Nitroproteins and non-nitrated proteins identified from nervous system tumor.
\r\n\tA number of advanced combustion technologies have been introduced to improve performance, fuel economy and emissions levels. Research in combustion technology has highlighted the importance of new fuels in reducing the petroleum dependence and achieving high efficiency with low pollutant formation.
\r\n\tThe purpose of this book is to collect interesting and original studies on combustion methods, advanced combustion strategies and new fuels able to achieve efficiency improvements and environment compliance.
\r\n\tContributions in which experimental, theoretical and computation approaches are applied to explore how fuel properties and composition affect advanced combustion systems and how advanced combustion technology can maximize engine efficiency and be environment-friendly are invited and appreciated.
The incidence of central nervous system (CNS) has been increasing over the last 30 years, and unfortunately, become younger and younger [1]. More remarkable, patients (20–40%) with systemic cancer will occur metastatic disease to the CNS [2]. Primary malignant brain tumors and other metastatic disease to the CNS threaten human health. Astrocytoma is a type of primary malignant brain tumor that range from 20 to 40% of glioma, which is the most common primary brain tumor in adults [3]. Here, we put research emphasis on two kinds of primary intracranial tumor, astrocytomas and pituitary adenomas. Astrocytomas cells possess the characteristic of high invasion to cause difficulty in therapy and high mortality (median survival = 9–12 months) [4]. A pituitary adenoma is quite common, and accounts for 10% of all primary intracranial neoplasias [5]. Even only a minority of pituitary adenomas (0.1–0.2%) develops into metastatic cancer, pituitary adenomas arise clinical problems: (a) Compress the adjacent brain organs appear symptoms including headache and visual failure. (b) An inappropriate hormone secretion led to hormone syndromes, including hypopituitarism, acromegaly, hyperprolactinemia and Cushing’s syndrome [6]. The molecular mechanisms of those diseases remain unclear, and the traditional treatment models contain surgical excision, radiotherapy, and medical therapies [7]. Discovering in-depth molecular mechanisms, new diagnosis strategy, novel therapeutic targets are urgent.
Protein tyrosine nitration is an important posttranslational modification (PTM) in nervous system tumors that is related with multiple abnormal pathophysiological processes [8]. The process of protein tyrosine nitration is formed from 3-nitrotyrosine group to position 3 of the tyrosine residue phenolic ring [9], which alters the electron density and pKa value (from ~10 for tyrosine into ~7.1 for 3-nitrotyrosine) of the tyrosine phenolic ring [10]. Such changes affect biochemical characteristics of the tyrosine residue that will change interaction between enzyme-substrate, antigen–antibody or receptor-ligand, when interacting regions were in nitration. Reactive nitrogen species (RNS) act as an important mediated material for protein nitration, and our studies [11] consistent with others [12, 13] have indicated that nitric oxide and protein nitration may play important roles in the nervous system tumors. Previous studies reported that (1) the inflammatory reaction is involved in nervous system tumors [14]; (2) NO and RNS are important inflammatory mediators [15]; and (3) increased production of NO, peroxinitrite and superoxide, occurs in nervous system tumors [16]; (4) higher levels of nitrotyrosine are observed in nervous system tumors than normal tissues with biochemical approaches and immunohistochemical, and only protein nitrotubulin and protein nitro-p53 have been determined in human nervous system tumors [17]. Furthermore, the amino acid analog 3-nitrotyrosine due to functional and morphological injury of mouse-neuroblastoma cell lines and rat-glioma cell lines [18]. These studies demonstrated the importance of protein tyrosine nitration in the pathogenesis of nervous system tumors. Illustrating the functions of nitroproteins might reveal in-depth molecular mechanisms and biological function of tyrosine nitration in human nervous system tumors. Literature-based review and comprehensive annotation of proteins on the SwissProt website were used to expound the nitroprotein domains/motifs, location of nitrotyrosine sites and possible signaling pathways relevant to nervous system tumors. Nitroproteins took part in multiple biological processes in the development of tumors as follows: (a) tumor cell migration and invasion [19]; (b) cell proliferation and apoptosis [20]; (c) chemotherapy resistance [21]; (d) signal transduction [22]; (e) phenotypic dedifferentiation [23]; (f) microtubule dynamic stabilization [24]; (g) tumor recurrence; (h) others such as immunoreaction and post-transcriptional regulation. Moreover, the discovery of tyrosine nitration being a reversible reaction [25] and having a competition between phosphorylation motif [26], led us to speculate that dynamic process of protein nitration might also be regulated and controlled. However, no definite target of intervention is found for tyrosine nitration in human nervous system tumors. It takes long time to study tumor-related nitroproteins and to illustrate molecular mechanisms in tumor formation.
Nitroproteomics methods were based on sample enrichment and mass spectrometry analysis. Modern nitroproteomics applies protein-separation-enrichment techniques such as gel methods and non-gel methods, including immunoprecipitation [11], anti-nitrotyrosine antibody-based enzyme-linked immunosorbent assay (ELISA) [27], and one/two-dimensional gel electrophoresis (1DGE/2DGE)-based Western blot analyses [9]. 1DGE/2DGE-based Western blots analyses can separate and preferentially enrich endogenous nitroproteins and also preliminarily determine the quantitative information of nitrotyrosine. Studies showed that the same protein was detected at multiple gel-spots on 2D electrophoresis gels, and single 2D electrophoresis gel-spot usually contains several proteins [28]. Therefore, 2D electrophoresis gel has advantages in protein component visualization, detection of protein species that are mainly derived from alternative splicing or PTMs [9]. Protein isoforms or variants present dynamic biological processes in vivo, and different protein species associated with different conditions and pathophysiological status [29]. We adopted 1DGE/2DGE-based Western blots analyses method: the scanned images of the silver-stained 2D electrophoresis gels and the visualization of Western blot membranes were input to a PDQuest system (Bio-Rad, version 7.1, Hercules, CA) to composite image that contained the Gaussian spots [30]. MS/MS is the mainstream technique to identify protein species and PTMs products with verification of amino acid sequence, splicing sites, and modification site [31]. However, it is also pointed out that the challenges faced by low abundance of tyrosine nitration and the elusive mass spectrometry result of a nitro group are existed [32]. For example, matrix-assisted laser desorption ionization (MALDI) is quite different from electrospray ionization (ESI)-MS when study the MS behaviors of a nitropeptide [33]. Photochemical decompositions of the nitro group (–NO2) induced by the high-energy laser decrease the precursor-ion intensity of a nitropeptide, making an MS spectrum much more complex in process of MALDI. However, the decomposition pattern of a nitropeptide was well clarified by the photochemical decomposition pattern ([M + H]+, [M + H – 16]+, [M + H –30]+, and [M + H – 32]+). Even ESI does not produce photochemical decompositions, scanning for the characteristic immonium ion (m/z 181.06) by the precursor ion could help accurately identify a nitropeptide or nitroprotein under ESI conditions [34]. Above key factors, including low abundance of nitroproteins, preferential enrichment methods, sensitivity of MS analysis, complicated MS behaviors of a nitro group, that all determine success or failure in the identity of in vivo nitroproteins. Thus, nitropeptide was detected by a vMALDI MS/MS method [9, 11]. Accumulation of MS/MS scans was used to increase the signal-to-noise ratio (S/N), which is needed for the detection of endogenous nitroproteins. A single MS/MS scan can determine an amino acid sequence to study proteome and phosphoproteome.
