Editing 1,3-Dipolar cycloaddition

{{Short description|A type of pericyclic chemical reaction}}
{{Use dmy dates|date=January 2020}}
{{primary sources|date=January 2018}}
{{Reactionbox
| Name = Huisgen 1,3-dipolar cycloaddition
| Type = Ring forming reaction
| NamedAfter = [[Rolf Huisgen]]
| Section3 = {{Reactionbox Identifiers
   | OrganicChemistryNamed = huisgen-1,3-dipolar-cycloaddition
   | RSC_ontology_id = 0000018
 }}
}}

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. [[reaction mechanism|Mechanistic]] investigation and [[organic synthesis|synthetic]] application were established in the 1960s, primarily through the work of [[Rolf Huisgen]].<ref>{{cite journal |last1=Bertrand |first1=Guy |last2=Wentrup |first2=Curt |title=Nitrile Imines: From Matrix Characterization to Stable Compounds |journal=Angewandte Chemie International Edition in English |date=17 March 1994 |volume=33 |issue=5 |pages=527–545 |doi=10.1002/anie.199405271}}</ref><ref>{{cite journal |last1=Huisgen |first1=Rolf |title=1,3-Dipolar Cycloadditions. Past and Future |journal=Angewandte Chemie International Edition in English |date=October 1963 |volume=2 |issue=10 |pages=565–598 |doi=10.1002/anie.196305651}}</ref> Hence, the reaction is sometimes referred to as the '''Huisgen cycloaddition''' (this term is often used to specifically describe the [[azide-alkyne Huisgen cycloaddition|1,3-dipolar cycloaddition]] between an organic [[azide]] and an [[alkyne]] to generate [[1,2,3-triazole]]). 1,3-dipolar cycloaddition is an important route to the [[regioselectivity|regio-]] and [[stereoselectivity|stereoselective]] synthesis of five-membered [[heterocyclic compound|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.

[[File:Example of 1,3-dipolar cycloaddition.tif|center|x100px]]

==Mechanistic overview==

Originally two proposed mechanisms describe the 1,3-dipolar cycloaddition: first, the concerted [[pericyclic]] [[cycloaddition]] mechanism, proposed by Rolf Huisgen;<ref name="kin">{{cite journal |title=Kinetics and Mechanism of 1,3-Dipolar Cycloadditions |first=Rolf |last=Huisgen |journal=[[Angewandte Chemie International Edition]] |volume=2 |issue=11 |date=November 1963 |pages=633–645 |doi=10.1002/anie.196306331}}</ref> and second, the stepwise mechanism involving a [[radical (chemistry)|diradical]] [[reaction intermediate|intermediate]], proposed by Firestone.<ref>{{cite journal |title=Mechanism of 1,3-dipolar cycloadditions |first=R |last=Firestone |journal=[[Journal of Organic Chemistry]] |volume=33 |issue=6 |year=1968 |pages=2285–2290 |doi=10.1021/jo01270a023}}</ref> After much debate, the former proposal is now generally accepted<ref>{{cite journal |title=1,3-Dipolar cycloadditions. 76. Concerted nature of 1,3-dipolar cycloadditions and the question of diradical intermediates |first=Rolf |last=Huisgen |journal=[[Journal of Organic Chemistry]] |volume=41 |issue=3 |year=1976 |pages=403–419 |doi=10.1021/jo00865a001}}</ref>—the 1,3-dipole reacts with the dipolarophile in a [[concerted reaction|concerted]], often asynchronous, and [[molecular symmetry|symmetry]]-allowed <sub>π</sub>4<sub>s</sub> + <sub>π</sub>2<sub>s</sub> fashion through a thermal six-electron [[transition state theory|Huckel aromatic transition state]]. However, a few examples exist of a stepwise mechanism for the catalyst-free 1,3-dipolar cycloaddition reactions of thiocarbonyl ylides,<ref>{{cite journal |title=First Two-Step 1,2-Dipolar Cycloadditons: Nonstereospecificity |first1=G. |last1=Mloston |first2=E. |last2=Langhals |first3=Rolf |last3=Huisgen |journal=[[J. Am. Chem. Soc.]] |volume=108 |issue=20 |year=1986 |pages=6401–66402 |doi=10.1021/ja00280a053}}</ref> and nitrile oxides<ref>{{cite journal |title=An example of a stepwise mechanism for the catalyst-free 1,3-dipolar cycloaddition between a nitrile oxide and an electron rich alkene |first1=Siadati |last1=Seyyed Amir |journal=[[Tetrahedron Letters]] |volume=56 |issue=34 |year=2015 |pages=4857–4863 |doi=10.1016/j.tetlet.2015.06.048}}</ref>

[[File:General mechanism of 1,3-dipolar cycloaddition.png|center|x100px|The generic mechanism of a 1,3-dipolar cycloaddition between a dipole and a dipolarophile to give a five-membered heterocycle, through a six-electron transition state. Note that the red curly arrows are conventionally used to denote the reaction process but do not necessarily represent the actual flow of electrons.]]

===Pericyclic mechanism===

Huisgen investigated a series of cycloadditions between the 1,3-dipolar [[diazo]] compounds and various dipolarophilic [[alkenes]].<ref name="kin" /> The following observations support the concerted pericyclic mechanism, and refute the stepwise diradical or the stepwise polar pathway.

*'''[[Substituent]] effects''': Different substituents on the dipole do not exhibit a large effect on the cycloaddition rate, suggesting that the reaction does not involve a charge-separated intermediate.
*'''[[Solvent effects]]''': Solvent polarity has little effect on the cycloaddition rate, in line with the pericyclic mechanism where polarity does not change much in going from the reactants to the transition state.
*'''[[Stereochemistry]]''': 1,3-dipolar cycloadditions are always [[stereospecificity|stereospecific]] with respect to the dipolarophile (i.e., [[Cis–trans isomerism|''cis''-alkenes]] giving ''syn''-products), supporting the concerted pericyclic mechanism in which two [[sigma bond]]s are formed simultaneously.
*'''[[Thermodynamic parameters]]''': 1,3-dipolar cycloadditions have an unusually large negative [[entropy of activation]] similar to that of the [[Diels-Alder reaction]], suggesting that the [[transition state]] is highly ordered, which is a signature of concerted pericyclic reactions.

===1,3-Dipole===

[[File:18 species of second-row 1,3-dipoles.tif|thumb|Structure and nomenclature of all second-row 1,3-dipoles consisting of carbon, nitrogen and oxygen centers. The dipoles are categorized as allyl-type or propargyl/allenyl-type based on the geometry of the central atom.]]
A 1,3-dipole is an organic molecule that can be represented as either an [[allyl]]-type or a [[propargyl]]/[[allene|allenyl]]-type [[zwitterion]]ic octet/sextet structures. Both types of 1,3-dipoles share four electrons in the π-system over three atoms. The allyl-type is bent whereas the propargyl/allenyl-type is linear in [[Molecular geometry|geometry]].<ref>{{cite journal |title=1,3-Dipolar Cycloadditions. Past and Future |first=Rolf |last=Huisgen |journal=[[Angewandte Chemie International Edition]] |volume=2 |issue=10 |year=1963 |pages=565–598 |doi=10.1002/anie.196305651}}</ref> 1,3-Dipoles containing higher-row elements such as [[sulfur]] or [[phosphorus]] are also known, but are utilized less routinely.

[[Resonance structures]] can be drawn to [[delocalized electron|delocalize]] both negative and positive charges onto ''any'' terminus of a 1,3-dipole (see the scheme below). A more accurate method to describe the electronic distribution on a 1,3-dipole is to assign the major resonance contributor based on experimental or theoretical data, such as [[Bond dipole moment|dipole moment]] measurements<ref>{{cite journal |title=Microwave Spectra of Diazomethane and its Deutero Derivatives |first1=A |last1=Cox |first2=L |last2=Thomas |first3=J |last3=Sheridan |journal=[[Nature (journal)|Nature]] |volume=181 |year=1958 |pages=1000–1001 |issue=4614 |doi=10.1038/1811000a0|bibcode=1958Natur.181.1000C |s2cid=4245746 }}</ref> or computations.<ref>{{cite journal |title=Expansion of molecular orbital wave functions into valence bond wave functions. A simplified procedure. |first1=P |last1=Hilberty |first2=C |last2=Leforestier |journal=[[Journal of the American Chemical Society]] |volume=100 |issue=7 |year=1978 |pages=2012–2017 |doi=10.1021/ja00475a007}}</ref> For example, [[diazomethane]] bears the largest negative character at the ''terminal'' nitrogen atom, while [[hydrogen azide|hydrazoic acid]] bears the largest negative character at the ''internal'' nitrogen atom.

