Cycloaddition

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In organic chemistry, a cycloaddition is a chemical reaction in which "two or more unsaturated molecules (or parts of the same molecule) 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. [1] Nonconcerted cycloadditions are not pericyclic. [2] As a class of addition reaction, cycloadditions permit carbon–carbon bond formation without the use of a nucleophile or electrophile.

Contents

Cycloadditions can be described using two systems of notation. An older but still common notation is based on the size of linear arrangements of atoms in the reactants. It uses parentheses: (i + j + …) where the variables are the numbers of linear atoms in each reactant. The product is a cycle of size (i + j + …). In this system, the standard Diels-Alder reaction is a (4 + 2)-cycloaddition, the 1,3-dipolar cycloaddition is a (3 + 2)-cycloaddition and cyclopropanation of a carbene with an alkene a (2 + 1)-cycloaddition. [1]

A more recent, IUPAC-preferred notation, first introduced by Woodward and Hoffmann, uses square brackets to indicate the number of electrons, rather than carbon atoms, involved in the formation of the product. In the [i + j + ...] notation, the standard Diels-Alder reaction is a [4 + 2]-cycloaddition, while the 1,3-dipolar cycloaddition is also a [4 + 2]-cycloaddition. [1]

Thermal cycloadditions and their stereochemistry

Thermal cycloadditions are those cycloadditions where the reactants are in the ground electronic state. They usually have (4n + 2) π electrons participating in the starting material, for some integer n. These reactions occur for reasons of orbital symmetry in a suprafacial-suprafacial (syn/syn stereochemistry) in most cases. Very few examples of antarafacial-antarafacial (anti/anti stereochemistry) reactions have also been reported. There are a few examples of thermal cycloadditions which have 4n π electrons (for example the [2 + 2]-cycloaddition). These proceed in a suprafacial-antarafacial sense (syn/anti stereochemistry), such as the cycloaddition reactions of ketene and allene derivatives, in which the orthogonal set of p orbitals allows the reaction to proceed via a crossed transition state, although the analysis of these reactions as [π2s + π2a] is controversial. Strained alkenes like trans-cycloheptene derivatives have also been reported to react in an antarafacial manner in [2 + 2]-cycloaddition reactions.

Doering (in a personal communication to Woodward) reported that heptafulvalene and tetracyanoethylene can react in a suprafacial-antarafacial [14 + 2]-cycloaddition. However, this reaction was later found to be stepwise, as it also produced the Woodward-Hoffmann forbidden suprafacial-suprafacial product under kinetic conditions. [3]

Erden and Kaufmann had previously found that the cycloaddition of heptafulvalene and N-phenyltriazolinedione also gave both suprafacial-antarafacial and suprafacial-suprafacial products. [4]

14plus2.png

Photochemical cycloadditions and their stereochemistry

Cycloadditions in which 4n π electrons participate can also occur via photochemical activation. Here, one component has an electron promoted from the HOMO (π bonding) to the LUMO (π* antibonding). Orbital symmetry is then such that the reaction can proceed in a suprafacial-suprafacial manner. An example is the DeMayo reaction. Another example is shown below, the photochemical dimerization of cinnamic acid. [5] The two trans alkenes react head-to-tail, and the isolated isomers are called truxillic acids .

Cinnamic Acid CycloAddition CinnamicAcidCycloAddition.png
Cinnamic Acid CycloAddition
Cycloaddition of trans-1,2-bis(4-pyridyl)ethene Bpe-resorcinol-cycloaddition.png
Cycloaddition of trans-1,2-bis(4-pyridyl)ethene

Supramolecular effects can influence these cycloadditions. The cycloaddition of trans-1,2-bis(4-pyridyl)ethene is directed by resorcinol in the solid-state in 100% yield. [6]

Some cycloadditions instead of π bonds operate through strained cyclopropane rings, as these have significant π character. For example, an analog for the Diels-Alder reaction is the quadricyclane-DMAD reaction:

Qcane.png

In the (i+j+...) cycloaddition notation i and j refer to the number of atoms involved in the cycloaddition. In this notation, a Diels-Alder reaction is a (4+2)cycloaddition and a 1,3-dipolar addition such as the first step in ozonolysis is a (3+2)cycloaddition. The IUPAC preferred notation however, with [i+j+...] takes electrons into account and not atoms. In this notation, the DA reaction and the dipolar reaction both become a [4+2]cycloaddition. The reaction between norbornadiene and an activated alkyne is a [2+2+2]cycloaddition.