Protein tyrosine nitration is an (PTM) in nervous system tumor such as astrocytoma and pituitary adenomas, and participates in multiple complex biological processes [9, 11, 35, 36]. For human astrocytoma and pituitary adenomas nitroproteomics studies, 2DGE-based nitrotyrosine Western blot analysis with MALDI-TOF were used to identify endogenous nitroproteins and nitrotyrosine sites from human pituitary control and adenoma tissues, and 2DGE-based nitro-tyrosine Western blot analysis with liquid chromatography-electrospray ionization-quadrupole ion trap (LC-ESI-Q-IT) were used to identify endogenous nitroproteins and nitrotyrosine sites from human astrocytoma brain tissues. Bioinformatics and pathway analysis were used to determine domains/motifs in a nitroprotein, location of nitrotyrosine sites, and possible signaling pathways. A total of eight nitrotyrosine-containing proteins in human pituitary control tissues [9, 36], and nine nitroproteins and three nitroprotein-interacting proteins in a human nonfunctional pituitary adenoma tissue [11], 18 nitroproteins and their 23 nitrotyrosine sites in human astrocytoma tissues [35], were identified with 2DE-MS/MS. The nitration site was located onto the corresponding functional domain, and each nitroprotein was carried out pathway analysis to speculate the possible biological function.
A clinically nonfunctional human pituitary adenoma tissue was obtained during surgery. The expression of FSH, LH, GH, prolactin, TSH, and ACTH were all negative in tumor cells [11]. A normal human pituitary tissue acted as control group was obtained from the post-mortem sample (a drowning male) [9, 36]. Human astrocytoma brain tissues (including different clinical staging-I/II/III/IV) were obtained from the Department of Neurosurgery of Xiangya Hospital, China [35]. The tissues were frozen in liquid nitrogen immediately, then stored at −80°C. According to the protein extraction manuals (Pierce, Rockford, IL, USA),supernatant of the tissue lysate was extracted for further analysis.
2DGE: The precast IPG strips (pH 3–10 NL; 180 × 3 × 0.5 mm) and 18-cm IPGstrip holder was used for 2DGE first dimension—isoelectic focusing (IEF) on an IPGphor instrument (GE Heathcare) to separate protein sample. After IEF, the IPG strip was processed for 2DGE second dimension—sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE), namely, the equilibrated proteins in the IPG strips were separated by molecular weight during electrophoresis on in 12% PAGE resolving gel (250 × 215 × 1.0 mm), and visualized with silver-staining [9, 36] or Coomassie brilliant blue G staining [35].
2DGE-based Western blotting: The 2DGE-separated proteins were transferred to a PVDF membrane, which were blocked by BSA, incubated with an anti-human nitrotyrosine antibody and secondary antibody, then visualized with 1-Step™ nitro blue tetrazolium/5-bromo-4-chloro-3-indolyl phosphate (NBT/BCIP) (Thermo Product No. 3404).
Image analysis of a 2D gel and of 2D-Western blotting: The scanned images of the 2D gels and the Western blot membranes were input to a PDQuest analysis system (Bio-Rad, version 7.1, Hercules, CA) to synthesize image. Gaussian spots were applied to all subsequent spot-matching and analyses. Each spot volume was normalized to the total optical density (OD) to minimize experimental factors on a spot volume [30].
LC-ESI-MS/MS: The nitrotyrosine-positive gel-spots were excised, digested, purified, eluted, air-dried, redissolved. Then, the peptide mixture was subjected to LC-ESI-quadrupole-time of flight (LC-ESI-qTOF) or LTQ-OrbiTrap Velos MS/MS analyses. The detailed operation process and parameter settings have been described [35].
MALDI-MS/MS: The immunopositive 2D gel spots were excised, digested, purified, eluted, air-dried, redissolved, and were spots onto MALDI-plate, which were subjected to MALDI-MS/MS analysis [37]. The detailed procedure has been described [9, 11, 36].
MS/MS data were used to identify the protein and nitrotyrosine sites by searching the SwissProt and NCBInr databases with SQUEST or Mascot software, with mass modifications of +45 Da (+NO2 – H) at Tyr, +57 Da (+NH2COCH2 – H) at Cys, +16 Da (oxidation) at Met. Protein domains and motifs analyses were carried out with ScanProsite software (
Literature-based bioinformatics and comprehensive annotation of protein in the SwissProt page were used to rationalize the functional characteristics of each nitroprotein, and to provide important clues to the biological significance of each nitroprotein relevant to tumors.
One1D gel-based Western blotting in combination with anti-nitrotyrosine antibody analysis revealed that the overall level of protein tyrosine nitration in astrocytoma was significantly higher than the controls (Figure 1).
The nitrotyrosine immunoactivities in different grade (I, II, III, and IV) of astrocytoma tissues relative to normal controls (N), detected with nitrotyrosine immunoaffinty-based western blotting (n = 3). Tumor = sum of different grade (I, II, III, and IV) of astrocytomas. *p < 0.05. Reproduced from Peng and Zhan [35], with permission from Springer, copyright 2015.
2DGE-based Western blot analysis of nitroproteins in an IV-grade astrocytoma tissue (500 μg protein per 2D gel). (A) Coomassie blue-stained 2DGE image (before transfer of proteins). (B) Coomassie blue-stained 2DGE image (after transfer of proteins). (C) Western blotting image of nitroproteins (anti-nitrotyrosine antibodies + secondary antibodies). (D) Negative control of Western blotting to show the cross-reaction of the secondary antibody (only the secondary antibody; no anti-nitrotyrosine antibody). Reproduced from Peng and Zhan [35], with permission from Springer, copyright 2015.
The challenges faced by low abundance of tyrosine nitration and the elusive mass spectrometry result of a nitro group are existed. Modern nitroproteomics applies protein-separation-enrichment techniques such as gel methods and non-gel methods, including immunoprecipitation [11, 37], anti-nitrotyrosine antibody-based enzyme-linked immunosorbent assay (ELISA) [27], and one/two-dimensional gel electrophoresis (1DGE/2DGE)-based Western blot analyses [9, 35]. 1DGE/2DGE-based Western blots analyses can separate and preferentially enrich endogenous nitroproteins and also preliminarily determine the quantitative information of nitrotyrosine. It should not be neglected that limitations of 2DGE-based method including coverage of proteome, dynamic range, sensitivity and throughput, which always were restricted by the amount of samples. Also, the non-nitrated tryptic peptides are much more than nitrated tryptic peptides after a 2DGE-separated nitroprotein was digested, which will interrupt MS/MS signal of nitrated tryptic peptides [38]. However, for the proteome study, a 2DGE gel could detect more than 1000 spots [39]. Different proteins may be contained within the same spot [40]. Many proteins were detected in several analyzed spots showing 2DE-MS separate ability at the protein species level [43]. Indeed, higher sensitivity had been expected when 2DE coupled with high-sensitivity LC–MS, and will detect, identify and quantify human proteome nearly 500,000 (with an estimated resolution) protein species [28]. We adopted 2DGE-based Western blots analyses method to separate and detect nitroproteins in nervous system tumors. Our previous study obtained enrichment of endogenous nitroproteins in human pituitary [9, 36] and astrocytoma [35].
The 2DGE-based Western blot coupled with anti-nitrotyrosine antibody was used to analyze nitroproteins in human astrocytoma tissues (Figure 2) [17]. Nearly 1100 protein spots were detected in each Coomassie-stained 2D gel. Most proteins were distributed within a range of pI 4–8 and Mr. of 15–150 kDa. A total of 57 nitrotyrosine-immunopositive gel spots were detected, and each positive spot corresponded to a Coomassie-stained 2D gel spot. In order to show non-specific nitrotyrosine-immunopositive Western blot spots, we setup a control experiment without primary antibody to determine cross-reactivity of the secondary antibody.
