Cycloaddition

<h2 id="thermal-cycloadditions-and-their-stereochemistry">Thermal cycloadditions and their stereochemistry</h2>
<p>Thermal cycloadditions are those cycloadditions where the reactants are in the ground electronic state. They usually have (4<i>n</i> + 2) π electrons participating in the starting material, for some integer <i>n</i>. These reactions occur for reasons of <a href="/facts/Orbital_symmetry/BrDxAkTK">orbital symmetry</a> in a <a href="/facts/Suprafacial/4CGzyIwl">suprafacial</a>-suprafacial (<i>syn</i>/<i>syn</i> stereochemistry) in most cases.  Very few examples of <a href="/facts/Antarafacial/4CGzyIwl">antarafacial</a>-antarafacial (<i>anti</i>/<i>anti</i> stereochemistry) reactions have also been reported. There are a few examples of thermal cycloadditions which have 4<i>n</i> π electrons (for example the [2 + 2]-cycloaddition). These proceed in a suprafacial-antarafacial sense (<i>syn</i>/<i>anti</i> stereochemistry), such as the cycloaddition reactions of <a href="/facts/Ketene/ByPehuE4">ketene</a> and <a href="/facts/Allenes/54hMEu5N">allene</a> derivatives, in which the <a href="/facts/Orthogonal/JVIjYPog">orthogonal</a> set of <a href="/facts/P_orbital/tKhgl6mL">p orbitals</a> allows the reaction to proceed via a crossed <a href="/facts/Transition_state/34PsdqRd">transition state</a>, although the analysis of these reactions as [π2s + π2a] is controversial.  Strained alkenes like <i>trans</i>-cycloheptene derivatives have also been reported to react in an antarafacial manner in [2 + 2]-cycloaddition reactions. 
</p><p><a href="/facts/William_von_Eggers_Doering/6K1H3qU0">Doering</a> (in a personal communication to <a href="/facts/Robert_Burns_Woodward/bAQeInCb">Woodward</a>) reported that <a href="/facts/Fulvalene_(compound_class)/qjqaxGtA">heptafulvalene</a> 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.
<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> 
</p><p>Erden and Kaufmann had previously found that the cycloaddition of heptafulvalene and N-phenyltriazolinedione also gave both suprafacial-antarafacial and suprafacial-suprafacial products. <a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a>
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<h2 id="photochemical-cycloadditions-and-their-stereochemistry">Photochemical cycloadditions and their stereochemistry</h2>
<p>Cycloadditions in which 4n π electrons participate can also occur via <a href="/facts/Photochemistry/GsXNBWon">photochemical</a> activation. Here, one component has an electron promoted from the <a href="/facts/HOMO/XyofpH0p">HOMO</a> (π bonding) to the <a href="/facts/LUMO/XyofpH0p">LUMO</a> (π* <a href="/facts/Antibonding/9lhLNyt3">antibonding</a>). Orbital symmetry is then such that the reaction can proceed in a suprafacial-suprafacial manner. An example is the <a href="/facts/DeMayo_reaction/vVKK9rvT">DeMayo reaction</a>. Another example is shown below, the photochemical dimerization of <a href="/facts/Cinnamic_acid/2oBQIQIw">cinnamic acid</a>.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> The two <i>trans</i> <a href="/facts/Alkene/RtYcS6kU">alkenes</a> react head-to-tail, and the isolated <a href="/facts/Isomer/PXlvDVdg">isomers</a> are called <i><a href="/facts/Truxillic_acid/IwC4fvKc">truxillic acids</a></i>.
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<p><a href="/facts/Supramolecular_chemistry/wwUfD0fk">Supramolecular effects</a> can influence these cycloadditions. The cycloaddition of <i>trans</i>-1,2-bis(4-pyridyl)ethene is directed by <a href="/facts/Resorcinol/fI1glr61">resorcinol</a> in the <a href="/facts/Solid-state_chemistry/MFpqNGSt">solid-state</a> in 100% <a href="/facts/Chemical_yield/fkBhd9dH">yield</a>.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a>
</p><p>Some cycloadditions instead of π bonds operate through strained <a href="/facts/Cyclopropane/BAUAYB7s">cyclopropane</a> rings, as these have significant π character. For example, an analog for the Diels-Alder reaction is the <a href="/facts/Quadricyclane/K8gGeGtd">quadricyclane</a>-<a href="/facts/DMAD/ekzooAzP">DMAD</a> reaction:
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<p>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 <a href="/facts/Ozonolysis/WEwBID8x">ozonolysis</a> is a (3+2)cycloaddition. The <a href="/facts/IUPAC/2AV6myCK">IUPAC</a> 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 <a href="/facts/Norbornadiene/FHj3Pnwr">norbornadiene</a> and an activated <a href="/facts/Alkyne/VHI4N5Wo">alkyne</a> is a [2+2+2]cycloaddition.
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<h2 id="types-of-cycloaddition">Types of cycloaddition</h2>
<p class="note">See also: Category:Cycloadditions</p>
<h3>Diels-Alder reactions</h3>
<p>The <a href="/facts/Diels-Alder_reaction/zc6dVpKl">Diels-Alder reaction</a> 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 <a href="/facts/Inverse_electron-demand_Diels%E2%80%93Alder_reaction/PI5J9RPY">inverse electron-demand Diels–Alder reaction</a>, <a href="/facts/Hexadehydro_Diels%E2%80%93Alder_reaction/4RqJIulC">hexadehydro Diels–Alder reaction</a> and the related <a href="/facts/Alkyne_trimerisation/7pDT3SKB">alkyne trimerisation</a>. The reaction can also be run in reverse in the <a href="/facts/Retro-Diels%E2%80%93Alder_reaction/Pjj4WQLW">retro-Diels–Alder reaction</a>.
</p>

