ARTICLE Received 12 Mar 2014 | Accepted 14 May 2014 | Published 9 Jul 2014 DOI: 10.1038/ncomms5123 Green synthesis of nitriles using non-noble metal oxides-based nanocatalysts Rajenahally V. Jagadeesh1, Henrik Junge1 & Matthias Beller1 (Hetero)aromatic and aliphatic nitriles constitute major building blocks for organic synthesis and represent a versatile motif found in numerous medicinally and biologically important compounds. In general, these nitriles are synthesized by traditional cyanation procedures using toxic cyanides. With respect to green chemistry, the development of more sustainable and cost-efficient processes for the synthesis of advanced nitriles is highly desired. Here we report an environmentally benign synthesis of all kinds of structurally diverse aryl, hetero- cyclic, allylic and aliphatic nitriles from easily available alcohols applying aqueous ammonia and molecular oxygen. Key to success for this synthesis is the use of nitrogen-doped graphene-layered non-noble metal oxides as stable and durable nanocatalysts. As an example a renewable synthesis of adiponitrile, an industrially important bulk chemical is presented. 1 Leibniz-Institut fu¨r Katalyse e.V. an der Universita¨t Rostock, Albert-Einstein Strae 29a, 18059 Rostock, Germany. Correspondence and requests for materials should be addressed to M.B. (email: [email protected]). NATURE COMMUNICATIONS | 5:4123 | DOI: 10.1038/ncomms5123 | www.nature.com/naturecommunications 1 & 2014 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms5123 rganic nitriles have an important role as integral part of characterization). All these materials were tested for their catalytic pharmaceuticals, agrochemicals and fine chemicals. In activity for the benchmark oxidation of benzyl alcohol to ben- Ofact in 2010, more than 30 pharmaceuticals bearing cyano zonitrile. As seen from Table 1, defined metal complexes as well groups were prescribed for diverse medicinal indications and as carbon supported non-pyrolyzed materials showed little 420 additional nitrile-containing compounds were in clinical activity (Table 1, entries 1–21). Similarly, pyrolyzed metal salts on development1,2. Besides, they serve as common building blocks carbon without any phenanthroline ligand present gave only for high performance materials, polymers and molecular slight conversion (Table 1, entries 22–28). Notably, pyrolysis of electronics2–4. In organic chemistry, nitriles serve as essential metal-phenanthroline complexes showed varying catalytic activ- intermediates for the production of a variety of heterocycles5,6, ities (Table 1 entries, 29–35). The pyrolyzed cobalt-phenanthro- as well as precursors for amines, amides, aldehydes and different line (Co3O4-NGr/C) and iron-phenanthroline (Fe2O3-NGr/C) carboxylic acid derivatives7,8. For their synthesis, commonly based materials are found to be excellent catalysts producing highly toxic HCN or metal cyanides (for example, HCN: benzonitrile in nearly quantitative yield (98%; Table 1, entries 29– À 1 TDLo ¼ 0.055 mg kg (human, intravenous); KCN: LD50 ¼ 30). The copper-based catalyst exhibited moderate activity (54% À 1 5–10 mg kg (oral in rats, mice, rabbits); Zn(CN)2: yield; Table 1, entry 31), whereas the other catalysts based on Mn, À 1 LD50 ¼ 54 mg kg (oral in rats)) have to be applied for Cr, V and Ni showed only poor activity (Table 1, entries 32–35). 