Intramolecular reaction

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

Contents

Relative rates

In intramolecular organic reactions, two reaction sites are contained within a single molecule. This configuration elevates the effective concentration of the reacting partners resulting in high reaction rates. 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 kn for the formation of an n-membered ring) is usually k5 > 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:

SN2intramolecular.png
Relative rate constants for cyclization (n = 5 set to krel = 100)
nkrelnkrelnkrel
30.161.7120.00001
40.00270.03140.0003
5100100.00000001150.0003

For the 'small rings' (3- and 4- membered), the slow rates is a consequence of 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 '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 of transannular 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.

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.,

RCHO + CH2=CHR' → RC(O)CH2CH2R'
The Nazarov cyclization reaction Nazarov cyclization.png
The Nazarov cyclization reaction
Wurtz-reaction Bicyclobutane synthesis.svg

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. [5] Another example is the 2+2 cycloaddition of norbornadiene to give quadricyclane.

Synthesis of quadricyclane from norbornadiene.png

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 reactions suppress intermolecular processes. One set of tools involves tethering as discussed below.

Tethered intramolecular [2+2] reactions

Tethered intramolecular [2+2] reactions entail the formation of cyclobutane and cyclobutanone via intramolecular 2+2 photocycloadditions. Tethering ensures formation of a multi-cyclic system.

Tethered intramolecular [2+2] reactions 23 fig. 1.png
Tethered intramolecular [2+2] reactions

The length of the tether affects the 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 -carbon of the enone. [6] When the tether consists only two carbons, the “bent” product is generated where the -carbon of the enone is connected to the terminal carbon of the alkene. [7]

Effects of the length of tether on [2+2] photocyclization reaction 23 fig. 2.png
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. [8]

Tethered [2+2] reaction in the total synthesis of ( +) - Ginkgolide B 23 fig. 3.png
Tethered [2+2] reaction in the total synthesis of (+) - 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) [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 a Pauson–Khand reaction of an alkene and an alkyne tethered together via a silyl ether. [11]

Pauson-Khand Silicon Tether.png

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.

CycloadditionSiliconTether.png

Without the tether, the exo isomer forms. [12]

Related Research Articles

In organic chemistry, a cycloaddition is a chemical reaction in which "two or more unsaturated molecules combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity". The resulting reaction is a cyclization reaction. Many but not all cycloadditions are concerted and thus pericyclic. Nonconcerted cycloadditions are not pericyclic. As a class of addition reaction, cycloadditions permit carbon–carbon bond formation without the use of a nucleophile or electrophile.

The 1,3-dipolar cycloaddition is a chemical reaction between a 1,3-dipole and a dipolarophile to form a five-membered ring. The earliest 1,3-dipolar cycloadditions were described in the late 19th century to the early 20th century, following the discovery of 1,3-dipoles. Mechanistic investigation and synthetic application were established in the 1960s, primarily through the work of Rolf Huisgen. Hence, the reaction is sometimes referred to as the Huisgen cycloaddition. 1,3-dipolar cycloaddition is an important route to the regio- and stereoselective synthesis of five-membered heterocycles and their ring-opened acyclic derivatives. The dipolarophile is typically an alkene or alkyne, but can be other pi systems. When the dipolarophile is an alkyne, aromatic rings are generally produced.

An alkyne trimerisation is a [2+2+2] cycloaddition reaction in which three alkyne units react to form a benzene ring. The reaction requires a metal catalyst. The process is of historic interest as well as being applicable to organic synthesis. Being a cycloaddition reaction, it has high atom economy. Many variations have been developed, including cyclisation of mixtures of alkynes and alkenes as well as alkynes and nitriles.

<span class="mw-page-title-main">Pauson–Khand reaction</span> Chemical reaction

The Pauson–Khand (PK) reaction is a chemical reaction, described as a [2+2+1] cycloaddition. In it, an alkyne, an alkene and carbon monoxide combine into a α,β-cyclopentenone in the presence of a metal-carbonyl catalyst.

The Paternò–Büchi reaction, named after Emanuele Paternò and George Büchi, who established its basic utility and form, is a photochemical reaction, specifically a 2+2 photocycloaddition, which forms four-membered oxetane rings from an excited carbonyl and reacting with an alkene.

Ring-closing metathesis (RCM) is a widely used variation of olefin metathesis in organic chemistry for the synthesis of various unsaturated rings via the intramolecular metathesis of two terminal alkenes, which forms the cycloalkene as the E- or Z- isomers and volatile ethylene.

<span class="mw-page-title-main">Azomethine ylide</span>

Azomethine ylides are nitrogen-based 1,3-dipoles, consisting of an iminium ion next to a carbanion. They are used in 1,3-dipolar cycloaddition reactions to form five-membered heterocycles, including pyrrolidines and pyrrolines. These reactions are highly stereo- and regioselective, and have the potential to form four new contiguous stereocenters. Azomethine ylides thus have high utility in total synthesis, and formation of chiral ligands and pharmaceuticals. Azomethine ylides can be generated from many sources, including aziridines, imines, and iminiums. They are often generated in situ, and immediately reacted with dipolarophiles.

