Ajda
Podgoršek
a,
Marco
Eissen
b,
Jens
Fleckenstein
b,
Stojan
Stavber
a,
Marko
Zupan
ac and
Jernej
Iskra
*a
aLaboratory of Organic and Bioorganic Chemistry, “Jožef Stefan” Institute, Jamova 39, 1000, Ljubljana, Slovenia. E-mail: jernej.iskra@ijs.si; Fax: +386 1 4773 822; Tel: +386 1 4773 631
bGymnasium Ganderkesee, Am Steinacker 12, 27777, Ganderkesee, Germany
cFaculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000, Ljubljana, Slovenia
First published on 17th November 2008
Various alkenes (internal, terminal, aryl and alkyl substituted) and 1,2-diphenylethyne were efficiently and selectively dibrominated using 2 equivalents of 48% aqueous hydrobromic acid, with air as an oxidant and sodium nitrite as a catalyst. Despite the presence of water, only trans dibromination occurred producing anti-1,2-dibromoalkanes and (E)-1,2-dibromo-1,2-diphenylethene. A comparison of resource demand, waste production and environmental, health and safety issues of the NaNO2 catalyzed aerobic bromination with molecular bromine and other oxidative bromination methods revealed that the proposed method is not only selective and effective but has a better environmental profile.
Alkenes are useful substrates for investigating the nature of active halogenating agents11 and are used many times in biomimetic studies of haloperoxidation, mainly with a metal catalyst.12 Research has focused on the selectivity of bromohydrin and dibromide formation in a vanadium(V) or molybdenium(VI) catalyzed oxybromination of alkenes using potassium bromide and hydrogen peroxide. Performing these reactions in water gave bromohydrin as the main product, despite a large excess of bromide ions.13 In a two-phase system using either H2O-CHCl39d,12c,d,13 or H2O-CH2Cl2,12d,e more dibrominated product together with bromohydrin was formed. Only when tetrabutylammonium bromide together with H2O2 and catalytic V2O5 in H2O-CH3CN was used as a tribromide precursor was the formation of dibromides from cyclohexene and styrene observed.9c A non-catalyzed oxidative bromination with H2O2/HBr in a two-phase system with either CCl4 or an ionic liquid also gave dibromides selectively.8a,14
In contrast with hydrogen peroxide, oxygen has seldom been used for oxidative halogenation despite it being the most abundant, cheapest and atom economical oxidant. Only a few examples of aerobic oxybrominations of aromatic compounds catalyzed by various metal catalysts are reported.10b,f,g Zhang et al. describe a metal-free catalyzed oxidative bromination of aromatic compounds and aryl ketones utilizing a combination of aqueous hydrobromic acid, molecular oxygen and sodium nitrite as the catalyst.10c A similar system was also used for aerobic iodination.10d To the best of our knowledge, there are only two examples of aerobic oxidative halogenation that includes the oxidative halogenation of alkenes using a metal species as a catalyst. Bromination of 1-octene10g and chlorination of cyclododecene and trans-5-decene15 resulted in the non-stereoselective formation of dihaloalkanes accompanied by products of addition of hydrohalic acid to the double bond.
This report presents a study on the selective and stereoselective aerobic dibromination of alkenes and alkynes using air at near ambient pressure as the oxidant, an equimolar amount of aqueous hydrogen bromide and sodium nitrite as a catalyst. Environmental aspects, such as resource demands and waste production together with health and safety issues, will be evaluated in comparison to Br2 addition and other oxidative bromination. Furthermore, the effect of the slow generation of the “active brominating agent” on the selectivity of bromination is discussed.
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Scheme 1 |
Next, the effect of the mode of addition of sodium nitrite on conversion was investigated. Five mol% of solid NaNO2 was added in one portion (Method A), in three portions every 2 hours (Method B) and as a 20 μL aqueous solution of 2.5 M NaNO2 (Method C). Table 1 shows that there is no significant difference when sodium nitrite is added either all at once or in three discrete portions. However, a slightly higher yield of dibrominated product 2 was obtained when sodium nitrite was added as a 2.5 M aqueous solution, possibly because the sodium nitrite was uniformly distributed in the reaction mixture. Interestingly, although additional water was present in the system less bromohydrin was formed. Therefore, in all subsequent experiments an aqueous solution of sodium nitrite was added.
