The irascible "aryl diazoleum" has finally been tamed!
Sandmeyer achieved the synthesis of aryl halides from the D10 metal 140 years ago using aryl diazo salts. Diazonium salts are generally more reactive than other halides due to their high electrophilicity, and as a result, diazo salts are still routinely prepared at laboratory scales and industrial plants, and aryl halides are usually prepared from aryl diazolides. Since the synthesis of aryl diazoleone salts with nitrite was first reported, there has been little change in the method of their preparation. Nitrosyl (NO+) ions are formed by the acidic degradation of nitrites such as sodium nitrite (NaNO2). This ion reacts with aniline and needs to be carried out at low temperatures, which is due to the instability of aryl diazolitium salts above 5 °C. Diazolysis reactions can often lead to a vigorous exothermic effect, which is caused by the rapid release of energy that accompanies the release of gases. Aryl diazo salts are often unpredictable and unstable, can explode in contact with air or even in solution, and have led to many serious safety accidents in academic research and industry, sometimes with fatal consequences. On December 23, 1969, a particularly serious explosion involving these chemicals occurred at Ciba in Basel. One building was destroyed, 3 workers were killed and 31 were seriously injured. Despite such dire reports, work on aryl diazolitions continues.
In order to mitigate the dangers associated with diazo chemistry, alternative deamination schemes have been developed, such as the use of pyridine as an leaver or the use of diazo as an intermediate, however, these reactions often do not reach the wide range of uses and plateau economy of the parent weight nitriding method. Although nitrate is thermodynamically a stronger oxidizing agent than nitrite, it is not used in the diazotization process, often due to the fact that it is considered an inert oxidant due to its high reduction kinetic stability. Under acidic conditions, nitrate ions and nitrates do not produce nitrosyl ions (NO+) for diazotization, but instead form nitrate ions (NO2+), which act as electrophiles for nitrification of aromatic hydrocarbons, rather than diazotization. Some microorganisms are able to use nitrate as a terminal electron acceptor for respiration. For example, Thiobacillus chemotrophic denitrification uses thiosulfate (S2O32-) to produce nitrous compounds and sulfate (SO42-) as NO3- reduction by-products. In plants, nitrate reduction is carried out by nitrate reductase. Eukaryotic nitrate reductase works through a hydrogen bond-assisted mechanism of oxygen atom transfer at the molybdenum active site. In conclusion, current methods of artificial nitrate reduction are still challenging. To this end, Professor Tobias Ritter's team from the Max Planck Institute in Germany uses thiosulfate or dihalogenated salts as electron donors based on nitrate reduction, which effectively avoids diazo accumulation. Aryl diazo is produced as a transient intermediate, resulting in a safer and more efficient one-step deamination halogenation from aniline, which was published in Science under the title "Nitrate reduction enables safer aryldiazonium chemistry".
【Nitrate Ion Reduction Strategy】The formation of NO2+ and the kinetic stability of NO3- under acidic conditions may be the reason why nitrate and its ester diazo reagents have been neglected for more than a century. The conversion of NO2- to NO2+ and the conversion of NO3- to NO2+ under the action of acid are redox neutral processes. Therefore, the use of nitrate as a diazotization reagent requires the generation of NO+ by the reduction pathway in the absence of strong acids. The reduction of single electrons to nitrogen dioxide allows the formation of NO+ by nitrogen tetroxide (N2O4) disproportionation. The proposed scheme relies on thiosulfate or dihalide as an electron donor for nitrate reduction, and readily available potassium nitrate or nitrate esters can be used. In the same reaction mixture, NO3- is kinetically compatible with various nucleophiles, including bromide, iodide, and thiosulfate. In contrast, previously used nitrites and alkyl nitrites are incompatible with some nucleophiles. As a result, these nucleophiles cannot be present during diazotization with nitrites, and diazo can accumulate or be separated, which leads to safety concerns for diazo chemistry. Since the nitrate reduction process is a rate-limiting step in this strategy, diazo is produced at very low concentrations as transient intermediates, which results in the following advantages over conventional diazo chemistry: (i) avoiding