Cycloalkyne

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In organic chemistry, a cycloalkyne is the cyclic analog of an alkyne (−C≡C−). A cycloalkyne consists of a closed ring of carbon atoms containing one or more triple bonds. Cycloalkynes have a general formula CnH2n−4. Because of the linear nature of the C−C≡C−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.

Contents

Background

Ring size determines the stability of simple cycloalkynes Strained cycloalkynes.svg
Ring size determines the stability of simple cycloalkynes

Due to the significant geometric constraints imposed by the R−C≡C−R functionality, cycloalkynes smaller than cyclodecyne (C10H16) result in highly strained structures. While the cyclononyne (C9H14) and cyclooctyne (C8H12) 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−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 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−C≡C 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 iodonium. [14]

In addition to the elimination-type pathways described, cycloalkynes can also be obtained through the oxidation of cyclic bishydrazones with mercury oxide [15] or lead tetraacetate [3] as well as through the thermal decomposition of selenadiazole. [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 a non-cyclic 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 a copper(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]

Related Research Articles

In chemistry, intramolecular describes a process or characteristic limited within the structure of a single molecule, a property or phenomenon limited to the extent of a single molecule.

The 1,3-dipolar cycloaddition is a chemical reaction between a 1,3-dipole and a dipolarophile to form a five-membered ring. The earliest 1,3-dipolar cycloadditions were described in the late 19th century to the early 20th century, following the discovery of 1,3-dipoles. Mechanistic investigation and synthetic application were established in the 1960s, primarily through the work of Rolf Huisgen. Hence, the reaction is sometimes referred to as the Huisgen cycloaddition. 1,3-dipolar cycloaddition is an important route to the regio- and stereoselective synthesis of five-membered heterocycles and their ring-opened acyclic derivatives. The dipolarophile is typically an alkene or alkyne, but can be other pi systems. When the dipolarophile is an alkyne, aromatic rings are generally produced.

In organic chemistry, arynes and benzynes are a class of highly reactive chemical species derived from an aromatic ring by removal of two substituents. Arynes are examples of didehydroarenes, although 1,3- and 1,4-didehydroarenes are also known. Arynes are examples of alkynes under high strain.

An alkyne trimerisation is a [2+2+2] cycloaddition reaction in which three alkyne units react to form a benzene ring. The reaction requires a metal catalyst. The process is of historic interest as well as being applicable to organic synthesis. Being a cycloaddition reaction, it has high atom economy. Many variations have been developed, including cyclisation of mixtures of alkynes and alkenes as well as alkynes and nitriles.

In chemical synthesis, click chemistry is a class of simple, atom-economy reactions commonly used for joining two molecular entities of choice. Click chemistry is not a single specific reaction, but describes a way of generating products that follow examples in nature, which also generates substances by joining small modular units. In many applications, click reactions join a biomolecule and a reporter molecule. Click chemistry is not limited to biological conditions: the concept of a "click" reaction has been used in chemoproteomic, pharmacological, biomimetic and molecular machinery applications. However, they have been made notably useful in the detection, localization and qualification of biomolecules.

<span class="mw-page-title-main">Pauson–Khand reaction</span> Chemical reaction

The Pauson–Khand (PK) reaction is a chemical reaction, described as a [2+2+1] cycloaddition. In it, an alkyne, an alkene and carbon monoxide combine into a α,β-cyclopentenone in the presence of a metal-carbonyl catalyst.

Ring-closing metathesis (RCM) is a widely used variation of olefin metathesis in organic chemistry for the synthesis of various unsaturated rings via the intramolecular metathesis of two terminal alkenes, which forms the cycloalkene as the E- or Z- isomers and volatile ethylene.

<span class="mw-page-title-main">Halonium ion</span> Any onium ion containing a halogen atom carrying a positive charge

A halonium ion is any onium ion containing a halogen atom carrying a positive charge. This cation has the general structure R−+X−R′ where X is any halogen and no restrictions on R, this structure can be cyclic or an open chain molecular structure. Halonium ions formed from fluorine, chlorine, bromine, and iodine are called fluoronium, chloronium, bromonium, and iodonium, respectively. The 3-membered cyclic variety commonly proposed as intermediates in electrophilic halogenation may be called haliranium ions, using the Hantzsch-Widman nomenclature system.