[[File:Major resonance structures of diazomethane and hydrazoic acid.tif|center|300px|Calculated major resonance structures of diazomethane and hydrazoic acid (doi = 10.1021/ja00475a007)]]

Consequently, this ambivalence means that the ends of a 1,3-dipole can be treated as both [[nucleophile|nucleophilic]] and [[electrophile|electrophilic]] at the same time. The extent of nucleophilicity and electrophilicity at each end can be evaluated using the [[frontier molecular orbital theory|frontier molecular orbitals]], which can be obtained computationally. In general, the atom that carries the largest orbital coefficient in the [[HOMO/LUMO|HOMO]] acts as the nucleophile, whereas that in the LUMO acts as the electrophile. The most nucleophilic atom is usually, but not always, the most electron-rich atom.<ref>{{cite book |first1=J.F. |last1=McGarrity |first2=Saul |last2=Patai |title=Diazonium and Diazo Groups |chapter=Basicity, acidity and hydrogen bonding |volume=1 |year=1978 |doi=10.1002/9780470771549.ch6 |pages=179–230|isbn=9780470771549 }}</ref><ref>{{cite journal |title=Direct observation of the methyldiazonium ion in fluorosulfuric acid |first1=Daniel |last1=Berner |first2=John |last2=McGarrity |journal=[[Journal of the American Chemical Society]] |volume=101 |issue=11 |year=1979 |pages=3135–3136 |doi=10.1021/ja00505a059}}</ref><ref>{{cite journal |title=Untersuchungen an Diazomethanen, VI. Mitteil.: Umsetzung von Diazoäthan mit Methyllithium |first1=Eugen |last1=Muller |first2=Wolfgans |last2=Rundel |journal=[[Chemische Berichte]] |volume=89 |issue=4 |year=1956 |pages=1065–1071 |doi=10.1002/cber.19560890436}}</ref> In 1,3-dipolar cycloadditions, identity of the dipole-dipolarophile pair determines whether the HOMO or the LUMO character of the 1,3-dipole will dominate (see discussion on frontier molecular orbitals below).

===Dipolarophile===

The most commonly used dipolarophiles are alkenes and alkynes. [[Heteroatom]]-containing dipolarophiles such as [[carbonyls]] and [[imines]] can also undergo 1,3-dipolar cycloaddition. Other examples of dipolarophiles include [[fullerene]]s and [[carbon nanotube|nanotubes]], which can undergo 1,3-dipolar cycloaddition with [[azomethine ylide]] in the [[Prato reaction]].

===Solvent effects===

1,3-Dipolar cycloadditions experience very little solvent effect because both the reactants and the transition states are generally non-polar. For example, the rate of reaction between phenyl diazomethane and [[ethyl acrylate]] or [[norbornene]] (see scheme below) changes only slightly upon varying solvents from cyclohexane to methanol.<ref>{{cite journal |title=Solvent Dependence of Cycloaddition Rates of Phenyldiazomethane and Activation Parameters |first1=Jochen |last1=Geittner |first2=Rolph |last2=Huisgen |first3=Hans-Ulrich |last3=Reissig |journal=Heterocycles |volume=11 |year=1978 |pages=109–120 |doi=10.3987/S(N)-1978-01-0109|doi-access=free }}</ref>

[[File:Solvent effect.tif|center|450px|Effect of solvent polarity on 1,3-dipolar cycloaddition reactions(doi:10.3987/S(N)-1978-01-0109.)]]

Lack of solvent effects in 1,3-dipolar cycloaddition is clearly demonstrated in the reaction between enamines and dimethyl diazomalonate (see scheme below).<ref>{{cite journal |title=α-Diazocarbonyl compounds and enamines - a dichotomy of reaction paths |first1=Rolph |last1=Huisgen |first2=Hans-Ulrich |last2=Reissig |first3=Helmut |last3=Huber |first4=Sabine |last4=Voss |journal=Tetrahedron Letters |volume=20 |issue=32 |year=1979 |pages=2987–2990 |doi=10.1016/S0040-4039(00)70991-9}}</ref> The polar reaction, N-cyclo''pen''tenyl [[pyrrolidine]] nucleophilic addition to the diazo compound, proceeds 1,500 times faster in polar [[Dimethyl sulfoxide|DMSO]] than in non-polar [[decalin]]. On the other hand, a close analog of this reaction, N-cyclo''hex''enyl pyrrolidine 1,3-dipolar cycloaddition to dimethyl diazomalonate, is sped up only 41-fold in DMSO relative to decalin.

[[File:The solvent effect on the reaction between enamines and diazomalonate.tif|center|750px|Rate of polar nucleophilic addition reaction versus 1,3-dipolar cycloaddition in decalin and in DMSO (doi:10.1016/S0040-4039(00)70991-9)]]

==Frontier molecular orbital theory==

[[File:Frontier molecular orbitals overlap in 1,3-dipolar cycloadditions.tif|center|400x1000px|Orbital overlaps in types I, II and III 1,3-dipolar cycloaddition.]]

1,3-Dipolar cycloadditions are pericyclic reactions, which obey the [[Dewar-Zimmerman rules]] and the [[Woodward–Hoffmann rules]]. In the Dewar-Zimmerman treatment, the reaction proceeds through a 5-center, zero-node, 6-electron Huckel transition state for this particular molecular orbital diagram. However, each orbital can be randomly assigned a sign to arrive at the same result. In the Woodward–Hoffmann treatment, frontier molecular orbitals (FMO) of the 1,3-dipole and the dipolarophile overlap in the symmetry-allowed <sub>π</sub>4<sub>s</sub> + <sub>π</sub>2<sub>s</sub> manner. Such orbital overlap can be achieved in three ways: type I, II and III.<ref>{{cite journal | title = Orbital energy control of cycloaddition reactivity | first = R | last = Sustmann | journal = [[Pure and Applied Chemistry]] | volume = 40 | issue = 4 | year = 1974 | pages = 569–593 | doi = 10.1351/pac197440040569 | doi-access = free }}</ref> The dominant pathway is the one which possesses the smallest HOMO-LUMO energy gap.

===Type I===

The dipole has a high-lying [[HOMO/LUMO|HOMO]] which overlaps with LUMO of the dipolarophile. A dipole of this class is referred to as a '''HOMO-controlled dipole''' or a '''nucleophilic dipole''', which includes [[azomethine ylide]], [[carbonyl ylide]], [[nitrile ylide]], [[azomethine imine]], [[carbonyl imine]] and [[diazoalkane]]. These dipoles add to electrophilic alkenes readily. Electron-withdrawing groups (EWG) on the dipolarophile would accelerate the reaction by lowering the LUMO, while electron-donating groups (EDG) would decelerate the reaction by raising the HOMO. For example, the reactivity scale of diazomethane against a series of dipolarophiles is shown in the scheme below. Diazomethane reacts with the electron-poor ethyl acrylate more than a million times faster than the electron rich butyl vinyl ether.<ref>{{cite journal | title = Kinetics of 1,3-dipolar cycloaddition reactions of diazomethane; A correlation with homo-lumo energies | first1 = Jochen | last1 = Geittner | first2 = Rolf | last2 = Huisgen | journal = Tetrahedron Letters | volume = 18 | issue = 10 | year = 1977 | pages = 881–884 | doi = 10.1016/S0040-4039(01)92781-9}}</ref>

This type resembles the normal-electron-demand Diels-Alder reaction, in which the diene HOMO combines with the dienophile LUMO.

[[File:The reactivity of Type I 1,3-dipole against dipolarophiles.tif|center|450px|doi:10.1016/S0040-4039(01)92781-9]]

===Type II===

HOMO of the dipole can pair with LUMO of the dipolarophile; alternatively, HOMO of the dipolarophile can pair with LUMO of the dipole. This two-way interaction arises because the energy gap in either direction is similar. A dipole of this class is referred to as a '''HOMO-LUMO-controlled dipole''' or an '''ambiphilic dipole''', which includes [[nitrile imide]], [[nitrone]], [[carbonyl oxide]], [[nitrile oxide]], and [[azide]]. Any substituent on the dipolarophile would accelerate the reaction by lowering the energy gap between the two interacting orbitals; i.e., an EWG would lower the LUMO while an EDG would raise the HOMO. For example, azides react with various electron-rich and electron-poor dipolarophile with similar reactivities (see reactivity scale below).<ref>{{cite journal | title = K1.3-Dipolare Cycloadditionen, XXXII. Kinetik der Additionen organischer Azide an CC-Mehrfachbindungen | first1 = Rolf | last1 = Huisgen | first2 = Gunter | last2 = Szeimies | first3 = Leander | last3 = Mobius| journal = Chemische Berichte | volume = 100 | issue = 8 | year = 1967 | pages = 2494–2507 | doi = 10.1002/cber.19671000806}}</ref>

[[File:The reactivity of Type II 1,3-dipole against dipolarophiles.tif|center|550px|doi:10.1021/ja01016a011]]

===Type III===

The dipole has a low-lying LUMO which overlaps with HOMO of the dipolarophile (indicated by red dashed lines in the diagram). A dipole of this class is referred to as a '''LUMO-controlled dipole''' or an '''electrophilic dipole''', which includes [[nitrous oxide]] and [[ozone]]. EWGs on the dipolarophile decelerate the reaction, while EDGs accelerate the reaction. For example, ozone reacts with the electron-rich 2-methylpropene about 100,000 times faster than the electron-poor tetrachloroethene (see reactivity scale below).<ref>{{cite journal | title = Rates of ozone-olefin reactions in carbon tetrachloride solutions | first1 = D. G.| last1 = Williamson | first2 = R. J. | last2 = Cvetanovic | journal = Journal of the American Chemical Society | year = 1968 | pages = 3668–3672 | doi = 10.1021/ja01016a011 | volume=90| issue = 14}}</ref>

This type resembles the [[Inverse electron-demand Diels–Alder reaction|inverse electron-demand Diels-Alder reaction]], in which the diene LUMO combines with the dienophile HOMO.