thermal runaway reactions, as nitrate reduction has a higher Gibbs free energy than aryl diazo halogenation, (ii) aniline is used directly as a starting material, avoiding the separation or storage of diazo salts, and (iii) most aryl diazo is at 5°Above C is unstable and restricts conventional reactions to be performed at low temperatures, but this protocol has no such limitations and allows diazo reactions to be used more widely; Here, the authors detail the organic and inorganic chemistry involved in the direct deamineralization and halogenation of aniline by aryl diazo as a transient intermediate, using abundant nitrates and nitrate esters and common sources of reducing agents and halides. All three deamination and halogenation reactions in this work can be performed under the same reaction conditions using nitrate and nitrate, and the yield of bromination and iodination using nitric acid is higher. In traditional diazotization methods, halides are oxidized by nitrite when mixed simultaneously, while the use of nitrate allows the presence of nucleophiles to deliver aryl halides in aniline in one step. CuI promotes both the reduction of nitrates and the conversion of aryl diazo to aryl halides by conventional Sandmeier-type reactions. The combination of nitrates and Cu(I) halides enables deamination, chlorination, bromination, and iodination of aniline and amino heterocycles. Deamino-iodine can also be performed in the absence of copper. In the absence of copper, sulfur-based reagents such as thiosulfate allow nitrate reduction, while iodide directly converts aryl diazo to aryl iodide. Chlorination is achieved using tetrabutylammonium chloride (TBACl), CuCl and nitrate. Bromination was carried out with TBANO3, Na2S2O3·5H2O, 1,2-dibromoethane and CuBr as bromine sources. KNO3, Na2S2O3·5H2O were used as reducing agents, and 1,2-diiodoethane was used as the iodine source for iodination. Acetonitrile is chosen as the reaction medium, and aprotic polar solvents such as acetonitrile reduce the amount of the original deamine by-product, but can dissolve the ions involved in the reaction.
Figure 1. Illustration of the new strategy [Mechanistic Studies] First, the authors observed unlabeled, partially labeled and fully labeled dinitrogen as reaction products by gas chromatography-mass spectrometry (GC-MS) and in-situ 15N NMR spectroscopy, which is consistent with the formation of aryl diazo and its subsequent conversion into products. However, during the entire reaction, no diazo salts were detected, which confirms that aryl diazo salts do not accumulate in large quantities, supporting the claim that they are formed only as short-lived intermediates. To obtain diazo intermediates, nitrates may eventually be converted to NO+ in two-electron reduction. Here, the authors speculate on two related but distinct nitrate reduction pathways, one being nitrate esters and the other being nitrates. In conventional diazotization reactions, NO+ is formed by the acidic degradation of nitrite or alkyl nitrite. Guided by density functional theory (DFT) calculations, the authors hypothesized that single electron transfer could reduce alkyl nitrates from dihalodecanoates such as Cu(I)Cl2−. During the chlorination reaction, CuCl reacts with TBACl to form [CuCl2]−, which can reduce 2-ethylhexylnirate 2 to NO2 and 8. Copper ion 8 further reacts with NO2 to form CuCl and nitrosyl chloride (NO2Cl), and NO2Cl is cleaved by homocleavage N-Cl bonds to form NO2 and chlorine radicals. NO2 formed by the degradation of NO2Cl is dimerized to form N2O4, which is redisproportionated to form NO+NO3−, and then aryl diazo is generated. Aryl chloride is then produced by diazo intermediates with CuCl by conventional Sandmeier reaction. In the absence of 2, the reaction of NO2Cl is directly used, and the intermediate effect of NO2Cl is consistent with the formation of deamination chlorination product 3. After the addition of chlorine radical scavenger 2-methyl-2-butene, the yield of halogenated products was higher. The experimental results showed that the chlorine adduct had a higher yield, which further supported the above mechanism. In the absence of CuI, nitrate 2 is converted to 2-ethylhexyl chloride by nucleophilic substitution with chlorine, with nitrate as the leaving group. For bromination reactions, nitrate 2 delivers aryl bromide in the presence of CuBr and TBABr. The combination of TBANO3 and 4 improved the response results (77% yield for TBANO3 and 4 compared to 63% for 2, CuBr and TBABr). Dibromoethane4 is converted to nitrate 9 by nucleophilic substitution of bromine. The released bromine is captured by CuBr to form CuBr2-, and