A similar 2DGE-based Western blot coupled with anti-nitrotyrosine antibody was used to analyze nitroproteins in human pituitary tissues [35, 38]. Each pituitary silver-stained 2D gel image (pI 3–10; Mr. 10–100 kDa) contained ca. 1000 protein spots, and a total of 32 nitrotyrosine immunopositive Western blot spots were detected in human pituitary tissues.
An immunoprecipitation, nitrotyrosine affinity column (NTAC)-based MS/MS approach was also used to enrich and identify nitroproteins from a pituitary adenoma tissue (Figure 3) [37]. Briefly, the NTAC was prepared with protein G beads cross-linked with anti-nitrotyrosine antibodies. A volume (600 μl) of protein extracts from 62 mg wet weight of a pituitary adenoma tissue was diluted (1,1, v/v) with binding/washing buffer. Then, 500 μl diluted sample was incubated with the prepared NTAC to enrich and isolate nitroproteins and nitroprotein–protein complexes, followed by tripsin digestion and MS/MS identification.
The use of NTAC to characterize nitroproteins and their complexes. A parallel control experiment was carried out without any anti-3-nitrotyrosine antibody. Reproduced from Zhan and Desiderio [11], with permission from Elsevier Science, copyright 2006.
MS/MS is the mainstream technique to identify protein species and PTMs products with verification of amino acid sequence, splicing sites, and modification site [31]. However, the very low abundance of tyrosine nitration in a proteome (one nitration in ~106 tyrosine residues) and the complicated mass spectrometry behaviors of a nitro group that we studied in nitroproteins complicate analyses [34, 38]. Different mass spectrometry has different advantages and complicated mass spectrometry behaviors, so choosing the proper method or combination with each other is necessary. For example, the MS behaviors of a nitropeptide differ significantly between matrix-assisted laser desorption ionization (MALDI)-and electrospray ionization (ESI)-MS on process of photochemical decompositions of the nitro group (–NO2) [33, 41]. Additionally, Specificity and sensitivity of the MALDI–LTQ MS/MS analytical system to characterize each nitroprotein and nitroprotein–protein complex should be considered. According to our previous experience [42], MALDI–LTQ has a number of advantages: (1) highly sensitive; (2) high accuracy measurement on amino acid sequence and nitration sites; (3) a prepared sample could be reanalyzed in several weeks.
For human astrocytoma and pituitary adenomas nitroproteomics studies, 2DGE-based nitrotyrosine Western blot analysis with MALDI-TOF were used to obtain endogenous nitroproteins from human pituitary control and adenoma tissues, and 2DGE-based nitrotyrosine Western blot analysis with liquid chromatography-electrospray ionization-quadrupole ion trap (LC-ESI-Q-IT) were used to obtain endogenous nitroproteins from human astrocytoma brain tissues, flowed by identification of nitroproteins, proteins interacted with nitroproteins and nitrotyrosine sites. A representative MS/MS spectrum was shown to identify nitropeptide (ITFDDnYIAC*C*VK) that is derived from sorcin (C9J0K6) in human astrocytoma tissue (Figure 4).
MS/MS spectrum of a nitropeptide (ITFDDnYIAC*C*VK) that is derived from sorcin (C9J0K6) in astrocytoma tissue. nY = nitrotyrosine residue. Reproduced from Peng and Zhan [35], with permission from Springer, copyright 2015.
A total of eight nitroproteins was identified in human normal pituitary tissues with 2DGE-MS/MS [9, 36], and nine nitroproteins were identified in a human nonfunctional pituitary adenoma tissue with NTAC-MS/MS [11], and 18 nitroproteins and their 20 nitrotyrosine sites was identified in a human astrocytoma tissue with 2DGE-MS/MS [35] (Table 1). Three nitroprotein–protein complexes were also identified in a human nonfunctional pituitary adenoma tissue: the nitrated beta-subunit of cAMP-dependent protein kinase (PKA) complex, the nitrated proteasome–ubiquitin complex, and the nitrated interleukin 1 family member 6–interleukin 1 receptor–interleukin 1 receptor-associated kinase-like 2 (IL1-F6–IL1-R–IRAK-2) complex [37].
Nervous system tumors/control | Nitrated protein name | nY site |
---|---|---|
Pituitary adenoma | Rho-GTPase-activating 5 [Q13017] (ARHGAP5) | nY550 |
Leukocyte immunoglobulin-like receptor A4 [P59901] | nY404 | |
Zinc finger protein 432 [O94892] | nY41 | |
PKA beta regulatory subunit [P31321] (PRKAR1B) | nY20 | |
Sphingosine-1-phosphate lyase 1 [O95470] | nY356, Y366 | |
Centaurin beta 1 [Q15027] | nY485 | |
Proteasome subunit alpha type 2 [P25787] (PSMA2) | nY228 | |
Interleukin 1 family member 6 [Q9UHA7] (IL1F6) | nY96 | |
Rhophilin 2 [Q8IUC4] (RHPN2) | nY258 | |
Pituitary control | Proteasome subunit alpha type 2 (PSMA2) | nY228 |
Mitochondrial co-chaperone protein HscB [Q8IWL3] | nY128 | |
Actin [P03996] (ACTA2, ACTG2, ACTC1) | nY296 | |
Synaptosomal-associated protein (SNAP91) | nY237 | |
Ig alpha Fc receptor [P24071] (FCAR) | nY223 | |
Progestin and adipoQ receptor family member III [Q6TCH7] (PAQR3) | nY33 | |
PKG 2 [Q13237] (PRKG2) | nY354 | |
Stanniocalcin 1[P52823] (STC1) | nY159 | |
Astrocytoma | Ras-related protein Rab-8B (H0YMN7) | nY77;nY78 |
Isoform 2 of Signal-induced proliferation-associated 1-like protein 2 (Q9P2F8–2) | nY1369, nY1387 | |
Regulating synaptic membrane exocytosis protein 1 (Q86UR5) | nY926 | |
Isoform 2 of Grainyhead-like protein 1 homolog (Q9NZI5–2) | nY400, nY402 | |
Probable G-protein coupled receptor 52 (Q9Y2T5) | nY281, nY284 | |
Sorcin (C9J0K6) | nY116 | |
Tubulin beta chain (P07437) | nY106 | |
Tubulin beta-2A chain (Q13885) | nY106, nY183, nY200 | |
Tubulin beta-2B chain (Q9BVA1) | nY106 | |
Tubulin beta-3 chain (Q13509) | nY106 | |
Ig kappa chain V-I region WAT (P80362) | nY49 | |
Coiled-coil domain-containing protein 105 (Q8IYK2) | nY372 | |
Helicase ARIP4 (E7EU19) | nY407 | |
General transcription factor 3C polypeptide 3 (Fragment) (H7C0C0) | nY110 | |
Isoform 2 of Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 2 (O43150–2) | nY75 | |
Isoform 2 of Toll-like receptor 9 (Q9NR96–2) | nY419 | |
Transducin-like enhancer protein 2 (B4DE62) | nY369 |
Nitroproteins and non-nitrated proteins identified from nervous system tumor.
Furthermore, the 2DE-MS/MS-identified nitrosorcin in astrocytoma tissues was confirmed with immunoprecipitation coupled with 1D gel-Western blot experiments (Figure 5). The tyrosine nitration of sorcin was measured by immunoprecipitation coupled with Western blotting between IV-grade astrocytoma and normal control (N) tissues. Thus overall status of tyrosine nitration in the whole tissues could be displayed with anti-nitrotyrosine antibody. The results confirmed the tyrosine nitration of sorcin in astrocytoma, and the level of tyrosine nitration of sorcin in astrocytoma is obviously higher than the control tissues.