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Entry | Methoda | Distribution (%)b | ||||||
1 | : | 2 | : | 3 | : | 4 | ||
a Method A: 5 mol% of solid NaNO2 was added in a single portion, Method B: 5 mol% of solid NaNO2 was added in three portions every 2 hours, Method C: 20 μL of 2.5 M aq. NaNO2 was added; b Determined by 1H NMR spectroscopy. | ||||||||
1 | A | / | : | 94 | : | 6 | : | / |
2 | B | / | : | 95 | : | 5 | : | / |
3 | C | / | : | 98 | : | 2 | : | / |
4 | C, without addition of NaNO2 | 66 | : | / | : | / | : | 34 |
5 | C, without an air balloon | 18 | : | 34 | : | / | : | 48 |
To highlight the role of sodium nitrite and the presence of air on the course of oxidative bromination of styrene (1), blank experiments both without sodium nitrite and air were performed. In the absence of sodium nitrite, the addition of HBr to styrene (1) is the sole reaction with 34% of (1-bromo-ethyl)-benzene (4) being formed (Table 1). In the absence of air only 34% of the dibrominated product 2 was formed and the addition of HBr on the double bond was the main reaction resulting in the formation of 4 in a 48% yield. From this we can conclude that catalytic amounts of sodium nitrite under aerobic conditions prevent the addition of hydrobromic acid to the alkene, while air as an oxidant enables the “in situ” formation of the brominating species and therefore the dibromination of the alkene.
To evaluate the scope of this catalytic system, optimum reaction conditions: 1 mmol of substrate, 2 mmol of 48% aqueous solution of HBr, 20 μL of 2.5 M aq. NaNO2 (5 mol%) and 10 mL of acetonitrile, were used to oxidatively brominate various internal and terminal aryl and alkyl substituted alkenes and 1,2-diphenylethyne. The results are represented in Schemes 2–5. Yields were determined by 1H NMR spectroscopy and are based on the starting compound, while the yields given in parentheses refer to isolated yields. Using this method, β-substituted styrenes were quantitatively and diastereoselectively converted to dibrominated products (Scheme 2). Bromination of trans-stilbene (8), ethyl trans-cinnamate (9) and acenaphthylene (11) gave anti-brominated products diastereo-specifically. cis-Stilbene (5) was also trans brominated under the above conditions yielding syn-1,2-dibromo-1,2-diphenylethane (6) accompanied by 5% of the anti isomer 7.
The introduction of a second substituent in the α position in styrene (1) modifies the stability of the carbocation intermediate so that besides the competitive addition of a nucleophile, deprotonation resulting in an addition–elimination process could become an important reaction channel. With α-methylstyrene (13), only an addition reaction occurred with the competitive formation of the dibromide 14 and the bromohydrin 15 in a ratio of 44/56. (Scheme 3). α-(Trifluoromethyl)styrene (16), that forms a more deactivated bromocarbonium ion, was brominated in a lower yield, nevertheless dibromoalkane 17 was the main product. Bromination of 1,1-diphenylethene (18) follows an addition-elimination mechanism to give 2-bromo-1,1-diphenylethene (20) and 35% of the addition product 19.
The aliphatic terminal alkene 21 and internal alkene 23 were quantitatively and selectively brominated to give 1,2-dibromooctane (22) and anti-4,5-dibromooctane (24), respectively (Scheme 4).
On completion, aerobic oxidative bromination was tested for bromination of the alkyne 25. Similarly to reactions with alkenes, 25 was also trans-brominated to (E)-1,2-dibromo-1,2-diphenylethene (26) stereospecifically with an isolated yield of 93% (Scheme 5).
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Scheme 2 |
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Scheme 3 |
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Scheme 4 |
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Scheme 5 |
In a small scale experiment, extraction or dilution with an appropriate organic solvent has to be applied in a work-up procedure. This method has the potential of producing a simpler work-up procedure due to the absence of any organic by-products and residues. On a larger scale, 5-times less MeCN is required for the reaction and a different work-up procedure, depending on the aggregate state of the formed product, was employed. Oxidative bromination of trans-stilbene (8) and trans-4-octene (23) were performed on a 5 mmol scale (5 mmol of alkene, 10 mmol of 48% aq. HBr, 70 μL of 3.6 M aq. NaNO2, 10 mL of CH3CN). After stirring the reaction mixture for either 16 h or 24 h at room temperature, the acetonitrile was distilled off and regenerated. In the case of the solid product 7, the crude reaction mixture was poured into water and the resultant white precipitate was filtered off, and after drying 95% of meso-1,2-dibromo-1,2-diphenylethane (7) was obtained. In the case of the liquid product 24, a minimum quantity of EtOAc was added, the resultant organic phase was dried over Na2SO4 and the solvent was evaporated. The result was anti-4,5-dibromooctane (24) in a 94% yield.
When comparing alternative protocols, the relevant environmental, health and safety aspects must also be taken into consideration. Regarding resource efficiency, the conventional procedure using molecular bromine16 (Scheme 6a) or hydrobromic acid and hydrogen peroxide8a (Scheme 6b) compare favourably to the twenty-four procedures examined.5b These procedures had been chosen to be juxtaposed to the larger-scale procedure for aerobic oxidative dibromination of trans-stilbene (8) with HBr/air/NaNO2(cat.) system (Scheme 6c).
