WikiHarold: linkage

2026-05-13T06:01:32Z

linkage

New page

{{Short description|Chemical reaction}}
{{correct title|reason=bracket|[4+4] photocycloaddition}}
The '''[4+4] Photocycloaddition''' is a [[Chemistry:Cycloaddition|cycloaddition]] reaction in which two unsaturated molecules connect via four atoms from each molecule (hence "4 + 4") to create an eight-membered ring. As a photochemical reaction, it is promoted by some form of light, as opposed to a thermal process.

== Introduction ==

The earliest example of a [4+4] photocycloaddition was the photodimerization of [[Chemistry:Anthracene|anthracene]], discovered in 1936.<ref>{{cite journal | title=The Structure of Anthracene | journal=J. Am. Chem. Soc. | year=1936 | author=Fieser, Louis F. | author2=Lothrop, Warren C. | pages=749–753 | volume=58 | issue=5 | doi=10.1021/ja01296a016| bibcode=1936JAChS..58..749F }}</ref> This reaction has remained one of the most reliable photocycloadditions and is the basis of continuing investigation.<ref>{{cite journal| title=The reversible [4 + 4] photocycloaddition of acridizinium derivatives | journal=J. Photochem. Photobiol. A | year= 2008 | author=Heiko, I. | author2=Luo, J. | pages=3–9 | volume=200 | issue=1 | doi=10.1016/j.jphotochem.2008.04.008| bibcode=2008JPPA..200....3I }}</ref>

[[Image:Anthracene Photodimerisation.svg|360px|center|Anthracene photodimerization]]

Other polycyclic aromatics undergo anthracene-like photocycloaddition, such as acridizinium salts. Biologically active natural products include [[Chemistry:Pleuromutilin|pleuromutilin]], kalmanol, crenulide, and longipenol.

[4+4] photocycloaddition approaches to the creation of cyclooctanoid systems offer several appealing features, including convergent assembly of the eight-membered ring from two relatively simpler four-carbon fragments, formation of two new carbon-carbon bonds, and the potential for introduction of up to four new stereocenters in one step.<ref>{{cite journal| title=Photocycloaddition of Four-Carbon-Tethered Pyridones. Intramolecular Hydrogen Bonding and Facilitated Amide Hydrolysis by a Proximal Secondary Alcohol. | journal=J. Org. Chem. | year=2002 | author=Zhu, M. | author2=Qiu, Z. | author3=Hiel, G.|author4-link=Scott Sieburth | author4=Sieburth, S. | pages=3487–3493 | volume=67 | issue=10 | doi=10.1021/jo025565n| pmid=12003564 }}</ref>

== Mechanism and stereochemistry ==

=== Prevailing mechanism ===

[4+4] reactions are forbidden in the ground state and often entropically disfavored in the excited state.<ref>{{cite journal | title=Transition Metal-Catalyzed Intramolecular [4+2] Cycloadditions: Mechanistic and Synthetic Investigations | author=Wender, P. | author2=Smith, T. | journal=Tetrahedron | year=1998 | volume=54 | issue=7 | pages=1255–1275 | doi=10.1016/S0040-4020(97)10223-X| doi-access=free }}</ref> The mechanism of the [4+4] photocycloaddition is proposed to begin with the photoexcitation of a 1,3-diene system into the excited state. Because the orbital symmetry of the highest occupied molecular orbital (HOMO) in the excited diene is the same as that of the lowest unoccupied molecular orbital (LUMO) in another ground state diene, they are able to form an exciplex that decays to form the closed cyclooctane ring structure. Below is a [[Chemistry:Frontier molecular orbital theory|Frontier Molecular Orbital]] diagram depicting the interaction between the two molecules of dienes.

[[File:4-4photocycloadditionfmo.svg|center|500px|FMO Orbital Theory depiction of a 4+4 photocycloaddition.]]

=== Stereochemistry ===

Stereochemical control within [4+4] reactions is not common, however it does exist. Enol-exo stereoselectivity is possible using certain [[Chemistry:Cross-link|cross-link]]ing techniques and has been met with moderate success.<ref>{{cite journal | title=Diastereocontrol in [4+4]-photocycloadditions of pyran-2-ones: effect of ring substituents and chiral ketal | year=2009 | author=Lei, L. | author2=Benderb, J. | author3=West F. G. | journal=Tetrahedron Lett. | pages=1188–1192 | doi=10.1016/j.tetlet.2008.12.117 | volume=50| issue=11 }}</ref>

[[File:4mesyloxypyran2ones 4-4cycloadditionstereochemistry2.svg|540px|center|English: 4-mesyloxypyran-2-ones with pendent furans occurred with high exo selectivity, displaying stereochemical control exists in 4+4 photocycloaddition reactions.]]