Nitrotyrosine immune activities in nitrosorcin-immunoprecipitated products from IV-astrocytoma and normal control (N) tissues. Reproduced from Peng and Zhan [35], with permission from springer, copyright 2015.
Comprehensive analysis of the functional characteristics of those nine nitroproteins and three nitroproten-protein complexes in a pituitary adenoma biological system revealed several important functional pathways involved in protein tyrosine nitration (Figure 6): Nitrated RHOGAP5 and nitrated rhophilin 2 are involved in the GTPase signal pathway. Nitrated CENT-beta 1 and nitrated PKAR1-beta are involved in the PKA signal pathway. IRAK-2 in the IL1-R complex and nitrated IL1-F6 are involved in the cytokine system. The nitrated proteasome–ubiquitin complex is an important enzymatic complex involved in the intracellular nonlysosomal proteolytic pathway. Nitrated LIRA4 might be involved in the immune system. Nitrated ZFP432 is involved in transcription regulatory systems. The nitrated S1P lyase 1 participates in sphingolipid metabolism to regulate cell proliferation, survival, and cell death as well as the immune system.
Experimental data-based model of nitroproteins and their functions in human nonfunctional pituitary adenomas. NO2−, nitroprotein. Reproduced from Zhan and Desiderio [11], with permission from Elsevier Science, copyright 2006.
Comprehensive analysis of the functional characteristics of 18 astrocytoma nitroproteins revealed those nitroproteins participated in multiple cancer-related biological processes (Figure 7): (a) microtubule dynamic stabilization and cytoprotection, which mainly involvedβVIII-tubulin, and β-tubulin; (b) tumor migration and metastasis, which mainly involved sorcin, isoform 2 of Toll-like receptor 9, isoform 2 of Arf-GAP with SH3 domain/ANK repeat and PH domain-containing protein 3, transducin-like enhancer protein 2, and GPR52; (c) chemotherapy resistance, which mainly involved Ras-related protein Rab 8, βIII-tubulin, βIVa-tubulin, βVI-tubulin, and sorcin; (d) cell proliferation and apoptosis, which mainly involved а-tubulin, isoform 2 of Grainyhead-like protein 1, Ras-related protein Rab 8, regulating synaptic membrane exocytosis protein 1, and coiled-coil domain-containing protein 105; (e) phenotypic dedifferentiation, which involved gamma-tubulin; (f) signal transduction, which mainly involved isoform 2 of signal-induced proliferation-associated 1-like protein 2; (g) others such as transcription, immune response, and transformation; (h) tumor malignancy and recurrence-free survival, which involvedβII-tubulin and βIII-tubulin.
Experimental data-based diagram that rationalizes nitrotyrosine-containing proteins in the glioma biological system. Reproduced from Peng and Zhan [35], with permission from Springer, copyright 2015.
Protein tyrosine nitration, as one of an important PTMs generated in nervous system tumor, participates in multiple complex biological processes, including cell proliferation and apoptosis, metastasis, migration, drug-resistance, cytoskeleton, signal transduction, immune response and cellular differentiation [43]. What is the mechanism for protein tyrosine nitration in carcinogenesis and development of malignant tumors? How to identify the protein targets and exact modified sites of tyrosine nitration? One/two-dimensional gel electrophoresis-based nitrotyrosine Western blot analysis and tandem mass spectrometry have been successfully applied in the analysis of nitroproteins in nervous system tumors.
Further study is needed to solve those limits on protein nitration: (1) Protein tyrosine nitration and heterogeneity of neoplasm. (2) Three-dimensional spatial structure of a nervous system tumor-related nitroprotein. (3) Consistency issues between body fluid and tissue. With the clarification of those issues on nitroproteins, protein tyrosine nitration will have a significant impact on the field of nervous system tumors.
The authors acknowledge the financial supports from the National Natural Science Foundation of China (Grant No. 81572278 and 81272798 to X.Z.), China “863” Plan Project (Grant No. 2014AA020610-1 to X.Z.), the Hunan Provincial Natural Science Foundation of China (Grant No. 14JJ7008 to X.Z.), and the Xiangya Hospital Funds for Talent Introduction (to X.Z.). The scientific contributions of Dr. Dominic M. Desiderio and Fang Peng are also acknowledged.
We declare that we have no financial and personal relationships with other people or organizations.
central nervous system enzyme-linked immunosorbent assay electrospray ionization false discovery rates isoelectic focusing matrix-assisted laser desorption ionization tandem mass spectrometry nitrotyrosine affinity column polyacrylamide gel electrophoresis posttranslational modification quadrupole ion trap reactive nitrogen species sodium dodecyl sulfate signal-to-noise ratio tetramethylethylenediamine one-dimensional gel electrophoresis two-dimensional gel electrophoresis
Butadiene-1,3 (BD) is diolefin containing two conjugated double bonds. In oxidation, BD exhibits properties inherent to all olefins, but higher reactivity was compared to but-1-ene and but-2-ene. Both BD and C4-olefins can be a feedstock for producing valuable chemicals by gas-phase oxidation [1, 2]. The oxidation on oxide catalysts in gas phase results in the formation of maleic anhydride together with crotonaldehyde and 2,5-dihydrofuran. Centy and Trifiro suggested a simple consecutive pathway for BD oxidation over V-P-oxide catalysts [3, 4], whereas Honicke et al. proposed multiple pathways from BD to crotonaldehyde, 2,5-dihydrofuran, 2-butene-1,4-dial, 2(5H)-furanone and furan, and finally to maleic anhydride over V2O5 catalysts [5]. Schroeder specified the oxidation pathway on V-Mo-oxide catalysts, including 3,4-epoxy-1-butene as a primary oxidation product [6]. Epoxidation of BD occurs over Ag catalysts [7, 8, 9, 10] used in industry for the production of ethylene oxide and intensively investigated in the oxidation of other olefins (e.g., [11, 12]). 3,4-Epoxy-1-butene is further converted into 2,3-dihydrofuran followed by hydrolysis to form 4-hydroxybutyraldehyde. The secondary transformations occur directly under epoxidation conditions on Ag catalysts promoted with B-P [13], Mo [14], and Mo-P-Sb [15] or by subsequent treatments of 3,4-epoxy-1-butene.
In the early 1980s, oxidation of n-butane has become the preferred method for manufacturing maleic anhydride [16, 17]. The invented synthesis of maleic anhydride from butane creates a competition for the gas-phase oxidation of BD since hydrogenation of maleic anhydride opens a possibility of producing various oxygenates, which produced from BD earlier. At the same time, the gas-phase oxidation of BD still suffers from formation of polymer resins, which leads to excessive consumption of raw materials and catalyst deactivation. This problem and large power consumption inherent to all gas-phase reactions are absent in the liquid-phase oxidation since the low temperature and application of appropriate solvents prevent the formation of the resins. The liquid-phase low-temperature oxidative reactions, in particular the oxidation of olefins, were intensively studied at the end of the last century [18, 19, 20, 21, 22, 23]. A renewed interest in this area is growing now [24, 25, 26, 27] and can be expected to be strengthened in the nearest future as a response to modern requirements of green chemistry to minimize power and materials consumption. In addition, the liquid-phase reactions are well applicable for the oxidation of various olefins and BD because of high reactivity of these hydrocarbons that allows the oxidation at low temperature. At the same time, BD becomes more affordable owing to permanent improvements in its manufacturing.
The title of this chapter concerns the application of green oxygen (air and hydrogen peroxide) in liquid-phase conditions. The liquid-phase oxidative reactions are an important part in chemistry of all olefins and, in particular, of the simplest representative of conjugated diolefins as they open many routes for the conversion of the hydrocarbons. We represent here an analysis of literature information concerning the oxidation of BD in liquids and references to the related reactions of olefins. In detail, we described the catalytic systems in the study of which we acquired our own experience.