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Scheme 6 Bromination methods using (a) molecular bromine,16 (b) hydrobromic acid and hydrogen peroxide,8a and (c) hydrobromic acid and oxygen. |
The protocols are from the laboratory stage. Against this background, the environmental factors E = ∑ Waste [kg]/Product [kg] given in Fig. 1 demonstrate that there is no significant difference regarding waste production and solvent demand between this method and other bromination methods5b with much higher E factors. Protocol (a) has the advantage that no water is used so waste water treatment is unnecessary.
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Fig. 1 Environmental factor E of different bromination methods shown in Scheme 6 using the software EATOS.17 For details see Table 2. Work-up procedures have not been described in detail8a,16 and, thus, were not considered here: (a) recrystallization; (b) washing with water, brine and drying over sodium sulfate; (c) pouring into 10 mL of water. |
Contrary to the quantitative results, the nature of the reagents used distinguishes themselves notably. Both, molecular bromine and an aqueous solution of hydrobromic acid have corrosive properties. Additionally, hydrogen peroxide is not only corrosive but can decompose in a runaway scenario.18 However, bromine is much more volatile and has a higher risk potential than hydrobromic acid. Another important issue is the use of toxic and environmentally problematic substances such as chloroform (solvent of protocol (a)) or tetrachloromethane (solvent of protocol (b)). Evidence, although limited, suggests that CCl4 is a carcinogen. Moreover it can have long-term adverse effects on the aquatic environment, is ozone depleting and a greenhouse gas. The authors of protocol (b) suggest dioxane as an alternative solvent, but dioxane is an irritant, highly flammable, can form explosive peroxides and potentially carcinogenic. Obviously, the advantage of substituting bromine with hydrobromic acid in protocol (b) becomes revoked because technology equipment has to avert the potential risk associated with the use of halogenated solvent or dioxane. In this regard, the application of acetonitrile, albeit highly flammable but merely harmful instead of toxic in protocol (c) respresents a significant progress and, furthermore, air is used instead of hydrogen peroxide.
The actual mechanism of aerobic oxidative bromination using hydrobromic acid and sodium nitrite as a catalyst is yet to be investigated. However, bromine was proposed as a reactive brominating species for the bromination of aromatic compounds and aryl ketones.10c Alkenes are convenient substrates to study the mechanism of halogenation and the nature of halogenating reagents. We performed a study on the effect of a brominating reagent's structure and the mode of its addition on the course of bromination of styrene (1) and observed some interesting results. Classical bromination of 1 with bromine in acetonitrile follows a different pathway to that of an HBr/air/NaNO2(cat.) system; only 60% of 1,2-dibromo-1-phenylethane (2) was formed, with the remainder being acetamide 27 and oxazole 28 formed by the incorporation of acetonitrile into the carbocation intermediate (Table 3, entry 2). An analogous reaction with an additional 10 equivalents of water, as is present when using aqueous HBr in aerobic oxidative bromination, yielded a similar amount of dibromide 2 (entry 3). Also, significant differences were noticeable when molecular bromine was added slowly to a solution of styrene (1) in acetonitrile by its diffusion via the gaseous phase. In this case similar results to aerobic oxidative bromination were obtained, with the selective formation of the dibrominated product 2 (entry 4), thus pointing to the importance of the slow formation of the brominating species during the course of the oxidative bromination. A similar result was observed when HBr3 was formed as a brominating agent prior to the addition of 1; less bromohydrine 3 was formed despite aqueous HBr being used (entry 5). When using BrOH/NaBr for bromination (entry 6) and when the brominating agent is formed in situviahaloperoxidase-like oxidation of HBr with hydrogen peroxide (entry 7), the formation of bromohydrin 3 is more expressed. It appears that the slow generation of bromine could be the key for the selective formation of vic-dibromides with the possibility of forming HBr3 due to an excess of HBr at the early stages of the reaction.