[[File:The reactivity of Type III 1,3-dipole against dipolarophiles.tif|center|550px|doi:10.1021/ja01016a011]]

===Reactivity===

Concerted processes such as the 1,3-cycloaddition require a highly ordered transition state (high negative entropy of activation) and only moderate enthalpy requirements. Using competition reaction experiments, relative rates of addition for different cycloaddition reactions have been found to offer general findings on factors in reactivity.

* '''Conjugation''', especially with aromatic groups, increases the rate of reaction by stabilization of the transition state. During the transition, the two sigma bonds are being formed at different rates, which may generate partial charges in the transition state that can be stabilized by charge distribution into conjugated substituents.
* More '''polarizable''' dipolarophiles are more reactive because diffuse electron clouds are better suited to initiate the flow of electrons.
* Dipolarophiles with high '''angular strain''' are more reactive due to increased energy of the ground state.
* Increased '''steric hindrance''' in the transition state as a result of unhindered reactants dramatically lowers the reaction rate.
* '''Hetero-dipolarophiles''' add more slowly, if at all, compared to C,C-diapolarophiles due to a lower gain in sigma bond energy to offset the loss of a pi bond during the transition state.
* '''Isomerism''' of the dipolarophile affects reaction rate due to sterics. ''trans''-isomers are more reactive (''trans''-stilbene will add diphenyl(nitrile imide) 27 times faster than ''cis''-stilbene) because during the reaction, the 120° bond angle shrinks to 109°, bringing eclipsing ''cis''-substituents towards each other for increased steric clash.
:[[File:Steric clash of dipolarophile substituents during 1,3-cycloaddition.png|300px|See Huisgen reference {{doi|10.1002/anie.196306331}}.|center]]

==Stereospecificity==

1,3-dipolar cycloadditions usually result in [[retention of configuration]] with respect to both the 1,3-dipole and the dipolarophile. Such high degree of stereospecificity is a strong support for the concerted over the stepwise reaction mechanisms. As mentioned before, many examples show that the reactions were stepwise, thus, presenting partial or no stereospecificity.

===With respect to dipolarophile===

''cis''-Substituents on the dipolarophilic alkene end up ''cis'', and ''trans''-substituents end up ''trans'' in the resulting five-membered cyclic compound (see scheme below).<ref>{{cite journal | title = The Stereospecificity of Diazomethane Cycloadditions | first1 = Werner | last1 = Bihlmaier | first2 = Jochen | last2 = Geittner | first3 = Rolf | last3 = Huisgen| first4 = Hans-Ulrich | last4 = ReissigP | journal = [[Heterocycles (journal)|Heterocycles]] | volume = 10 | year = 1978 | pages = 147–152 | url = http://www.heterocycles.jp/newlibrary/libraries/journal/10/1 | doi = 10.3987/S-1978-01-0147| doi-access = free }}</ref>

[[File:General scheme describing the stereospecificity of 1,3-dipolar cycloaddition and of the dipolarophile.tif|center|600px|doi:10.3987/S-1978-01-0147]]

===With respect to dipole===

Generally, the stereochemistry of the dipole is not of major concern because only few dipoles could form [[stereogenic center]]s, and resonance structures allow bond rotation which scrambles the stereochemistry. However, the study of azomethine ylides has verified that cycloaddition is also stereospecific with respect to the dipole component. [[Diastereomer|Diastereopure]] azomethine ylides are generated by [[electrocyclic reaction|electrocyclic ring opening]] of [[aziridines]], and then rapidly trapped with strong dipolarophiles before bond rotation can take place (see scheme below).<ref>{{cite journal | title = Stereospecific Conversion of cis-trans Isomeric Aziridines to Open-Chain Azomethine Ylides | first1 = Rolf | last1 = Huisgen | first2 = Wolfgang | last2 = Scheer | first3 = Helmut | last3 = Huber | journal = [[Journal of the American Chemical Society]] | volume = 89 | issue = 7 | year = 1967 | pages = 1753–1755 | doi = 10.1021/ja00983a052}}</ref><ref>{{cite journal | title =  Conrotatory ring opening of cyanostilbene oxides to carbonyl ylides | first1 = Alexander | last1 = Dahmen | first2 = Helmut | last2 = Hamberger | first3 = Rolf | last3 = Huisgen | first4 = Volker | last4 = Markowski | journal = Journal of the Chemical Society D: Chemical Communications  | year = 1971 | pages = 1192–1194 | doi = 10.1039/C29710001192 | issue=19}}</ref> If weaker dipolarophiles are used, bonds in the dipole have the chance to rotate, resulting in impaired cycloaddition stereospecificity.

These results altogether confirm that 1,3-dipolar cycloaddition is stereospecific, giving retention of both the 1,3-dipole and the dipolarophile.

[[File:Stereospecificity of the two termini of the dipole in 1,3-dipolar cycloaddition.tif|center|700px|doi:10.1021/ja00983a052]]

==Diastereoselectivity==

When two or more [[stereocenter]]s are generated during the reaction, diastereomeric transition states and products can be obtained. In the Diels-Alder cycloaddition, the [[Diels–Alder reaction|''endo'']] [[diastereoselectivity]] due to [[secondary orbital interactions]] is usually observed. In 1,3-dipolar cycloadditions, however, two forces influence the diastereoselectivity: the attractive [[pi interaction|π-interaction]] (resembling secondary orbital interactions in the Diels-Alder cycloaddition) and the repulsive [[steric effects|steric]] interaction. Unfortunately, these two forces often cancel each other, causing poor diastereoselection in 1,3-dipolar cycloaddition.

Examples of substrate-controlled diastereoselective 1,3-dipolar cycloadditions are shown below. First is the reaction between {{chem name|benzonitrile N-benzylide}} and [[methyl acrylate]]. In the transition state, the phenyl and the methyl ester groups stack to give the ''cis''-substitution as the exclusive final [[pyrroline]] product. This favorable π-interaction offsets the steric repulsion between the phenyl and the methyl ester groups.<ref>{{cite journal | title = Photocycloaddition of arylazirenes with electron-deficient olefins | first1 = Albert| last1 = Padwa | first2 = Joel | last2 = Smolanoff | journal = Journal of the American Chemical Society | year = 1971 | pages = 548–550 | doi = 10.1021/ja00731a056 | volume=93| issue = 2}}</ref> Second is the reaction between nitrone and [[dihydrofuran]]. The ''exo''-selectivity is achieved to minimize steric repulsion.<ref>{{cite journal | title =A Synthesis of dl-isoretronecanol | first1 = Takashi |last1 = Iwashita | first2 = Takenori | last2 = Kusumi | first3 = Hiroshi | last3 = Kakisawa | journal = Chemistry Letters | volume = 8 | year = 1979 | pages = 1337–1340 | url = https://www.jstage.jst.go.jp/article/cl1972/8/11/8_11_1337/_article | doi = 10.1246/cl.1979.1337 | issue=11| url-access = subscription }}</ref> Last is the intramolecular azomethine ylide reaction with alkene. The diastereoselectivity is controlled by the formation of a less strained ''cis''-[[bicyclic molecule|fused ring system]].<ref>{{cite journal | title = A short and stereospecific synthesis of (±)-α-lycorane | first1 = Chia-Lin |last1 = Wang | first2 = William | last2 = Ripka | first3 = Pat | last3 = Confalone | journal = Tetrahedron Letters | year = 1984 | pages = 4613–4616 | doi = 10.1016/S0040-4039(01)91213-4 | volume=25| issue = 41 }}</ref>

[[File:Substrate-controlled diastereoselectivity of 1,3-dipolar cycloaddition.tif|center|400px|doi:10.1021/ja00731a056]]

===Directed 1,3-dipolar cycloaddition===

Trajectory of the cycloaddition can be controlled to achieve a diastereoselective reaction. For example, metals can [[chelation|chelate]] to the dipolarophile and the incoming dipole and direct the cycloaddition selectively on one face. The example below shows addition of nitrile oxide to an [[enantiomer]]ically pure [[allyl alcohol]] in the presence of a magnesium ion. The most stable [[conformational isomerism|conformation]] of the alkene places the [[hydroxyl]] group above the plane of the alkene. The magnesium then chelates to the hydroxyl group and the oxygen atom of nitrile oxide. The cycloaddition thus comes from the top face selectively.<ref>{{cite journal | title = Metal-Assisted Stereocontrol of 1,3-Dipolar Cycloaddition Reactions | first = Shuji | last = Kanemasa | journal = Synlett | year = 2002 | pages = 1371–1387 | doi = 10.1055/s-2002-33506 | volume = 2002 | issue = 9 }}</ref>