Olefins readily interact with radical species. The most susceptible to radical attack is allyl position to produce allyl oxygenates [28, 29]. In the absence of an allylic carbon atom, one of the double bonds of BD is involved in the oxidation. Neat or dissolved in a nonpolar solvent, BD interacts with oxygen at moderate temperature according to radical chain mechanism to form oligomeric butadiene polyperoxide, C4H6O2 [30]. The reaction is accelerated by increasing the temperature or adding free radical initiators and inhibited by adding acids. From the NMR analysis, molecular structure of the polyperoxide formed at 50°C in the presence of 37 Torr of oxygen was composed of equal amounts of 1,4- and 1,2-butadiene units separated by peroxide units [31]. The structure of the polyperoxide (the ratio of 1,4- to 1,2-butadiene units) does not depend on the reaction temperature, whereas the content of bound oxygen in the polyperoxide varies with oxygen pressure. The ratio of peroxide to hydrocarbon units is below 1 at a low oxygen partial pressure. Thermal decomposition as well as hydrogenation of polyperoxide leads to the formation of 3-butene-1,2-diol and 2-butene-1,4-diol or corresponding saturated diols, preferably 1,4-derivatives (Scheme 1) [30, 32, 33, 34, 35].
Formation and reductive decomposition of the polyperoxide [30].
Decomposition of the polyperoxide forms not only 3-butene-1,2-diol and 2-butene-1,4-diol but also side products such as formaldehyde, acrolein (from 1,2-units), and resinous insoluble material (presumably resulting from the reaction of the 1,4-units with aldehydes) [31]. Therefore, the preferred formation of 1,4-oxygenates from the thermal decomposition of polyperoxide is not a strong support of predominance of 1,4-units in the polyperoxide structure.
The rate of decomposition of the polyperoxide increases with increasing temperature, addition of bases (amines) [36], or metal ions as radical initiators. Butadienyl polyperoxide is readily decomposed in the presence of metal ions of variable oxidation state. Therefore, the transition metal compounds participate as catalysts in the radical chain oxidation of BD with oxygen. The oxidation products are similar to those obtained under the decomposition of the polyperoxide. 3-Butene-1,2-diol and 2-butene-1,4-diol can be obtained with the selectivity sufficiently high for the chain radical process, especially if one considers the low stability of these products with respect to secondary oxidation. Thus, a mixture of 3-butene-1,2-diol and 2-butene-1,4-diol has been prepared by oxidative dihydroxylation of BD with oxygen in acetic acid solution of Pd(OAc)2. From a practical point of view, the most valuable 2-butene-1,4-diol has been formed with selectivity of 25% [37].
We tested Pd and Au catalysts in the radical chain oxidation of BD in polar media. Both soluble palladium acetate and insoluble supported metals caused the formation of the products, the most part of which appeared from decomposition of the intermediate butadienyl polyperoxide [32] (Scheme 2). The main products are 3-butene-1,2-diol and 2-butene-1,4-diol. 4-Hydroxybut-2-enal can be formed in the decomposition of polyperoxide and in oxidation of 2-butene-1,4-diol. Oxidative dehydration of 2-butene-1,4-diol produces furan. Both butanediols can be esterified to form corresponding diacetates, but only 2-butene-1,4-diol diacetate has been found in the reaction solution. Acrolein occurs from breaking C─C bond under decomposition of polyperoxide or, possibly, from secondary conversion of 3-butene-1,2-diol. C8 oxygenates originate from polyperoxide fragments containing less than 1:1 ratio of butadiene to oxygen units. In addition, there are impurities of C6 cyclic oxygenates occurring from cyclodimerization of BD (Diels-Alder reaction) followed by oxidation of 4-vinylcyclohexene. The amount of the products is given in Table 1.
GC-detected products of the radical chain oxidation of BD.
Catalyst (mg) | BD (mmol) | Solvent | T (°C) | Time (h) | Products (mmol) | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|
1 + 2 | 3 | 4 | 5 | 6 | Others1 | Peroxide2 | |||||
Pd(OAc)2 2.5 | 70 | HOAc/H2O 88/12 | 70 | 2 | 2.5 | 0.6 | 0.1 | <0.1 | 1.3 | 0.2 | 8.5 |
Pd(OAc)2 2.5 | 70 | HOAc/dioxane/H2O 19/75/6 | 80 | 2 | 4.6 | 3.1 | <0.1 | 0.4 | 7.8 | 0.1 | 9.4 |
0.5%Au/SiO2 120 | 70 | HOAc/dioxane/H2O 44/50/6 | 80 | 4 | 4.7 | 3.2 | <0.1 | 0.1 | 8.9 | 2.0 | 9.1 |
0.5%Au/SiO2 120 | 70 | HOAc/dioxane/H2O 44/50/6 | 80 | 6 | 8.5 | 5.3 | 0.4 | 1.3 | 10.7 | 7.1 | 7.0 |
5%Pd/C 3000 | 100 | DMA/H2O 94/6 | 90 | 3 | 10.3 | 0.4 | 0 | 4.8 | 2.2 | 0.73 | 0.8 |
5%Pd0.5%Te/C 3000 | 100 | DMA/H2O 94/6 | 90 | 3 | 0.5 | 0.1 | 0 | 0.1 | 0.1 | 0.84 | 0.2 |
GC detected products from oxidation of BD (70 mmol) by oxygen (O2/N2 = 10/90, 60 atm) in a solvent (100mL).
C8 diols and acetates, and C6 cyclic oxygenates.
Iodometric titration.
0.1mmol сrotonaldehyde and methyl vinyl ketone.
0.4 mmol сrotonaldehyde and methyl vinyl ketone.
In addition to the stable compounds, a large amount of peroxide compounds have been iodometrically detected in acetic acid and acetic acid/dioxane solutions (Table 1). Peroxide oxygen refers to butadienyl polyperoxide since the addition of Ph3P reducer to the solution results in disappearance of the peroxide and formation of 2-butene-1,4-diol together with minor amounts of furan and 3-butene-1,2-diol. The polyperoxide exhibited sufficient stability in several oxidation tests but almost completely decomposed with a large amount of Pd/C catalysts. As a result, enhanced formation of 2-butene-1,4-diol and 4-hydroxybut-2-enal is achieved in this case (fifth row inTable 1).
The addition of Te to Pd/C catalyst lowers the production of all oxidation products. Bottom row in Table 1 shows the inhibitory effect of Te on the chain radical oxidation reaction. At the same time, more noticeable becomes formation of the oxidation products non typical for the chain radical mechanism. These are crotonaldehyde and methyl vinyl ketone, which show the possibility of a nonradical heterolytic mechanism of oxidation on the PdTe/C catalyst.
Palladium catalysts are widely used in the liquid-phase heterolytic oxidation of olefins [38]. The most significant mechanisms for practice are acetoxylation of ethylene to vinyl acetate and Wacker oxidation of olefins converting ethylene to acetaldehyde and but-1-ene to methyl ethyl ketone. A mechanism of olefin oxygenation under the action of Pd(II) complexes established by Moiseev et al. and Henry et al. [39, 40] is now described in numerous publications (e.g., chapter by Reinhard Jira in book [24]). The mechanism includes the formation of Pd(II) complex with olefin and inner sphere transformations resulting in the reduction of Pd2+ to form carbonyl compound and Pd0 black. Assisted by Cu(II) chloride or other intermediate oxidant, reoxidation of Pd0 with oxygen closes the catalytic cycle, allowing the use of oxygen as a stoichiometric oxidant.