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Entry | Reagent | Time (h) | Distribution (%)a | ||||||
2 | : | 3 | : | 27 | : | 28 | |||
a Determined by 1H NMR spectroscopy. b Styrene (1 mmol) was added to the solution of Br2 (1 mmol) (and H2O (10 mmol)) in CH3CN (10 mL). c A similar reactivity was observed to that reported in ref. 19. d Bromine vapours were added by diffusion from the gaseous phase20 to the solution of styrene (1 mmol) in CH3CN (10 mL). e Br2 (1 mmol) and HBr (1 mmol) were mixed together in CH3CN (10 mL) followed by the addition of styrene (1 mmol). f Br2 (1 mmol) and NaOH (1 mmol) were mixed together and then the solution of styrene (1 mmol) in CH3CN (10 mL) and H2O (10 mmol) was added. g 30% aq. H2O2 (1 mmol) and 48% aq. HBr (2 mmol) were added to the solution of styrene (1 mmol) in CH3CN (10 mL). | |||||||||
1 | HBr (2eq.), NaNO2 (0.05 eq.), air | 5 | 98 | : | 2 | : | / | : | / |
2 | Br2 (1eq.)b,c | 3 | 60 | : | / | : | 20 | : | 20 |
3 | Br2 (1eq.), H2O (10 eq.)b | 3 | 61 | : | 23 | : | 11 | : | 5 |
4 | Br2 (1eq.)d | 24 | 96 | : | 4 | : | / | : | / |
5 | HBr3 (1eq.)e | 3 | 98 | : | 2 | : | / | : | / |
6 | BrOH/NaBr (1eq.), H2O (10 eq.)f | 3 | 84 | : | 14 | : | 1 | : | 1 |
7 | H2O2 (1eq.), HBr (2 eq.)g | 24 | 90 | : | 10 | : | / | : | / |
Also, what is noteworthy is the selective formation of trans-addition products in aerobic bromination. This result is different to bromination with bromine in chlorinated solvents, where cis-addition was also observed in the bromination of acenaphthylene (11, trans : cis 70 : 30),21trans-stilbene (8, trans : cis 84 : 16)22 and diphenylethyne (25, trans : cis 60 : 40).23 Alternatively, when H2O2/HBr was used for bromination in a biphasic system with CCl4 or an ionic liquid only trans-bromination takes place in the bromination of methyl trans-cinnamate.8a,24 A similar effect was observed in bromination with pyridinium tribromide, where a reaction with trans-stilbene (8) in CH2Cl2 produces an 86 : 14 mixture of trans : cis-adducts, while the reaction in a water suspension yields only the trans-adduct.22
Nitrogen oxides were suggested to be the catalyst in this reaction due to a well known decomposition of nitrite under acidic conditions into a mixture of nitrogen oxides. By mixing NaNO2 with a strong acid (HClO4) in MeCN, colorless bubbles immediately start to evolve and solution remained colorless even after a prolonged period of time in air. When HBr is used as an acid, dark yellow bubbles appear and the solution gradually becomes yellow-orange which, together with the fact that a solution of bromine in MeCN is red-brown, suggests the formation of a different decomposition product of NaNO2 with HBr. A review of available literature suggests that the formation of a nitrosyl bromide could explain the yellow-orange colour of the solution (Scheme 7A). NOBr reportedly decomposes at room temperature into nitric oxide and bromine (Scheme 7B).25a We turned to UV-vis spectroscopy to determine the presence of NOBr as a product of the decomposition of NaNO2 with HBr in acetonitrile. In the spectra obtained for a solution of Br2 in MeCN, two peaks at 269 (s) and 390 (br) nm are observed, whereas for a degassed suspension of NaNO2 in MeCN treated with HBr, a spectra is obtained with peaks at 269 (br) and 330 (br) nm. According to the literature data, NOBr has a peak at 225 nm that is in our case overlapped by the strong signal of Br2,25b,c while a broad band at 330 nm corresponds with the literature one.25b However, after 30 min only absorption signals for Br2 are observed. Our conclusion is that during NaNO2 catalyzed aerobic dibromination of alkenes, nitrite is first transformed into NOBr, which then decomposes to bromine and nitric oxide (Scheme 7). Thus, a small amount of bromine is already formed in this pre-catalytic phase and is rapidly consumed by the alkene. This shifts the equilibrium towards complete decomposition of NOBr.
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Scheme 7 |
At which point, nitric oxide enters into the catalytic cycle of aerobic bromination, where it is oxidized into NO2 by air. This in turn oxidizes HBr into Br2 (Scheme 8). It appears that the slow generation of bromine is crucial for selective trans-dibromination of alkenes, while the presence of unreacted HBr in the reaction mixture makes the formation of HBr3 possible and its role in selective dibromination can not be precluded (Table 3, entries 4, 5).
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Scheme 8 |
Both, environmental and health and safety aspects were also considered and compared with alternative protocols and aerobic dibromination. The obtained E-factors show that this aerobic protocol is similar to bromination using Br2 and an H2O2/HBr system in chlorinated solvents. However, aerobic bromination with HBr/NaNO2/air replaces Br2 with the less volatile aqueous HBr and hydrogen peroxide with air, while chlorinated solvents are eliminated altogether. These and the good selectivity and yield makes this method a promising alternative to other dibromination protocols.
Footnote |
† Electronic supplementary information (ESI) available: NMR spectra of (2,3-dibromo-1,1,1-trifluoropropan-2-yl)benzene 20, Environmental factor E of different bromination methods, UV-vis spectra of Br2 in CH3CN and UV-vis spectra of NOBr. See DOI: 10.1039/b814989e |
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