In organic chemistry the Brook rearrangement refers to any [1,n] carbon to oxygen silyl migration. The rearrangement was first observed in the late 1950s by Canadian chemist Adrian Gibbs Brook (1924–2013), after which the reaction is named. These migrations can be promoted in a number of different ways, including thermally, photolytically or under basic/acidic conditions. In the forward direction, these silyl migrations produce silyl ethers as products which is driven by the stability of the oxygen-silicon bond.

The Stetter reaction is a reaction used in organic chemistry to form carbon-carbon bonds through a 1,4-addition reaction utilizing a nucleophilic catalyst. While the related 1,2-addition reaction, the benzoin condensation, was known since the 1830s, the Stetter reaction was not reported until 1973 by Dr. Hermann Stetter. The reaction provides synthetically useful 1,4-dicarbonyl compounds and related derivatives from aldehydes and Michael acceptors. Unlike 1,3-dicarbonyls, which are easily accessed through the Claisen condensation, or 1,5-dicarbonyls, which are commonly made using a Michael reaction, 1,4-dicarbonyls are challenging substrates to synthesize, yet are valuable starting materials for several organic transformations, including the Paal–Knorr synthesis of furans and pyrroles. Traditionally utilized catalysts for the Stetter reaction are thiazolium salts and cyanide anion, but more recent work toward the asymmetric Stetter reaction has found triazolium salts to be effective. The Stetter reaction is an example of umpolung chemistry, as the inherent polarity of the aldehyde is reversed by the addition of the catalyst to the aldehyde, rendering the carbon center nucleophilic rather than electrophilic.

The Nazarov cyclization reaction is a chemical reaction used in organic chemistry for the synthesis of cyclopentenones. The reaction is typically divided into classical and modern variants, depending on the reagents and substrates employed. It was originally discovered by Ivan Nikolaevich Nazarov (1906–1957) in 1941 while studying the rearrangements of allyl vinyl ketones.

In organosilicon chemistry, silyl enol ethers are a class of organic compounds that share the common functional group R3Si−O−CR=CR2, composed of an enolate bonded to a silane through its oxygen end and an ethene group as its carbon end. They are important intermediates in organic synthesis.

In organic chemistry, an intramolecular Diels-Alder cycloaddition is a Diels–Alder reaction in which the diene and the dienophile are both part of the same molecule. The reaction leads to the formation of the cyclohexene-like structure as usual for a Diels–Alder reaction, but as part of a more complex fused or bridged cyclic ring system. This reaction can gives rise to various natural derivatives of decalin.

Trimethylenemethane cycloaddition is the formal [3+2] annulation of trimethylenemethane (TMM) derivatives to two-atom pi systems. Although TMM itself is too reactive and unstable to be stored, reagents which can generate TMM or TMM synthons in situ can be used to effect cycloaddition reactions with appropriate electron acceptors. Generally, electron-deficient pi bonds undergo cyclization with TMMs more easily than electron-rich pi bonds.

In organic chemistry, enone–alkene cycloadditions are a version of the [2+2] cycloaddition This reaction involves an enone and alkene as substrates. Although the concerted photochemical [2+2] cycloaddition is allowed, the reaction between enones and alkenes is stepwise and involves discrete diradical intermediates.

The nitrone-olefin [3+2] cycloaddition reaction is the combination of a nitrone with an alkene or alkyne to generate an isoxazoline or isoxazolidine via a [3+2] cycloaddition process. This reaction is a 1,3-dipolar cycloaddition, in which the nitrone acts as the 1,3-dipole, and the alkene or alkyne as the dipolarophile.

<span class="mw-page-title-main">Photoredox catalysis</span>

Photoredox catalysis is a branch of photochemistry that uses single-electron transfer. Photoredox catalysts are generally drawn from three classes of materials: transition-metal complexes, organic dyes, and semiconductors. While organic photoredox catalysts were dominant throughout the 1990s and early 2000s, soluble transition-metal complexes are more commonly used today.

<span class="mw-page-title-main">Alkene carboamination</span>

Alkene carboamination is the simultaneous formation of C–N and C–C bonds across an alkene. This method represents a powerful strategy to build molecular complexity with up to two stereocenters in a single operation. Generally, there are four categories of reaction modes for alkene carboamination. The first class is cyclization reactions, which will form a N-heterocycle as a result. The second class has been well established in the last decade. Alkene substrates with a tethered nitrogen nucleophile have been used in these transformations to promote intramolecular aminocyclization. While intermolecular carboamination is extremely hard, people have developed a strategy to combine the nitrogen and carbon part, which is known as the third class. The most general carboamination, which takes three individual parts and couples them together is still underdeveloped.

