// Workers AI · dad joke modeWhy was alkynylation a triple threat? It had a bond to share.
In organic chemistry, alkynylation is an addition reaction in which a terminal alkyne (−C≡CR') is added to a carbonyl group (C=O) to form an propargylic alcohol (R2C(−OH)−C≡C−R').[1][2]
When the acetylide is formed from acetylene (HC≡CH), the reaction gives an α-ethynyl alcohol. This process is often referred to as ethynylation. Such processes often involve metal acetylide intermediates.
Implementation
[edit]The principal reaction of interest involves the addition of the acetylene (HC≡CR') to a ketone (R2C=O) or aldehyde (R−CH=O):
- R2C=O + HC≡CR' → R2C(OH)C≡CR'
The reaction proceeds with retention of the triple bond. For aldehydes and unsymmetrical ketones, the product is chiral, hence there is interest in asymmetric variants. These reactions invariably involve metal-acetylide intermediates.
This reaction was discovered by chemist John Ulric Nef in 1899 while experimenting with reactions of elemental sodium, phenylacetylene, and acetophenone.[3][4] For this reason, the reaction is sometimes referred to as Nef synthesis. Sometimes this reaction is erroneously called the Nef reaction, a name more often used to describe a different reaction (see Nef reaction).[1][3][5] Walter Reppe coined the term ethynylation during his work with acetylene and carbonyl compounds.[1]
In a typical implementation, a terminal alkyne, e.g., ethyl propiolate is deprotonated by n-butyllithium to form lithium acetylelide, which adds to ketones.
- R≡CH+ BuLi → RC≡CLi + BuH
- R≡CLi + R'2C=O → RC≡C−C(OLi)R'2
A variety of bases can be employed in place of alkyl lithiums, e.g. Grignard reagents[1]
An acidic work-up affords the alkynyl alcohol:[6][7]
- RC≡C−C(OLi)R'2 + H+ → RC≡C−C(OH)R'2 + Li+
Common solvents for the reaction are ethers, acetals, dimethylformamide,[1] and dimethyl sulfoxide.[8]
Modifications
[edit]Several modifications of alkynylation reactions are known:
- In the Arens–van Dorp synthesis the compound ethoxyacetylene[9] is converted to a Grignard reagent and reacted with a ketone, the reaction product is a propargyl alcohol.[10][11]
- In the Isler modification of the Arens–Van Dorp Synthesis, ethoxyacetylene is replaced by β-chlorovinyl ethyl ether, and the lithium acetylide is generated in situ using lithium amide.[10]
- Catalytic variants are the basis of industrial processes.
- Asymmetric alkynylations have been developed.[12][1] Various catalytic additions of alkynes to electrophiles in water have also been developed.[13]
Uses
[edit]Alkynylation finds use in synthesis of pharmaceuticals, particularly in the preparation of steroid hormones.[14] For example, ethynylation of 17-ketosteroids produces important contraceptive medications known as progestins. Examples include drugs such as Norethisterone, Ethisterone, and Lynestrenol.[15] Hydrogenation of these compounds produces anabolic steroids with oral bioavailability, such as Norethandrolone.[16]
Alkynylation is used to prepare commodity chemicals such as propargyl alcohol,[1][17] butynediol, 2-methylbut-3-yn-2-ol (a precursor to isoprenes such as vitamin A), 3-hexyne-2,5-diol (a precursor to Furaneol),[18] and sulcatone (a precursor to Linalool).
Variations
[edit]Favorskii reaction
[edit]The Favorskii reaction is an alternative set of reaction conditions, which involves prereaction of the acetylene with an alkali metal hydroxide such as KOH.[1] The reaction proceeds through equilibria, making the reaction reversible:
![{\displaystyle {\mathrm {HC} {\equiv }\mathrm {CH} {}+{}\mathrm {KOH} {}\mathrel {\longrightleftharpoons } {}\mathrm {HC} {\equiv }\mathrm {CK} {}+{}\mathrm {H} {\vphantom {A}}_{\smash[{t}]{2}}\mathrm {O} }}](https://wikimedia.org/api/rest_v1/media/math/render/svg/39c40e09f4a421d1f0030eec236cc6ea39b2a77f)
To overcome this reversibility, the reaction often uses an excess of base to trap the water as hydrates.[1]
Reppe chemistry
[edit]Chemist Walter Reppe pioneered catalytic, industrial-scale ethynylations using acetylene with alkali metal and copper(I) acetylides:[1]
These reactions are used to manufacture propargyl alcohol and butynediol.[17] Alkali metal acetylides, which are often more effective for ketone additions, are used to produce 2-methyl-3-butyn-2-ol from acetylene and acetone.
See also
[edit]Alkyne coupling reactions
[edit]References
[edit]- 1 2 3 4 5 6 7 8 9 10 Viehe, Heinz Günter (1969). Chemistry of Acetylenes (1st ed.). New York: Marcel Dekker, inc. pp. 169& 207–241. doi:10.1002/ange.19720840843.
- ↑ Trost, B.M.; Li, C.-J. (2014). Modern Alkyne Chemistry: Catalytic and Atom-Economic Transformations. Weinheim: Wiley VCH.
