In organic synthesis, cyanation is the attachment or substitution of a cyanide group on various substrates. Such transformations are high-value because they generate C-C bonds. Furthermore nitriles are versatile functional groups.
Typically, alkyl nitriles are formed via SN1 or SN2-type cyanation with alkyl electrophiles. Illustrative is the synthesis of benzyl cyanide by the reaction of benzyl chloride and sodium cyanide.[1] In some cases cuprous cyanide is used instead of sodium cyanide.[2]
Cyanation of ketones or aldehydes yields the corresponding cyanohydrins, which can be done directly with the cyanide ion (the cyanohydrin reaction) or by using bisulfite, followed by displacement of sulfite:[3][4]
Cyanation of aldehyde with bisulfite
A related reaction is hydrocyanation, which installs the elements of H-CN.
Cyanation of arenesedit
Cyanation of arenes offers access to benzoic acid derivatives, as well as the utility of aryl nitriles themselves in as fine chemicals:
A variety of mechanistically distinct pathways are known to cyanate arenes:
In addition, palladium-catalyzed cyanations of aryl halides have been extensively explored. Generally, KCN or its less toxic surrogate Zn(CN)2 are used as nucleophilic cyanide sources. To further diminish toxicity concerns, potassium ferricyanide has also been used as a cyanide source. Catalytic cycles are believed to proceed through a standard Pd (0/II) pathway with reductive elimination forging the key C-C bond. Deactivation of Pd(II) with excess cyanide is a common problem.[7] Palladium catalysis conditions for aryl iodides, bromides, and even chlorides have been developed:[8]
Nickel-catalyzed cyanations avoid the use of precious metals, and can take advantage of benzyl cyanide or acetonitrile as a cyanide source, via reductive C-C bond cleavage:[9]
Sandmeyer cyanation is a means of converting aniline derivatives to benzonitriles.[10] The cyanation is generally postulated to be two-electron, while with radical mediators in absence of metals, the reaction is likely radical.[11]
With arene as a two-electron nucleophileedit
Metalated arenes can be cyanated with electrophilic cyanide sources, including cyanamides, cyanates, dimethylmalononitrile, or ethyl (ethoxymethylene)cyanoacetate. These methods can proceed with or without transition metal mediation:[12]
With arene as a radical electrophileedit
Radical approaches to arene C-H cyanation are known. Photoredox mediators (metallic or organic) are most common:[13][14]
Referencesedit
^Adams, Roger; Thal, A. F. (1922). "Benzyl cyanide". Organic Syntheses. 2: 9. doi:10.15227/orgsyn.002.0009.
^J. V. Supniewski; P. L. Salzberg (1928). "Allyl Cyanide". Org. Synth. 8: 4. doi:10.15227/orgsyn.008.0004.
^Mowry, David T. (1948). "The Preparation of Nitriles". Chemical Reviews. 42 (2): 189–283. doi:10.1021/cr60132a001. ISSN 0009-2665. PMID 18914000.
^Corson, B. B.; Dodge, R. A.; Harris, S. A.; Yeaw, J. S. (1926). "Mandelic Acid". Org. Synth. 6: 58. doi:10.15227/orgsyn.006.0058.
^Warzecha, Klaus-Dieter. "cyanide substitution of bromobenzene".
^Wu, Jeff (2002). "Catalytic Rosenmund–von Braun reaction in halide-based ionic liquids". Tetrahedron Letters. 43 (3): 387–389. doi:10.1016/s0040-4039(01)02168-2.
^Cohen, Daniel (2015). "Mild Palladium-Catalyzed Cyanation of (Hetero)aryl Halides and Triflates in Aqueous Media". Organic Letters. 17 (2): 202–205. doi:10.1021/ol5032359. PMC4301087. PMID 25555140.
^Ueda, Yohei (2019). "Nickel-catalyzed cyanation of aryl halides and triflates using acetonitrile via C–CN bond cleavage assisted by 1,4-bis(trimethylsilyl)-2,3,5,6-tetramethyl-1,4-dihydropyrazine". Chemical Science. 10 (4): 994–999. doi:10.1039/c8sc04437f. PMC6349056. PMID 30774893.
^H. T. Clarke; R. R. Read (1925). "o-Tolunitrile and p-Tolunitrile". Org. Synth. 4: 69. doi:10.15227/orgsyn.004.0069.
^Reeves, Jonathan (2015). "Transnitrilation from Dimethylmalononitrile to Aryl Grignard and Lithium Reagents: A Practical Method for Aryl Nitrile Synthesis". Journal of the American Chemical Society. 137 (29): 9481–9488. doi:10.1021/jacs.5b06136. PMID 26151426.
^Ravelli, Davide; Protti, Stefano; Fagnoni, Maurizio (2016). "Carbon-Carbon Bond Forming Reactions via Photogenerated Intermediates". Chemical Reviews. 116 (17): 9850–9913. doi:10.1021/acs.chemrev.5b00662. PMID 27070820.
^Li, Jie Jack (2015). C-H Bond Activation in Organic Synthesis. CRC Press, Taylor & Francis Group.