[[File:Directed dipolar cycloaddition.tif|center|450px]]

Such diastereodirection has been applied in the synthesis of [[epothilone]]s.<ref>{{cite journal | title = Stereoselective Syntheses of Epothilones A and B via Directed Nitrile Oxide Cycloaddition. | first1 = Jeffrey |last1 = Bode | first2 = Erick | last2 = Carreira | journal = Journal of the American Chemical Society | year = 2011 | pages = 3611–3612 | doi = 10.1021/ja0155635 | pmid=11472140 | volume=123 | issue=15}}</ref>

[[File:Use of directed cycloaddition in Epothilones synthesis.tif|center|600px]]

==Regioselectivity==

For asymmetric dipole-dipolarophile pairs, two [[regioisomer|regioisomeric products]] are possible. Both [[electronic effect|electronic/stereoelectronic]] and steric factors contribute to the regioselectivity of 1,3-dipolar cycloadditions.<ref>{{cite journal | author = Vsevolod V. Rostovtsev | author2 = Luke G. Green | author3 = Valery V. Fokin | author4 = K. Barry Sharpless| title = A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective Ligation of Azides and Terminal Alkynes | year = 2002 | journal = [[Angewandte Chemie International Edition]] | volume = 41 | issue = 14 | pages = 2596–22599 | doi = 10.1002/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4| pmid=12203546}}</ref>

===Electronic/stereoelectronic effect===

The dominant electronic interaction is the combination between the largest HOMO and the largest LUMO. Therefore, regioselectivity is governed by the atoms that bear the largest orbital HOMO and LUMO coefficients.<ref>{{cite journal | title = Geometries of nitrilium betaines. The clarification of apparently anomalous reactions of 1,3-dipoles | first1 = Pierluigi | last1 = Caramella | first2 = K.N. | last2 = Houk |journal = Journal of the American Chemical Society | year = 1976 | pages = 6397–6399 | doi = 10.1021/ja00436a062 | volume=98| issue = 20 }}</ref><ref>{{cite journal | title = A derivation of the shapes and energies of the molecular orbitals of 1,3-dipoles. Geometry optimizations of these species by MINDO/2 and MINDO/3 | first1 = Pierluigi| last1 = Caramella | first2 = Ruth W. | last2 = Gandour | first3 = Janet A. | last3 = Hall | first4 = Cynthia G. | last4 = Deville | first5 = K. N. | last5 = Houk | journal = Journal of the American Chemical Society | year = 1977 | pages = 385–392 | doi = 10.1021/ja00444a013 | volume=99| issue = 2}}</ref>

For example, consider the cycloaddition of diazomethane to three dipolarophiles: [[methyl acrylate]], [[styrene]] or [[methyl cinnamate]]. The carbon of diazomethane bears the largest HOMO, while the end olefinic carbons of methyl acrylate and styrene bear the largest LUMO. Hence, cycloaddition gives the substitution at the C-3 position regioselectively. For methyl cinnamate, the two substituents (Ph v.s. COOMe) compete at withdrawing electrons from the alkene. The carboxyl is the better electron-withdrawing group, causing the β-carbon to be most electrophilic. Thus, cycloaddition yields the [[carboxylic acid|carboxyl group]] on C-3 and the [[phenyl group]] on C-4 regioselectively.

[[File:Electronic effects on the regioselectivity of 1,3-dipolar cycloaddition.tif|center|400px|doi:10.1021/ja00444a013 and doi:10.1021/ja00436a062]]

===Steric effect===

Steric effects can either cooperate or compete with the aforementioned electronic effects. Sometimes steric effects completely outweighs the electronic preference, giving the opposite regioisomer exclusively.<ref>{{cite journal | title = Kinetics and Mechanism of 1,3-Dipolar Cycloadditions | first = Rolf | last = Huisgen | journal = [[Angewandte Chemie International Edition]] | volume = 2 | issue = 11 | date = November 1963 | pages = 633–645 | doi = 10.1002/anie.196306331 }}</ref>

For example, diazomethane generally adds to methyl acrylate to give 3-carboxyl [[pyrazoline]]. However, by putting more steric demands into the system, we start to observe the isomeric 4-carboxyl pyrazolines. The ratio of these two regioisomers depends on the steric demands. At the extreme, increasing the size from [[hydrogen]] to [[butyl|t-butyl]] shifts the regioselectivity from 100% 3-carboxyl to 100% 4-carboxyl substitution.<ref>{{cite book |last1= Padwa |first1= Albert |title= 1,3-Dipolar Cycloaddition Chemistry |series=General Heterocyclic Chemistry Series |volume=1 |year= 1983 |publisher=Wiley-Interscience |location=United States of America |isbn=978-0-471-08364-1 |pages=141–145}}</ref><ref>{{Cite thesis |type=PhD Thesis|title=thesis |last= Koszinowski|first=J. |year=1980 }}</ref>

[[File:Steric effects on the regioselectivity of 1,3-dipolar cycloaddition.tif|center|1000px|{{ISBN|0-471-08364-X}}. and Koszinowski, J. (1980) (PhD Thesis)]]

==Synthetic applications==

1,3-dipolar cycloadditions are important ways toward the synthesis of many important 5-membered heterocycles such as [[triazoles]], [[furans]], [[isoxazoles]], [[pyrrolidines]], and others. Additionally, some cycloadducts can be cleaved to reveal the linear skeleton, providing another route toward the synthesis of [[aliphatic compound]]s. These reactions are tremendously useful also because they are stereospecific, diastereoselective and regioselective. Several examples are provided below.

===Nitrile oxides===

1,3-dipolar cycloaddition with nitrile oxides is a widely used masked-[[aldol reaction]]. Cycloaddition between a nitrile oxide and an alkene yields the cyclic isoxazoline product, whereas the reaction with an alkyne yields the isoxazole. Both isoxazolines and isoxazoles can be cleaved by [[hydrogenation]] to reveal aldol-type β-hydroxycarbonyl or [[Claisen condensation|Claisen]]-type β-dicarbonyl products, respectively.

Nitrile oxide-alkyne cycloaddition followed by hydrogenation was utilized in the synthesis of Miyakolide as illustrated in the figure below.<ref>{{cite journal | title = Synthesis and Absolute Stereochemical Assignment of (+)-Miyakolide | first1 = David | last1 = Evans | first2 = David | last2 = Ripin | first3 = David | last3 = Halstead | first4 = Kevin | last4 = Campos | journal = [[Journal of the American Chemical Society]] | volume = 121 | issue = 29 | year = 1999 | pages = 6816–6826 | doi = 10.1021/ja990789h}}</ref>

[[File:Application of nitrile oxide in the synthesis of miyakolide.tif|900px|center]]

===Carbonyl ylides===

1,3-dipolar cycloaddition reactions have emerged as powerful tools in the synthesis of complex cyclic scaffolds and molecules for medicinal, biological, and mechanistic studies. Among them, [3+2] [[cycloaddition]] reactions involving carbonyl ylides have extensively been employed to generate oxygen-containing five-membered cyclic molecules.<ref>Synthetic Reactions of M=C and M=N Bonds: Ylide Formation, Rearrangement, and 1,3-Dipolar Cycloaddition; Hiyama, T. W., J., Ed.; Elsevier, 2007; Vol. 11.</ref>

====Preparation of carbonyl ylides for 1,3-dipolar cycloaddition reactions====

[[Ylides]] are regarded as positively charged [[heteroatoms]] connected to negatively charged carbon atoms, which include ylides of [[sulfonium]], [[thiocarbonyl]], [[oxonium ion|oxonium]], [[nitrogen]], and [[carbonyl]].<ref>{{Cite journal | doi=10.1021/cr00003a001|title = Ylide formation from the reaction of carbenes and carbenoids with heteroatom lone pairs| journal=Chemical Reviews| volume=91| issue=3| pages=263–309|year = 1991|last1 = Padwa|first1 = Albert.| last2=Hornbuckle| first2=Susan F.}}</ref> Several methods exist for generating carbonyl ylides, which are necessary intermediates for generating oxygen-containing five-membered ring structures, for [3+2] cycloaddition reactions.

=====Synthesis of carbonyl ylides from diazomethane derivatives by photocatalysis=====

One of the earliest examples of carbonyl ylide [[chemical synthesis|synthesis]] involves [[photocatalysis]].<ref name="Janulis, E. P. 1983">{{Cite journal | doi=10.1021/ja00356a044|title = Structure of an electronically stabilized carbonyl ylide| journal=Journal of the American Chemical Society| volume=105| issue=18| pages=5929–5930|year = 1983|last1 = Janulis|first1 = Eugene P.| last2=Arduengo| first2=Anthony J.}}</ref> [[Photolysis]] of diazotetrakis(trifluoromethyl)cyclopentadiene* (DTTC) in the presence of [[tetramethylurea]] can generate the carbonyl ylide by an [[intermolecular]] [[nucleophilic]] attack and subsequent [[aromatization]] of the DTTC moiety.<ref name="Janulis, E. P. 1983"/> This was isolated and characterized by [[X-ray crystallography]] due to the stability imparted by aromaticity, [[deactivating groups|electron withdrawing]] trifluoromethyl groups, and the [[activating group|electron donating]] dimethylamine groups. Stable carbonyl ylide [[1,3-dipole|dipoles]] can then be used in [3+2] cycloaddition reactions with dipolarophiles.

