Alkynation

Alkynation is an addition reaction in organic synthesis where a metal acetylide reacts with a carbonyl group to form an α-alkynyl alcohol.[1] When the acetylide is formed from acetylene, the reaction forms an α-ethynyl alcohol. This process is often referred to as Ethynylation.

History

The principle of this reaction was discovered by chemist John Ulric Nef in 1899 while experimenting with a diethyl ether solution consisting of elemental sodium, phenylacetylene, and acetophenone.[2][3] 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][2][4] Chemist Walter Reppe coined the term ethynylation during his work with acetylene and carbonyl compounds.[1]

Uses

Pharmaceuticals

Alkynation finds some use in synthesis of pharmaceuticals, particularly in the preparation of steroid hormones.[5] For example, ethynylation of 17-ketosteroids produces important contraceptive medications known as progestins. Examples include drugs such as Norethisterone, Ethisterone, and Lynestrenol.[6] Hydrogenation of these compounds produces anabolic steroids with oral bioavailability, such as Norethandrolone.[7]

Commodity chemicals

Alkynation is used to prepare commodity chemicals such as propargyl alcohol,[1][8] butynediol, 2-methyl-3-butyn-2-ol (a precursor to isoprenes such as vitamin A), 3-hexyne-2,5-diol (a precursor to Furaneol),[9] and 2-methyl-2-hepten-6-one (a precursor to Linalool).

Reaction conditions

Non-catalytic conditions

Typically a stiochiometric amount of an alkali metal acetylide undergoes nucleophilic addition with an aldehyde or a ketone with retention of the triple bond:

RCOR' + NaC≡CR" → RR'C(ONa)C≡CR"

The work-up for the reaction of uses an acid, such as acetic acid or sulfuric acid, to remove the alkali metal and liberate the free alcohol.[10][11]

RR'C(ONa)C≡CR" + CH3COOH → RR'C(OH)C≡CR" + CH3COONa

Common solvents used for the reaction include liquid ammonia, aliphatic amines, ethers, acetals, dimethylformamide,[1] and dimethyl sulfoxide.[12]

Catalytic conditions

Catalytic ethynylations using transition metals and acetylene are also possible, but the reaction often requires high temperatures and pressures to drive a chemical equilibrium toward reaction products:[1]

RR'C=O + HC≡CH ⇌ RR'C(OH)C≡CH

Variations

Grignard reagents

Main article: Grignard reaction

Grignard reagents of acetylene or alkynes can be used to perform alkynations on compounds which are liable to polymerization reactions via enolate intermediates. However, substituting lithium for sodium or potassium acetylides accomplishes similar results, often giving this route little advantage over the conventional reaction.[1]

Favorskii reaction

Main article: Favorskii reaction

The Favorskii reaction is an alternative set of reaction conditions which proceeds via an adduct of acetylene formed from an alkali metal hydroxide.[1] The reaction proceeds through three stages of chemical equilibrium, making the reaction reversible:

  1. HC≡CH + KOH ⇌ HC≡CK + H2O
  2. KOH + H2O ⇌ KOH⋅H2O
  3. RR'C=O + HC≡CK ⇌ RR'C(OK)C≡CH

To overcome this reversibility, the reaction often uses an excess of base to trap the water as hydrates.[1]

Disadvantages

The applicable substrates that can undergo a Favorskii reaction are limited when compared to the conventional reaction because using an excess of hydroxide base introduces aldol condensation as a more significant competing side reaction.[1] Since enolates do not react with acetylene, the reaction can be often be a poor substitute for the conventional reaction, especially when reaction is used on aldehydes. Successful reactions with aldehydes often require special solvents to be used, such as DMSO[12] or 1,2-dimethoxyethane with a trace amount of ethanol.[1] Additionally, LiOH fails to form the necessary adduct with alkynes to initiate the reaction.

Advantages

Hydroxide bases are inexpensive relative to generating an alkoxide or acetylide with reagents such as elemental lithium, sodium, or potassium. Additionally, the stringent reaction conditions used by most alternatives, such as excluding moisture and atmospheric oxygen, are less important, making the reaction easier to perform.[12]

Reppe chemistry

Chemist Walter Reppe pioneered catalytic, industrial-scale ethynylations using acetylene with alkali metal and copper(I) acetylides:[1]

Today these reactions are still used to manufacture propargyl alcohol and butynediol.[8] 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

Alkyne coupling reactions

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 Viehe, Heinz Günter (1969). Chemistry of Acetylenes (1st ed.). New York: Marcel Dekker, inc. pp. 169 & 207–241. doi:10.1002/ange.19720840843.
  2. 1 2 Wolfrom, Melville L. (1960). "John Ulric Nef: 1862—1915". Biographical Memoirs (PDF) (1st ed.). Washington, DC: National Academy of Sciences. p. 218. Retrieved 24 February 2016.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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. doi:10.1021/ja01645a010.
  7. ↑ 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. doi:10.1021/ja01155a015.
  8. 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 3527306730.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ Coffman, Donald D. (1940). "Dimethylethhynylcarbinol". Organic Syntheses. 40: 20. doi:10.15227/orgsyn.020.0040.
  12. 1 2 3 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.
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