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The1,3-dipolar cycloaddition is achemical reaction between a1,3-dipole and adipolarophile 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 andsynthetic application were established in the 1960s, primarily through the work ofRolf Huisgen.^[1][2] Hence, the reaction is sometimes referred to as theHuisgen cycloaddition (this term is often used to specifically describe the1,3-dipolar cycloaddition between an organicazide and analkyne to generate1,2,3-triazole). 1,3-dipolar cycloaddition is an important route to theregio- andstereoselective synthesis of five-memberedheterocycles 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.

Originally two proposed mechanisms describe the 1,3-dipolar cycloaddition: first, the concertedpericycliccycloaddition mechanism, proposed by Rolf Huisgen;^[3] and second, the stepwise mechanism involving adiradicalintermediate, proposed by Firestone.^[4] After much debate, the former proposal is now generally accepted^[5]—the 1,3-dipole reacts with the dipolarophile in aconcerted, often asynchronous, andsymmetry-allowed_π4_s +_π2_s fashion through a thermal six-electronHuckel aromatic transition state. However, a few examples exist of a stepwise mechanism for the catalyst-free 1,3-dipolar cycloaddition reactions of thiocarbonyl ylides,^[6] and nitrile oxides^[7]

Huisgen investigated a series of cycloadditions between the 1,3-dipolardiazo compounds and various dipolarophilicalkenes.^[3] 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 alwaysstereospecific with respect to the dipolarophile (i.e.,cis-alkenes givingsyn-products), supporting the concerted pericyclic mechanism in which twosigma bonds are formed simultaneously.
• Thermodynamic parameters: 1,3-dipolar cycloadditions have an unusually large negativeentropy of activation similar to that of theDiels-Alder reaction, suggesting that thetransition state is highly ordered, which is a signature of concerted pericyclic reactions.

A 1,3-dipole is an organic molecule that can be represented as either anallyl-type or apropargyl/allenyl-typezwitterionic 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 ingeometry.^[8] 1,3-Dipoles containing higher-row elements such assulfur orphosphorus are also known, but are utilized less routinely.

Resonance structures can be drawn todelocalize both negative and positive charges ontoany 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 asdipole moment measurements^[9] or computations.^[10] For example,diazomethane bears the largest negative character at theterminal nitrogen atom, whilehydrazoic acid bears the largest negative character at theinternal nitrogen atom.

Consequently, this ambivalence means that the ends of a 1,3-dipole can be treated as bothnucleophilic andelectrophilic at the same time. The extent of nucleophilicity and electrophilicity at each end can be evaluated using thefrontier molecular orbitals, which can be obtained computationally. In general, the atom that carries the largest orbital coefficient in theHOMO 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.^[11][12][13] 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).

The most commonly used dipolarophiles are alkenes and alkynes.Heteroatom-containing dipolarophiles such ascarbonyls andimines can also undergo 1,3-dipolar cycloaddition. Other examples of dipolarophiles includefullerenes andnanotubes, which can undergo 1,3-dipolar cycloaddition withazomethine ylide in thePrato reaction.

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 andethyl acrylate ornorbornene (see scheme below) changes only slightly upon varying solvents from cyclohexane to methanol.^[14]

Lack of solvent effects in 1,3-dipolar cycloaddition is clearly demonstrated in the reaction between enamines and dimethyl diazomalonate (see scheme below).^[15] The polar reaction, N-cyclopentenylpyrrolidine nucleophilic addition to the diazo compound, proceeds 1,500 times faster in polarDMSO than in non-polardecalin. On the other hand, a close analog of this reaction, N-cyclohexenyl pyrrolidine 1,3-dipolar cycloaddition to dimethyl diazomalonate, is sped up only 41-fold in DMSO relative to decalin.

1,3-Dipolar cycloadditions are pericyclic reactions, which obey theDewar-Zimmerman rules and theWoodward–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_π4_s +_π2_s manner. Such orbital overlap can be achieved in three ways: type I, II and III.^[16] The dominant pathway is the one which possesses the smallest HOMO-LUMO energy gap.