[[File:Photolysis of DTTC in the presence of tetramethylurea. Modified from Janulis, E. P.; Arduengo, A. J. J. Am. Chem. Soc. 1983, 105, 5929..png|center|Scheme 1. Photolysis of DTTC in the presence of tetramethylurea. Modified from Janulis, E. P.; Arduengo, A. J. J. Am. Chem. Soc. 1983, 105, 5929.]]

Another early example of carbonyl ylide synthesis by photocatalysis was reported by Olah ''et al''.<ref>Prakash, G. K. S.; Ellis, R. W.; Felberg, J. D.; Olah, G. A. [http://pubs.acs.org/doi/pdf/10.1021/ja00266a059 Formaldehyde 0-Methylide, [CH2=O+-CH2]: The 
Parent Carbonyl Ylide] J Am Chem Soc 1986, 108, 1341.</ref> Dideuteriodiazomethane was photolysed in the presence of [[formaldehyde]] to generate the dideuterioformaldehyde carbonyl ylide.

[[File:Photolysis of Dideuteriodiazomethane with formaldehyde. Modified from Prakash, G. K. S.; Ellis, R. W.; Felberg, J. D.; Olah, G. A. J Am Chem Soc 1986, 108, 1341..png|center|Scheme 2. Photolysis of dideuteriodiazomethane with formaldehyde. Modified from Prakash, G. K. S.; Ellis, R. W.; Felberg, J. D.; Olah, G. A. J Am Chem Soc 1986, 108, 1341.]]

=====Synthesis of carbonyl ylides from hydroxypyrones by proton transfer=====

Carbonyl ylides can be synthesized by [[acid catalysis]] of hydroxy-3-pyrones in the absence of a metal [[catalyst]].<ref>Sammes, P. G.; Street, L. J. [http://pubs.rsc.org/en/content/articlepdf/1982/c3/c39820001056 Intra molecular Cyclo additions with Oxido pyrylium Ylides] J. Chem. Soc., Chem. Commun. 1982, 1056.</ref> An initial [[tautomerization]] occurs, followed by [[elimination reaction|elimination]] of the [[leaving group]] to aromatize the [[pyrone]] ring and to generate the carbonyl ylide. A cycloaddition reaction with a dipolarophile lastly forms the oxacycle. This approach is less widely employed due to its limited utility and requirement for pyrone skeletons.

[[File:Acid-Catalyzed Synthesis of Carbonyl Ylides from Hydroxy-3-Pyrones. Modified from Sammes, P. G.; Street, L. J. J. Chem. Soc., Chem. Commun. 1982, 1056..png|center|Scheme 3. Acid-catalyzed synthesis of carbonyl ylides from hydroxy-3-pyrones. Modified from Sammes, P. G.; Street, L. J. J. Chem. Soc., Chem. Commun. 1982, 1056.]]

5-hydroxy-4-pyrones can also be used to synthesize carbonyl ylides by an [[Intramolecular reaction|intramolecular]] [[hydrogen transfer]].<ref>Garst, M. E.; McBride, B. J.; Douglass III, J. G. [http://www.sciencedirect.com/science/article/pii/S0040403900817426 Intramolecular cycloadditions with 2-(ω-alkenyl)-5-hydroxy-4-pyrones] Tetrahedron Lett. 1983, 24, 1675.</ref> After hydrogen transfer, the carbonyl ylide can then react with dipolarophiles to form oxygen-containing rings.

[[File:Intramolecular Hydrogen Transfer-Mediated Synthesis of Carbonyl Ylides from 5-Hydroxy-4-Pyrones. Modified from Garst, M. E.; McBride, B. J.; Douglass III, J. G. Tetrahedron Lett. 1983, 24, 1675..png|center|Scheme 4. Intramolecular hydrogen transfer-mediated synthesis of carbonyl ylides from 5-hydroxy-4-pyrones. Modified from Garst, M. E.; McBride, B. J.; Douglass III, J. G. Tetrahedron Lett. 1983, 24, 1675.]]

=====Synthesis of α-halocarbonyl ylides from dihalocarbenes===== 
Dihalocarbenes have also been employed to generate carbonyl ylides, exploiting the electron withdrawing nature of dihalocarbenes.<ref>{{Cite journal|url=http://pubs.acs.org/doi/pdf/10.1021/jo00212a009|doi = 10.1021/jo00212a009|title = Dichlorocarbene from flash vacuum pyrolysis of trimethyl(trichloromethyl)silane. Possible observation of 1,1-dichloro-3-phenylcarbonyl ylide|year = 1985|last1 = Gisch|first1 = John F.|last2 = Landgrebe|first2 = John A.|journal = The Journal of Organic Chemistry|volume = 50|issue = 12|pages = 2050–2054|url-access = subscription}}</ref><ref>{{Cite journal | doi=10.1021/jo00172a015|title = Dibromocarbonyl ylides. Deoxygenation of aldehydes and ketones by dibromocarbene| journal=The Journal of Organic Chemistry| volume=48| issue=24| pages=4519–4523|year = 1983|last1 = Huan|first1 = Zhenwei| last2=Landgrebe| first2=John A.| last3=Peterson| first3=Kimberly}}</ref><ref>{{Cite journal | doi=10.1021/jo00400a009|title = Halogenated carbonyl ylides in the reactions of mercurial dihalocarbene precursors with substituted benzaldehydes| journal=The Journal of Organic Chemistry| volume=43| issue=6| pages=1071–1076|year = 1978|last1 = Martin|first1 = Charles W.| last2=Lund| first2=Paul R.| last3=Rapp| first3=Erich| last4=Landgrebe| first4=John A.}}</ref> Both [[phenyl(trichloromethyl)mercury]] and phenyl(tribromomethyl)mercury are sources [[dichlorocarbenes]] and [[dibromocarbenes]], respectively. The carbonyl ylide can be generated upon reaction of the dihalocarbenes with [[ketones]] or [[aldehydes]]. However, the synthesis of α-halocarbonyl ylides can also undesirably lead to the loss of [[carbon monoxide]] and the generation of the deoxygenation product.

[[File:Α-Halocarbonyl Ylide Synthesis via Dihalocarbene Intermediates. Modified from Padwa, A.; Hornbuckle, S. F. Chem Rev 1991, 91, 263..png|center|Scheme 5. α-Halocarbonyl ylide synthesis through dihalocarbene intermediates. Modified from Padwa, A.; Hornbuckle, S. F. Chem Rev 1991, 91, 263.]]

=====Synthesis of carbonyl ylides from diazomethane derivatives by metal catalysis=====

A universal approach for generating carbonyl ylides involves [[metal catalysis]] of α-diazocarbonyl compounds, generally in the presence of dicopper or dirhodium catalysts.<ref>Hodgson, D. M.; Bruckl, T.; Glen, R.; Labande, A. H.; Selden, D. A.; Dossetter, A. G.; Redgrave, A. J. [http://www.pnas.org/content/101/15/5450.full?sid=bbcd462e-8ce5-4a6a-82ab-2948b6e4855e Catalytic enantioselective intermolecular cycloadditions of 2-diazo-3,6-diketoester-derived carbonyl ylides with alkene dipolarophiles] Proceedings of the National Academy of Sciences of the United States of America 2004, 101, 5450.</ref> After release of [[nitrogen gas]] and conversion to the [[metallocarbene]], an intermolecular reaction with a carbonyl group can generate the carbonyl ylide. Subsequent cycloaddition reaction with an [[alkene]] or [[alkyne]] dipolarophile can afford oxygen-containing five-membered rings. Popular catalysts that give modest yields towards synthesizing oxacycles include Rh<sub>2</sub>(OAc)<sub>4</sub> and Cu(acac)<sub>2</sub>.<ref>{{Cite journal | doi=10.1021/jo00102a037|title = Intramolecular Cycloaddition of Isomunchnone Dipoles to Heteroaromatic .pi.-Systems| journal=The Journal of Organic Chemistry| volume=59| issue=23| pages=7072–7084|year = 1994|last1 = Padwa|first1 = Albert| last2=Hertzog| first2=Donald L.| last3=Nadler| first3=William R.}}</ref><ref>Hamaguchi, M.; Ibata, T. [https://www.jstage.jst.go.jp/article/cl1972/4/5/4_5_499/_pdf New Type of Mesoionic System. 1,3-Dipolar Cycloaddition of Isomunchnon With Ethylenic Compounds] Chem Lett 1975, 499.</ref>

[[File:Metal-Catalyzed Synthesis of Carbonyl Ylides. Reproduced from Hodgson, D. M.; Bruckl, T.; Glen, R.; Labande, A. H.; Selden, D. A.; Dossetter, A. G.; Redgrave, A. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5450..png|center|Scheme 6. Metal-catalyzed synthesis of carbonyl ylides. Reproduced from Hodgson, D. M.; Bruckl, T.; Glen, R.; Labande, A. H.; Selden, D. A.; Dossetter, A. G.; Redgrave, A. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5450.]]

