Observation of replacement of carbon in benzene with nitrogen in a low-temperature plasma.

Selective activation of benzene has been mainly limited to the C-H activation. Simple replacement of one carbon in benzene with another atom remains unresolved due to the high dissociation energy. Herein, we demonstrate a direct breakage of the particularly strong C = C bond in benzene through ion-molecule reaction in a low-temperature plasma, in which one carbon atom was replaced by one atomic nitrogen with the formation of pyridine. The mechanism for the formation of pyridine from benzene has been proposed based on the extensive investigation with tandem mass spectrometry. The reaction pathway also works to other aromatics such as toluene and o-xylene. This finding provides a new avenue for selective conversion of aromatics into nitrogen-containing compounds.

Benzene is an extremely stable aromatic ring, and is hardly replaced one carbon atom in C = C bond by other heteroatoms without breaking the aromatic ring. Although the interactions between benzene and diverse heteroatoms including N123456, O789, Si1011 and P1213 have been extensively investigated, there has been little experimental evidence to produce heterocyclic compounds from benzene13. The exclusive example on the selective breakage of carbon-carbon bond in benzene can be dated back to two decades ago, in which Muedas et al.13 presented an evidence on the insertion of a phosphorus atom into the skeleton of benzene and formation of a seven-membered ring, which was achieved through the reaction with PI3 in an ion-molecule reaction. Recently, Cooks et al.14 reported a strategy for the direct insertion of one nitrogen into C-C bond of saturated alkanes to form iminium salts via simple one-step reactions involving gas phase ions and high energy plasma processes. Considering the significance of heterocyclic compound directly derived from benzene in chemical industry, it is desirable to have some strategies developed for this reaction. While the reduction of carbon-carbon bond in benzene could be achieved with facilitation by plasma15, there has been no report so far on the selective replacement of one carbon atom in benzene with heteroatom.

In this study, we observed that one carbon atom in benzene can be directly replaced with nitrogen atom producing pyridine through ion-molecule reaction in a low-temperature plasma. The formation of pyridine was confirmed with its exact mass measurement, tandem mass spectrometry and isotopic labeling study, and the reaction product was collected and identified via chromatography technique. According to the results from mass spectrometry, the underlying reaction pathway for the pyridine formation from benzene was proposed, in which it involves a carbon replacement with nitrogen-containing species and the ring-opening and closing reactions. Since this process has been regarded as impossible using typical synthesis routes for a long time, this finding paves the way for the direct synthesis of heterocyclic compounds from benzene.

Results

The experiment was carried out by introducing benzene vapor with air into a low-temperature plasma region (Figure S1). The reaction product was on-line monitored using a high resolution Orbitrap mass spectrometer. Besides the peaks at mass-over-charge ratio (m/z) 94.0651 (C6H8N+), 110.0600 (C6H8ON+) and 126.0551 (C6H8NO2+), the most abundant ionic species observed was m/z 80.0494 (Figure 1A), which was different from the typical molecular ion of benzene (m/z 78.0469) as shown in Figure S2 in mass spectrometry (MS) analysis16. In a previous study under a similar plasma condition but with benzene in helium, ion [M + 2]+ was observed and was identified as C6H8+ based on deuterium isotopic labeling experiments15. The chemical formula of the ion m/z 80.0494 observed in this study was assigned as C5H6N+ (Figures S3 and S4). This peak was the most abundant in the spectrum (Figure 1A), which suggests that this reaction was highly efficient in producing this unusual product.

Figure 1

(A) Mass spectrum of the product from the plasma reaction of benzene using a high resolution Exactive Orbitrap mass spectrometry. (B) Fragmentation pattern of the product (m/z 80) from the plasma reaction with benzene. (C) Fragmentation pattern of m/z 80 from pyridine standard sample using nano-ESI.

To confirm the chemical structure of the product C5H6N+ (m/z 80) generated from benzene, MS/MS analysis was performed and the fragmentation pattern was compared with that from pyridine (analytical standard). As shown in Figure 1B and C, both cations C5H6N+ (m/z 80) generated from benzene through the plasma reaction and from pyridine standard sample by nano-electrospray ionization (nano-ESI) have identical fragmentation patterns, with fragments of m/z 28 (CNH2+), 50 (C4H2+), 51 (C4H3+), 53 (C4H5+) and 78 (C5NH4+) observed at similar relative intensities. This result suggests the product C5H6N+ (m/z 80) probably has a structure of pyridine. D6-benzene was also used for the plasma reaction and ions at m/z 85.0810 and 86.0871 were observed, corresponding to C5D5HN+ and C5D6N+, respectively (Figures 2A, S5 and S6). The most abundant ion C5D5HN+ at m/z 85.0810 could be attributed to the transfer of a proton from water in air during the reaction. In its MS/MS spectrum, a similar dissociation pathway as those from benzene and pyridine was observed, with fragments of m/z 29 (CNHD+), 30 (CND2+), 51 (C4HD+), 52 (C4D2+), 53 (C4HD2+), 54 (C4D3+), 57 (C4HD4+), 58 (C4D5+), 81 (C5NHD3+) and 82 (C5ND4+) (Figures 2B and S6D), confirming the occurrence of conversion from benzene to pyridine. Further convinced evidence on the production of pyridine from benzene has been obtained by gas chromatography/mass spectrometry (GC/MS) analyses. When pure benzene was used for the analysis, no pyridine peak was observed in the chromatogram (Figure 2C). However, the retention peak of pyridine appeared at 3.44 min for the collected product from the plasma reaction of benzene (Figure 2D) by using the apparatus as shown in Figure S7. This is in good agreement with the retention behavior of pyridine standard (Figure S8).

