Analkyne trimerisation is a [2+2+2] cycloaddition reaction in which threealkyne units (C≡C) react to form abenzene ring. The reaction requires a metalcatalyst. The process is of historic interest as well as being applicable toorganic synthesis.^[1] Being a cycloaddition reaction, it has highatom economy. Many variations have been developed, including cyclisation of mixtures of alkynes andalkenes as well as alkynes andnitriles.

Trimerisation of acetylene to benzene is highly exergonic, proceeding with a free energy change of 142 kcal/mol at room temperature. Kinetic barriers however prevent the reaction from proceeding smoothly. The breakthrough came in 1948, whenWalter Reppe and W. J. Schweckendiek reported their wartime results showing thatnickel compounds are effective catalysts:^[2][3]

3 RC₂H → C₆R₃H₃

Since this discovery, many other cyclotrimerisations have been reported.^[4]

In terms of mechanism, the reactions begin with the formation ofmetal-alkyne complexes. The combination of two alkynes within the coordination sphere affords a metallacyclopentadiene.^[5] Starting from the metallacyclopentadiene intermediate, many pathways can be considered including metallocycloheptatrienes, metallanorbornadienes, and a more complicated structure featuring a carbenoid ligand.^[4]

Catalysts used includecyclopentadienylcobalt dicarbonyl andWilkinson's catalyst.

Trimerisation of unsymmetrical alkynes gives two isomeric benzenes. For example,phenylacetylene affords both 1,3,5- and 1,2,4-C₆R₃H₃. The substitution pattern about the product arene is determined in two steps: formation of the metallocyclopentadiene intermediate and incorporation of the third equivalent ofalkyne.Steric bulk on thealkyne coupling partners and catalyst have been invoked as the controlling elements of regioselectivity.

Chiral catalysts have been employed in combination with arynes to produce non-racemicatropisomeric products.^[6]

Catalysts for cyclotrimerisation are selective for triple bonds, which gives the reaction a fairly wide substrate scope. Many functional groups are tolerated. Regioselective intermolecular trimerization of unsymmetrical alkynes remains an unsolved problem.^[4]

Perhaps the most useful development in this area, at least from the commercial perspective is the cotrimerization ofnitriles and alkynes. This reaction is a practical route to some substitutedpyridines.^[7]

Some catalysts are deactivated by formation of stable, 18-electron η⁴-complexes.Cyclobutadiene,cyclohexadiene, andarene complexes have all been observed as off-cycle, inactivated catalysts.^[8] In addition to high-order polymers and dimers and trimers, which originate from low regio- and chemoselectivities,enyne side products derived from alkyne dimerisation have been observed. Rhodium catalysts are particularly adept at enyne formation (see below).^[9] Fornickel catalysis, formation of larger rings (particularlycyclooctatetraene) can be a problem.

Alkyne trimerization is of no practical value, although the reaction was highly influential. The cotrimerization of alkynes and nitriles in the presence oforganocobalt catalysts has been commercialized for the production of substituted pyridines.^[10]

Cyclization involving substrates in which some or all of the alkyne units aretethered together can provide fused ring systems. The length of the tether(s) controls the sizes of the additional rings. Addition of a 1,5-diyne with an alkyne produces abenzocyclobutene, astrained structure that can then be induced to undergo further reactions.^[11]

All three alkyne units can be tethered, leading to creation of three rings in a single step, with each of the two additional ring sizes controlled by the respective tether lengths.^[12]

Crowded triynes can cyclize to products exhibitinghelical chirality. In one example remarkable for the formation of three new aromatic rings in one step, the triyne shown is transformed into the helical product via treatment withcyclopentadienylcobalt dicarbonyl.^[13] As of 2004, this process had yet to be rendered asymmetric,^{[original research?]} but the products could be separated through chiralHPLC.^[13]Cyclisation carried out with adiyne and a separate alkyne affords greater control.^{[clarification needed]} Using commercially availablecyclopentadienylcobalt dicarbonyl, CpCo(CO)₂, as catalyst,bis(trimethylsilyl)acetylene (BTMSA) will react with a diyne-1,2-disubstituted benzene to form ananthroquinone aromatic system:^[14]

Benzyne, generatedin situ from a benzene ring bearingortho-distributedtriflate andtrimethylsilyl substituents, can be used to generate anaryne in place of an acetylene and combined with a suitable diyne. Such a benzene derivative reacts with 1,7-octadiyne in the presence of a suitable catalyst to generate a naphthalene system.^[15] This is an example of ahexadehydro Diels–Alder reaction.