Analogous to light olefins, BD reacts under homogeneous conditions in an aqueous solution of PdCl2 catalyst and CuCl2 oxidant. The oxygenation is directed to one of the double bonds with the retention of the second double bond to produce crotonaldehyde [41, 42]. The oxidation conditions are identical to those applied for oxidation of ethylene to acetaldehyde and 1-butene to methyl ethyl ketone (Wacker-type oxidation), but the kinetics is different [43], in particular the order of reaction with respect to Cl− and H+ ions. Unlike the oxidation of ethylene and other olefins, the oxidation of BD is zero-order with respect to the hydrocarbon. The kinetic parameters of BD oxidation are determined by high reactivity of the conjugated π-bonds, in particular by a strong BD to Pd2+ bonding in the intermediate complex. Unlike propylene, the oxygenation of the BD double bond is directed at the terminal rather than inner carbon atom to form crotonaldehyde. This is probably due to the stabilizing effect of the second double bond. In the presence of Pd2+ ions and another strong oxidizing agents of P-Mo-V heteropolyacids, BD is converted to furan in the similar conditions [44]. It seems like crotonaldehyde was initially formed and then converted under oxidizing conditions to furan, as in a similar homogeneous system [45]. Oxygen is a final stoichiometric oxidant, but the strong intermediate oxidant (Cu2+ or heteropolyacid) is necessary for easy regeneration of the ionic palladium in the oxidation of BD and olefins, as well.
We have observed catalysis by PdCl2 when the radical chain oxidation of BD to diols, furan, and acrolein proceeds along with nonradical oxidation to form mainly crotonaldehyde together with small amounts of methyl vinyl ketone and furan (Scheme 3) (first row in Table 2). It is interesting that the system does not contain an oxidizing agent, except oxygen. There is no need of any intermediate oxidant since reoxidation of Pd0 to Pd2+ is provided by peroxide intermediates generated in a radical process. Telluric acid inhibits the radical process but does not operate as an oxidant for Pd0 to maintain the nonradical oxidation by Pd2+. As a result, the PdCl2 with H6TeO6 solution is inactive in oxidation of BD (second row in Table 2). By contrast, the heterogeneous 5%Pd2%Te/C catalyst is able to provide nonradical oxidation, with the radical chain oxidation being inhibited by Te. As a result of inhibiting action of Te, the large amount of the catalyst and low concentration of BD appear unfavorable for the development of the chain process. The oxidation on the 5%Pd2%Te/C catalyst in aqueous dimethylacetamide (DMA) has been observed to give crotonaldehyde and methyl vinyl ketone as main products (third row in Table 2). Interestingly, crotonaldehyde is a predominant product of heterolytic oxidation with PdCl2, but nearly equal amounts of crotonaldehyde and methyl vinyl ketone are produced on the 5%Pd2%Te/C catalyst in the same conditions.
Nonradical reaction of BD on PdTe/C catalyst in polar solvents.
Catalyst(mg) | BD (mmol) | Time (h) | Products (mmol) | ||||||
---|---|---|---|---|---|---|---|---|---|
Furan | Acrolein | Methyl vinyl ketone | Croton-aldehyde | 3-Butene-1,2-diol | 2-Butene-1,4-diol, 4-hydroxybut-2-enal | Others | |||
PdCl2 120 | 43 | 3 | 0.4 | 1.1 | 0.3 | 1.6 | 3.2 | 3.9 | 0.2 |
PdCl2 120, H6TeO6 800 | 43 | 3 | 0.2 | 0.5 | <0.1 | 0.4 | <0.1 | 0.5 | 0.1 |
5% Pd 2% Te/C 2000 | 22 | 6 | 0.1 | <0.1 | 0.8 | 0.6 | — | 0.2 | 0.3 |
GC detected products from oxidation of BD by oxygen (O2/N2 = 10/90, 60 atm) in DMA (30 mL, 3% H2O), T 90°C.
Besides DMA, other polar solvents can be used in this oxidation. The presence of proton additive is required in the solvent (Table 3). No reaction has been observed in anhydrous acetonitrile.
Solvent (g) | Catalyst (g) | Н2О (%) | H2SO4 (mmol/L) | Time (h) | Products (mmol) | ||
---|---|---|---|---|---|---|---|
Furan | Methyl vinyl ketone | Croton aldehyde1 | |||||
DMA | 1 | 17 | — | 4 | 0.2 | 1.4 | 1.2 |
Dioxane | 0.5 | — | 5 | 6 | 0.5 | 1.0 | 0.7 |
Acetonitrile | 1 | 17 | — | 5 | <0.1 | 1.0 | 0.8 |
Acetonitrile | 1 | 17 | 8 | 5 | 0.3 | 1.7 | 0.9 |
Acetonitrile | 0.5 | — | 2 | 4 | 0.8 | 2.0 | 1.2 |
Acetonitrile | 0.5 | — | — | 3 | 0 | 0 | 0 |
GC detected products from oxidation of BD (4.5 mmol) by oxygen (O2/N2 = 10/90, 40 atm) on 5% Pd 2%Te/C catalyst in a solvent (35 mL), T 100°C.
Crotonaldehyde can be partly subjected to further oxidation to crotonic acid.
According to XPS analysis, the 5%Pd2%Te/C catalyst contains both reduced Pd0 and ionic Pd2+, and two oxidation states of tellurium Te0 and Te4+ [46]. The Pd2+ to Pd0 ratio on the catalyst surface becomes larger with an increase in tellurium content that indicates an oxidizing influence of TeO2. It can be expected that the oxidation state of the surface is enhanced under the reaction conditions. Nevertheless, dissolution of Pd and Te during reaction does not exceed 1% of the content of both components in the solid catalyst, the solution exhibiting no catalytic activity. Therefore, activity of the catalyst refers to the active components on the surface of carrier and is associated with their reversible redox transformations. Based on the known mechanisms of homogeneous oxidation of olefin, one can propose two possibilities for oxidation of BD by oxygen on the PdTe species, both assuming a nonradical heterolytic interaction. Perhaps the mechanism is in general similar to that postulated for the oxidation of BD and olefins in the presence of Pd2+ complexes, oxygen, and intermediate oxidant (Scheme 4, Route 1). It involves surface Pd2+ ions and TeO2 oxidant providing regeneration of Pd2+.
Tentative routes for nonradical oxidation of BD on PdTe/C catalyst.
However, there is a difference in products composition. Crotonaldehyde and furan are produced in above-mentioned oxidations of BD with homogeneous Pd2+ catalysts [41, 42], whereas methyl vinyl ketone is the second product formed in our oxidation on the PdTe catalyst. To explain this difference, one can consider an oxidation of BD by hydrogen peroxide as an alternative or parallel reaction (Route 2 in Scheme 4). Hydrogen peroxide is generated from oxygen on Pd0 species. The high reactivity of olefins with respect to peroxide compounds is known [47]. It is known that hydrogen peroxide does not accumulate during reaction. But it is found in trace amounts in the reaction solution and can form a reactive peroxide compound of Te4+ on the surface of the catalyst. In both mechanisms proposed, Te serves as a carrier of molecular or peroxide oxygen, and the surface of Pd2+/Pd0 activates reagents due to the adsorption of O2 and BD. Thus, the PdTe/C catalyst opens the possibility of oxidation of BD by a nonradical heterolytic mechanism due to the combined effect of the two active components.
