Inorganic chemistry, acycloalkyne is the cyclicanalog of analkyne (−C≡C−). A cycloalkyne consists of a closedring ofcarbon atoms containing one or moretriple bonds. Cycloalkynes have a general formulaCnH2n−4. Because of the linear nature of theC−C≡C−C alkyne unit, cycloalkynes can be highlystrained and can only exist when the number of carbon atoms in the ring is great enough to provide the flexibility necessary to accommodate thisgeometry. Large alkyne-containingcarbocycles may be virtually unstrained, while the smallest constituents of this class of molecules may experience so much strain that they have yet to be observed experimentally.[1] Cyclooctyne (C8H12) is the smallest cycloalkyne capable of being isolated and stored as a stable compound.[2] Despite this, smaller cycloalkynes can be produced and trapped through reactions with other organic molecules or throughcomplexation totransition metals.
Due to the significant geometric constraints imposed by theR−C≡C−R functionality, cycloalkynes smaller than cyclodecyne (C10H16) result in highly strained structures. While the cyclononyne (C9H14) andcyclooctyne (C8H12) are isolable (though strongly reactive) compounds, cycloheptyne (C7H10), cyclohexyne (C6H8) andcyclopentyne (C5H6) only exist as transient reaction intermediates or asligands coordinating to a metal center.[3] There is little experimental evidence supporting the existence ofcyclobutyne (C4H4) or cyclopropyne (C3H2), aside from studies reporting the isolation of anosmiumcomplex with cyclobutyne ligands.[4] Initial studies which demonstrated the transient intermediacy of the seven-, six- and five-membered cycloalkynes relied on trapping of the high-energy alkyne with a suitable reaction partner, such as a cyclicdienes ordiazo compounds to generate theDiels–Alder ordiazoalkane 1,3-dipolar cycloaddition products, respectively.[5] Stable small-ring cycloalkynes have subsequently been isolated in complex with varioustransition metals such asnickel,palladium andplatinum.[6] Despite long being considered to be chemical curiosities with limited synthetic applications, recent work has demonstrated the utility of strained cycloalkynes in bothtotal synthesis of complexnatural products andbioorthogonal chemistry.[7][8]
Angle strain in cycloalkynes arises from the deformation of theR−C≡C bond angle which must occur in order to accommodate the molecular geometry of rings containing less than ten carbons. The strain energies associated with cyclononyne (C9H14) and cyclooctyne (C8H12) are approximately 2.9 kcal/mol and 10 kcal/mol, respectively.[9] This upwards trend in energy for the isolable constituents of this class is indicative of a rapid escalation of angle strain with an inverse correlation to ring size. Analysis byphotoelectron spectroscopy has indicated that the alkyne bond in small cyclic systems is composed of two non-degenerateπ bonds – a highly reactive strained bond perpendicular to a lower-energy π bond.[10]Cis-bending of theR−C≡C bond angle results in the drastic lowering of the energy of thelowest unoccupied molecular orbital, a phenomenon which accounts for the reactivity of strained cycloalkynes from the perspective ofmolecular orbital theory.[11]
Initial efforts toward the synthesis of strained cycloalkynes showed that cycloalkynes could be generated via the elimination ofhydrochloric acid from 1-chloro-cycloalkene in modest yield. The desired product could be obtained as a mixture with the correspondingallene as the major product.[12]
Further work in this area was aimed at developing milder reaction conditions and generating more robust yields. To circumvent the generation of the undesiredallene, the Kobayashi method foraryne generation was adapted for the synthesis of cycloalkynes.[13]
More recently, a superior method for generating strained cycloalkynes was developed by Fujita. It involves base inducedβ-elimination ofvinyliodonium salts. The vinyl iodonium proved to be a particularly useful synthetic precursor to strained cycloalkynes due to its high reactivity which arises from the strong electron withdrawing ability of the positively charged iodine species as well as theleaving group ability of the iodonium.[14]
In addition to the elimination-type pathways described, cycloalkynes can also be obtained through the oxidation of cyclic bishydrazones withmercury oxide[15] orlead tetraacetate[3] as well as through the thermal decomposition of selenadiazole.[16]
Strained cycloalkynes are able to undergo all addition reactions typical to open chain alkynes. Due to the activated nature of the cyclic carbon–carbon triple bond, many alkyne addition-type reactions such as the Diels–Alder, 1,3-dipolar cycloadditions andhalogenation may be performed using very mild conditions and in the absence of thecatalysts frequently required to accelerate the transformation in a non-cyclic system. In addition to alkyne reactivity, cycloalkynes are able to undergo a number of unique, synthetically useful transformations.
One particularly intriguing mode of reactivity is the ring insertion of cyclohexyne into cyclicketones. The reaction is initiated by the alkoxide-mediated generation of the reactive cycloalkyne species in situ, followed by the α-deprotonation of the ketone to yield the correspondingenolate. The two compounds then undergo a formal[2+2]-photocycloaddition to yield a highly unstable cyclobutanolate intermediate which readily decomposes to theenone product.[17]
This reaction was utilized as the key step in Carreira's total synthesis of guanacastapenes O and N. It allowed for the expedient construction of the 5-7-6 ring system and provided useful synthetic handles for subsequent functionalization.[18][19]
Cyclooctyne, the smallest isolable cycloalkyne, is able to undergoazide-alkyneHuisgen cycloaddition under mild,physiological conditions in the absence of acopper(I) catalyst due to strain. This reaction has found widespread application as abioorthogonal transformation for live cell imaging.[20] Although the mild, copper-catalyzed variant of the reaction, CuAAC (copper-catalyzed azide–alkyne cycloaddition) with linear alkynes had been known, development of the copper-free reaction was significant in that it provided facile reactivity while eliminating the need for a toxic metal catalyst.[21]
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