Editing Intramolecular reaction (section)

==Tools and concepts==
Many tools and concepts have been developed to exploit the advantages of intramolecular cyclizations.  For example, installing large substituents exploits the [[Thorpe-Ingold effect]].  [[High dilution reaction]]s suppress intermolecular processes.  One set of tools involves tethering as discussed below.

===<span id="Tethered intramolecular 2+2 reactions">Tethered intramolecular [2+2] reactions</span>===
Tethered intramolecular [2+2] reactions entail the formation of [[cyclobutane]] and [[cyclobutanone]] via intramolecular [[2+2 photocycloaddition]]s. Tethering ensures formation of a multi-cyclic system.
[[File:23 fig. 1.png|center|407 px|Tethered intramolecular [2+2] reactions]]

The length of the tether affects the [[stereochemistry|stereochemical outcome]] of the [2+2] reaction. Longer tethers tend to generate the "straight" product where the terminal carbon of the alkene is linked to the <math>\alpha</math>-carbon of the [[Alpha-beta Unsaturated carbonyl compounds|enone]].<ref>{{cite journal|author1=Coates, R. M. |author2=Senter, P. D. |author3=Baker, W. R. |journal=J. Org. Chem.|year=1982|volume=47|page=3597|title=Annelative Ring Expansion via Intramolecular [2 + 2] Photocycloaddition of α,β-Unsaturated γ-Lactones and Reductive Cleavage: Synthesis of Hydrocyclopentacyclooctene-5-carboxylates|issue=19|doi=10.1021/jo00140a001}}</ref> When the tether consists only two carbons, the “bent” product is generated where the <math>\beta</math>-carbon of the enone is connected to the terminal carbon of the alkene.<ref>{{cite journal |last1=Tamura |first1=Y. |last2=Kita |first2=Y. |last3=Ishibashi |first3=H. |last4=Ikeda |first4=M. |title=Intramolecular photocycloaddition of 3-allyloxy- and 3-allylamino-cyclohex-2-enones: formation of oxa- and aza-bicyclo[2,1,1]hexanes |journal=[[Journal of the Chemical Society|J. Chem. Soc. D]] |year=1971 |volume=19 |issue=19 |pages=1167 |doi=10.1039/C29710001167 }}</ref>
[[File:23 fig. 2.png|center|407 px|Effects of the length of tether on [2+2]  photocyclization  reaction]]

Tethered [2+2] reactions have been used to synthesize organic compounds with interesting ring systems and [[topologies]]. For example, [2+2] photocyclization was used to construct the tricyclic core structure in [[ginkgolide]] B.<ref>{{cite journal|author1=Corey, E. J. |author2=Kang, M. C. |author3=Desai, M. C. |author4=Ghosh, A. K. |author5=Houpis, I. N. |journal=J. Am. Chem. Soc.|year=1988|volume=110|pages=649–651|title=Total Synthesis of (.+-.)-Ginkgolide B|issue=2|doi=10.1021/ja00210a083|pmc=6746322|pmid=31527923}}</ref>
[[File:23 fig. 3.png|center|407 px|Tethered [2+2] reaction in the total synthesis of (<u>+)</u>  - Ginkgolide B]]

===Molecular tethers===
Otherwise-intermolecular reactions can be made temporarily intramolecular by linking both reactants by a [[tether]] with all the advantages associated to it. Popular choices of tether contain a [[carbonate ester]], [[boronic ester]],  [[silyl ether]], or a [[silyl acetal]] link ('''silicon tethers''')<ref>{{cite book |title=Templated Organic Synthesis |editor-first=François |editor-last=Diederich |editor2-first=Peter J. |editor2-last=Stang |year=2007 |chapter=Use of the Temporary Connection in Organic Synthesis |pages=274–395 |first1=Liam R. |last1=Cox |first2=Steven V. |last2=Ley |doi=10.1002/9783527613526 |isbn=9783527296668 }}</ref><ref>{{cite journal | last1 = Bracegirdle | first1 = S. | last2 = Anderson | first2 = E. A. | year = 2010 | title =  Recent advances in the use of temporary silicon tethers in metal-mediated reactions| journal = Chem. Soc. Rev. | volume = 39 | issue = 11 | pages = 4114–4129 | doi = 10.1039/C0CS00007H | pmid = 20838677 }}</ref> which are fairly inert in many organic reactions yet can be cleaved by specific reagents.  The main hurdle for this strategy to work is selecting the proper length for the tether and making sure reactive groups have an optimal orientation with respect to each other.  An examples is a [[Pauson–Khand reaction]] of an alkene and an alkyne tethered together via a silyl ether.<ref>{{cite journal |title=The use of silicon-based tethers for the Pauson-Khand reaction |last1=Dobbs |first1=A. |last2=Miller |first2=I. |last3=Martinovic |first3=S. |journal=[[Beilstein Journal of Organic Chemistry]] |year=2007 |issue=3 |page=21 |volume=2007 |doi=10.1186/1860-5397-3-21 |pmc=1949821 |pmid=17617903 |doi-access=free }}</ref>

[[Image:Pauson-Khand Silicon Tether.png|300px|Pauson-Khand silicon tether]]

In this particular reaction, the tether angle bringing the reactive groups together is effectively reduced by placing [[isopropyl]] groups on the  silicon atom via the [[Thorpe–Ingold effect]]. No reaction takes place when these bulky groups are replaced by smaller methyl groups. Another example is a [[photochemical]] [2+2][[cycloaddition]] with two alkene groups tethered through a silicon acetal group (racemic, the other [[enantiomer]] not depicted), which is subsequently cleaved by [[TBAF]] yielding the endo-diol.

:[[Image:CycloadditionSiliconTether.png|400px|Cycloaddition silicon tether]]

Without the tether, the [[exo isomer]] forms.<ref>{{cite journal | last1 = Booker-Milburn | first1 = Kevin I. | last2 = Gulten | first2 = Sirin | last3 = Sharpe | first3 = Andrew | year = 1997| title =  Diastereoselective intramolecular photochemical [2 + 2] cycloaddition reactions of tethered l-(+)-[[valinol]] derived tetrahydrophthalimides | journal = [[Chem. Commun.]] | volume = 1997 | issue = 15 | pages = 1385–1386 | doi = 10.1039/a702386c }}</ref>