9,10 nucleophilic substitutions of alkyl and aryl halides or the To demonstrate the recycling of the catalyst, Co3O4-NGr/C was classic Sandmeyer reaction11. Apart from the toxicity, which led used for the benchmark reaction. Up to four times the catalyst to one of the worst environmental disasters in Europe (cyanide can be easily used without re-activation (see Methods section). spill in Baia Mare, Romania, 2000), the use of metal cyanides Applying cobalt (Co3O4-NGr/C; Co-phenanthroline/C-800) generates significant amount of waste. and iron (Fe2O3-NGr/C; Fe-phenanthroline/C-800) oxide-based Today in the chemical industry, ammoxidation is the preferred catalysts, we demonstrated the general synthesis of nitriles from method to produce acrylonitrile, methacrylonitrile, aryl nitriles corresponding alcohols in liquid phase. (limited to simple benzonitriles) and heteroaromatic nitriles (limited to cyanopyridines and pyrazine nitriles) on a bulk- scale12–15. However, most of these processes are performed under Table 1 | Synthesis of benzonitrile using different catalysts. drastic conditions and consequently they are restricted to non- functionalized substrates. In fact, no general ammoxidation CN reaction exists so far, which allows for the synthesis of a broad OH Catalyst + NH + range of functionalized nitriles including more valuable 3 H2O O2, t-amyl alcohol 1 heterocycles. Hence, there is a general need for alternative and 130 °C 2 sustainable routes for –CN introduction in structurally diverse molecules. In this respect, the use of alcohols as starting Entry Catalyst Pyrolysis Conversion Yield materials16–22 is highly desired, as they are easily accessible and (°C, h, Ar) (%) (%) 16–22 of increasing importance as renewable feedstock . Key to 1 Co(OAc)2 Á 4H2O—31 success for such reactions is the development of suitable, selective 2 Co(OAc)2-phenanthroline — 8 5 3 Co(OAc)2-phenanthroline/C 8 6 and cost-effective catalyst systems. In the past, heterogeneous 4 Fe(OAc) —21 22 23–27 2 ruthenium and homogeneous copper-based catalysts have 5 Fe(OAc)2-phenanthroline — 4 3 been used for the conversion of alcohols and amines to the 6 Fe(OAc)2-phenanthroline/C — 4 3 7 Cu(OAc)2 Á H2O—63 corresponding nitriles. Despite these developments, still practical, 8 Cu(OAc)2-phenanthroline — 20 15 and easily re-usable, as well as cost-efficient heterogeneous 9 Cu(OAc)2-phenanthroline/C — 20 15 catalysts are highly desired for the synthesis of advanced nitriles 10 Mn(OAc)2 Á 4H2O—32 11 Mn(OAc) -phenanthroline — 5 3 from alcohols. 2 12 Mn(OAc)2-phenanthroline/C — 5 3 In the last decade, the development of non-noble metal-based 13 Cr(acac)3 —41 28–31 32–34 catalysts , especially nanomaterials , for organic synthesis 14 Cr(acac)3-phenanthroline — 7 3 has become a prime topic and is crucial for the advancement of 15 Cr(acac)3-phenanthroline/C — 7 4 16 V(acac)3 —21 green and sustainable industrial processes. Last year, we reported 17 V(acac)3-phenanthroline — 5 3 the preparation of nanoscale cobalt and iron oxides, which 18 V(acac)3-phenanthroline/C — 6 3 constitute excellent catalysts for highly selective hydrogenation 19 Ni(OAc)2 Á 4H2O—21 33,34 20 Ni(OAc)2-phenanthroline — 3 1 process . We also showed that pyrolysis of metal acetate- 21 Ni(OAc)2-phenanthroline/C — 3 1 nitrogen ligated complexes on carbon leads to the formation of 22 