of the oxybromination. A test reaction was performed with a glass liner inside the autoclave. Conversion and selectivities were largely identical to those obtained in absence of the coating (entry 6 vs. 4). This indicates that either the reactor walls are not involved in the overall process or the bromide oxidation step is not rate limiting for this transformation.

Finally several bromide salts were tested (entries 7–9). Both KBr and [NBu₄]Br exhibited comparable reactivities to NaBr whereas [NH₄]Br was less effective. Therefore NaBr was kept as the standard bromine source for the rest of this work.

In summary, oxybromination of o-cresol could be achieved readily using H₂O₂/NaBr as the bromine source in an H₂O/scCO₂ biphasic system. More than 90% conversion and 90% selectivity for the monobrominated product was achieved. In a preparative scale experiment under the conditions of Table 1, entry 4, a mixture of the ortho- and para-brominated products (2a : 3a = 40 : 60) was isolated in 78% yield along with 8% of the disubstituted product 4a by flash chromatography after a classical work up.

Oxybromination of phenol derivatives

A series of phenol derivatives was submitted to the conditions described above. The results are shown in Table 2. After 3 hours, 98% conversion of phenol 1b with 88% monobromophenol selectivity was observed (entry 1a). It is assumed that the observed high monobromination selectivity results from two main factors: (i) for electronic reasons, an ortho- or para-bromination substitution has a deactivating effect toward a further electrophilic bromination of a phenol derivative , (ii) a brominated phenol is less water soluble than phenol itself.¹⁶ Indeed, the orange colour of the water phase indicates that the brominating species is mainly water soluble. Therefore, the partition of substrate, primary product and brominating agent in the biphasic mixture (Fig. 2) is expected to affect the selectivity control.

Fig. 2 Biphasic H₂O/scCO₂ system for the oxybromination of cresol using NaBr/H₂O₂.

Table 2 Oxybromination of phenol derivatives in H₂O/scCO₂

Entry	Substrate	Water solubility^a /g L^–1 (at pH = 7)	NaBr (equiv.)	t/h	Conv.^b (%)	Selectivity^c (%)
						Mono-Br	Di-Br	Tri-Br
a Conditions: substrate : NaHCO3 : NaBr : H2O2 = 1 : 0.1 : 3 : 3, 40 °C; solubilities from Acros Chemicals. b GC conversion with octan-1-ol as internal standard. c Selectivity is expressed as the ratio of the GC peak areas.
1a		80	3	3	98	88	11	1
1b			3	6	100	52	33	15
1c			1	4	57	93	7	0
1d			6	4	100	3	5	92
2a		20	3	3	74	94	6	—
2b			3	3.5	89	93	7	—
2c			1	4	41	98	2	—
3a		1	3	3	38	97	3	—
3b			3	6	58	91	9	—
3c			3	20	75	82	18	—
3d			1	20	35	96	4	—
4		0.5	3	20	0	—	—	—

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Increasing the reaction time resulted in a further reaction of the monobrominated adducts allowing the formation of di- and tribromophenol (entry 1b). Tuning the NaBr stoichiometry opens a further possibility to regulate the selectivity toward mono- or tribromophenol: a 1 : 1 ratio for 1b : NaBr led to a good monobromo selectivity (93%), albeit at conversion of only 57% (entry 1c). In the presence of 6 equivalents of NaBr, the reaction led to a full conversion along with 92% tribromophenol selectivity (entry 1d).

The influence of the water solubility of the substrates mentioned above is also evident from the relative reactivities of the substituted phenols 1a–d. o-Cresol1a proved less reactive than phenol 1b, even though it should be electronically more activated. Most significantly, the electronically almost identical substrate 1c proved far less reactive than 1a, in parallel to a largely reduced water solubility. Finally, the most hydrophobic substrate 1d proved unreactive. However, an additional deactivation effect by blocking the protic OH can not be excluded in this case.

Oxybromination of aniline derivatives

Given the successful and straightforward oxybromination of phenol derivatives in the H₂O/scCO₂ system, amino-substituted aromatics were tested under similar reaction conditions (Table 3). Aniline5a reacted smoothly and 98% conversion was achieved after 4 hours (entry 1). In contrast to the situation observed with phenol 1b, the disubstituted products 7a were formed with high preference from 5a. The o,o′- and o,p-isomers were typically observed in a ratio of 45 : 55. The monosubstituted product 6a (ortho : para = 70 : 30) can be obtained with good selectivity at reasonable conversion by reducing the amount of bromine source (entry 1b). Excellent yield for the monobrominated products (ortho : para = 35 : 65) were also achieved with substrate 5b (entry 2). The N-substituted derivatives 5c and 5d were far less reactive, which may again reflect their largely reduced water solubility (entries 3 and 4).