October 27, 2023
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In organic synthesis cyanation is the attachment or substitution of a cyanide group on various substrates Such transformations are high value because they generate C C bonds Furthermore nitriles are versatile functional groups Contents 1 Cyanation to form sp3 nitriles 2 Cyanation of arenes 2 1 With arene as two electron electrophile 2 2 With arene as a two electron nucleophile 2 3 With arene as a radical electrophile 3 ReferencesCyanation to form sp3 nitriles editTypically alkyl nitriles are formed via SN1 or SN2 type cyanation with alkyl electrophiles Illustrative is the synthesis of benzyl cyanide by the reaction of benzyl chloride and sodium cyanide 1 In some cases cuprous cyanide is used instead of sodium cyanide 2 Cyanation of ketones or aldehydes yields the corresponding cyanohydrins which can be done directly with the cyanide ion the cyanohydrin reaction or by using bisulfite followed by displacement of sulfite 3 4 nbsp Cyanation of aldehyde with bisulfiteA related reaction is hydrocyanation which installs the elements of H CN Cyanation of arenes editCyanation of arenes offers access to benzoic acid derivatives as well as the utility of aryl nitriles themselves in as fine chemicals nbsp A variety of mechanistically distinct pathways are known to cyanate arenes With arene as two electron electrophile edit While the classical Rosenmund Von Braun reaction utilizes stoichiometric copper I cyanide as a cyanation source 5 newer variants have been developed that are catalytic in copper 6 nbsp In addition palladium catalyzed cyanations of aryl halides have been extensively explored Generally KCN or its less toxic surrogate Zn CN 2 are used as nucleophilic cyanide sources To further diminish toxicity concerns potassium ferricyanide has also been used as a cyanide source Catalytic cycles are believed to proceed through a standard Pd 0 II pathway with reductive elimination forging the key C C bond Deactivation of Pd II with excess cyanide is a common problem 7 Palladium catalysis conditions for aryl iodides bromides and even chlorides have been developed 8 nbsp Nickel catalyzed cyanations avoid the use of precious metals and can take advantage of benzyl cyanide or acetonitrile as a cyanide source via reductive C C bond cleavage 9 nbsp Sandmeyer cyanation is a means of converting aniline derivatives to benzonitriles 10 The cyanation is generally postulated to be two electron while with radical mediators in absence of metals the reaction is likely radical 11 With arene as a two electron nucleophile edit Metalated arenes can be cyanated with electrophilic cyanide sources including cyanamides cyanates dimethylmalononitrile or ethyl ethoxymethylene cyanoacetate These methods can proceed with or without transition metal mediation 12 nbsp With arene as a radical electrophile edit Radical approaches to arene C H cyanation are known Photoredox mediators metallic or organic are most common 13 14 nbsp References edit Adams Roger Thal A F 1922 Benzyl cyanide Organic Syntheses 2 9 doi 10 15227 orgsyn 002 0009 J V Supniewski P L Salzberg 1928 Allyl Cyanide Org Synth 8 4 doi 10 15227 orgsyn 008 0004 Mowry David T 1948 The Preparation of Nitriles Chemical Reviews 42 2 189 283 doi 10 1021 cr60132a001 ISSN 0009 2665 PMID 18914000 Corson B B Dodge R A Harris S A Yeaw J S 1926 Mandelic Acid Org Synth 6 58 doi 10 15227 orgsyn 006 0058 Warzecha Klaus Dieter cyanide substitution of bromobenzene Wu Jeff 2002 Catalytic Rosenmund von Braun reaction in halide based ionic liquids Tetrahedron Letters 43 3 387 389 doi 10 1016 s0040 4039 01 02168 2 Cohen Daniel 2015 Mild Palladium Catalyzed Cyanation of Hetero aryl Halides and Triflates in Aqueous Media Organic Letters 17 2 202 205 doi 10 1021 ol5032359 PMC 4301087 PMID 25555140 Jin Fuqiang 2000 Palladium catalyzed cyanation reactions of aryl chlorides Tetrahedron Letters 41 18 3271 3273 doi 10 1016 s0040 4039 00 00384 1 Ueda Yohei 2019 Nickel catalyzed cyanation of aryl halides and triflates using acetonitrile via C CN bond cleavage assisted by 1 4 bis trimethylsilyl 2 3 5 6 tetramethyl 1 4 dihydropyrazine Chemical Science 10 4 994 999 doi 10 1039 c8sc04437f PMC 6349056 PMID 30774893 H T Clarke R R Read 1925 o Tolunitrile and p Tolunitrile Org Synth 4 69 doi 10 15227 orgsyn 004 0069 Barbero Margherita 2016 Copper free Sandmeyer cyanation of arenediazonium o benzenedisulfonimides Organic amp Biomolecular Chemistry 14 4 1437 1441 doi 10 1039 c5ob02321a hdl 2318 1554335 PMID 26676962 Reeves Jonathan 2015 Transnitrilation from Dimethylmalononitrile to Aryl Grignard and Lithium Reagents A Practical Method for Aryl Nitrile Synthesis Journal of the American Chemical Society 137 29 9481 9488 doi 10 1021 jacs 5b06136 PMID 26151426 Ravelli Davide Protti Stefano Fagnoni Maurizio 2016 Carbon Carbon Bond Forming Reactions via Photogenerated Intermediates Chemical Reviews 116 17 9850 9913 doi 10 1021 acs chemrev 5b00662 PMID 27070820 Li Jie Jack 2015 C H Bond Activation in Organic Synthesis 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