The dipole has a high-lyingHOMO which overlaps with LUMO of the dipolarophile. A dipole of this class is referred to as aHOMO-controlled dipole or anucleophilic dipole, which includesazomethine ylide,carbonyl ylide,nitrile ylide,azomethine imine,carbonyl imine anddiazoalkane. 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.^[17]

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

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 aHOMO-LUMO-controlled dipole or anambiphilic dipole, which includesnitrile imide,nitrone,carbonyl oxide,nitrile oxide, andazide. 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).^[18]

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 aLUMO-controlled dipole or anelectrophilic dipole, which includesnitrous oxide andozone. 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).^[19]

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

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.
• Morepolarizable dipolarophiles are more reactive because diffuse electron clouds are better suited to initiate the flow of electrons.
• Dipolarophiles with highangular strain are more reactive due to increased energy of the ground state.
• Increasedsteric 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 thancis-stilbene) because during the reaction, the 120° bond angle shrinks to 109°, bringing eclipsingcis-substituents towards each other for increased steric clash.

1,3-dipolar cycloadditions usually result inretention 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.

cis-Substituents on the dipolarophilic alkene end upcis, andtrans-substituents end uptrans in the resulting five-membered cyclic compound (see scheme below).^[20]

Generally, the stereochemistry of the dipole is not of major concern because only few dipoles could formstereogenic centers, 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.Diastereopure azomethine ylides are generated byelectrocyclic ring opening ofaziridines, and then rapidly trapped with strong dipolarophiles before bond rotation can take place (see scheme below).^[21][22] 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.

When two or morestereocenters are generated during the reaction, diastereomeric transition states and products can be obtained. In the Diels-Alder cycloaddition, theendodiastereoselectivity due tosecondary orbital interactions is usually observed. In 1,3-dipolar cycloadditions, however, two forces influence the diastereoselectivity: the attractiveπ-interaction (resembling secondary orbital interactions in the Diels-Alder cycloaddition) and the repulsivesteric 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 benzonitrile N-benzylide andmethyl acrylate. In the transition state, the phenyl and the methyl ester groups stack to give thecis-substitution as the exclusive finalpyrroline product. This favorable π-interaction offsets the steric repulsion between the phenyl and the methyl ester groups.^[23] Second is the reaction between nitrone anddihydrofuran. Theexo-selectivity is achieved to minimize steric repulsion.^[24] Last is the intramolecular azomethine ylide reaction with alkene. The diastereoselectivity is controlled by the formation of a less strainedcis-fused ring system.^[25]

Trajectory of the cycloaddition can be controlled to achieve a diastereoselective reaction. For example, metals canchelate to the dipolarophile and the incoming dipole and direct the cycloaddition selectively on one face. The example below shows addition of nitrile oxide to anenantiomerically pureallyl alcohol in the presence of a magnesium ion. The most stableconformation of the alkene places thehydroxyl 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.^[26]

Such diastereodirection has been applied in the synthesis ofepothilones.^[27]

For asymmetric dipole-dipolarophile pairs, tworegioisomeric products are possible. Bothelectronic/stereoelectronic and steric factors contribute to the regioselectivity of 1,3-dipolar cycloadditions.^[28]

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.^[29][30]

For example, consider the cycloaddition of diazomethane to three dipolarophiles:methyl acrylate,styrene ormethyl 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 thecarboxyl group on C-3 and thephenyl group on C-4 regioselectively.

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.^[31]

For example, diazomethane generally adds to methyl acrylate to give 3-carboxylpyrazoline. 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 fromhydrogen tot-butyl shifts the regioselectivity from 100% 3-carboxyl to 100% 4-carboxyl substitution.^[32][33]

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

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 byhydrogenation to reveal aldol-type β-hydroxycarbonyl orClaisen-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.^[34]

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.^[35]

Ylides are regarded as positively chargedheteroatoms connected to negatively charged carbon atoms, which include ylides ofsulfonium,thiocarbonyl,oxonium,nitrogen, andcarbonyl.^[36] Several methods exist for generating carbonyl ylides, which are necessary intermediates for generating oxygen-containing five-membered ring structures, for [3+2] cycloaddition reactions.