Wacker-type oxidation of olefins and analogous Pd-catalyzed nonradical oxidation of BD produce usually carbonyl compounds, but special additives are required for obtaining dioxygenates. Nevertheless, the oxidative 1,2-addition to olefins is known to occur under the action of Pd2+ complex and oxoanion strong oxidants, such as periodate [48] or nitrate anions, in acetic acid solution to form glycol derivatives [49, 50, 51]. Mechanism of the oxidation is based on a nonradical inner sphere interaction of olefin with oxidant in Pd2+ complex. Similar interaction is probably realized in oxidation of BD in the presence of palladium as the catalyst of nonradical heterolytic olefin oxidation and Sb, Bi, Te, or Se promoters. Heterogeneous catalysts containing these active components have shown unique catalytic properties in oxidation of BD selectively to 2-butene-1,4-diol diacetate (Scheme 5) [52, 53].
Oxidative 1,4-addition to BD.
XPS analysis of the Pd and PdTe catalysts indicates that Te-oxide is able to increase positive charge on Pd surface [46], thus being an oxidation promoter for palladium. The ionic state of surface palladium is responsible for heterolytic oxidation. Acetic acid is used as a solvent for this reaction. The mechanism of formation of 2-butene-1,4-diol diacetate is proposed by Takehira et al. for PdTe catalyst (Scheme 6) [54], and fundamentally identical one is proposed for the RhTe catalyst [55]. The details in intermediate structures explain the preferential formation of trans-2-butene-1,4-diol in the case of Pd-containing catalyst and cis-isomer in the case of Rh.
Mechanism of 1,4-oxidative addition to BD [54].
Exceptionally high selectivity of BD to 2-butene-1,4-diol diacetate conversion is explained by a concert interaction of BD with surface Pd and with acetate anions. Adsorbed on Pd, BD forms π-allyl-type intermediate that undergoes acetoxylation on the terminal carbon atom. Resulting monoacetoxyl reacts with the second acetate to give 2-butene-1,4-diol diacetates and 3-butene-1,2-diol diacetate in amounts proportional to the reactivity of carbon atoms 1 and 2 (Scheme 6). In fact, only 2-butene-1,4-diol diacetates are produced. Analogous mechanisms are realized in homogeneous oxidation of various dienes in the presence of Pd complexes and p-benzoquinone oxidizing agent, instead of Te. Oxidation of diene alcohols [56] and substituted conjugated diolefins [57] proceed effectively, but BD reacts with low yield and selectivity.
As noted earlier, Te-oxide is able to inhibit radical chain oxidation of BD, the selectivity of which is lower than the selectivity of the heterolytic process. Besides, Te operates as an inhibitor of radical polymerization of BD and oxidation products, thus preventing the formation of side high-boiling products. Acetic acid (possibly, other carboxylic acids) also contributes to the achievement of high selectivity in BD oxidation. Being not only solvent but also reagent (OAc− anions), it is involved in an intermediate interaction with olefin to form the surface Pd intermediate, and finally stabilizes the product as ester, preventing its secondary transformations. Based on the unique properties of the PdTe/C-HOAc catalytic systems, the industrial process for the production of 2-butene-1,4-diol diacetate has been developed by Mitsubishi Chemical. BD is oxidized to 2-butene-1,4-diol diacetate with selectivity of 98%. Possible further improvements of the process can be connected with the application of other platinum metals (Pt, Rh, and Ir) combined with various promotors.
If acetic acid is replaced by alcohol, 1,4-dialkoxylation of conjugated dienes was developed in Pd(OAc)2 solution. p-Benzoquinone was used as the oxidant and methanesulfonic acid as a promoter [58]. The oxidation is suggested to follow mechanism including the formation of the (π-allyl)palladium(benzoquinone) intermediate (Scheme 7).
1,4-Dialkoxylation of conjugated dienes [38].
In other case, dialkoxybutenes are prepared by reacting BD in the presence of carbon-supported Group VIII noble metals with Te or Se additives. Similar to diacetates, the formation of ethers in alcohol solvent increased the stability of dioxygenated products against secondary oxidation. However, the formation of 3,4-dimethoxy-1-butene and 1,4-dimethoxy-2-butene in comparable amounts is in contrast with Scheme 6 and indicates a radical mechanism of BD oxidation, when 2-butene-1,4-diol and 3-butene-1,2-diol are formed as primary products and then converted to ethers in the alcohol medium [59].
We have prepared PdTe/C catalysts by hydrolytic deposition of palladium under the reductive conditions, followed by treatment with H6TeO6. The procedure is similar to one often described for the synthesis of PdTe catalysts. No evidences for the occurrence of binary Pd–Te phases have been provided by XRD, and XPS analysis evidences Pd0, PdO, Te0, and TeO2 [60]. The absence of the Pd-Te phase and the partially oxidized state of the active metals have also been reported by Takehira [54] for Pd-Te-C catalysts. As assumed, Te is located in the outer layer of supported particles. The characteristics of the PdTe/C catalysts were detailed by HAADF-STEM analysis of the surface and line EDX analysis of composition of the supported particles [60]. The results represent an unusual distribution of components on the surface, where Te does not form an individual crystalline phase but is located on the surface of Pd particles in a highly dispersed state. These data explain properties of the PdTe catalysts. In particular, the ability of Te to inhibit the radical reactions is in part due to the coverage of the palladium surface, which normally tends to initiate radical chains.
The primary products in BD oxidation on PdTe/C catalyst in methanol and further conversion of them under the oxidation conditions are shown in Scheme 8, and the amounts are given in Table 4.
Products of BD oxidation on PdTe/C catalyst in methyl alcohol.
Catalyst, conditions | Products (mmol) | |||||||
---|---|---|---|---|---|---|---|---|
1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | |
5%Pd0.5%Te/C, 10 mmol BD, 100°C, 3 h | 0.54 | 1.16 | 0.35 | 1.58 | 0.17 | 1.48 | 0 | 0.73 |
5%Pd0.5%Te/C, H2SO4, 10 mmol BD, 100°C, 3 h | 0.45 | 2.02 | 0.08 | 0.12 | 1.42 | 2.30 | 0 | 1.81 |
5%Pd2.7Te/C, H2SO4, 10 mmol BD, 120°C, 2 h | 0.24 | 0.06 | 0 | 0.06 | 0.66 | 2.80 | 2.0 | 0 |
5%Pd2.7Te/C, H2SO4, 40 mmol BD, 120°C, 2 h | 0.23 | 0.06 | 0 | 0.07 | 0.78 | 6.70 | 3.90 | 0 |
Products of BD oxidation in solvent CH3OH (10% H2O) (30 mL), H2SO4 (0.1 mmol where indicated).
As well as in DMA, nonradical heterolytic oxidation of BD in alcohol medium leads to the formation of crotonaldehyde (1) and methyl vinyl ketone (4). Besides, 1,4-dimethoxy-2-butene (6) is produced analogously to 2-butene-1,4-diol diacetate in acetic acid. The primary products undergo further transformations depending on the reaction conditions. Sulfuric acid promotes oxidation, especially toward 1,4-oxidative addition (comparison of first and second rows in Table 4). An increase in Te content lowers the reaction rate but increases proportion of products formed through 1,4-addition (third row in Table 4). Composition of oxidation products obtained in the presence of the Pd0.5Te/C catalyst and H2SO4 is differed from the one in the radical chain oxidation (compare data given in Tables 1 and 4). 3,4-Dimethoxy-1-butene and acrolein that indicate nonradical oxidation do not appear. Peroxide compounds were also not detected in the solution after the reaction. The chain process does not develop due to the presence of Te and low concentration of BD used to eliminate the formation of the radical chains. Moreover, the radical products do not appear even at increased concentration of BD (fourth row in Table 4). Similarly to acetic acid, methyl alcohol in a mixture with sulfuric acid converts the oxidation products to methyl esters. However, oxidation in the alcohol medium is slower than in acetic acid, and further improvement of the selectivity of the formation of 1,4-addition products is required.
