Cycloalkyne

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In organic chemistry, a cycloalkyne is the cyclic analog of an alkyne. A cycloalkyne consists of a closed ring of carbon atoms containing one or more triple bonds. Cycloalkynes have a general formula Cn H2n-4 Because of the linear nature of the C-CΞC-C alkyne unit, cycloalkynes can be highly strained and can only exist when the number of carbon atoms in the ring is great enough to provide the flexibility necessary to accommodate this geometry. Large alkyne containing carbocycles 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 through complexation to transition metals.

Background

Due to the significant geometric constraints imposed by the R-CΞC-R functionality, cycloalkynes smaller than cyclodecyne (C10H16) result in highly strained structures. While the nine (C9H14) and eight (C8H12) membered cycloalkyne analogues are isolable, though strongly reactive, compounds, cycloheptyne (C7H10), cyclohexyne (C6H8) and cyclopentyne (C5H6) only exist as transient reaction intermediates or as ligands coordinating to a metal center.[3] There is little experimental evidence supporting the existence of cyclobutyne (C4H4) or cyclopropyne (C3H2), aside from studies reporting the isolation of an osmium complex 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 cyclic dienes or diazo compounds to generate the Diels–Alder or Diazoalkane 1,3-dipolar cycloaddition products, respectively.[5] Stable small ring cycloalkynes have subsequently been isolated in complex with various transition metals such as nickel, palladium and platinum.[6] Despite long being considered to be chemical curiosities with limited synthetic applications, recent work has demonstrated the utility of strained cycloalkynes in both total synthesis of complex natural products and bioorthogonal chemistry. [7][8]

Angle strain

Angle strain in cycloalkynes arises from the deformation of the R-CΞC 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 by photoelectron spectroscopy has indicated that the alkyne bond in small cyclic systems is composed of two non-degenerate π bonds – a highly reactive strained bond perpendicular to a lower energy π bond. [10] Cis-bending of the R-CΞC bond angle results in the drastic lowering of the energy of the lowest unoccupied molecular orbital, a phenomenon which accounts for the reactivity of strained cycloalkynes from the perspective of molecular orbital theory. [11]

Synthesis

Initial efforts toward the synthesis of strained cycloalkynes showed that cycloalkynes could be generated via the elimination of hydrochloric acid from 1-chloro-cycloalkene in modest yield. The desired product could be obtained as a mixture with the corresponding allene 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 undesired allene, the Kobayashi method for aryne 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 induced β-elimination of vinyl iodonium 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 the leaving group ability of the iodonio. [14] In addition to the elimination-type pathways described, cycloalkynes can also be obtained through the oxidation of cyclic bis-hydrozones with mercury oxide as well as through the thermal decomposition of selenadiazole. [15][16]

Reactions

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 and halogenation may be performed using very mild conditions and in the absence of the catalysts frequently required to accelerate the transformation in an acyclic system. In addition to alkyne reactivity, cycloalkynes are able to undergo a number of unique, synthetically useful transformations.

Cyclohexyne ring insertion

One particularly intriguing mode of reactivity is the ring insertion of cyclohexyne into cyclic ketones. 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 corresponding enolate. The two compounds then undergo a formal 2+2 photocycloaddition to yield a highly unstable cyclobutanolate intermediate which readily decomposes to the enone 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]

Copper-free click reaction with cyclooctyne

Cyclooctyne, the smallest isolable cycloalkyne is able to undergo azide-alkyne Huisgen cycloaddition under mild, physiological conditions in the absence of Cu(I) catalyst due to strain. This reaction has found widespread application as a bioorthogonal 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]

