1,3-Dipolar cycloaddition
Huisgen 1,3-dipolar cycloaddition | |
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Named after | Rolf Huisgen |
Reaction type | Ring forming reaction |
Identifiers | |
Organic Chemistry Portal | huisgen-1,3-dipolar-cycloaddition |
RSC ontology ID | RXNO:0000018 |
The 1,3-dipolar cycloaddition is a
Mechanistic overview
Originally two proposed mechanisms describe the 1,3-dipolar cycloaddition: first, the concerted
Pericyclic mechanism
Huisgen investigated a series of cycloadditions between the 1,3-dipolar
- 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 stereospecific with respect to the dipolarophile (i.e., cis-alkenes giving syn-products), supporting the concerted pericyclic mechanism in which two sigma bonds are formed simultaneously.
- Diels-Alder reaction, suggesting that the transition stateis highly ordered, which is a signature of concerted pericyclic reactions.
1,3-Dipole
A 1,3-dipole is an organic molecule that can be represented as either an
Consequently, this ambivalence means that the ends of a 1,3-dipole can be treated as both
Dipolarophile
The most commonly used dipolarophiles are alkenes and alkynes.
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.[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-cyclopentenyl pyrrolidine nucleophilic addition to the diazo compound, proceeds 1,500 times faster in polar DMSO than in non-polar decalin. 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.
Frontier molecular orbital theory
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 π4s + π2s 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.
Type I
The dipole has a high-lying
This type resembles the normal-electron-demand Diels-Alder reaction, in which the diene HOMO combines with the dienophile LUMO.
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
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).[19]
This type resembles the inverse electron-demand Diels-Alder reaction, in which the diene LUMO combines with the dienophile HOMO.
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.
Stereospecificity
1,3-dipolar cycloadditions usually result in
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).[20]
With respect to dipole
Generally, the stereochemistry of the dipole is not of major concern because only few dipoles could form
These results altogether confirm that 1,3-dipolar cycloaddition is stereospecific, giving retention of both the 1,3-dipole and the dipolarophile.
Diastereoselectivity
When two or more
Examples of substrate-controlled diastereoselective 1,3-dipolar cycloadditions are shown below. First is the reaction between 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.[23] Second is the reaction between nitrone and dihydrofuran. The exo-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 strained cis-fused ring system.[25]
Directed 1,3-dipolar cycloaddition
Trajectory of the cycloaddition can be controlled to achieve a diastereoselective reaction. For example, metals can
Such diastereodirection has been applied in the synthesis of epothilones.[27]
Regioselectivity
For asymmetric dipole-dipolarophile pairs, two
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.[29][30]
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 carboxyl group on C-3 and the phenyl group on C-4 regioselectively.
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.[31]
For example, diazomethane generally adds to methyl acrylate to give 3-carboxyl
Synthetic applications
1,3-dipolar cycloadditions are important ways toward the synthesis of many important 5-membered heterocycles such as
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-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]
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.[35]
Preparation of carbonyl ylides for 1,3-dipolar cycloaddition reactions
Synthesis of carbonyl ylides from diazomethane derivatives by photocatalysis
One of the earliest examples of carbonyl ylide
Another early example of carbonyl ylide synthesis by photocatalysis was reported by Olah et al.[38] Dideuteriodiazomethane was photolysed in the presence of formaldehyde to generate the dideuterioformaldehyde carbonyl ylide.
Synthesis of carbonyl ylides from hydroxypyrones by proton transfer
Carbonyl ylides can be synthesized by
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 an intramolecular hydrogen transfer.[40] After hydrogen transfer, the carbonyl ylide can then react with dipolarophiles to form oxygen-containing rings.
Synthesis of α-halocarbonyl ylides from dihalocarbenes
Dihalocarbenes have also been employed to generate carbonyl ylides, exploiting the electron withdrawing nature of dihalocarbenes.
Synthesis of carbonyl ylides from diazomethane derivatives by metal catalysis
A universal approach for generating carbonyl ylides involves
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 mechanism to expand the scope of synthetic molecules with respect to regio- and 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[47] and rhodium metallocarbenes,[48] 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.
However, it is uncertain whether the metallocarbene intermediate generates the carbonyl ylide. In some cases, metallocarbenes can also react directly with dipolarophiles.
The mechanism of the 1,3-dipolar cycloaddition reaction between the carbonyl ylide dipole and
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
The archetypal regioselectivity of the 1,3-dipolar cycloaddition reaction mediated by carbonyl ylide dipoles has been examined by Padwa and coworkers.
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 πC-Rh→πC=O 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 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 generate
One early example conferred stereoselectivity in terms of endo and exo products with metal catalysts and Lewis acids.[60] Reactions with just the metal catalyst Rh2(OAc)4 prefer the exo product while reactions with the additional Lewis acid Yb(OTf)3 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)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 the endo and exo 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 the
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 to enantioselectivity.
Azomethine ylides
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.[63]
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 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
For example, Bertozzi et al. reported the
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.[68]
For instance, Ting et al. introduced an azido functionality onto specific
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