One of the earliest examples of carbonyl ylidesynthesis involvesphotocatalysis.^[37]Photolysis of diazotetrakis(trifluoromethyl)cyclopentadiene* (DTTC) in the presence oftetramethylurea can generate the carbonyl ylide by anintermolecularnucleophilic attack and subsequentaromatization of the DTTC moiety.^[37] This was isolated and characterized byX-ray crystallography due to the stability imparted by aromaticity,electron withdrawing trifluoromethyl groups, and theelectron donating dimethylamine groups. Stable carbonyl ylidedipoles can then be used in [3+2] cycloaddition reactions with dipolarophiles.

Another early example of carbonyl ylide synthesis by photocatalysis was reported by Olahet al.^[38] Dideuteriodiazomethane was photolysed in the presence offormaldehyde to generate the dideuterioformaldehyde carbonyl ylide.

Carbonyl ylides can be synthesized byacid catalysis of hydroxy-3-pyrones in the absence of a metalcatalyst.^[39] An initialtautomerization occurs, followed byelimination of theleaving group to aromatize thepyrone 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.

5-hydroxy-4-pyrones can also be used to synthesize carbonyl ylides by anintramolecularhydrogen transfer.^[40] After hydrogen transfer, the carbonyl ylide can then react with dipolarophiles to form oxygen-containing rings.

Dihalocarbenes have also been employed to generate carbonyl ylides, exploiting the electron withdrawing nature of dihalocarbenes.^[41][42][43] Bothphenyl(trichloromethyl)mercury and phenyl(tribromomethyl)mercury are sourcesdichlorocarbenes anddibromocarbenes, respectively. The carbonyl ylide can be generated upon reaction of the dihalocarbenes withketones oraldehydes. However, the synthesis of α-halocarbonyl ylides can also undesirably lead to the loss ofcarbon monoxide and the generation of the deoxygenation product.

A universal approach for generating carbonyl ylides involvesmetal catalysis of α-diazocarbonyl compounds, generally in the presence of dicopper or dirhodium catalysts.^[44] After release ofnitrogen gas and conversion to themetallocarbene, an intermolecular reaction with a carbonyl group can generate the carbonyl ylide. Subsequent cycloaddition reaction with analkene oralkyne dipolarophile can afford oxygen-containing five-membered rings. Popular catalysts that give modest yields towards synthesizing oxacycles include Rh₂(OAc)₄ and Cu(acac)₂.^[45][46]

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 themechanism to expand the scope of synthetic molecules with respect toregio- andstereo-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^[47] and rhodium metallocarbenes,^[48] involves an initial formation of a metal-carbenoid complex from thediazo 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.

However, it is uncertain whether the metallocarbene intermediate generates the carbonyl ylide. In some cases, metallocarbenes can also react directly with dipolarophiles.^[49] In these cases, the metallocarbene, such as the dirhodium(II)tetracarboxylate carbene, is stabilized throughhyperconjugative metalenolate-type interactions.^{[50][51][52][53]} 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 metalligands.

The mechanism of the 1,3-dipolar cycloaddition reaction between the carbonyl ylide dipole andalkynyl oralkenyl dipolarophiles has been extensively investigated with respect to regioselectivity and stereoselectivity. Assymmetric dipolarophiles have one orientation for cycloaddition, only oneregioisomer, but multiplestereoisomers can be obtained.^[53] On the contrary,unsymmetric dipolarophiles can have multiple regioisomers and stereoisomers. These regioisomers and stereoisomers may be predicted based onfrontier molecular orbital (FMO) theory,steric interactions, andstereoelectronic interactions.^[54][55]

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 theHOMO-LUMO energy gaps between the dipole and dipolarophile can rationalize and predict the regioselectivity of experimental outcomes.^[56][57] The HOMOs and LUMOs can belong to either the dipole or dipolarophile, for which HOMO_dipole-LUMO_{dipolarophile} or HOMO_{dipolarophile}-LUMO_dipole interactions can exist. Overlap of theorbitals with the largest coefficients can ultimately rationalize and predict results.