References

  1. ↑ Can cyclopropyne really be made? Paul Saxe and Henry F. Schaefer J. Am. Chem. Soc.; 1980; 102(9) pp 3239 - 3240; doi:10.1021/ja00529a057
  2. ↑ cycloalkyne (chemical compound) - Britannica Online Encyclopedia
  3. ↑ Angle Strained Cycloalkynes Adolf Krebs and Jurgen Wilke Topics in Current Chemistry; 1983; 109 pp 189 - 233; doi:10.1007/BFb0018059
  4. ↑ Cyclobutyne: the ligand. The synthesis and molecular structure of osmium cluster Os3(CO)9(.mu.3-.eta.2-C2CH2CH2)(.mu.-SPh)(.mu.-H)" Richard D. Adams , Gong Chen , Xiaosu Qu, Wengan Wu and John H. Yamamoto J. Am. Chem. Soc.; 1992; 114(27) pp 10977 – 10978; doi:10.1021/ja00053a053
  5. ↑ Zur Existenz niedergliedriger Cycloalkine, 1 Georg Wittig and Adolf Krebs Chem. Ber.; 1961; 94(12) pp 3260 - 3275; doi:10.1002/cber.19610941213
  6. ↑ Metal Complexes of Small Cycloalkynes and Arynes Martin A. Bennett and Heinz P. Schwemlein Angew. Chem.; 1989; 28(10) pp 1296 - 1320; doi:10.1002/anie.198912961
  7. ↑ Arynes and Cyclohexyne in Natural Product Synthesis Christian M. Gampe and Erick M. Carreira Angew. Chem.; 2012; 51(16) pp 3766 - 3778; doi:10.1002/anie.201107485
  8. ↑ Strained Cycloalkynes as New Protein Sulfenic Acid TrapsThomas H. Poole, Julie A. Reisz, Weiling Zhao, Leslie B. Poole, Christina M. Furdui and S. Bruce King J. Am. Chem. Soc.; 2014; 136(17) pp 6167 - 6170; doi:10.1021/ja500364r
  9. ↑ Über das intermediäre Auftreten von Cyclopentin G. Wittig, A. Krebs and R. Pohlke Angew. Chem.; 1960; 72(9) pp 324; doi:10.1002/ange.19600720914
  10. ↑ Splitting of the degenerate acetylenic πmos; a probe for ring strain Hartmut Schmidt and Armin Schweig Tet. Lett.; 1974; 15(16) pp 1471 - 1474; doi:10.1016/S0040-4039(01)93113-2
  11. ↑ Die Ringspannung von Cycloalkinen und ihre spektroskopischen Auswirkungen Herbert Meier, Hermann Petersen and Heinz Kolshorn Chem. Ber.; 1980; 113(7) pp 2398 - 2409; doi:10.1002/cber.19801130708
  12. ↑ The Equilibration of Cyclic Allenes and Acetylenes William R. Moore and Harold R. Ward J. Am. Chem. Soc.; 1963; 85(1) pp 86 - 89; doi:10.1021/ja00884a018
  13. ↑ Fluoride-induced 1,2-elimination of o-(trimethylsilyl)phenyl triflate to benzyne under mild conditions Yoshio Himeshima, Takaaki Sonoda and Hiroshi Kobayashi Chem. Lett.; 1983; 12(8) pp 1211 - 1214; doi:10.1246/cl.1983.1211
  14. ↑ Generation of Cycloalkynes by Hydro-Iodonio-Elimination of Vinyl Iodonium Salts Tadashi Okuyama and Morifumi Fujita Acc. Chem. Res.; 2005; 38(8) pp 679 - 686; doi:10.1021/ar040293r
  15. ↑ Many-Membered Carbon Rings. VI. Unsaturated Nine-membered Cyclic Hydrocarbons A. T. Blomquist , Liang Huang Liu and James C. Bohrer J. Am. Chem. Soc.; 1952; 74(14) pp 3643 - 3647; doi:10.1021/ja01134a052
  16. ↑ Bildung und fragmentierung von cycloalkeno-1,2,3-selenadiazolen H. Meier and E. Voigt Tetrahedron; 1972; 28(1) pp 187 - 198; doi:10.1016/0040-4020(72)80068-1
  17. ↑ Cyclohexyne Cycloinsertion by an Annulative Ring Expansion Cascade Christian M. Gampe, Samy Boulos and Erick M. Carreira Angew. Chem.; 2010; 122(24) pp 4186 - 4189; doi:10.1002/ange.201001137
  18. ↑ Total Syntheses of Guanacastepenes N and O Christian M. Gampe and Erick M. Carreira Angew. Chem.; 2011; 50(13) pp 2962 - 2965; doi:10.1002/anie.201007644
  19. ↑ Cyclohexyne Cycloinsertion in the Divergent Synthesis of Guanacastepenes Christian M. Gampe and Erick M. Carreira Angew. Chem.; 2012; 18(49) pp 15761 - 15771; doi:10.1002/chem.201202222
  20. ↑ Copper-free click chemistry for dynamic in vivo imaging Jeremy M. Baskin, Jennifer A. Prescher, Scott T. Laughlin, Nicholas J. Agard, Pamela V. Chang, Isaac A. Miller, Anderson Lo, Julian A. Codelli and Carolyn R. Bertozzi Proc. Natl. Acad. Sci. USA; 2007; 104(43) pp 16793 - 16797; doi:10.1073/pnas.0707090104
  21. ↑ Copper-catalyzed azide-alkyne cycloaddition (CuAAC) and beyond: new reactivity of copper(I) acetylides Jason E. Hein and Valery V. Fokin Chem. Soc. Rev.; 2010; 39(4) pp 1302 - 1315; doi:10.1039/b904091a
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