<p>Reactions involving heteroatoms are known, including the <a href="/facts/Aza-Diels%E2%80%93Alder_reaction/oIQSso5W">aza-Diels–Alder reaction</a> and <a href="/facts/Oxo-Diels%E2%80%93Alder_reaction/yXrn2l5c">oxo-Diels–Alder reaction</a>.
</p>
<h3>Huisgen cycloadditions</h3>
<p>The <a href="/facts/Huisgen_cycloaddition/DNyagu07">Huisgen cycloaddition</a> reaction is a (2+3)cycloaddition.
</p>

<h3>Nitrone-olefin cycloaddition</h3>
<p>The <a href="/facts/Nitrone-olefin_3%2B2_cycloaddition/fl5Tu89j">Nitrone-olefin cycloaddition</a> is a (3+2)cycloaddition.
</p>

<h3>Cheletropic reactions</h3>
<p><a href="/facts/Cheletropic_reaction/Rq2AKz8m">Cheletropic reactions</a> 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 <a href="/facts/Sulfur_dioxide/jDK1fIDs">sulfur dioxide</a> with a <a href="/facts/Diene/F5NxrLPW">diene</a>.
</p>

<h2 id="other">Other</h2>
<p>Other cycloaddition reactions exist: <a href="/facts/(4%2B3)_cycloaddition/8Tw6zmQX">(4+3) cycloadditions</a>, <a href="/facts/6%2B4_cycloaddition/XHYKVRQc">[6+4] cycloadditions</a>, <a href="/facts/Woodward-Hoffmann_rules/4tW2tBIF">[2 + 2] photocycloadditions</a>, <a href="/facts/Metal-centered_cycloaddition_reactions/pjnYd1tU">metal-centered cycloaddition</a> and <a href="/facts/4%2B4_photocycloaddition/hLu3z1RD">[4+4] photocycloadditions</a>
</p>
<h2 id="formal-cycloadditions">Formal cycloadditions</h2>
<p>Cycloadditions often have metal-catalyzed and stepwise <a href="/facts/Radical_(chemistry)/qFymuVoT">radical</a> 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.
</p><p>One example of a formal [3+3]cycloaddition between a cyclic <a href="/facts/Enone/gAflh5z4">enone</a> and an <a href="/facts/Enamine/TaubsvCU">enamine</a> catalyzed by <a href="/facts/N-Butyllithium/v4Rz4Dc1"><i>n</i>-butyllithium</a> is a <a href="/facts/Stork_enamine_reaction/3SVV41zS">Stork enamine</a> / <a href="/facts/Nucleophilic_addition/1HL9WlD6">1,2-addition</a> <a href="/facts/Cascade_reaction/lWpMYkLM">cascade reaction</a>:<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a>
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<h3>Iron-catalyzed 2+2 olefin cycloaddition</h3>
<p>Iron[<a href="/facts/Diiminopyridine/XBE83TLk">pyridine(diimine)</a>] 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.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a><a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a>
</p>

<h2 id="references">References</h2>

<ol>
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<li id="fn:5"><p>Izzotti, Anthony; Gleason, James (2022-06-07), "Do Antarafacial Cycloadditions Occur? Cycloaddition of Heptafulvalene with Tetracyanoethylene", Chemistry: A European Journal, 28 (49), doi:10.1002/chem.202201418, PMID 35671245 <a href="https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/chem.202201418" target="_blank">https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/chem.202201418</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li>
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<li id="fn:9"><p>Movassaghi, Mohammad; Bin Chen (2007). "Stereoselective Intermolecular Formal [3+3] Cycloaddition Reaction of Cyclic Enamines and Enones". Angew. Chem. Int. Ed. 46 (4): 565–568. doi:10.1002/anie.200603302. PMC 3510678. PMID 17146819. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510678" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510678</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li>
<li id="fn:10"><p>Jordan M. Hoyt; Valeria A. Schmidt; Aaron M. Tondreau; Paul J. Chirik (2015-08-28). "Iron-catalyzed intermolecular [2+2] cycloadditions of unactivated alkenes". Science. 349 (6251): 960–963. Bibcode:2015Sci...349..960H. doi:10.1126/science.aac7440. PMID 26315433. S2CID 206640239. <a href="/wiki/Paul_Chirik" target="_blank">/wiki/Paul_Chirik</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li>
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</ol>

Cycloaddition open-in-new

Cycloaddition