Types of cycloaddition

Diels-Alder reactions

The Diels-Alder reaction is perhaps the most important and commonly taught cycloaddition reaction. Formally it is a [4+2] cycloaddition reaction and exists in a huge range of forms, including the inverse electron-demand Diels–Alder reaction, hexadehydro Diels–Alder reaction and the related alkyne trimerisation. The reaction can also be run in reverse in the retro-Diels–Alder reaction.

Diels-Alder (1,3-butadiene + ethylene) red.svg

Reactions involving heteroatoms are known, including the aza-Diels–Alder reaction and oxo-Diels–Alder reaction.

Huisgen cycloadditions

The Huisgen cycloaddition reaction is a (2+3)cycloaddition.

Thermal Huisgen cycloaddition.png

Nitrone-olefin cycloaddition

The Nitrone-olefin cycloaddition is a (3+2)cycloaddition.

NitrGen.svg

Cheletropic reactions

Cheletropic reactions are a subclass of cycloadditions. The key distinguishing feature of cheletropic reactions is that on one of the reagents, both new bonds are being made to the same atom. The classic example is the reaction of sulfur dioxide with a diene.

Cheletropic reaction of butadiene with SO2.svg

Other

Other cycloaddition reactions exist: (4+3) cycloadditions, [6+4] cycloadditions, [2 + 2] photocycloadditions, metal-centered cycloaddition and [4+4] photocycloadditions

Formal cycloadditions

Cycloadditions often have metal-catalyzed and stepwise radical analogs, however these are not strictly speaking pericyclic reactions. When in a cycloaddition charged or radical intermediates are involved or when the cycloaddition result is obtained in a series of reaction steps they are sometimes called formal cycloadditions to make the distinction with true pericyclic cycloadditions.

One example of a formal [3+3]cycloaddition between a cyclic enone and an enamine catalyzed by n-butyllithium is a Stork enamine / 1,2-addition cascade reaction: [7]

An intermolecular formal [3+3] cycloaddition between an cyclic iminium chloride and cyclopentenone. 3+3 cycloaddition - cyclic iminium to cyclic enone.svg
An intermolecular formal [3+3] cycloaddition between an cyclic iminium chloride and cyclopentenone.

Iron-catalyzed 2+2 olefin cycloaddition

Iron[ pyridine(diimine)] catalysts contain a redox active ligand in which the central iron atom can coordinate with two simple, unfunctionalized olefin double bonds. The catalyst can be written as a resonance between a structure containing unpaired electrons with the central iron atom in the II oxidation state, and one in which the iron is in the 0 oxidation state. This gives it the flexibility to engage in binding the double bonds as they undergo a cyclization reaction, generating a cyclobutane structure via C-C reductive elimination; alternatively a cyclobutene structure may be produced by beta-hydrogen elimination. Efficiency of the reaction varies substantially depending on the alkenes used, but rational ligand design may permit expansion of the range of reactions that can be catalyzed. [8] [9]

Related Research Articles

<span class="mw-page-title-main">Alkene</span> Hydrocarbon compound containing one or more C=C bonds

In organic chemistry, an alkene, or olefin, is a hydrocarbon containing a carbon–carbon double bond. The double bond may be internal or in the terminal position. Terminal alkenes are also known as α-olefins.

<span class="mw-page-title-main">Diels–Alder reaction</span> Chemical reaction

In organic chemistry, the Diels–Alder reaction is a chemical reaction between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene derivative. It is the prototypical example of a pericyclic reaction with a concerted mechanism. More specifically, it is classified as a thermally allowed [4+2] cycloaddition with Woodward–Hoffmann symbol [π4s + π2s]. It was first described by Otto Diels and Kurt Alder in 1928. For the discovery of this reaction, they were awarded the Nobel Prize in Chemistry in 1950. Through the simultaneous construction of two new carbon–carbon bonds, the Diels–Alder reaction provides a reliable way to form six-membered rings with good control over the regio- and stereochemical outcomes. Consequently, it has served as a powerful and widely applied tool for the introduction of chemical complexity in the synthesis of natural products and new materials. The underlying concept has also been applied to π-systems involving heteroatoms, such as carbonyls and imines, which furnish the corresponding heterocycles; this variant is known as the hetero-Diels–Alder reaction. The reaction has also been generalized to other ring sizes, although none of these generalizations have matched the formation of six-membered rings in terms of scope or versatility. Because of the negative values of ΔH° and ΔS° for a typical Diels–Alder reaction, the microscopic reverse of a Diels–Alder reaction becomes favorable at high temperatures, although this is of synthetic importance for only a limited range of Diels–Alder adducts, generally with some special structural features; this reverse reaction is known as the retro-Diels–Alder reaction.