====Mechanism of the 1,3-dipolar cycloaddition reaction mediated by metal catalysis of diazocarbonyl compounds====

The universality and extensive use of 1,3-dipolar cycloaddition reactions mediated by metal catalysis of diazocarbonyl molecules, for synthesizing oxygen-containing five-membered rings, has spurred significant interest into its mechanism. Several groups have investigated the [[reaction mechanism|mechanism]] to expand the scope of synthetic molecules with respect to [[regioselectivity|regio-]] and [[stereoselectivity|stereo-selectivity]]. However, due to the high turn over frequencies of these reactions, the intermediates and mechanism remains elusive.
The generally accepted mechanism, developed by characterization of stable ruthenium-carbenoid complexes<ref>{{Cite journal | doi=10.1002/chem.19960020311|title = Aryloxycarbonylcarbene Complexes of Bis(oxazolinyl)pyridineruthenium as Active Intermediates in Asymmetric Catalytic Cyclopropanations| journal=Chemistry - A European Journal| volume=2| issue=3| pages=303–306|year = 1996|last1 = Park|first1 = Soon-Bong| last2=Sakata| first2=Naoya| last3=Nishiyama| first3=Hisao}}</ref> and rhodium metallocarbenes,<ref>{{Cite journal | doi=10.1021/ja016928o|pmid = 11697986|title = A Stable Dirhodium Tetracarboxylate Carbenoid: Crystal Structure, Bonding Analysis, and Catalysis| journal=Journal of the American Chemical Society| volume=123| issue=45| pages=11318–11319|year = 2001|last1 = Snyder|first1 = James P.| last2=Padwa| first2=Albert| last3=Stengel| first3=Thomas| last4=Arduengo| first4=Anthony J.| last5=Jockisch| first5=Alexander| last6=Kim| first6=Hyo-Joong}}</ref> involves an initial formation of a metal-carbenoid complex from the [[diazo]] compound. Elimination of nitrogen gas then affords a metallocarbene. An intramolecular nucleophilic attack by the carbonyl oxygen regenerates the metal catalyst and forms the carbonyl ylide. The carbonyl ylide can then react with an alkene or alkyne, such as dimethyl acetylenedicarboxylate (DMAD) to generate the oxacycle.

[[File:Accepted Mechanism of the 1,3-Dipolar Cycloaddition Reaction Mediated by Metal Catalysis of Diazocarbonyl Compounds. Modified from M. Hodgson, D. et al. In Organic Reactions; John Wiley & Sons, Inc.png|center|Scheme 7. Accepted mechanism of the 1,3-dipolar cycloaddition reaction mediated by metal catalysis (example dirhodium catalyst) of diazocarbonyl compounds. Modified from M. Hodgson, D.; H. Labande, A.; Muthusamy, S. In Organic Reactions; John Wiley & Sons, Inc.: 2004.]]

However, it is uncertain whether the metallocarbene intermediate generates the carbonyl ylide. In some cases, metallocarbenes can also react directly with dipolarophiles.<ref name="Hodgson, D. M. 2001">Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A. [http://pubs.rsc.org/en/content/articlepdf/2001/cs/b000708k?page=search Catalytic enantioselective rearrangements and cycloadditions involving ylides from diazo compounds] Chem Soc Rev 2001, 30, 50.</ref> In these cases, the metallocarbene, such as the dirhodium(II)tetracarboxylate carbene, is stabilized through [[hyperconjugation|hyperconjugative]] metal [[enolate|enolate-type]] interactions.<ref>{{Cite journal | doi=10.1002/adsc.200303092|title = Theoretical Studies on Diastereo- and Enantioselective Rhodium-Catalyzed Cyclization of Diazo Compoundvia Intramolecular C—H Bond Insertion| journal=Advanced Synthesis & Catalysis| volume=345| issue=910| pages=1159–1171|year = 2003|last1 = Yoshikai|first1 = Naohiko| last2=Nakamura| first2=Eiichi}}</ref><ref>{{Cite journal | doi=10.1021/ja017823o|pmid = 12059244|title = Mechanism of C−H Bond Activation/C−C Bond Formation Reaction between Diazo Compound and Alkane Catalyzed by Dirhodium Tetracarboxylate| journal=Journal of the American Chemical Society| volume=124| issue=24| pages=7181–7192|year = 2002|last1 = Nakamura|first1 = Eiichi| last2=Yoshikai| first2=Naohiko| last3=Yamanaka| first3=Masahiro}}</ref><ref>Costantino, G.; Rovito, R.; Macchiarulo, A.; Pellicciari, R. [http://www.sciencedirect.com/science/article/pii/S0166128001007473 Structure of metal–carbenoid intermediates derived from the dirhodium(II)tetracarboxylate mediated decomposition of α-diazocarbonyl compounds: a DFT study] J Mol Struc-Theochem 2002, 581, 111.</ref><ref name="M. Hodgson, D. 2004">M. Hodgson, D.; H. Labande, A.; Muthusamy, S. In Organic Reactions; John Wiley & Sons, Inc.: 2004.</ref> Subsequent 1,3-dipolar cycloaddition reaction occurs through a transient metal-complexed carbonyl ylide. Therefore, a persistent metallocarbene can influence the stereoselectivity and regioselectivity of the 1,3-dipolar cycloaddition reaction based on the stereochemistry and size of the metal [[ligands]].

[[File:The dirhodium(II)tetracarboxylate metallocarbene stabilized by πC-Rh→πC=O hyperconjugation..png|center|The dirhodium(II)tetracarboxylate metallocarbene stabilized by πC-Rh→πC=O hyperconjugation. Modified from M. Hodgson, D.; H. Labande, A.; Muthusamy, S. In Organic Reactions; John Wiley & Sons, Inc.: 2004.]]

The mechanism of the 1,3-dipolar cycloaddition reaction between the carbonyl ylide dipole and [[alkynyl]] or [[alkenyl]] dipolarophiles has been extensively investigated with respect to regioselectivity and stereoselectivity. As [[symmetric]] dipolarophiles have one orientation for cycloaddition, only one [[regioisomer]], but multiple [[stereoisomers]] can be obtained.<ref name="M. Hodgson, D. 2004"/> On the contrary, [[chiral ligand|unsymmetric]] dipolarophiles can have multiple regioisomers and stereoisomers. These regioisomers and stereoisomers may be predicted based on [[frontier molecular orbital theory|frontier molecular orbital (FMO) theory]], [[steric effects|steric interactions]], and [[electronic effect|stereoelectronic interactions]].<ref>{{Cite journal | doi=10.1021/jo051743b| pmid=16356001|title = Efficient Catalytic Effects of Lewis Acids in the 1,3-Dipolar Cycloaddition Reactions of Carbonyl Ylides with Imines| journal=The Journal of Organic Chemistry| volume=70| issue=26| pages=10782–10791|year = 2005|last1 = Suga|first1 = Hiroyuki| last2=Ebiura| first2=Yasutaka| last3=Fukushima| first3=Kazuaki| last4=Kakehi| first4=Akikazu| last5=Baba| first5=Toshihide}}</ref><ref name="Padwa, A. 1990">{{Cite journal | doi=10.1021/ja00164a034|title = Tandem cyclization-cycloaddition reaction of rhodium carbenoids. Scope and mechanistic details of the process| journal=Journal of the American Chemical Society| volume=112| issue=8| pages=3100–3109|year = 1990|last1 = Padwa|first1 = Albert| last2=Fryxell| first2=Glen E.| last3=Zhi| first3=Lin}}</ref>

[[File:Products of the 1,3-Dipolar Cycloaddition Reaction Between Carbonyl Ylide Dipoles and Alkenyl or Alkynyl Dipolarophiles. Modified from M. Hodgson, D.; H. Labande, A.; Muthusamy, S. In Organic Reactions; John Wiley & Sons, Inc. 2004..png|center|Scheme 9. Products of the 1,3-dipolar cycloaddition reaction between carbonyl ylide dipoles and alkenyl or alkynyl dipolarophiles. Modified from M. Hodgson, D.; H. Labande, A.; Muthusamy, S. In Organic Reactions; John Wiley & Sons, Inc.: 2004.]]

