Inchemistry,intramolecular describes aprocess or characteristic limited within thestructure of a singlemolecule, a property or phenomenon limited to the extent of a single molecule.

In intramolecularorganic reactions, two reaction sites are contained within a single molecule. This configuration elevates the effectiveconcentration of the reacting partners resulting in highreaction rates. Many intramolecular reactions are observed where theintermolecular 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 constantsk_n for the formation of ann-membered ring) is usuallyk₅ >k₆ >k₃ >k₇ >k₄ as shown below for a series of ω-bromoalkylamines. This somewhat complicated rate trend reflects the interplay of these entropic and strain factors:

For the'small rings' (3- and 4- membered), the slow rates is a consequence ofangle 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'unstrained rings' (5-, 6-, and 7-membered). The formation of'medium-sized rings' (8- to 13-membered) is particularly disfavorable due to a combination of an increasingly unfavorable entropic cost and the additional presence oftransannular strain arising from steric interactions across the ring. Finally, for'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.^[1][2]

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.

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 ofaldol condensation.
• Madelung synthesis ofindoles
• Smiles rearrangement
• Hydroacylation is almost invariably practiced intramolecularly to produce ketones.^[3]

RCHO + CH₂=CHR' → RC(O)CH₂CH₂R'

• Nazarov cyclization reaction for the synthesis ofcyclopentenones

• TheWurtz reaction, involving reductive coupling of alkyl halides, essentially is only useful when conducted intramolecularly. Its utility is illustrated with the synthesis of strained rings:^[4]

Some transformations that are enabled or enhanced intramolecularly. For example, theacyloin condensation of diesters almost uniquely produces 10-membered carbocycles, which are difficult to construct otherwise.^[5] Another example is the 2+2 cycloaddition ofnorbornadiene to givequadricyclane.

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

Tethered intramolecular [2+2] reactions entail the formation ofcyclobutane andcyclobutanone via intramolecular2+2 photocycloadditions. Tethering ensures formation of a multi-cyclic system.

The length of the tether affects thestereochemical 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${\displaystyle \alpha }$-carbon of theenone.^[6] When the tether consists only two carbons, the “bent” product is generated where the${\displaystyle \beta }$-carbon of the enone is connected to the terminal carbon of the alkene.^[7]

Tethered [2+2] reactions have been used to synthesize organic compounds with interesting ring systems andtopologies. For example, [2+2] photocyclization was used to construct the tricyclic core structure inginkgolide B.^[8]

Otherwise-intermolecular reactions can be made temporarily intramolecular by linking both reactants by atether with all the advantages associated to it. Popular choices of tether contain acarbonate ester,boronic ester,silyl ether, or asilyl acetal link (silicon tethers)^[9][10] 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 aPauson–Khand reaction of an alkene and an alkyne tethered together via a silyl ether.^[11]

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

Without the tether, theexo isomer forms.^[12]

• Reaction mechanisms
• Molecular physics
• Organic chemistry

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