<span class="mw-page-title-main">Wolff rearrangement</span>

The Wolff rearrangement is a reaction in organic chemistry in which an α-diazocarbonyl compound is converted into a ketene by loss of dinitrogen with accompanying 1,2-rearrangement. The Wolff rearrangement yields a ketene as an intermediate product, which can undergo nucleophilic attack with weakly acidic nucleophiles such as water, alcohols, and amines, to generate carboxylic acid derivatives or undergo [2+2] cycloaddition reactions to form four-membered rings. The mechanism of the Wolff rearrangement has been the subject of debate since its first use. No single mechanism sufficiently describes the reaction, and there are often competing concerted and carbene-mediated pathways; for simplicity, only the textbook, concerted mechanism is shown below. The reaction was discovered by Ludwig Wolff in 1902. The Wolff rearrangement has great synthetic utility due to the accessibility of α-diazocarbonyl compounds, variety of reactions from the ketene intermediate, and stereochemical retention of the migrating group. However, the Wolff rearrangement has limitations due to the highly reactive nature of α-diazocarbonyl compounds, which can undergo a variety of competing reactions.

<span class="mw-page-title-main">Vinyl cation</span> Organic cation

The vinyl cation is a carbocation with the positive charge on an alkene carbon. Its empirical formula is C
2H+
3. More generally, a vinylic cation is any disubstituted carbon, where the carbon bearing the positive charge is part of a double bond and is sp hybridized. In the chemical literature, substituted vinylic cations are often referred to as vinyl cations, and understood to refer to the broad class rather than the C
2H+
3 variant alone. The vinyl cation is one of the main types of reactive intermediates involving a non-tetrahedrally coordinated carbon atom, and is necessary to explain a wide variety of observed reactivity trends. Vinyl cations are observed as reactive intermediates in solvolysis reactions, as well during electrophilic addition to alkynes, for example, through protonation of an alkyne by a strong acid. As expected from its sp hybridization, the vinyl cation prefers a linear geometry. Compounds related to the vinyl cation include allylic carbocations and benzylic carbocations, as well as aryl carbocations.

The nitrone-olefin [3+2] cycloaddition reaction is the combination of a nitrone with an alkene or alkyne to generate an isoxazoline or isoxazolidine via a [3+2] cycloaddition process. This reaction is a 1,3-dipolar cycloaddition, in which the nitrone acts as the 1,3-dipole, and the alkene or alkyne as the dipolarophile.

The term bioorthogonal chemistry refers to any chemical reaction that can occur inside of living systems without interfering with native biochemical processes. The term was coined by Carolyn R. Bertozzi in 2003. Since its introduction, the concept of the bioorthogonal reaction has enabled the study of biomolecules such as glycans, proteins, and lipids in real time in living systems without cellular toxicity. A number of chemical ligation strategies have been developed that fulfill the requirements of bioorthogonality, including the 1,3-dipolar cycloaddition between azides and cyclooctynes, between nitrones and cyclooctynes, oxime/hydrazone formation from aldehydes and ketones, the tetrazine ligation, the isocyanide-based click reaction, and most recently, the quadricyclane ligation.

In organometallic chemistry, a transition metal alkyne complex is a coordination compound containing one or more alkyne ligands. Such compounds are intermediates in many catalytic reactions that convert alkynes to other organic products, e.g. hydrogenation and trimerization.

Montréalone is a mesoionic heterocyclic chemical compound. It is named for the city of Montréal, Canada, which is the location of McGill University, where it was first discovered.

<span class="mw-page-title-main">Activation of cyclopropanes by transition metals</span>

In organometallic chemistry, the activation of cyclopropanes by transition metals is a research theme with implications for organic synthesis and homogeneous catalysis. Being highly strained, cyclopropanes are prone to oxidative addition to transition metal complexes. The resulting metallacycles are susceptible to a variety of reactions. These reactions are rare examples of C-C bond activation. The rarity of C-C activation processes has been attributed to Steric effects that protect C-C bonds. Furthermore, the directionality of C-C bonds as compared to C-H bonds makes orbital interaction with transition metals less favorable. Thermodynamically, C-C bond activation is more favored than C-H bond activation as the strength of a typical C-C bond is around 90 kcal per mole while the strength of a typical unactivated C-H bond is around 104 kcal per mole.