- 1 2 Wolfrom, Melville L. (1960). "John Ulric Nef: 1862—1915" (PDF). Biographical Memoirs (1st ed.). Washington, DC: National Academy of Sciences. p. 218. Retrieved 24 February 2016.
- ↑ Nef, John Ulric (1899). "Ueber das Phenylacetylen, seine Salze und seine Halogensubstitutionsproducte". Justus Liebigs Annalen der Chemie. 308 (3): 264–328. doi:10.1002/jlac.18993080303.
- ↑ Smith, Michael B.; March, Jerry (2007). "Chapter 16. Addition to Carbon–Hetero Multiple Bonds". March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.). Hoboken, New Jersey: John Wiley & Sons, Inc. pp. 1359–1360. doi:10.1002/9780470084960.ch16. ISBN 9780471720911.
- ↑ Midland, M. Mark; Tramontano, Alfonso; Cable, John R. (1980). "Synthesis of alkyl 4-hydroxy-2-alkynoates". The Journal of Organic Chemistry. 45 (1): 28–29. doi:10.1021/jo01289a006.
- ↑ Coffman, Donald D. (1940). "Dimethylethhynylcarbinol". Organic Syntheses. 40: 20. doi:10.15227/orgsyn.020.0040.
- ↑ Sobenina, L. N.; Tomilin, D. N.; Petrova, O. V.; Mikhaleva, A. I.; Trofimov, B. A. (2013). "Synthesis of secondary propargyl alcohols from aromatic and heteroaromatic aldehydes and acetylene in the system KOH-H2O-DMSO". Russian Journal of Organic Chemistry. 49 (3): 356–359. doi:10.1134/S107042801303007X. S2CID 94135082.
- ↑ Jones, E. R. H.; Eglinton, Geoffrey; Whiting, M. C.; Shaw, B. L. (1954). "Ethoxyacetylene". Organic Syntheses. 34: 46. doi:10.15227/orgsyn.034.0046.
- 1 2 Wang, Zerong, ed. (2009). "Arens–Van Dorp Reaction (Isler Modification)". Comprehensive Organic Name Reactions and Reagents (1st ed.). Hoboken, NJ: Wiley-Interscience. doi:10.1002/9780470638859.conrr023. ISBN 9780471704508.
- ↑ Van Dorp, D. A.; Arens, J. F. (1947). "Synthesis of Vitamin A Aldehyde-". Nature. 160 (4058): 189. Bibcode:1947Natur.160..189V. doi:10.1038/160189a0. PMID 20256189. S2CID 4137483.
- ↑ Trost, Barry M.; Weiss, Andrew H. (2009). "The enantioselective addition of alkyne nucleophiles to carbonyl groups". Advanced Synthesis & Catalysis. 351 (7–8): 963–983. doi:10.1002/adsc.200800776. PMC 3864370. PMID 24353484.
- ↑ Li, C.-J. (2010). "The development of catalytic nucleophilic additions of terminal alkynes in water". Acc. Chem. Res. 43 (4): 581–590. doi:10.1021/ar9002587. PMID 20095650.
- ↑ Sandow, Jürgen; Scheiffele, Ekkehard; Haring, Michael; Neef, Günter; Prezewowsky, Klaus; Stache, Ulrich (2000). "Hormones". Ullmann's Encyclopedia of Industrial Chemistry. doi:10.1002/14356007.a13_089. ISBN 3527306730.
- ↑ Sondheimer, Franz; Rosenkranz, G.; Miramontes, L.; Djerassi, Carl (1954). "Steroids. LIV. Synthesis of 19-Nor-17α-ethynyltestosterone and 19-Nor-17α-methyltestosterone". Journal of the American Chemical Society. 76 (16): 4092–4094. Bibcode:1954JAChS..76.4092D. doi:10.1021/ja01645a010.
- ↑ Hershberg, E. B.; Oliveto, Eugene P.; Gerold, Corinne; Johnson, Lois (1951). "Selective Reduction and Hydrogenation of Unsaturated Steroids". Journal of the American Chemical Society. 73 (11): 5073–5076. Bibcode:1951JAChS..73.5073H. doi:10.1021/ja01155a015.
- 1 2 Pässler, Peter; Hefner, Werner; Buckl, Klaus; Meinass, Helmut; Meiswinkel, Andreas; Wernicke, Hans-Jürgen; Ebersberg, Günter; Müller, Richard; Bässler, Jürgen; Behringer, Hartmut; Mayer, Dieter (2008). "Acetylene". Ullmann's Encyclopedia of Industrial Chemistry. doi:10.1002/14356007.a01_097.pub3. ISBN 978-3527306732.
- ↑ Fahlbusch, Karl-Georg; Hammerschmidt, Franz-Josef; Panten, Johannes; Pickenhagen, Wilhelm; Schatkowski, Dietmar; Bauer, Kurt; Garbe, Dorothea; Surburg, Horst (2003). "Flavors and Fragrances". Ullmann's Encyclopedia of Industrial Chemistry. doi:10.1002/14356007.a11_141. ISBN 3527306730.