Cycloaddition: Difference between revisions

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{{short description|Chemical reaction which forms a cyclic molecule}}

A '''cycloaddition''' is a [[pericyclic]] [[chemical reaction]], in which "two or more unsaturated molecules (or parts of the same molecule) combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity."<ref name=goldbook>{{cite web|last=International Union of Pure and Applied Chemistry (IUPAC)|title=Cycloaddition|url=http://goldbook.iupac.org/C01496.html|accessdate=26 February 2014}}</ref> The resulting reaction is a [[cyclization]] reaction. Many but not all cycloadditions are concerted. As a class of [[addition reaction]], cycloadditions permit carbon–carbon bond formation without the use of a [[nucleophile]] or [[electrophile]].

[[File:Non-ionic Cycloadditions.png|thumb|261x261px|Non-ionic Cycloadditions]]

In [[organic chemistry]], a '''cycloaddition''' is a [[chemical reaction]] in which "two or more [[Unsaturated hydrocarbon|unsaturated]] molecules (or parts of the same molecule) combine with the formation of a cyclic [[adduct]] in which there is a net reduction of the [[Multiplicity (chemistry)#Molecules|bond multiplicity]]". The resulting reaction is a [[cyclization]] reaction. Many but not all cycloadditions are [[Concerted reaction|concerted]] and thus [[pericyclic]].<ref name="goldbook">{{Citation|title=cycloaddition|url=https://goldbook.iupac.org/html/C/C01496.html|work=IUPAC Compendium of Chemical Terminology|year=2009|publisher=IUPAC|doi=10.1351/goldbook.C01496|isbn=978-0-9678550-9-7|access-date=2018-10-13|doi-access=free|url-access=subscription}}</ref> Nonconcerted cycloadditions are not pericyclic.<ref>{{Citation|title=pericyclic reaction|url=https://goldbook.iupac.org/html/P/P04491.html|work=IUPAC Compendium of Chemical Terminology|year=2009|publisher=IUPAC|doi=10.1351/goldbook.P04491|isbn=978-0-9678550-9-7|access-date=2018-10-13|doi-access=free|url-access=subscription}}</ref> As a class of [[addition reaction]], cycloadditions permit carbon–carbon bond formation without the use of a [[nucleophile]] or [[electrophile]].

Cycloadditions can be described using two systems of notation. An older, but still common, notation is based on the size of linear arrangements of atoms in the reactants. It uses [[parentheses]]: {{nowrap|(''i'' + ''j'' + …)}} where the variables are the numbers of linear atoms in each reactant. The product is a cycle of size {{nowrap|(''i'' + ''j'' + …)}}. In this system, the standard [[Diels-Alder reaction]] is a (4 &nbsp;+ &nbsp;2)-cycloaddition, the [[1,3-dipolar cycloaddition]] is a (3 &nbsp;+ &nbsp;2)-cycloaddition and [[cyclopropanation]] of a carbene with an alkene a (2 &nbsp;+ &nbsp;1)-cycloaddition.<ref name=goldbook />

A more recent, IUPAC-preferred notation, first introduced by [[Robert Burns Woodward|Woodward]] and [[Roald Hoffmann|Hoffmann]], uses [[square brackets]] to indicate the number of ''electrons'', rather than carbon atoms, involved in the formation of the product. In the [''i'' + ''j'' + …...] notation, the standard Diels-Alder reaction is a [4 + 2]-cycloaddition, while the 1,3-dipolar cycloaddition is also a [4 + 2]-cycloaddition.<ref name=goldbook />

==Thermal cycloadditions and their stereochemistry==

Thermal cycloadditions are those cycloadditions where the reactants are in the ground electronic state. They usually have (4''n'' + 2) π electrons participating in the starting material, for some integer ''n''. These reactions occur, for reasons of [[orbital symmetry]], in a [[suprafacial]]-suprafacial or(''syn''/''syn'' stereochemistry) in most cases. Very few examples of [[antarafacial]]-antarafacial manner (rare''anti''/''anti'' stereochemistry). reactions have also been reported. There are a few examples of thermal cycloadditions which have 4''n'' π electrons (for example the [2 + 2] -cycloaddition);. theseThese proceed in a suprafacial-antarafacial sense (''syn''/''anti'' stereochemistry), such as the dimerisationcycloaddition reactions of [[ketene]] and [[Allenes|allene]] derivatives, in which the [[orthogonal]] set of [[p orbital]]s allows the reaction to proceed via a crossed [[transition state]], although the analysis of these reactions as [_π2_s + _π2_a] is controversial. Strained alkenes like ''trans''-cycloheptene derivatives have also been reported to react in an antarafacial manner in [2 + 2]-cycloaddition reactions.