<span class="mw-page-title-main">Ynone</span> Organic compounds of the form RC≡CC(=O)R’

In organic chemistry, an ynone is an organic compound containing a ketone functional group and a C≡C triple bond. Many ynones are α,β-ynones, where the carbonyl and alkyne groups are conjugated. Capillin is a naturally occurring example. Some ynones are not conjugated.

Cyclopentyne is a cycloalkyne containing five carbon atoms in the ring. Due to the ideal bond angle of 180° at each atom of the alkyne but the structural requirement that the bonds form a ring, this chemical is a highly strained structure, and the triple bond is highly reactive. The triple bond easily undergoes both [2+2] and [4+2] cycloaddition reactions. Unlike benzyne, which undergoes a [2+2] addition with loss of stereochemistry at the alkene partner, cyclopentyne reacts with alkenes with retention of geometry of the partner, an example of the relevance of orbital symmetry even for highly reactive structures. The structure can also form a π complex with lithium cations, which affects the cycloaddition reactivity. It can even interact strongly enough with copper species to form a novel type of metallacycle.

Vinylcyclopropane [5+2] cycloaddition is a type of cycloaddition between a vinylcyclopropane (VCP) and an olefin or alkyne to form a seven-membered ring.

In organic chemistry, the Conia-ene reaction is an intramolecular cyclization reaction between an enolizable carbonyl such as an ester or ketone and an alkyne or alkene, giving a cyclic product with a new carbon-carbon bond. As initially reported by J. M. Conia and P. Le Perchec, the Conia-ene reaction is a heteroatom analog of the ene reaction that uses an enol as the ene component. Like other pericyclic reactions, the original Conia-ene reaction required high temperatures to proceed, limiting its wider application. However, subsequent improvements, particularly in metal catalysis, have led to significant expansion of reaction scope. Consequently, various forms of the Conia-ene reaction have been employed in the synthesis of complex molecules and natural products.

<span class="mw-page-title-main">Cyclooctyne</span> Chemical compound

Cyclooctyne is the cycloalkyne with a formula C
8H
12. Its molecule has a ring of 8 carbon atoms, connected by seven single bonds and one triple bond.