Co(OAc)2/C 800, 2, Ar 6 4 23 Fe(OAc)2/C 800, 2, Ar 6 3 nanoscale metal oxides (Co3O4-NGr/C; Fe2O3-NGr/C), which are 24 Cu(OAc)2/C 800, 2, Ar 9 6 surrounded by nitrogen-doped graphene layers (NGr). In the 25 Mn(OAc)2/C 800, 2, Ar 3 2 present work, we demonstrate the selectivity of such non-noble 26 Cr(acac)3/C 800, 2, Ar 3 2 27 V(acac)3/C 800, 2, Ar 3 2 metal oxides-based nanocatalysts (Co3O4-NGr/C; Fe2O3-NGr/C) 28 Ni(OAc)2/C 800, 2, Ar 2 1 activated by nitrogen-doped graphene surfaces in challenging 29 Co-phenanthroline/C 800, 2, Ar 499 98 oxidation reactions for the synthesis of all kinds of aromatic, 30 Fe-phenanthroline/C 800, 2, Ar 499 98 heterocyclic and aliphatic nitriles from alcohols and aqueous (aq.) 31 Cu-phenanthroline/C 800, 2, Ar 56 54 32 Mn-phenanthroline/C 800, 2, Ar 30 26 ammonia using molecular oxygen. 33 Cr-phenanthroline/C 800, 2, Ar 19 7 34 V-phenanthroline/C 800, 2, Ar 12 4 35 Ni-phenanthroline/C 800, 2, Ar 5 3 Results 36 Phenanthroline/C 800, 2, Ar 1 o1 37 Vulcan 800, 2, Ar 1 o1 Preparation and activity of metal oxide-based nanocatalysts.A series of non-noble metal-based catalysts was prepared by pyro- Reaction conditions: 0.5 mmol benzyl alcohol; weight of catalyst corresponds to 4.0–4.5 mol% metal (metal:phenanthroline ¼ 1:2, in case of Fe ¼ 1:3), 100 ml aq. NH3 (28–30% NH3 basis), lysis of the respective metal acetate-phenanthroline complexes on 5 bar O2,4mlt-amyl alcohol, 130 °C, 18 h. Conversions and yields were determined by GC Vulcan at 800 °C under argon (see Supplementary Methods, (using 100 ml n-hexadecane as standard). The most active calalyst are shown in bold. Supplementary Figs 1–11; and Supplementary Table 1 for detailed 2 NATURE COMMUNICATIONS | 5:4123 | DOI: 10.1038/ncomms5123 | www.nature.com/naturecommunications & 2014 Macmillan Publishers Limited. All rights reserved. NATURE COMMUNICATIONS | DOI: 10.1038/ncomms5123 ARTICLE Synthesis of substituted and functionalized benzonitriles. (Figs 1 and 2). Interesting halogenated benzonitriles were pre- Benzonitriles, which are substructures of different products of pared in 93–97% yields. For example, 2,6-dichlorobenzonitrile, our daily lives, have been obtained in good to excellent yields which is a herbicide and a key intermediate for the preparation a General reaction scheme OH Co3O4-NGr/C or Fe2O3-NGr/C CN R + NH R 3 + H2O O2, t-amyl alcohol,130 °C b Halogenated and substituted benzonitriles Br CN F CN Cl CN CN F CN F Br F Cl I 3: 97% (97%), 96%*, 24 h 4: 96%, 95%*, 26 h 5: 95%, 94%*, 24 h† 6: 98% (95%) 97%*, 20 h 7: 96%, 93%*, 24 h F F CN CN CN CN CN F F F F F F 8: 95% (92%), 93%*, 24 h 9: 96%, 93%*, 26 h 10: 95%, 95%*, 20 h‡ 11: 96%, 94%*, 20 h‡ 12: 98%, 98%*, 26 h CN CN F O CN F F O F F O O F 13: 96%, 97%*, 20 h 14: 98% (97%), 97%*, 22 h 15: 96% (94%), 96%*, 20 h c ‘Challenging’ functionalized benzonitriles CN CN CN CN O CN Cl HO O N O 2 NO2 O NO2 NH2 16: 96%, 94%*, 26 h 17: 89% , 88%*, 26 h 18: 92%, 92%* 28 h§ 19: 96% (93%), 93%*, 24 h 20: (80%), (76%)*, 30 h|| CN CN CN CN CN S F F O S F S CN O O 21: 97%, 96%, 22 h 22: 96%, 94%*, 24 h 23: 94% (93%), 92%*, 24 h|| 24: 97%, 97%, 20 h 25: 97%, 96%*, 20 h CN CN CN S CN NC F Si # # 26: 93%, 94%*, 22 h 27: 88%, 88%*, 30 h 28: 90%, 89%*, 30 h 29: 85%, 86%*, 24 h** CN CN O B O 30: 98% (97%), 96%*, 20 h 31: 93% (90%), 92%*, 20 h Figure 1 | Synthesis of substituted and functionalized benzonitriles.