The following outline is provided as an overview of and topical guide to organic chemistry:

<span class="mw-page-title-main">Photochemistry</span> Sub-discipline of chemistry

Photochemistry is the branch of chemistry concerned with the chemical effects of light. Generally, this term is used to describe a chemical reaction caused by absorption of ultraviolet, visible (400–750 nm), or infrared radiation (750–2500 nm).

<span class="mw-page-title-main">Pericyclic reaction</span> Reaction with a cyclic transition state

In organic chemistry, a pericyclic reaction is the type of organic reaction wherein the transition state of the molecule has a cyclic geometry, the reaction progresses in a concerted fashion, and the bond orbitals involved in the reaction overlap in a continuous cycle at the transition state. Pericyclic reactions stand in contrast to linear reactions, encompassing most organic transformations and proceeding through an acyclic transition state, on the one hand and coarctate reactions, which proceed through a doubly cyclic, concerted transition state on the other hand. Pericyclic reactions are usually rearrangement or addition reactions. The major classes of pericyclic reactions are given in the table below. Ene reactions and cheletropic reactions are often classed as group transfer reactions and cycloadditions/cycloeliminations, respectively, while dyotropic reactions and group transfer reactions are rarely encountered.

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.

<span class="mw-page-title-main">Cheletropic reaction</span> Chemical reaction in which a ring is formed/broken by adding/removing a single atom

In organic chemistry, cheletropic reactions, also known as chelotropic reactions, are a type of pericyclic reaction. Specifically, cheletropic reactions are a subclass of cycloadditions. The key distinguishing feature of cheletropic reactions is that on one of the reagents, both new bonds are being made to the same atom.

<span class="mw-page-title-main">Povarov reaction</span> Chemical reaction

The Povarov reaction is an organic reaction described as a formal cycloaddition between an aromatic imine and an alkene. The imine in this organic reaction is a condensation reaction product from an aniline type compound and a benzaldehyde type compound. The alkene must be electron rich which means that functional groups attached to the alkene must be able to donate electrons. Such alkenes are enol ethers and enamines. The reaction product in the original Povarov reaction is a quinoline. Because the reactions can be carried out with the three components premixed in one reactor it is an example of a multi-component reaction.

<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.

<span class="mw-page-title-main">Woodward–Hoffmann rules</span> Set of rules pertaining to pericyclic reactions

The Woodward–Hoffmann rules are a set of rules devised by Robert Burns Woodward and Roald Hoffmann to rationalize or predict certain aspects of the stereochemistry and activation energy of pericyclic reactions, an important class of reactions in organic chemistry. The rules originate in certain symmetries of the molecule's orbital structure that any molecular Hamiltonian conserves. Consequently, any symmetry-violating reaction must couple extensively to the environment; this imposes an energy barrier on its occurrence, and such reactions are called symmetry-forbidden. Their opposites are symmetry-allowed.

In organic chemistry, neighbouring group participation has been defined by the International Union of Pure and Applied Chemistry (IUPAC) as the interaction of a reaction centre with a lone pair of electrons in an atom or the electrons present in a sigma or pi bond contained within the parent molecule but not conjugated with the reaction centre. When NGP is in operation it is normal for the reaction rate to be increased. It is also possible for the stereochemistry of the reaction to be abnormal when compared with a normal reaction. While it is possible for neighbouring groups to influence many reactions in organic chemistry this page is limited to neighbouring group effects seen with carbocations and SN2 reactions.

<span class="mw-page-title-main">1,3-dipole</span> Dipolar compound with electron delocalization and charge separation over 3 atoms

In organic chemistry, a 1,3-dipolar compound or 1,3-dipole is a dipolar compound with delocalized electrons and a separation of charge over three atoms. They are reactants in 1,3-dipolar cycloadditions.

<span class="mw-page-title-main">Antarafacial and suprafacial</span> Classification of pericyclic and electrocyclic chemical reactions

In organic chemistry, antarafacial and suprafacial (s) are two topological concepts in organic chemistry describing the relationship between two simultaneous chemical bond making and/or breaking processes in or around a reaction center. The reaction center can be a p- or spn-orbital, a conjugated system (π) or even a sigma bond (σ).

In chemistry, frontier molecular orbital theory is an application of molecular orbital theory describing HOMO–LUMO interactions.

A (4+3) cycloaddition is a cycloaddition between a four-atom π-system and a three-atom π-system to form a seven-membered ring. Allyl or oxyallyl cations (propenylium-2-olate) are commonly used three-atom π-systems, while a diene plays the role of the four-atom π-system. It represents one of the relatively few synthetic methods available to form seven-membered rings stereoselectively in high yield.