Figure 2

(A) The mass spectrum of the product from the plasma reaction with D6-benzene.(B) Fragmentation pattern of the molecular ion (m/z 85) generated by the plasma reaction of D6-benzene. (C) GC/MS chromatogram of pure benzene. (D) GC/MS chromatogram of the product from benzene. (Note: The insets in (C) and (D) are the corresponding mass spectra of the marked peaks.)

In an effort of identifying the source of nitrogen atom involved in the replacement of the carbon from benzene, different gases, including air, pure N2, and the mixture of N2 and NO (99:1, v/v), were used for the plasma reaction. The results shown in Figure S9 clearly demonstrate that NO-containing gas more favors the generation of pyridine than air and pure N2 in this reaction. 15NO was then added into the reaction for tracing the nitrogen source via isotope ratio analysis. After a reaction period of 30 min, the liquid sample was analyzed using an Orbitrap mass spectrometer. As expected, the peak intensity of 15N-labeled cation (C5H615N+) sharply increased, and the ratio between 15N-labeled cation (C5H615N+) and C5H614N+ was 1.53 (Figure 3A). On the contrary, the peak intensity ratio was only 0.05 for the reaction using NO (Figure 3B). This provides a direct evidence that the pyridine product was generated from the reaction with exogenous nitrogen-containing species rather than contaminants in the original benzene solvent.

Figure 3

Comparison of the peak intensity of C5H615N from the respective reaction of benzene and NO and 15NO.

Mass spectrum of (A) the reaction product between benzene and 15N containing species such as 15NO generated from the discharge reaction of O2 and 15NH3 and (B) the general reaction product obtained from benzene and NO (the inset is the close-up image of the marked section). Note: 15NH3 was generated by addition of 0.3349 g 15NH4Cl into 2 mL of 1.0 mol L−1 NaOH solution.

Discussion

Besides the dielectric barrier discharge apparatus (Figure S1), other reaction systems such as paper- or needle-based discharge (Figure S10) were also used to investigate the discharge reaction products of benzene at atmospheric pressure without any other auxiliary gases. It is interesting that the same reaction product patterns were observed (Data not shown). These results demonstrate that the production of C6H8N+ under the discharge of benzene is a general case.

To give some insights into the formation of C5H6N+ from benzene, efforts were carried out to its origin. As shown in Figure 1, besides the peak C5H6N+ at m/z 80.0494, three other abundant peaks, assigned to C6H8N+ (m/z 94.0651), C6H8ON+ (m/z 110.0600) and C6H8NO2+ (m/z 126.0551), were also observed in the mass spectrum. However, the intensity for these peaks became much lower for the collected reaction products (Figure S11). Further MS/MS analysis of these species showed that C5H6N+ can be originated as the most abundant species from C6H8O2N+ (m/z 126) and C6H8ON+ (m/z 110) through loss of one molecule H2O and CO or C group by collision induced dissociation (CID) as shown in Figure 4. For the ion m/z 94, no direct experimental results were found to be related with the production of m/z 80 (C5H6N+) as shown in Figure 4C. Also, the component of m/z 94 varied from C6H8N to C6H6O with reaction time (Figures S12), and their possible formation mechanisms were suggested as Scheme S1. From Figure S12, it can be seen that the formation of C6H8N and C6H6O should be one pair of competing reactions. Further detailed investigation is needed to elucidate the source and conversion of C6H8N to C6H6O (m/z 94) as well as C6H8ON+ (m/z 110) and C6H8O2N+ (m/z 126).

Figure 4

MS/MS spectra of the peaks at (A) m/z 126, (B) m/z 110 and (C) m/z 94 produced from the plasma reaction of benzene.

