Editing Cycloaddition

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

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}}</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}}</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 (''syn''/''syn'' stereochemistry) in most cases.  Very few examples of [[antarafacial]]-antarafacial (''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). These proceed in a suprafacial-antarafacial sense (''syn''/''anti'' stereochemistry), such as the cycloaddition 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 [<sub>π</sub>2<sub>s</sub> + <sub>π</sub>2<sub>a</sub>] 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 |
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==
Cycloadditions in which 4n π electrons participate can also occur via [[Photochemistry|photochemical]] activation. Here, one component has an electron promoted from the [[HOMO]] (π bonding) to the [[LUMO]] (π* [[antibonding]]). Orbital symmetry is then such that the reaction can proceed in a suprafacial-suprafacial manner. An example is the [[DeMayo reaction]]. Another example is shown below, the photochemical dimerization of [[cinnamic acid]].<ref>{{cite journal | author = Hein, Sara M. | title = An Exploration of a Photochemical Pericyclic Reaction Using NMR Data | journal = Journal of Chemical Education | volume = 83 |date=June 2006 | pages = 940&ndash;942 | doi = 10.1021/ed083p940 | issue = 6 |bibcode = 2006JChEd..83..940H }}</ref> The two ''trans'' [[alkene]]s react head-to-tail, and the isolated [[isomer]]s are called ''[[truxillic acid]]s''.

:[[Image:CinnamicAcidCycloAddition.png|400px|center|Cinnamic Acid CycloAddition]]

[[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}}</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==
{{See also|Category:Cycloadditions}}

===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]], [[hexadehydro Diels–Alder reaction]] and the related [[alkyne trimerisation]]. The reaction can also be run in reverse in the [[retro-Diels–Alder reaction]].

:[[File:Diels-Alder (1,3-butadiene + ethylene) red.svg|300px|Diels–Alder reaction]]

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

===Huisgen cycloadditions===
The [[Huisgen cycloaddition]] reaction is a (2+3)cycloaddition.
:[[File:Thermal_Huisgen_cycloaddition.png|600px|1,3-cycloaddition]]

===Nitrone-olefin cycloaddition===
The [[nitrone-olefin 3+2 cycloaddition|Nitrone-olefin cycloaddition]] is a (3+2)cycloaddition.
:[[File:NitrGen.svg|Nitrone olefin cycloaddition]]

===Cheletropic reactions===
[[Cheletropic reaction]]s are a subclass of cycloadditions. The key distinguishing feature of cheletropic reactions is that on one of the reagents, both new bonds are being made to the same atom. The classic example is the reaction of [[sulfur dioxide]] with a [[diene]].

:[[File:Cheletropic reaction of butadiene with SO2.svg|150px]]

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

==Formal cycloadditions==
Cycloadditions often have metal-catalyzed and stepwise [[Radical (chemistry)|radical]] analogs, however these are not strictly speaking pericyclic reactions. When in a cycloaddition charged or radical intermediates are involved or when the cycloaddition result is obtained in a series of reaction steps they are sometimes called '''formal cycloadditions''' to make the distinction with true pericyclic cycloadditions.

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|500px|An intermolecular formal [3+3] cycloaddition between 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|author1=Jordan M. Hoyt|author2=Valeria A. Schmidt|author3=Aaron M. Tondreau|author4=Paul J. Chirik|author-link4=Paul 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|author1=Myles W. Smith|author2=Phil S. Baran|author-link2=Phil 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==
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{{Reaction mechanisms}}

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[[Category:Cycloadditions| ]]
[[Category:Reaction mechanisms]]
[[Category:Ring forming reactions]]