In organic chemistry, a dipolar compound or simply dipole is an electrically neutral molecule carrying a positive and a negative charge in at least one canonical description. In most dipolar compounds the charges are delocalized. Unlike salts, dipolar compounds have charges on separate atoms, not on positive and negative ions that make up the compound. Dipolar compounds exhibit a dipole moment.

The term bioorthogonal chemistry refers to any chemical reaction that can occur inside of living systems without interfering with native biochemical processes. The term was coined by Carolyn R. Bertozzi in 2003. Since its introduction, the concept of the bioorthogonal reaction has enabled the study of biomolecules such as glycans, proteins, and lipids in real time in living systems without cellular toxicity. A number of chemical ligation strategies have been developed that fulfill the requirements of bioorthogonality, including the 1,3-dipolar cycloaddition between azides and cyclooctynes, between nitrones and cyclooctynes, oxime/hydrazone formation from aldehydes and ketones, the tetrazine ligation, the isocyanide-based click reaction, and most recently, the quadricyclane ligation.

The inverse electron demand Diels–Alder reaction, or DAINV or IEDDA is an organic chemical reaction, in which two new chemical bonds and a six-membered ring are formed. It is related to the Diels–Alder reaction, but unlike the Diels–Alder reaction, the DAINV is a cycloaddition between an electron-rich dienophile and an electron-poor diene. During a DAINV reaction, three pi-bonds are broken, and two sigma bonds and one new pi-bond are formed. A prototypical DAINV reaction is shown on the right.

A metal-centered cycloaddition is a subtype of the more general class of cycloaddition reactions. In such reactions "two or more unsaturated molecules unite directly to form a ring", incorporating a metal bonded to one or more of the molecules. Cycloadditions involving metal centers are a staple of organic and organometallic chemistry, and are involved in many industrially-valuable synthetic processes.

<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.

References

  1. 1 2 3 "cycloaddition", IUPAC Compendium of Chemical Terminology, IUPAC, 2009, doi: 10.1351/goldbook.C01496 , ISBN   978-0-9678550-9-7 , retrieved 2018-10-13
  2. ↑ "pericyclic reaction", IUPAC Compendium of Chemical Terminology, IUPAC, 2009, doi: 10.1351/goldbook.P04491 , ISBN   978-0-9678550-9-7 , retrieved 2018-10-13
  3. ↑ Izzotti, Anthony; Gleason, James (2022-06-07), "Do Antarafacial Cycloadditions Occur? Cycloaddition of Heptafulvalene with Tetracyanoethylene", Chemistry: a European Journal, doi:10.1002/chem.202201418
  4. ↑ Erden, Ihsan; KauFmann, Dieter (1981-01-01). "Cycloadditionsreaktionen des heptafulvalens". Tetrahedron Letters (in German). 22 (3): 215–218. doi:10.1016/0040-4039(81)80058-5. ISSN   0040-4039.
  5. ↑ Hein, Sara M. (June 2006). "An Exploration of a Photochemical Pericyclic Reaction Using NMR Data". Journal of Chemical Education. 83 (6): 940–942. Bibcode:2006JChEd..83..940H. doi:10.1021/ed083p940.
  6. ↑ L. R. MacGillivray; J. L. Reid; J. A. Ripmeester (2000). "Supramolecular Control of Reactivity in the Solid State Using Linear Molecular Templates". J. Am. Chem. Soc. 122 (32): 7817–7818. doi:10.1021/ja001239i.
  7. ↑ Movassaghi, Mohammad; Bin Chen (2007). "Stereoselective Intermolecular Formal [3+3] Cycloaddition Reaction of Cyclic Enamines and Enones". Angew. Chem. Int. Ed. 46 (4): 565–568. doi:10.1002/anie.200603302. PMC   3510678 . PMID   17146819.
  8. ↑ Jordan M. Hoyt; Valeria A. Schmidt; Aaron M. Tondreau; Paul J. Chirik (2015-08-28). "Iron-catalyzed intermolecular [2+2] cycloadditions of unactivated alkenes". Science. 349 (6251): 960–963. Bibcode:2015Sci...349..960H. doi:10.1126/science.aac7440. PMID   26315433. S2CID   206640239.
  9. ↑ Myles W. Smith; Phil S. Baran (2015-08-28). "As simple as [2+2]". Science. 349 (6251): 925–926. Bibcode:2015Sci...349..925S. doi:10.1126/science.aac9883. PMID   26315420. S2CID   42226757.
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