According to the experimental results, a possible mechanism for pyridine formation from benzene is suggested in Figure 5a. The intermediate C6H8O2N+ with m/z 126 (Figure 4A) is first formed through the interaction between benzene and NO+, H2O in air or H2ONO+, probably derived from a three body dissociation of NO+, H2O in air and neutral molecules26. The rapid loss of H2O molecule1718 from C6H8O2N+ results in the production of C6H5NHO+ (m/z 108)19202122, followed by ring- opening and closing reactions with formation of C5H6N+ (m/z 80). In addition to this proposed pathway (Figure 5a), other similar mechanism (Figure 5b) might simultaneously undergo due to the existence of the isomers2324. For instance, the peak at m/z 109 (Figure 4A) could be attributed to the loss of OH group from the isomeric species of C6H5NH2OOH+ (m/z 126), followed by formation of C5NH6+. The suggested schemes agree well with the formation of pyridine from m/z 110 C6H8ON+ (Figure 4B) as well as the corresponding isotopically labeled products from D6-benzene (Figures S13–S14).

Figure 5

The proposed possible formation mechanism of pyridine from benzene.

The reaction pathway also works to other aromatics such as toluene (Figures S15–S21 and Schemes S2–S3) and o-xylene (Figure S22). The occurrence of conversion from toluene to 3-picoline based on extensive investigation, as given in the supplementary material, supports that it is generally applicable to perform a direct replacement of one carbon atom in benzene related aromatics with nitrogen atom in the plasma reaction. Due to the limit of the experiment results on the reaction intermediates, there may be other processes leading to the observed products.

In summary, a reaction pathway for the replacement of one carbon atom in benzene with atomic nitrogen, leading to the generation of nitrogen-heterocyclic compounds, was observed in a plasma process. We anticipate the reaction pathway described herein open a door to produce a wide variety of hetero-rings using aromatics as the starting materials.

Methods

On-line monitoring the reaction product

The isotopically labeled D6-benzene and D8-toluene (99.96 atom% D), as well as pyridine, 2-picoline, 3-picoline, 4-picoline, and o-xylene, were purchased from Sigma-Aldrich (St. Louis, MO). The used benzene and toluene (Beijing Chemical Works, Beijing, China) were chromatographic grade. The isotopically labeled 15NH4Cl (>98 atom% N) was purchased from Shanghai Engineering Research Center of Stable Isotope (Shanghai, China). All chemicals were used as received. For on-line monitoring the products from the plasma reaction of benzene, D6-benzene, toluene, D8-toluene and o-xylene, the experiments were carried out on a plasma reaction chamber (Figure S1) in an air, nitrogen (N2) or nitric oxide (NO) atmosphere. Due to the strong toxicity of NO, it was balanced with 99% nitrogen gas (N2). The plasma reaction was carried out in a quartz tube (O.D.: 4.0 mm, I.D.: 3.0 mm, and length: 4.0 cm) with one stainless steel electrode inside and the other one touching the outside of the tube. The gas flow rate was maintained at 0.3 L·min−1. The plasma reaction was controlled with a custom-built 5 W alternating current (AC) power supply (2.5 kVp-p with a frequency of 3.0 kHz).

Sample collection

For collecting the plasma reaction product, the apparatus as shown in Figure S7 was used. A 5 W AC power supply, as described above, was applied on a surface dielectric barrier discharge electrode for the plasma reaction. The reaction gas flow rate was maintained at 0.15 L·min−1, and the reaction temperature was kept at the room temperature. The collected sample was used for analysis without pretreatment unless explicitly indicated otherwise.

Mass spectrometry analysis

A Thermo Scientific Exactive Orbitrap mass spectrometer in a high-resolution mass measurement mode was employed to assign the composition of the resulting products. A TSQ Quantum Access Max (Thermo Scientific, San Jose, CA), operated in the selected reaction monitoring (SRM) mode, was used, and the specific product ions produced by collision-induced dissociation (CID) were monitored. The Xcalibur software was used for control of the TSQ Quantum Access Max MS system and data acquisition. Argon gas (99.995% purity) was used as collision gas. The temperature for MS inlet capillary was 300°C.

GC-MS analysis

The GC-MS analysis was completed on a TRACE GC-DSQ (Thermo Fisher Scientific, San Jose, CA) equipped with an AB-5MS capillary column (30 m × 0.25 mm i.d. × 0.25 μm). The analysis of the collected sample was operated in a split mode (50:1). High purity helium was used as carrier gas, and the flow rate was 1.0 mL·min−1; injector temperature: 250°C; detector temperature: 250°C; column temperature: 60°C for 2 min to 300°C at 10°C·min−1; mass spectrometry scan mode: Full scan; Mass range: m/z 30–650; electron impact: 70 eV. Xcalibur 2.0 software (Thermo Fisher Scientific Corp., San Jose, CA) was used for instrument control and data acquisition.

Author Contributions

Z.Z., Z.O. and X.Z. supervised the project. Z.Z., S.Z., H.Y., X.Z., X.F. and Z.O. conceived and designed the experiments. Z.Z., X.G., C.Y., Y.S. and X.X. performed the experiments. Z.Z., Z.O. and X.Z. wrote the paper and analyzed the data. All authors discussed the results and commented on the manuscript.