The archetypal regioselectivity of the 1,3-dipolar cycloaddition reaction mediated by carbonyl ylide dipoles has been examined by Padwa and coworkers.^[55][58] Using a Rh₂(OAc)₄ catalyst in benzene, diazodione underwent a 1,3-dipolar cycloaddition reaction withmethyl propiolate and methylpropargylether. The reaction withmethyl propiolate affords two regioisomers with the major resulting from the HOMO_dipole-LUMO_{dipolarophile} 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_{dipolarophile}-LUMO_dipole 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.

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.^[49][59] 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_C-Rh→π_C=O hyperconjugation.). In this situation, the metal ligands will influence the regioselectivity and stereoselectivity of the 1,3-dipolar cycloaddition reaction.

Thestereoselectivity 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 sp² 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 sp³ carbons are generated in the product species.

1,3-dipolar cycloaddition reactions between carbonyl ylide dipoles and alkenyl dipolarophiles can generatediastereomeric products.^[53] Theexo product is characterized with dipolarophile substituents beingcis to the ether bridge of the oxacycle. Theendo product is characterized with the dipolarophile substituents beingtrans to the ether bridge of the oxacycle. Both products can be generated throughpericyclic transitions states involvingconcerted synchronous or concerted asynchronous processes.

One early example conferred stereoselectivity in terms ofendo andexo products with metal catalysts and Lewis acids.^[60] Reactions with just the metal catalyst Rh₂(OAc)₄ prefer theexo product while reactions with the additional Lewis acid Yb(OTf)₃ prefer theendo product. Theendo 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)₃ (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.^[53]

The first approach employs chiral metal catalysts to modulate theendo andexo stereoselectivity. The chiral catalysts, in particular Rh₂[(S)-DOSP]₄ and Rh₂[(S)-BPTV]₄ can induce modest asymmetric induction and was used to synthesize theantifungal agent pseudolaric acid A.^[61] This is a result of thechiral metal catalyst remaining associated with the carbonyl ylide during the cycloaddition, which confers facial selectivity. However, the exact mechanisms are not yet fully understood.

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.^[62] The chiral Lewis acid catalyst is believed to coordinate to the dipolarophile, which lowers the LUMO of the dipolarophile while also leading toenantioselectivity.

1,3-Dipolar cycloaddition between an azomethine ylide and an alkene furnishes an azacyclic structure, such aspyrrolidine. This strategy has been applied to the synthesis of spirotryprostatin A.^[63]

Ozonolysis is a very important organic reaction. Alkenes and alkynes can be cleaved by ozonolysis to givealdehyde,ketone orcarboxylic acid products.

The 1,3-dipolar cycloaddition between organic azides and terminal alkynes (i.e., theHuisgen cycloaddition) has been widely utilized forbioconjugation.

The Huisgen reaction generally does not proceed readily under mild conditions. Meldalet al. and Sharplesset al. independently developed acopper(I)-catalyzed version of the Huisgen reaction, CuAAC (for Copper-catalyzed Azide-Alkyne Cycloaddition), which proceeds very readily in mild, includingphysiological, conditions (neutralpH, roomtemperature andwater solution).^[64][65] This reaction is alsobioorthogonal: azides and alkynes are both generally absent from biological systems and therefore these functionalities can bechemoselectively reacted even in thecellular 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. Although copper(I) istoxic, many protectiveligands have been developed to both reduce cytotoxicity and improve rate of CuAAC, allowing it to be used inin vivo studies.^[66]

For example, Bertozziet al. reported themetabolic incorporation of azide-functionalizedsaccharides into theglycan of thecell membrane, and subsequent labeling withfluorophore-alkyne conjugate. The result is that the cell membrane isfluorescently labeled, and can therefore beimaged using afluorescence microscope.^[67]

To avoid toxicity of copper(I), Bertozziet al. developed the strain-promoted azide-alkyne cycloaddition (SPAAC) between organic azide and strainedcyclooctyne. 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.^[68]

For instance, Tinget al. introduced an azido functionality onto specificproteins on thecell surface using aligase enzyme. The azide-tagged protein is then labeled with cyclooctyne-fluorophore conjugate to yield a fluorescently labeled protein.^[69]

• Nitrogen heterocycle forming reactions
• Cycloadditions

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