=====Regioselectivity of the 1,3-dipolar cycloaddition reaction mediated by metal catalysis of diazocarbonyl compounds=====

Regioselectivity of 1,3-dipolar cycloaddition reactions between carbonyl ylide dipoles and alkynyl or alkenyl dipolarophiles is essential for generating molecules with defined regiochemistry. FMO theory and analysis of the [[HOMO-LUMO]] energy gaps between the dipole and dipolarophile can rationalize and predict the regioselectivity of experimental outcomes.<ref>{{Cite journal | doi=10.1021/ja00803a017|title = Frontier molecular orbitals of 1,3 dipoles and dipolarophiles| journal=Journal of the American Chemical Society| volume=95| issue=22| pages=7287–7301|year = 1973|last1 = Houk|first1 = K. N.| last2=Sims| first2=Joyner.| last3=Duke| first3=R. E.| last4=Strozier| first4=R. W.| last5=George| first5=John K.}}</ref><ref>{{Cite journal | doi=10.1021/ja00525a006|title = Theoretical studies of the structures and reactions of substituted carbonyl ylides| journal=Journal of the American Chemical Society| volume=102| issue=5| pages=1504–1512|year = 1980|last1 = Houk|first1 = K. N.| last2=Rondan| first2=Nelson G.| last3=Santiago| first3=Cielo| last4=Gallo| first4=Catherine J.| last5=Gandour| first5=Ruth Wells| last6=Griffin| first6=Gary W.}}</ref> The HOMOs and LUMOs can belong to either the dipole or dipolarophile, for which HOMO<sub>dipole</sub>-LUMO<sub>dipolarophile</sub> or HOMO<sub>dipolarophile</sub>-LUMO<sub>dipole</sub> interactions can exist. 
Overlap of the [[atomic orbital|orbitals]] with the largest coefficients can ultimately rationalize and predict results.

[[File:Diagram of the Molecular Orbital Interactions of HOMOdipole-LUMOdipolarophile or HOMOdipolarophile-LUMOdipole Between a Carbonyl Ylide Dipole and Alkenyl Dipolarophile..png|center|Scheme 10. diagram of the molecular orbital interactions of HOMOdipole-LUMOdipolarophile or HOMOdipolarophile-LUMOdipole between a carbonyl ylide dipole and alkenyl dipolarophile.]]

The archetypal regioselectivity of the 1,3-dipolar cycloaddition reaction mediated by carbonyl ylide dipoles has been examined by Padwa and coworkers.<ref name="Padwa, A. 1990"/><ref>{{Cite journal | doi=10.1021/cr950022h| pmid=11848752|title = Cascade Processes of Metallo Carbenoids| journal=Chemical Reviews| volume=96| issue=1| pages=223–270|year = 1996|last1 = Padwa|first1 = Albert| last2=Weingarten| first2=M. David}}</ref> Using a Rh<sub>2</sub>(OAc)<sub>4</sub> catalyst in benzene, diazodione underwent a 1,3-dipolar cycloaddition reaction with [[methyl group|methyl]] propiolate and methyl [[propargyl]] [[ether]]. The reaction with [[methyl propiolate]] affords two regioisomers with the major resulting from the HOMO<sub>dipole</sub>-LUMO<sub>dipolarophile</sub> interaction, which has the largest coefficients on the carbon proximal to the carbonyl group of the carbonyl ylide and on the methyl propiolate terminal alkyne carbon. The reaction with methyl propargyl ether affords one regioisomer resulting from the HOMO<sub>dipolarophile</sub>-LUMO<sub>dipole</sub> interaction, which has largest coefficients on the carbon distal to the carbonyl group of the carbonyl ylide and on the methyl propargyl ether terminal alkyne carbon.

[[File:Regioselectivity and Molecular Orbital Interactions of the 1,3-Dipolar Cycloaddition Reaction Between a Diazodione and Methyl Propiolate or Methyl Propargyl Ether. Modified from Padwa, A.; Weingarten, M. D. Chem Rev 1996, 96, 223..png|center|Scheme 11. Regioselectivity and molecular orbital interactions of the 1,3-dipolar cycloaddition reaction between a diazodione and methyl propiolate or methyl propargyl ether. Modified from Padwa, A.; Weingarten, M. D. Chem Rev 1996, 96, 223.]]

Regioselectivities of 1,3-dipolar cycloaddition reactions mediated by metal catalysis of diazocarbonyl compounds may also be influenced by the metal through formation of stable metallocarbenes.<ref name="Hodgson, D. M. 2001"/><ref>{{Cite journal | doi=10.1021/jo951576n|title = Ligand-Induced Selectivity in the Rhodium(II)-Catalyzed Reactions of α-Diazo Carbonyl Compounds†| journal=The Journal of Organic Chemistry| volume=61| pages=63–72|year = 1996|last1 = Padwa|first1 = Albert| last2=Austin| first2=David J.}}</ref> Stabilization of the metallocarbene, via metal enolate-type interactions, will prevent the formation of carbonyl ylides, resulting in a direct reaction between the metallocarbene dipole and an alkynyl or alkenyl dipolarophile (see image of The dirhodium(II)tetracarboxylate metallocarbene stabilized by π<sub>C-Rh</sub>→π<sub>C=O</sub> hyperconjugation.). In this situation, the metal ligands will influence the regioselectivity and stereoselectivity of the 1,3-dipolar cycloaddition reaction.

=====Stereoselectivity and asymmetric induction of the 1,3-dipolar cycloaddition reaction mediated by metal catalysis of diazocarbonyl compounds=====

The [[stereoselectivity]] of 1,3-dipolar cycloaddition reactions between carbonyl ylide dipoles and alkenyl dipolarophiles has also been closely examined. For alkynyl dipolarophiles, stereoselectivity is not an issue as relatively planar sp<sup>2</sup> carbons are formed, while regioselectivity must be considered (see image of the Products of the 1,3-Dipolar Cycloaddition Reaction Between Carbonyl Ylide Dipoles and Alkenyl or Alkynyl Dipolarophiles). However, for alkenyl dipolarophiles, both regioselectivity and stereoselectivity must be considered as sp<sup>3</sup> carbons are generated in the product species.

1,3-dipolar cycloaddition reactions between carbonyl ylide dipoles and alkenyl dipolarophiles can generate [[diastereomeric]] products.<ref name="M. Hodgson, D. 2004"/> The [[endo-exo isomerism|''exo'' product]] is characterized with dipolarophile substituents being [[cis-trans isomerism|''cis'']] to the ether bridge of the oxacycle. The [[endo-exo isomerism|''endo'' product]] is characterized with the dipolarophile substituents being [[cis-trans isomerism|''trans'']] to the ether bridge of the oxacycle. Both products can be generated through [[pericyclic reaction|pericyclic]] transitions states involving [[concerted]] synchronous or concerted asynchronous processes.

One early example conferred stereoselectivity in terms of ''endo'' and ''exo'' products with metal catalysts and Lewis acids.<ref>Suga, H.; Kakehi, A.; Ito, S.; Inoue, K.; Ishida, H.; Ibata, T. [https://www.jstage.jst.go.jp/article/bcsj/74/6/74_6_1115/_pdf Stereocontrol in a Ytterbium Triflate-Catalyzed 1,3-Dipolar Cycloaddition Reaction of Carbonyl Ylide with N-Substituted Maleimides and Dimethyl Fumarate] B Chem Soc Jpn 2001, 74, 1115.</ref> Reactions with just the metal catalyst Rh<sub>2</sub>(OAc)<sub>4</sub> prefer the ''exo'' product while reactions with the additional Lewis acid Yb(OTf)<sub>3</sub> prefer the ''endo'' product. The ''endo'' selectivity observed for Lewis acid cycloaddition reactions is attributed to the optimized orbital overlap of the carbonyl π systems between the dipolarophile coordinated by Yb(Otf)<sub>3</sub> (LUMO) and the dipole (HOMO). After many investigations, two primary approaches for influencing the stereoselectivity of carbonyl ylide cycloadditions have been developed that exploit the chirality of metal catalysts and Lewis acids.<ref name="M. Hodgson, D. 2004"/>

[[File:Facial Selectivity of the 1,3-Dipolar Cycloaddition Reaction using a Metal Catalyst and Lewis Acid.png|center|Facial Selectivity of the 1,3-Dipolar Cycloaddition Reaction using a Metal Catalyst and Lewis Acid]]

[[File:Rationale for the Endo Selectivity of the 1,3-Dipolar Cycloaddition Reaction with a Lewis Acid.png|center|Rationale for the Endo Selectivity of the 1,3-Dipolar Cycloaddition Reaction with a Lewis Acid]]

The first approach employs chiral metal catalysts to modulate the ''endo'' and ''exo'' stereoselectivity. The chiral catalysts, in particular Rh<sub>2</sub>[(''S'')-DOSP]<sub>4</sub> and Rh<sub>2</sub>[(''S'')-BPTV]<sub>4</sub> can induce modest asymmetric induction and was used to synthesize the [[antifungal protein|antifungal]] agent pseudolaric acid A.<ref>{{Cite journal | doi=10.1002/anie.200602056| pmid=16906616|title = Total Synthesis of Pseudolaric Acid A| journal=Angewandte Chemie International Edition| volume=45| issue=37| pages=6197–6201|year = 2006|last1 = Geng|first1 = Zhe| last2=Chen| first2=Bin| last3=Chiu| first3=Pauline}}</ref> This is a result of the [[chiral]] metal catalyst remaining associated with the carbonyl ylide during the cycloaddition, which confers facial selectivity. However, the exact mechanisms are not yet fully understood.

