Editing Intramolecular reaction

{{short description|Process or characteristic limited to the structure of a single molecule}}

In [[chemistry]], '''intramolecular''' describes a [[Chemical process|process]] or characteristic limited within the [[Chemical structure|structure]] of a single [[molecule]], a property or phenomenon limited to the extent of a single molecule.

== Relative rates ==
In intramolecular [[organic reaction]]s, two reaction sites are contained within a single molecule. This configuration elevates the effective [[concentration]] of the reacting partners resulting in high [[reaction rate]]s.  Many intramolecular reactions are observed where the [[intermolecular]] version does not take place.

Intramolecular reactions, especially ones leading to the formation of 5- and 6-membered rings, are rapid compared to an analogous intermolecular process. This is largely a consequence of the reduced entropic cost for reaching the transition state of ring formation and the absence of significant strain associated with formation of rings of these sizes. For the formation of different ring sizes via cyclization of substrates of varying tether length, the order of reaction rates (rate constants ''k<sub>n</sub>'' for the formation of an ''n''-membered ring) is usually ''k''<sub>5</sub> > ''k''<sub>6</sub> > ''k''<sub>3</sub> > ''k''<sub>7</sub> > ''k''<sub>4</sub> as shown below for a series of ω-bromoalkylamines. This somewhat complicated rate trend reflects the interplay of these entropic and strain factors:
[[File:SN2intramolecular.png|center|frameless|320x320px]]
{| class="wikitable" style="margin-left: auto; margin-right: auto; border: none;"
|+Relative rate constants for cyclization
(''n'' = 5 set to ''k''<sub>rel</sub> = 100)
|-
|+
!''n'' 
!''k''<sub>rel</sub>
!''n''
!''k''<sub>rel</sub>
!''n''
!''k''<sub>rel</sub>
|-
|3
|0.1
|6
|1.7
|12
|0.00001
|-
|4
|0.002
|7
|0.03
|14
|0.0003
|-
|5
|100
|10
|0.00000001
|15
|0.0003
|}
For the '''<nowiki/>'small rings'<nowiki/>''' (''3- and 4- membered''), the slow rates is a consequence of [[Ring strain|angle strain]] experienced at the transition state. Although three-membered rings are more strained, formation of aziridine is faster than formation of azetidine due to the proximity of the leaving group and nucleophile in the former, which increases the probability that they would meet in a reactive conformation. The same reasoning holds for the '''<nowiki/>'unstrained rings'<nowiki/>''' (''5-, 6-, and 7-membered''). The formation of '''<nowiki/>'medium-sized rings'<nowiki/>''' (''8- to 13-membered'') is particularly disfavorable due to a combination of an increasingly unfavorable entropic cost and the additional presence of [[transannular strain]] arising from steric interactions across the ring. Finally, for '''<nowiki/>'large rings'''' (''14-membered or higher''), the rate constants level off, as the distance between the leaving group and nucleophile is now so large the reaction is now effectively intermolecular.<ref>{{Cite book|title=Introduction to Organic Chemistry|last1=Streitwieser|first1=Andrew|last2=Heathcock|first2=Clayton H.|last3=Kosower|first3=Edward M.|publisher=Medtech (Scientific International, reprint of 1998 revised 4th edition, Macmillan)|year=2017|isbn=9789385998898|location=New Delhi|pages=198}}</ref><ref>{{Cite book|url=https://archive.org/details/organicchemistry00clay_0/page/454|title=Organic chemistry|date=2001|publisher=Oxford University Press|author=Jonathan Clayden|isbn=0198503474|location=Oxford|pages=454]|oclc=43338068}}</ref> 

Although the details may change somewhat, the general trends hold for a variety of intramolecular reactions, including radical-mediated and (in some cases) transition metal-catalyzed processes.

== Examples==
Many reactions in organic chemistry can occur in either an intramolecular or intermolecular senses.  Some reactions are by definition intramolecular or are only practiced intramolecularly, e.g., 
* [[Dieckmann condensation]] of diesters is the intramolecular version of [[aldol condensation]].
* [[Madelung synthesis]] of [[indole]]s
* [[Smiles rearrangement]]
* [[Hydroacylation]] is almost invariably practiced intramolecularly to produce ketones.<ref name=Willis>{{cite journal|author=Michael C. Willis|title=Transition Metal Catalyzed Alkene and Alkyne Hydroacylation|journal=[[Chem. Rev.]]|year=2009|doi=10.1021/cr900096x|volume=110|issue=2 |pages=725–748|pmid=19873977 }}</ref>
:RCHO  +  CH<sub>2</sub>=CHR'   →   RC(O)CH<sub>2</sub>CH<sub>2</sub>R'
* [[Nazarov cyclization reaction]] for the synthesis of [[cyclopentenone]]s
:[[File:Nazarov cyclization.png|center|320px|The Nazarov cyclization reaction]]
*The [[Wurtz reaction]], involving reductive coupling of alkyl halides, essentially is only useful when conducted intramolecularly.  Its utility is illustrated with the synthesis of strained rings:<ref>{{OrgSynth|first1 = Gary M.|last1 = Lampman|first2 = James C.|last2 = Aumiller|title = Bicyclo[1.1.0]butane|year = 1971|volume = 51 |pages = 55|doi = 10.15227/orgsyn.051.0055}}</ref>  
:[[File:Wurtz-reaction Bicyclobutane synthesis.svg|300px|center]]

Some transformations that are enabled or enhanced intramolecularly.  For example, the [[acyloin condensation]] of diesters almost uniquely produces 10-membered carbocycles, which are difficult to construct otherwise.<ref>{{March6th|page=1461}}</ref>  Another example is the 2+2 cycloaddition of [[norbornadiene]] to give [[quadricyclane]].
:[[File:Synthesis of quadricyclane from norbornadiene.png|350px|center]]

==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>

==References==
{{reflist}}
{{Reaction mechanisms}}

{{DEFAULTSORT:Intramolecular Reaction}}
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