Trimerisation of three2-butyne (dimethylacetylene) molecules yieldshexamethylbenzene.^[16] The reaction is catalyzed by triphenylchromium tri-tetrahydrofuranate^[17] or by acomplex oftriisobutylaluminium andtitanium tetrachloride.^[18]

Trimerisation of threediphenylacetylene molecules yieldshexaphenylbenzene. The reaction is catalyzed bydicobalt octacarbonyl.^[19]

Cyclotrimerization presents an alternative to the functionalization of pre-formed aromatic compounds throughelectrophilic ornucleophilic substitution, theregioselectivity of which can sometimes be difficult to control.

Other methods for the direct formation of aromatic rings from substituted, unsaturated precursors include theDötz reaction, palladium-catalyzed [4+2]benzannulation of enynes with alkynes,^[20] and Lewis-acid-mediated [4+2] cycloaddition of enynes with alkynes.^[21] Cyclization of transient benzyne species with alkynes, catalyzed by palladium, can also produce substituted aromatic compounds.^[22]

• Musso, F.; Solari, E.; Floriani, C. (1997). "Hydrocarbon Activation with Metal Halides: Zirconium Tetrachloride Catalyzing the Jacobsen Reaction and Assisting the Trimerization of Alkynes via the Formation of η⁶-Arene−Zirconium(IV) Complexes".Organometallics.16 (22): 4889.doi:10.1021/om970438g.
• Rodríguez, J. Gonzalo; Martín-Villamil, Rosa; Fonseca, Isabel (1997). "Tris(2,4-pentanedionato)vanadium-catalysed cyclotrimerization and polymerization of 4-(N,N-dimethylamino)phenylethyne: X-ray structure of 1,2,4-tris[4-(N,N -dimethylamino)phenyl]benzene".Journal of the Chemical Society, Perkin Transactions 1 (6):945–948.doi:10.1039/a605474i.ISSN 0300-922X.
• Sakurai, H.; Nakadaira, Y.; Hosomi, A.; Eriyama, Y.; Hirama, K.; Kabuto, C. (1984). "Chemistry of organosilicon compounds. 193. Intramolecular cyclotrimerization of macrocylic and acyclic triynes with Group 6 metal carbonyls. The formation of fulvene and benzene".J. Am. Chem. Soc.106 (26): 8315.Bibcode:1984JAChS.106.8315S.doi:10.1021/ja00338a063.
• Amer, I.; Bernstein, T.; Eisen, M.; Blum, J.; Vollhardt, K. P. C. (1990). "Oligomerization of alkynes by the RhCl₃-aliquat 336 catalyst system Part 1. Formation of benzene derivatives".J. Mol. Catal.60 (3): 313.doi:10.1016/0304-5102(90)85254-F.
• Lee, C. L.; Hunt, C. T.; Balch, A. L. (1981). "Novel reactions of metal-metal bonds. Reactions of Pd₂{(C₆H₅)₂PCH₂P(C₆H₅)₂}₂Cl₂ with acetylenes, olefins, and isothiocyanates".Inorg. Chem.20 (8): 2498.doi:10.1021/ic50222a026.
• Aalten, H. L.; van Koten, G.; Riethorst, E.; Stam, C. H. (1989). "The Hurtley reaction. 2. Novel complexes of disubstituted acetylenes with copper(I) benzoates having a reactive ortho carbon-chlorine or carbon-bromine bond. X-ray structural characterization of tetrakis(2-chlorobenzoato)bis(diethyl acetylenedicarboxylate)tetracopper(I)".Inorg. Chem.28 (22): 4140.doi:10.1021/ic00321a020.
• Hardesty, J. H.; Koerner, J. B.; Albright, T. A.; Lee, G. B. (1999). "Theoretical Study of the Acetylene Trimerization with CpCo".J. Am. Chem. Soc.121 (25): 6055.Bibcode:1999JAChS.121.6055H.doi:10.1021/ja983098e.
• Ozerov, O. V.; Patrick, B. O.; Ladipo, F. T. (2000). "Highly Regioselective [2 + 2 + 2] Cycloaddition of Terminal Alkynes Catalyzed by η6-Arene Complexes of Titanium Supported by Dimethylsilyl-Bridgedp-tert-Butyl Calix[4]arene Ligand".J. Am. Chem. Soc.122 (27): 6423.Bibcode:2000JAChS.122.6423O.doi:10.1021/ja994543o.

• Carbon-carbon bond forming reactions
• Cycloadditions
• Multiple component reactions

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