Two competitive methods for direct epoxidation of olefins are gas-phase oxidation with oxygen over silver catalyst and liquid-phase reactions with organic hydroperoxides or hydrogen peroxide in the presence of soluble or supported W, Mo, Ti complexes. The gas-phase epoxidation is typical for obtaining light epoxides, whereas epoxidation with peroxide compounds in liquid is applicable for a wide range of substrates containing double bonds. Both type reactions are based on interaction of olefin with electrophilic oxygen species. Under liquid-phase epoxidation, catalytically active metal complexes react with peroxides to attach the reactive oxygen as ligand which attack the double bond of olefin. Hydrogen peroxide is effective oxygen donor and has an advantage of low-temperature reaction giving environmentally benign water as a by-product [61, 62].
The liquid-phase epoxidation of BD with H2O2 is known to occur over titanium silicates in CH3OH [63] and in CH3CN solution of heteropoly compounds [64, 65]. The data for these reactions are given in Table 5.
Catalyst1 | H2O21 (mmol) | BD (bar) | Time (h) | Epoxide (mmol) | Sel.BD (%) | H2O2 efficiency (%) | Reference |
---|---|---|---|---|---|---|---|
TS-1(6 mg)2 | 0.5 | 1.5 | 1 | 0.25 | n.d. | 52 | [63] |
TBA4[γ-SiW10O34(H2O)2] (3 μmol)3 | 0.3 | 2.5 | 9 | 0.30 | 99 | 99 | [64] |
TBA-PW11(10 μmol)4 | 0.9 | 1 | 5.5 | 0.51 | 88 | 88 | [65] |
EMIm-PW11(10 μmol)4 | 0.9 | 1 | 5 | 0.65 | 91 | 90 | [65] |
EMIm-PW11(2.3 μmol)5 | 1.0 | 1 | 5 | 0.20 | 97 | 100 | [65] |
Epoxidation of BD with H2O2 in solvents.
Catalyst, H2O2 and epoxide produced were normalized to 2 mL of the reaction mixture.
CH3OH solvent, room temperature.
CH3CN solvent, room temperature.
CH3CN solvent, 60 °C.
CH3CN solvent, 50 °C.
Both catalysts are activators of hydrogen peroxide, capable of forming peroxide complexes. Thoroughly investigated for various olefins, the mechanism of epoxidation is realized for the conversion of BD to 3,4-epoxy-1-butene. Coordinated on metal ion, the electrophilic oxygen interacts with one of the equivalent double bonds of BD leaving intact the second C═C bond. Oxygen transfer from peroxide ligand to double bond of olefin has been proved using isotopic reagents [64]. The addition of oxygen to the second bond of BD is more difficult; therefore, the formation of a diepoxide is not detected in reactions with hydrogen peroxide.
Lacunary polyoxotungstates are effective catalysts for epoxidation of olefins with H2O2 [66]. Besides olefins, [HPW11O39]6−and [γ-SiW10O34(H2O)2]4− anions catalyze epoxidation of BD with diluted aqueous H2O2 in acetonitrile solution. Epoxidation of BD has been shown to proceed with high selectivity for 3,4-epoxy-1-butene. Appearance of small admixtures of furan, 3-butene-1,2-diol, and 2-butene-1,4-oxygenates is associated with isomerization and hydrolysis of 3,4-epoxy-1-butene. The unproductive radical decomposition of H2O2 is minimal or absent when the reaction is carried out at a low temperature and at a low concentration of hydrogen peroxide. This is favorable for maintaining high selectivity for 3,4-epoxy-1-butene, because the secondary oxidation of 3,4-epoxy-1-butene by radical intermediates is prevented. As a result, only negligible amount of acrolein appears in the product. Moreover, small additives of EMImBr have been found to inhibit radical decomposition of H2O2, thus increasing the selectivity of BD to 3,4-epoxy-1-butene conversion and efficiency of H2O2 consumption. As a result, the efficiency of H2O2 consumption for producing 3,4-epoxy-1-butene is extremely high, it approaches to 100% under favorable conditions. Both Si- and P-centered heteropolytungstates exhibit equally effective catalysis.
Under reaction conditions, the catalytically active anions are generated from starting lacunary polyoxotungstate anion. It has been shown by NMR that [HPW11O39]6− anion is a precursor of tungsten-depleted anions [PW4] and [PW2], which operate as the most effective activators of hydrogen peroxide and are responsible for epoxidation (Scheme 9) [65]. This is confirmed by the high reactivity of a specially synthesized anion {PO4[WO(O2)2]4}3− in epoxidation of olefins [67].
Transformations of heteropolytungstates in oxidation of BD to 3,4-epoxy-1-butene (EpB) [65].
Despite the limited use of 3,4-epoxy-1-butene itself, it is nevertheless a raw material for the synthesis of various C4-oxygenates such as 1,4-butanediol [68], 3-butene-1,2-diol and 2-butene-1,4-diol [69, 70, 71], and 2,5-dihydrofuran [72]. Therefore, low-temperature and selective epoxidation of BD can be considered as a principal stage of alternative synthesis of demanded and valuable chemicals.
Close nature of BD and light olefins is manifested in similar reaction properties, so that liquid-phase oxidation reactions of BD and olefins have similar mechanisms in many features. The oxidation of olefins and BD in liquid medium enables realization of several routes and obtaining a wide range of products, which are more diverse if compared with gas-phase oxidation. We have considered here the radical chain oxidative conversion of BD realized through the stable polyperoxide intermediate, the formation of which is, to a certain extent, inherent to many olefins. Palladium is able to catalyze homolytic (radical) and heterolytic (Wacker-type) oxidation of olefins. Very close to olefins, the properties of BD are manifested in reactions assisted by homogeneous and more often heterogeneous Pd-containing catalysts. (Note that the tendency to heterogenization of soluble catalysts is observed in liquid-phase reactions.) We observe an interesting phenomenon when the mechanism and products of the Pd-catalyzed oxidation are controlled by promoters. In dependence on other components, the catalytic action of Pd is switched from radical oxidation to nonradical oxygenation directed to one carbon atom or 1,4-position of BD when Pd is promoted with Te or related metals. The effect of Te as an oxidation promoter of palladium and a radical inhibitor allows PdTe catalysts to show substantial efficiency in the well-known industrial synthesis of 1,4-diacetoxybutene in acetic acid and also in other oxidations of BD such as formation of crotonaldehyde and methyl ethyl ketone in aqueous media. The reaction medium and concentration of reagents are also important factors to vary the mechanism of oxidation. Low concentration of BD in the reaction mixture reduces the development of the chain process and makes it possible to realize the oxidation by the heterolytic mechanism. Polar organics are conventional solvents for various oxidations, but acetic acid and methanol exhibit special properties creating conditions for preferable formation of esters of 1,4-butanediol. The identity in mechanisms is also observed in epoxidation of olefins and BD with hydrogen peroxide, where the same catalytically active Ti silicates and polyoxometalates are successfully used to attain highly selective conversion of hydrocarbon and H2O2. All this shows that liquid-phase oxidation have a great potential in converting the BD into valuable oxygenates. To develop this area, extremely productive can be appeal to analogy in chemistry of BD and olefins. A large body of information relating to the oxidation of olefins can be productively applied to understand the mechanisms in oxidation of BD and to develop a strategy for synthesis of purposed oxidation products.
This work was conducted within the framework of budget project No 0303-2016-0006 for Boreskov Institute of Catalysis.
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\n\nPolicy last updated: 2016-06-09
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