CuBr2- is subsequently reduced to form nitrate 9 to produce NO2 and 11. Slow formation in situ of nitrate 9 provides a higher yield than the addition of stoichiometric 9 or 2 at the beginning of the reaction, probably because in this case, competitive side reactions occur in the presence of higher concentrations of nitrate. Similar to the chlorination reaction, electrophilic bromine is formed in the bromination reaction. The addition of Na2S2O3·5H2O as a scavenger inhibited the dibromination of 1, resulting in a higher separation yield of aryl bromide, which was 49% without thiosulfate and 77% when thiosulfate was added. Deamino-iodine treatment was performed with nitrate 2, CuI and TBAI in 68% yield. In the absence of CuI, thiosulfate is used instead of cuprate as a stoichiometric reducing agent, 1 converts to 6 in 98% yield. Thiosulfate is oxidized with iodine to form tetrasulfate (S4O62-), and iodine and ethylene are produced from 1,2-diiodoethane. However, S4O62- cannot be dynamically reduced to NO3-. However, the authors found that I2 as a redox medium can catalyze the conversion of tetrasulfate to sulfur dioxide (SO2), sulfate (SO42-), and sulfur (S8). When SO2 is used directly as a nitric acid reducing agent, the reaction proceeds smoothly but in lower yields than with thiosulfate. It can be concluded that the slow release of the effective nitric acid reducing agent SO2 from S2O32- to S4O62- is the key to high yields, and that the stoichiometric addition of SO2 at the beginning of the reaction results in a low reaction efficiency. Similarly, the initial excess of sulfur dioxide further reduced the yield, probably because of the Lewis acid-Lewis base adduct that competes with aniline. Electron paramagnetic resonance (EPR) experiments confirmed that NO3- and SO2 generate NO2. When aniline 1 reacts with NO2 formed by the reaction of nitric acid with sulfur dioxide, the corresponding diazo salt is experimentally observed in the absence of copper redox medium and can be captured by nucleophiles, further confirming the proposed mechanism. The iodide formed during thiosulfate oxidation is a suitable nucleophile for the formation of aryl iodide from diazo intermediates.
Figure 2. Mechanism exploration experiments【Scope of application】Experiments have shown that aromatic hydrocarbons and aromatic derivatives with a variety of structural and electronic properties can participate in the nitrate reduction deamine halogenation reaction. Substrate-related reaction conditions do not need to be optimized during substrate preparation. Reactions are performed with industrial-grade solvents, commercially available raw materials, and reagents, and do not require mobile equipment. The reaction takes place under air conditions with a yield of 70% at 50 vol water and 98 percent at 5 vol moisture. The nitrogen-based species formed in the reaction are responsible for the formation of NO+, such as NO2, which is gaseous, so the reaction is carried out in a closed system. However, the use of airtight containers is not necessary for deamination, chlorination and bromination. Deaminate iodidation, on the other hand, requires a closed system – probably because the solubility of SO2 in acetonitrile decreases at high temperatures, and changes in reactor size and volume have no significant effect on reaction yield. The unique mechanism of nitrate reduction diazotization can solve several limitations of traditional diazo chemistry, including the avoidance of functional group oxidation. These disadvantages are side reactions due to the use of nitrite and high concentrations of reactive diazo salts, which do not occur when diazo is produced as a transient intermediate in the absence of a strong, dynamically reactive oxidant such as nitrite. With nitrates and nitrate esters2, antioxidant-labile thioethers are tolerated, ortho-substituted aniline can have functionalized yields of up to 96%, and amino-heterocyclic or aniline with heterocyclic substituents can also be involved in such reactions.
Figure 3. Summarizing the scope of substrate application, this study reports a novel method based on nitrate reduction that avoids the accumulation of diazo compounds by using sulfites or copper dihalogenated as electron donors, resulting in safer and more efficient aminohalogen reactions. This new method has led to a paradigm shift in nitroso chemistry to produce nitroso intermediates, thus avoiding the safety hazards that exist in traditional nitroso chemistry. This innovation provides a new avenue for a single-step reaction from aniline, avoiding the need for nitroso salt separation or storage. Source: Frontiers of Polymer Science