Control over the configuration at newly established bridgehead centers by use of preexisting stereocenters has been largely unsuccessful, apart from one specialized example.<ref>{{cite journal | title=Diastereoselective [4 + 4]-photocycloaddition reactions of pyran-2-ones: rapid access to functionalized 5-8-5 skeletons | year=2006 | author=Song, D. | author2=McDonald, R. | author3=West, F. G. | journal=Org. Lett. | pages=4075–4078 | volume=8 | issue=18 | doi=10.1021/ol061576h| pmid=16928077 }}</ref>

== Synthetic applications ==

Application of the [4+4] photocycloaddition is scarce because of competition with the [2+2] cycloaddition. However, when accessible, this method can be used to build 8-membered ring with complex stereocenters and structures in one step, as is seen in proposed syntheses for Taxol<ref>{{cite journal| title=A [4 + 4] 2-Pyridone Approach to Taxol. 3. Stereocontrol during Elaboration of the Cyclooctane | journal=J. Org. Chem. | year=2000 | author=Lee, Y.-G. | author2=McGee, K. F. | author3=Chen, J. | author4=Rucando, D. | author5=Sieburth, S. McN. | pages=6676–6681 | volume=65 | issue=20 | doi=10.1021/jo005532c| pmid=11052118 }}</ref> and molecules of the [[Chemistry:Fusicoccin|fusicoccin]] family.<ref>{{cite journal| title=Fusicoccin Synthesis by Intramolecular [4+4] Photocycloaddition of 2-Pyridones: Stereocontrol of the Cycloaddition and Elaboration of the Pentacyclic Product | journal=Synthesis | year=2001 | author=McGee, K. F. | author2=Al-Tel, T. H. | author3=Sieburth, S. McN. | pages=1185–1196 | volume=112 | issue=8 | doi=10.1055/s-2001-15066| s2cid=95258628 }}</ref> Additionally, while this reaction first forms fused rings, subsequent cleavages can afford macrocycles.<ref>{{cite journal| title=Beyond the medium ring: A [4 + 4] Cycloaddition/Fragmentation Synthesis of Eleven-membered Rings | journal=Tetrahedron Lett. | year=1997 | author=Sieburth, S. McN. | author2= Al-Tel, T. H. | author3= Rucando, D. | pages=8433–8434 | doi=10.1016/S0040-4039(97)10272-6 | volume=38| issue=49 }}</ref>

[[Image:Key step building the BC rings of Taxol in a proposed synthesis.svg|720px|center|Forming the BC rings of Taxol]]

In this partial synthesis of the BC rings of Taxol, the framework buildup utilized an intramolecule [4+4] photocycloaddition of a relatively linear and simple 2-pyridone derivative, folding it into the desired fused rings with correct stereochemistry at C3, C8, and C15 (compare with Taxol on the right) and two double bonds on the B ring ready to accept ''trans''-addition. Consequent lactam-ring opening and functionalization were expected to give Taxol.

[[Image:Attempted formation of 5+8+5 fused rings.svg|680px|center|Wrong isomer]]

Similarly, molecules of the fusicoccin family, featuring 5-8-5 ring systems, could be constructed rapidly using this reaction. Although the high stereoselectivity of this reaction to form ''trans''-isomers made it unsuitable for the specific target molecules, the general ease to create the four tertiary chiral centers is still noteworthy.

[[Image:Eleven-membered ring form 4+4 photocycloaddition.svg|720px|center|Creating an eleven-membered ring by reduction of 8+5 fused rings]]

Use of [4+4] photocycloaddition need not be limited to the creation of 8-membered rings. By linking up a network of rings and then breaking the shared bonds, a single macrocycle with built-in stereocenters could be achieved.

== Limitations ==

Inevitably, [4+4] photocycloadditions carry the side reaction of [2+2] photocycloadditions. However, since these reactions are reversible, the most stable product may be formed through thermodynamic control.<ref>{{cite journal | title=The [4 + 4] cycloaddition and its strategic application in natural product synthesis | author=Sieburth, S. McN. | author2=Cunard, N. T. | journal=Tetrahedron | year=1996 | volume=52 | issue=18 | pages=6251–6282 | doi=10.1016/0040-4020(95)01077-7}}</ref>

[[File:Cisfused5-8ringconstruction.svg|center|500px|A 4+4 cycloaddition occurring over two 2+2 cycloaddition steps.]]

== See also ==

* [2+2] Photocycloaddition

== References ==
{{Reflist}}

{{DEFAULTSORT:4 4 Photocycloaddition}}
[[Category:Cycloadditions]]
[[Category:Photochemistry]]

{{Sourceattribution|4+4 Photocycloaddition}}

Physics:4+4 Photocycloaddition - Revision history

WikiHarold: linkage