[[William von Eggers Doering|Doering]] (in a personal communication to [[Robert Burns Woodward|Woodward]]) reported that [[Fulvalene (compound class)|heptafulvalene]] and tetracyanoethylene can react in a suprafacial-antarafacial [14 + 2]-cycloaddition. However, this reaction was later found to be stepwise, as it also produced the Woodward-Hoffmann forbidden suprafacial-suprafacial product under kinetic conditions.

<ref>{{Citation |last1=Izzotti|first1=Anthony|

last2=Gleason|first2=James|

date=2022-06-07|

title=Do Antarafacial Cycloadditions Occur? Cycloaddition of Heptafulvalene with Tetracyanoethylene|

url=https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/chem.202201418|

journal=Chemistry: A European Journal|volume=28 |issue=49 |pages=e202201418 |

doi=10.1002/chem.202201418|pmid=35671245 |url-access=subscription}}

</ref>

Erden and Kaufmann had previously found that the cycloaddition of heptafulvalene and N-phenyltriazolinedione also gave both suprafacial-antarafacial and suprafacial-suprafacial products. <ref>{{Cite journal|last1=Erden|first1=Ihsan|last2=KauFmann|first2=Dieter|date=1981-01-01|title=Cycloadditionsreaktionen des heptafulvalens|url=https://dx.doi.org/10.1016/0040-4039%2881%2980058-5|journal=Tetrahedron Letters|language=de|volume=22|issue=3|pages=215–218|doi=10.1016/0040-4039(81)80058-5|issn=0040-4039|url-access=subscription}}</ref>

[[File:14plus2.png|center|frameless|400x400px]]

==Photochemical cycloadditions and their stereochemistry==

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[[Image:Bpe-resorcinol-cycloaddition.png|right|thumb|Cycloaddition of ''trans''-1,2-bis(4-pyridyl)ethene]]

[[Supramolecular chemistry|Supramolecular effects]] can influence these cycloadditions. The cycloaddition of ''trans''-1,2-bis(4-pyridyl)ethene is directed by [[resorcinol]] in the [[solid-state chemistry|solid-state]] in 100% [[chemical yield|yield]].<ref>{{cite journal |author1=L. R. MacGillivray |author2=J. L. Reid |author3=J. A. Ripmeester | title = Supramolecular Control of Reactivity in the Solid State Using Linear Molecular Templates | year = 2000 | journal = [[J. Am. Chem. Soc.]] | volume = 122 | issue = 32 | pages = 7817–7818 | doi=10.1021/ja001239i|bibcode=2000JAChS.122.7817M }}</ref>

Some cycloadditions instead of π bonds operate through strained [[cyclopropane]] rings;, as these have significant π character. For example, an analog for the Diels-Alder reaction is the [[quadricyclane]]-[[DMAD]] reaction:

[[Image:Qcane.png|500px|center]]

In the (i+j+...) cycloaddition notation i and j refer to the number of atoms involved in the cycloaddition. In this notation, a Diels-Alder reaction is a (4+2)cycloaddition and a 1,3-dipolar addition such as the first step in [[ozonolysis]] is a (3+2)cycloaddition. The [[IUPAC]] preferred notation however, with [i+j+...] takes electrons into account and not atoms. In this notation, the DA reaction and the dipolar reaction both become a [4+2]cycloaddition. The reaction between [[norbornadiene]] and an activated [[alkyne]] is a [2+2+2]cycloaddition.

==Types of cycloaddition==

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===Diels-Alder reactions===

The [[Diels-Alder reaction]] is perhaps the most important and commonly taught cycloaddition reaction. Formally it is a [4+2] cycloaddition reaction and exists in a huge range of forms, including the [[inverse electron-demand Diels–Alder reaction]], [[Hexadehydrohexadehydro Diels-AlderDiels–Alder reaction]] and the related [[alkyne trimerisation]]. The reaction can also be run in reverse in the [[retro-Diels–Alder reaction]].

:[[File:Diels-alderAlder (1,3-butadiene -+ Ethyleneethylene) red.pngsvg|Diels-Alder300px|Diels–Alder reaction]]

Reactions involving heteroatoms are known;, including the [[Azaaza-Diels–Alder reaction|aza-Diels–Alder]] and [[Imine oxo-Diels–Alder reaction]].

===Huisgen cycloadditions===

The [[Huisgen cycloaddition]] reaction is a (2+3)cycloaddition.

:[[File:HuisgenThermal_Huisgen_cycloaddition.png|500px600px|1,3-cycloaddition]]

===Nitrone-olefin cycloaddition===

The [[nitrone-olefin 3+2 cycloaddition|Nitrone-olefin cycloaddition]] is a (3+2)cycloaddition.