References

  1. ↑ Saxe, Paul; Schaefer, Henry F. (1980). "Can cyclopropyne really be made?". J. Am. Chem. Soc. 102 (9): 3239–3240. doi:10.1021/ja00529a057.
  2. ↑ Cycloalkyne (chemical compound) – Britannica Online Encyclopedia
  3. 1 2 Krebs, Adolf; Wilke, Jürgen (1983). "Angle Strained Cycloalkynes". Topics in Current Chemistry . 109: 189–233. doi:10.1007/BFb0018059. ISBN   3-540-11907-8.
  4. ↑ Adams, Richard D.; Chen, Gong; Qu, Xiaosu; Wu, Wengan; Yamamoto, John H. (1992). "Cyclobutyne: the ligand. The synthesis and molecular structure of osmium cluster Os3(CO)9(μ3-η2-C2CH2CH2)(μ-SPh)(μ-H)". J. Am. Chem. Soc. 114 (27): 10977–10978. doi:10.1021/ja00053a053.
  5. ↑ Wittig, Georg; Krebs, Adolf (1961). "Zur Existenz niedergliedriger Cycloalkine, 1". Chem. Ber. 94 (12): 3260–3275. doi:10.1002/cber.19610941213.
  6. ↑ Bennett, Martin A.; Schwemlein, Heinz P. (1989). "Metal Complexes of Small Cycloalkynes and Arynes". Angew. Chem. 28 (10): 1296–1320. doi:10.1002/anie.198912961.
  7. ↑ Gampe, Christian M.; Carreira, Erick M. (2012). "Arynes and Cyclohexyne in Natural Product Synthesis". Angew. Chem. 51 (16): 3766–3778. doi:10.1002/anie.201107485. PMID   22422638.
  8. ↑ Poole, Thomas H.; Reisz, Julie A.; Zhao, Weiling; Poole, Leslie B.; Furdui, Christina M.; King, S. Bruce (2014). "Strained Cycloalkynes as New Protein Sulfenic Acid Traps". J. Am. Chem. Soc. 136 (17): 6167–6170. doi:10.1021/ja500364r. PMC   4017607 . PMID   24724926.
  9. ↑ Wittig, G.; Krebs, A.; Pohlke, R. (1960). "Über das intermediäre Auftreten von Cyclopentin". Angew. Chem. 72 (9): 324. doi:10.1002/ange.19600720914.
  10. ↑ Schmidt, Hartmut; Schweig, Armin (1974). "Splitting of the degenerate acetylenic πmos; a probe for ring strain". Tetrahedron Lett. 15 (16): 1471–1474. doi:10.1016/S0040-4039(01)93113-2.
  11. ↑ Meier, Herbert; Petersen, Hermann; Kolshorn, Heinz (1980). "Die Ringspannung von Cycloalkinen und ihre spektroskopischen Auswirkungen". Chem. Ber. 113 (7): 2398–2409. doi:10.1002/cber.19801130708.
  12. ↑ Moore, William R.; Ward, Harold R. (1963). "The Equilibration of Cyclic Allenes and Acetylenes". J. Am. Chem. Soc. 85 (1): 86–89. doi:10.1021/ja00884a018.
  13. ↑ Himeshima, Yoshio; Sonoda, Takaaki; Kobayashi, Hiroshi (1983). "Fluoride-induced 1,2-elimination of o-(trimethylsilyl)phenyl triflate to benzyne under mild conditions". Chem. Lett. 12 (8): 1211–1214. doi:10.1246/cl.1983.1211.
  14. ↑ Okuyama, Tadashi; Fujita, Morifumi (2005). "Generation of Cycloalkynes by Hydro-Iodonio-Elimination of Vinyl Iodonium Salts". Acc. Chem. Res. 38 (8): 679–686. doi:10.1021/ar040293r. PMID   16104691.
  15. ↑ Blomquist, A. T.; Liu, Liang Huang; Bohrer, James C. (1952). "Many-Membered Carbon Rings. VI. Unsaturated Nine-membered Cyclic Hydrocarbons". J. Am. Chem. Soc. 74 (14): 3643–3647. doi:10.1021/ja01134a052.
  16. ↑ Meier, H.; Voigt, E. (1972). "Bildung und fragmentierung von cycloalkeno-1,2,3-selenadiazolen". Tetrahedron . 28 (1): 187–198. doi:10.1016/0040-4020(72)80068-1.
  17. ↑ Gampe, Christian M.; Boulos, Samy; Carreira, Erick M. (2010). "Cyclohexyne Cycloinsertion by an Annulative Ring Expansion Cascade". Angew. Chem. 122 (24): 4186–4189. doi:10.1002/ange.201001137.
  18. ↑ Gampe, Christian M.; Carreira, Erick M. (2011). "Total Syntheses of Guanacastepenes N and O". Angew. Chem. 50 (13): 2962–2965. doi:10.1002/anie.201007644. PMID   21370370.
  19. ↑ Gampe, Christian M.; Carreira, Erick M. (2012). "Cyclohexyne Cycloinsertion in the Divergent Synthesis of Guanacastepenes". Angew. Chem. 18 (49): 15761–15771. doi:10.1002/chem.201202222. PMID   23080228.
  20. ↑ Baskin, Jeremy M.; Prescher, Jennifer A.; Laughlin, Scott T.; Agard, Nicholas J.; Chang, Pamela V.; Miller, Isaac A.; Lo, Anderson; Codelli, Julian A.; Bertozzi, Carolyn R. (2007). "Copper-free click chemistry for dynamic in vivo imaging". Proc. Natl. Acad. Sci. USA . 104 (43): 16793–16797. Bibcode:2007PNAS..10416793B. doi: 10.1073/pnas.0707090104 . PMC   2040404 . PMID   17942682.
  21. ↑ Hein, Jason E.; Fokin, Valery V. (2010). "Copper-catalyzed azide–alkyne cycloaddition (CuAAC) and beyond: new reactivity of copper(I) acetylides". Chem. Soc. Rev. 39 (4): 1302–1315. doi:10.1039/b904091a. PMC   3073167 . PMID   20309487.
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