Table 3 Oxybromination of aniline derivatives in H₂O/scCO₂

Entry	Substrate	NaBr (equiv.)	Time/h	Conv.^a (%)	Sel.^b (%) 6/7/(8)
a Conditions: substrate : NaHCO3 : NaBr : H2O2 = 1 : 0.1 : 3 : 3, 40 °C; GC conversion with octan-1-ol as internal standard. b Selectivity is expressed as the ratio of the GC peak areas.
1		3	4	98	29/70/(1)
		1	4	65	96/3/(1)
2		3	4	94	91/9
		1	4	43	98/2
3		3	20	22	99/1
4		3	20	0	—

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Conclusion

This work provides a new method for the production of brominated phenol and aniline derivatives using NaBr–H₂O₂ as a bromine source in the benign H₂O/scCO₂ biphasic reaction medium. This system is suitable for the reaction of sufficiently water soluble substrates; mono-, di-, or tribrominated products could be obtained with high selectivities under suitable conditions. This new procedure represents an attractive green approach to brominated aromatics for several reasons: (i) it avoids the use and handling of Br₂; (ii) no VOCs are used as solvents; (iii) the two components of the reaction medium, water and CO₂, are non-toxic, non-flamable, cheap and readily available; (iv) the intrinsic reactivity of the biphasic system avoids the use of additional acids or metal catalysts.

Experimental

Safety warning

Experiments using compressed gases must only be conducted in suitable equipment and under appropriate safety precautions.

Reagents and analytics

Reactants were purchased from Acros and used without further purification. GC analyses were performed on a Hewlett Packard 5890 series II instrument, using octan-1-ol as standard. GC /MS were recorded on a Hewlett Packard 5973 quadrupole-spectrometer (EI, 70 eV). NMR spectra were recorded on a Brucker DPX-300 spectrometer (¹H: 300 MHz, ¹³C: 75 MHz).

Typical procedure

A 10 mL window-equipped stainless steel autoclave was charged with NaHCO₃ (8.4 mg, 0.1 mmol), NaBr (309 mg, 3 mmol), o-cresol (108 mg, 1 mmol), 2 mL water and finally H₂O₂ (175 µL, 3 mmol). Then, a weighed amount of CO₂ (8 g) was added using a compressor. The reactor was heated to 40 °C, whereby the pressure rose to 100–110 bar. After the given reaction time , the reactor was cooled down to 0 °C and CO₂ was removed through a double cold trap within 20 minutes. The water phase in the reactor and the cold traps were extracted with ether and the combined extracts analysed by GC using octan-1-ol as standard. Products were identified by GC /MS and ¹H NMR and comparison to authentic samples.

2-bromo-6-methylphenol: ¹H NMR (CDCl₃, 300 MHz, 298 K): 2.28 (s, 3H, CH₃); 5.35 (s, 1H, OH); 6.64–6.77 (m, 1H, ArH); 6.95–7.06 (m, 1H, ArH); 7.20–7.32 (m, 1H, ArH); MS (EI, 70 eV): 188, 186 (M⁺, 42); 107 (–Br, 100).

4-bromo-6-methylphenol: ¹H NMR (CDCl₃, 300 MHz, 298 K): 2.24 (s, 3H, CH₃); 4.78 (s, 1H, OH); 6.51–6.63 (m, ArH); 7.10–7–19 (m, 1H, ArH); 7.19–7.26 (m, 1H, ArH); MS (EI, 70 eV): 188, 186 (M⁺, 72); 107 (–Br, 100).

2,4-dibromo-6-methylphenol: ¹H NMR (CDCl₃, 300 MHz, 298 K): 2.28 (s, 3H, CH₃); 4.92 (s, 1H, OH); 7.02 (s, 1H, ArH); 7.24 (s, 1H, ArH); MS (EI, 70 eV): 268 (52), 266 (100), 264 (53); 187 (70); 185 (70).

Acknowledgements

Financial support of the German Ministry of Science and Education (bmbf; Lighthouse Project “Sustainable Aromatic Chemistry”) and the Fonds der Chemische Industrie is gratefully acknowledged.

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