:[[File:NitrGen.pngsvg|Nitrone olefin cycloaddition]]

===Iron-catalyzed 2+2 olefin cycloaddition===

Iron[pyridine(diimine)] catalysts contain a redox active ligand in which the central iron atom can coordinate with two simple, unfunctionalized olefin double bonds. The catalyst can be written as a resonance between a structure containing unpaired electrons with the central iron atom in the II oxidation state, and one in which the iron is in the 0 oxidation state. This gives it the flexibility to engage in binding the double bonds as they undergo a cyclization reaction, generating a cyclobutane structure via C-C reductive elimination; alternatively a cyclobutene structure may be produced by beta-hydrogen elimination. Efficiency of the reaction varies substantially depending on the alkenes used, but rational ligand design may permit expansion of the range of reactions that can be catalyzed.<ref>{{cite journal|title=Iron-catalyzed intermolecular [2+2] cycloadditions of unactivated alkenes|author1=Jordan M. Hoyt |author2=Valeria A. Schmidt |author3=Aaron M. Tondreau |author4=Paul J. Chirik |journal=Science|date=2015-08-28|volume=349|issue=6251|pages=960–963|doi=10.1126/science.aac7440}}</ref><ref>{{cite journal|title=As simple as [2+2]|author1=Myles W. Smith |author2=Phil S. Baran |journal=Science|date=2015-08-28|volume=349|issue=6251|pages=925–926|doi=10.1126/science.aac9883}}</ref>

===Cheletropic reactions===

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==Other==

Other cycloaddition reactions exist: [[(4+3) cycloaddition|[4+3] cycloadditions]]s, [[6+4 cycloaddition|[6+4] cycloadditions]], [[2+2Woodward-Hoffmann Photocycloadditionrules|[2 + 2] photocycloadditions]], [[Metal-centered cycloaddition reactions|metal-centered cycloaddition]] and [[4+4 photocycloaddition| [4+4] photocycloadditions]]

==Formal cycloadditions==

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One example of a formal [3+3]cycloaddition between a cyclic [[enone]] and an [[enamine]] catalyzed by [[N-Butyllithium|''n''-butyllithium]] is a [[Stork enamine reaction|Stork enamine]] / [[nucleophilic addition|1,2-addition]] [[cascade reaction]]:<ref>{{cite journal | last = Movassaghi | first = Mohammad |author2=Bin Chen | title = Stereoselective Intermolecular Formal [3+3] Cycloaddition Reaction of Cyclic Enamines and Enones | journal = [[Angew. Chem. Int. Ed.]] | volume = 46 | pages = 565&ndash;568 | year = 2007 | doi = 10.1002/anie.200603302 | pmid = 17146819 | issue = 4 | pmc=3510678}}</ref>

[[Image:3+3- cycloaddition - cyclic iminium to cyclic enone.svg|center|600px500px|IntermolecularAn Formalintermolecular formal [3+3] Cycloadditioncycloaddition Reactionbetween an cyclic iminium chloride and cyclopentenone.]]

===Iron-catalyzed 2+2 olefin cycloaddition===

Iron<nowiki>[</nowiki>[[Diiminopyridine|pyridine(diimine)]]] catalysts contain a redox active ligand in which the central iron atom can coordinate with two simple, unfunctionalized olefin double bonds. The catalyst can be written as a resonance between a structure containing unpaired electrons with the central iron atom in the II oxidation state, and one in which the iron is in the 0 oxidation state. This gives it the flexibility to engage in binding the double bonds as they undergo a cyclization reaction, generating a cyclobutane structure via C-C reductive elimination; alternatively a cyclobutene structure may be produced by beta-hydrogen elimination. Efficiency of the reaction varies substantially depending on the alkenes used, but rational ligand design may permit expansion of the range of reactions that can be catalyzed.<ref>{{cite journal|title=Iron-catalyzed intermolecular [2+2] cycloadditions of unactivated alkenes|author1=Jordan M. Hoyt |author2=Valeria A. Schmidt |author3=Aaron M. Tondreau |author4=Paul J. Chirik |journalauthor-link4=SciencePaul Chirik|date=2015-08-28|title=Iron-catalyzed intermolecular [2+2] cycloadditions of unactivated alkenes|journal=Science|volume=349|issue=6251|pages=960–963|bibcode=2015Sci...349..960H|doi=10.1126/science.aac7440|pmid=26315433|s2cid=206640239 }}</ref><ref>{{cite journal|title=As simple as [2+2]|author1=Myles W. Smith |author2=Phil S. Baran |journalauthor-link2=SciencePhil S. Baran|date=2015-08-28|title=As simple as [2+2]|journal=Science|volume=349|issue=6251|pages=925–926|bibcode=2015Sci...349..925S|doi=10.1126/science.aac9883|pmid=26315420 |s2cid=42226757 }}</ref>

==References==