<span class="mw-page-title-main">Activation of cyclopropanes by transition metals</span>

In organometallic chemistry, the activation of cyclopropanes by transition metals is a research theme with implications for organic synthesis and homogeneous catalysis. Being highly strained, cyclopropanes are prone to oxidative addition to transition metal complexes. The resulting metallacycles are susceptible to a variety of reactions. These reactions are rare examples of C-C bond activation. The rarity of C-C activation processes has been attributed to Steric effects that protect C-C bonds. Furthermore, the directionality of C-C bonds as compared to C-H bonds makes orbital interaction with transition metals less favorable. Thermodynamically, C-C bond activation is more favored than C-H bond activation as the strength of a typical C-C bond is around 90 kcal per mole while the strength of a typical unactivated C-H bond is around 104 kcal per mole.

Carbonyl olefin metathesis is a type of metathesis reaction that entails, formally, the redistribution of fragments of an alkene and a carbonyl by the scission and regeneration of carbon-carbon and carbon-oxygen double bonds respectively. It is a powerful method in organic synthesis using simple carbonyls and olefins and converting them into less accessible products with higher structural complexity.

In organic chemistry, the Conia-ene reaction is an intramolecular cyclization reaction between an enolizable carbonyl such as an ester or ketone and an alkyne or alkene, giving a cyclic product with a new carbon-carbon bond. As initially reported by J. M. Conia and P. Le Perchec, the Conia-ene reaction is a heteroatom analog of the ene reaction that uses an enol as the ene component. Like other pericyclic reactions, the original Conia-ene reaction required high temperatures to proceed, limiting its wider application. However, subsequent improvements, particularly in metal catalysis, have led to significant expansion of reaction scope. Consequently, various forms of the Conia-ene reaction have been employed in the synthesis of complex molecules and natural products.

References

  1. ↑ Streitwieser, Andrew; Heathcock, Clayton H.; Kosower, Edward M. (2017). Introduction to Organic Chemistry. New Delhi: Medtech (Scientific International, reprint of 1998 revised 4th edition, Macmillan). p. 198. ISBN   9789385998898.
  2. ↑ Jonathan Clayden (2001). Organic chemistry. Oxford: Oxford University Press. pp. 454]. ISBN   0198503474. OCLC   43338068.
  3. ↑ Michael C. Willis (2009). "Transition Metal Catalyzed Alkene and Alkyne Hydroacylation". Chem. Rev. 110 (2): 725–748. doi:10.1021/cr900096x. PMID   19873977.
  4. ↑ Lampman, Gary M.; Aumiller, James C. (1971). "Bicyclo[1.1.0]butane". Organic Syntheses . 51: 55. doi:10.15227/orgsyn.051.0055.
  5. ↑ Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, p. 1461, ISBN   978-0-471-72091-1
  6. ↑ Coates, R. M.; Senter, P. D.; Baker, W. R. (1982). "Annelative Ring Expansion via Intramolecular [2 + 2] Photocycloaddition of α,β-Unsaturated γ-Lactones and Reductive Cleavage: Synthesis of Hydrocyclopentacyclooctene-5-carboxylates". J. Org. Chem. 47 (19): 3597. doi:10.1021/jo00140a001.
  7. ↑ Tamura, Y.; Kita, Y.; Ishibashi, H.; Ikeda, M. (1971). "Intramolecular photocycloaddition of 3-allyloxy- and 3-allylamino-cyclohex-2-enones: formation of oxa- and aza-bicyclo[2,1,1]hexanes". J. Chem. Soc. D . 19 (19): 1167. doi:10.1039/C29710001167.
  8. ↑ Corey, E. J.; Kang, M. C.; Desai, M. C.; Ghosh, A. K.; Houpis, I. N. (1988). "Total Synthesis of (.+-.)-Ginkgolide B". J. Am. Chem. Soc. 110 (2): 649–651. doi:10.1021/ja00210a083. PMC   6746322 . PMID   31527923.
  9. ↑ Cox, Liam R.; Ley, Steven V. (2007). "Use of the Temporary Connection in Organic Synthesis". In Diederich, François; Stang, Peter J. (eds.). Templated Organic Synthesis. pp. 274–395. doi:10.1002/9783527613526. ISBN   9783527296668.
  10. ↑ Bracegirdle, S.; Anderson, E. A. (2010). "Recent advances in the use of temporary silicon tethers in metal-mediated reactions". Chem. Soc. Rev. 39 (11): 4114–4129. doi:10.1039/C0CS00007H. PMID   20838677.
  11. ↑ Dobbs, A.; Miller, I.; Martinovic, S. (2007). "The use of silicon-based tethers for the Pauson-Khand reaction". Beilstein Journal of Organic Chemistry . 2007 (3): 21. doi: 10.1186/1860-5397-3-21 . PMC   1949821 . PMID   17617903.
  12. ↑ Booker-Milburn, Kevin I.; Gulten, Sirin; Sharpe, Andrew (1997). "Diastereoselective intramolecular photochemical [2 + 2] cycloaddition reactions of tethered l-(+)-valinol derived tetrahydrophthalimides". Chem. Commun. 1997 (15): 1385–1386. doi:10.1039/a702386c.
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