[[File:Asymmetric Induction of the 1,3-Dipolar Cycloaddition Reaction with Chiral Metal Catalysts.png|center|Asymmetric induction of the 1,3-dipolar cycloaddition reaction with chiral metal catalysts]]

The second approach employs a chiral Lewis acid catalyst to induce facial stereoselectivity after the generation of the carbonyl ylide using an achiral metal catalyst.<ref>{{Cite journal | doi=10.1021/jo049007f| pmid=15624905|title = Chiral 2,6-Bis(oxazolinyl)pyridine−Rare Earth Metal Complexes as Catalysts for Highly Enantioselective 1,3-Dipolar Cycloaddition Reactions of 2-Benzopyrylium-4-olates| journal=The Journal of Organic Chemistry| volume=70| issue=1| pages=47–56|year = 2005|last1 = Suga|first1 = Hiroyuki| last2=Inoue| first2=Kei| last3=Inoue| first3=Shuichi| last4=Kakehi| first4=Akikazu| last5=Shiro| first5=Motoo}}</ref> The chiral Lewis acid catalyst is believed to coordinate to the dipolarophile, which lowers the LUMO of the dipolarophile while also leading to [[enantioselective synthesis|enantioselectivity]].

[[File:Asymmetric Induction of the 1,3-Dipolar Cycloaddition Reaction with Chiral Lewis Acid Catalysts.png|center|Asymmetric induction of the 1,3-dipolar cycloaddition reaction with chiral Lewis acid catalysts]]

===Azomethine ylides===
{{See also|Azomethine ylide}}
1,3-Dipolar cycloaddition between an azomethine ylide and an alkene furnishes an azacyclic structure, such as [[pyrrolidine]]. This strategy has been applied to the synthesis of spirotryprostatin A.<ref>{{cite journal | title = Concise, Asymmetric Total Synthesis of Spirotryprostatin A | first1 = Tomoyuki | last1 = Onishi | first2 = Paul | last2 = Sebahar | first3 = Robert | last3 = Williams | journal = Organic Letters | volume = 5 | issue = 17 | year = 2003 | pages = 3135–3137 | doi = 10.1021/ol0351910 | pmid=12917000}}</ref>

[[File:Application of azomethine ylide in the synthesis of spirotryprostatin.tif|900px|center]]

===Ozone===

[[Ozonolysis]] is a very important organic reaction. Alkenes and alkynes can be cleaved by ozonolysis to give [[aldehyde]], [[ketone]] or [[carboxylic acid]] products.

==Biological applications==

The 1,3-dipolar cycloaddition between organic azides and terminal alkynes (i.e., the [[azide-alkyne Huisgen cycloaddition|Huisgen cycloaddition]]) has been widely utilized for [[bioconjugation]].

===Copper catalysis===

The Huisgen reaction generally does not proceed readily under mild conditions. Meldal ''et al.'' and Sharpless ''et al.'' independently developed a [[copper]](I)-catalyzed version of the Huisgen reaction, CuAAC (for Copper-catalyzed Azide-Alkyne Cycloaddition), which proceeds very readily in mild, including [[physiological]], conditions (neutral [[pH]], room [[temperature]] and [[aqueous solution|water solution]]).<ref>{{cite journal | title = Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides | first1 = Christian |last1 = Tornoe | first2 = Caspar | last2 = Christensen | first3 = Morten | last3 = Meldal | journal = Journal of Organic Chemistry | year = 2002 | pages = 3057–3064 | doi = 10.1021/jo011148j | pmid=11975567 | volume=67 | issue=9| s2cid = 11957672 }}</ref><ref>{{cite journal | title = A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective Ligation of Azides and Terminal Alkynes | first1 = Vsevolod |last1 = Rostovtsev | first2 = Luke | last2 = Green | first3 = Valery | last3 = Fokin | first4 = Barry K. | last4 = Sharpless | journal = Angewandte Chemie International Edition | year = 2002 | volume = 41 | issue = 14 | pages = 2596–2599 | doi = 10.1002/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4 | pmid = 12203546}}</ref> This reaction is also [[bioorthogonal chemistry|bioorthogonal]]: azides and alkynes are both generally absent from biological systems and therefore these functionalities can be [[chemoselectivity|chemoselectively]] reacted even in the [[cell (biology)|cellular context]]. They also do not react with other functional groups found in nature, so they do not perturb biological systems. The reaction is so versatile that it is termed the [[Click chemistry|"Click" chemistry]]. Although copper(I) is [[cytotoxicity|toxic]], many protective [[ligand]]s have been developed to both reduce cytotoxicity and improve rate of CuAAC, allowing it to be used in ''[[in vivo]]'' studies.<ref>{{cite journal | title = Increasing the Efficacy of Bioorthogonal Click Reactions for Bioconjugation: A Comparative Study | first1 = Christen | last1 = Besanceney-Webler | first2 = Hao | last2 = Jiang | first3 = Tianqing | last3 = Zheng | first4 = Lei | last4 = Feng | first5 = David | last5 = Soriano del Amo | first6 = Wei | last6 = Wang | first7 =Liana M. | last7 = Klivansky | first8 = Florence L. | last8 = Marlow | first9 = Yi | last9 = Liu | first10 = Peng | last10 = Wu | journal = Angewandte Chemie International Edition | year = 2011 | volume = 50 | issue = 35 | pages = 8051–8056 | doi = 10.1002/anie.201101817 | pmid=21761519 | pmc=3465470}}</ref>

[[File:Copper catalyzed AAC.tif|350px|center]]

For example, Bertozzi ''et al.'' reported the [[metabolic]] incorporation of azide-functionalized [[saccharide]]s into the [[glycan]] of the [[cell membrane]], and subsequent labeling with [[fluorophore]]-alkyne conjugate. The result is that the cell membrane is  [[fluorescent label|fluorescently labeled]], and can therefore be [[Fluorescence imaging|imaged]] using a [[fluorescence microscope]].<ref>{{cite journal | title = Targeted metabolic labeling of yeast N-glycans with unnatural sugars | first1 = Mark |last1 = Breidenbach | first2 = Jennifer | last2 = Gallagher | first3 = David | last3 = King | first4 = Brian | last4 = Smart | first5 = Peng | last5 = Wu | first6 = Carolyn | last6 = Bertozzi | journal = Proceedings of the National Academy of Sciences of the United States of America | year = 2010 | volume = 107 | pages = 3988–3993 | doi = 10.1073/pnas.0911247107 | issue=9 | pmid=20142501 | pmc=2840165| bibcode = 2010PNAS..107.3988B| doi-access = free }}</ref>

[[File:Metabolic labeling with GlcNAz and click chemistry.tif|center|800px]]

===Strain-promoted cycloaddition===

To avoid toxicity of copper(I), Bertozzi ''et al.'' developed the strain-promoted azide-alkyne cycloaddition (SPAAC) between organic azide and strained [[cyclooctyne]]. The angle distortion of the cyclooctyne helps to speed up the reaction by both reducing the activation strain and enhancing the interactions, thereby enabling it to be used in physiological conditions without the need for the catalyst.<ref>{{cite journal | title = A Strain-Promoted [3 + 2] Azide−Alkyne Cycloaddition for Covalent Modification of Biomolecules in Living Systems | first1 = Nicholas | last1 = Agard | first2 = Jennifer | last2 = Prescher | first3 = Carolyn | last3 = Bertozzi | journal = Journal of the American Chemical Society | year = 2004 | volume =  126| issue = 46 | pages = 15046–15047 | doi = 10.1021/ja044996f | pmid=15547999}}</ref>

[[File:Strained promoted AAC.tif|350px|center]]

For instance, Ting ''et al.'' introduced an azido functionality onto specific [[proteins]] on the [[cell membrane|cell surface]] using a [[ligase]] enzyme. The azide-tagged protein is then labeled with cyclooctyne-fluorophore conjugate to yield a fluorescently labeled protein.<ref>{{cite journal | title = Redirecting lipoic acid ligase for cell surface protein labeling with small-molecule probes | first1 = Marta | last1 = Fernandez-Suarez| first2 = Hemanta | last2 = Baruah | first3 = Laura | last3 = Martinez-Hernandez | first4 = Kathleen | last4 = Xie | first5 = Jeremy | last5 = Baskin | first6 = Carolyn | last6 = Bertozzi | first7 = Alice | last7 = Ting | journal = Nature Biotechnology | year = 2007 | volume = 25 | issue = 12 | pages = 1483–1487 | doi = 10.1038/nbt1355 | pmid=18059260 | pmc=2654346}}</ref>

[[File:Enzyme-mediated labeling with azidooctanoic acid and SPAAC.tif|center|650px]]

==References==
<references/>
{{Organic reactions}}
[[Category:Nitrogen heterocycle forming reactions]]
[[Category:Cycloadditions]]