1,3-dipolar cycloaddition
Encyclopedia
The 1,3-dipolar cycloaddition, also known as the Huisgen cycloaddition or Huisgen reaction, is an organic
chemical reaction
belonging to the larger class of concerted, pericyclic cycloaddition
s. It is the reaction between a 1,3-dipole
and a dipolarophile, most of which are substituted alkene
s, to form a five-membered ring. Rolf Huisgen
first saw the prospects of varying the 1,3-dipole and its high value for synthesis of 5-membered heterocycles.
Proof of the concerted mechanism:
Countless additional calculations and experiments have been performed in addition to verify the concerted mechanism.
In reactions with hetero-dipolarophiles, the direction of addition is based on the maximization of gains in sigma bond energy during reaction. However, there are several exceptions that include multistep reaction pathways.
When the dipolarophiles are alkenes or alkynes, the dominant force in dictating direction of addition are substituents effects, primarily steric.
The allyl anion-type orbital of the dipole is involved in the reaction, where the terminal centers are both nucleophilic and electrophilic, depending on the resonance structures.
In an FMO consideration of 1,3-cycloadditions, both combinations of HOMO-LUMO considerations contribution to the interaction energies. These reactions can be categorized into three major types based on the conjugated substituents.
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...
chemical reaction
Chemical reaction
A chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, typically following the input of some type of energy, such as heat, light or electricity...
belonging to the larger class of concerted, pericyclic cycloaddition
Cycloaddition
A cycloaddition is a pericyclic chemical reaction, in which "two or more unsaturated molecules combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity." The resulting reaction is a cyclization reaction.Cycloadditions are usually described by the...
s. It is the reaction between a 1,3-dipole
1,3-dipole
In organic chemistry, a 1,3-dipolar compound or 1,3-dipole is a dipolar compound with delocalized electrons and a separation of charge over three atoms...
and a dipolarophile, most of which are substituted alkene
Alkene
In organic chemistry, an alkene, olefin, or olefine is an unsaturated chemical compound containing at least one carbon-to-carbon double bond...
s, to form a five-membered ring. Rolf Huisgen
Rolf Huisgen
Rolf Huisgen is a German chemist. He was born in Gerolstein and studied in Munich under the supervision of Heinrich Otto Wieland. After completing his Ph.D. in 1943 and his habilitation in 1947, he became professor at the University of Tübingen in 1949...
first saw the prospects of varying the 1,3-dipole and its high value for synthesis of 5-membered heterocycles.
Proof of mechanism
Although this was once hotly contested, the possibility of a diradical intermediate, defended by Firestone at the time, has largely been disproved by the work of Huisgen. It is now accepted that the mechanism is a concerted process.Proof of the concerted mechanism:
- Increasing carbonyl groups on the 1,3-dipole decreases reactivity by ground state stabilization.
- Solvent effects are minor so the reaction occurs through the concerted mechanism which lacks a zwitterionic intermediate. If the reaction occurred through a charge-separated intermediate, an increase in reaction rate with solvent polarity would be expected.
- The reaction proceeds with cis-addition as two bonds are formed simultaneously so there is no intermediate that can rotate to scramble the product stereochemistry.
Countless additional calculations and experiments have been performed in addition to verify the concerted mechanism.
Reactivity
Concerted processes such as the 1,3-cycloaddition require a highly ordered transition state (high negative entropic energy) 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 imine) 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.
Product orientation
Although there are general guidelines for orientation of products, the actual selectivity in these cycloaddition reactions is varied. For example, in azide-alkyne coupling reactions without Cu(I) catalyst, the products are generated in a 1:1 ratio of 1,4 and 1,5 products .In reactions with hetero-dipolarophiles, the direction of addition is based on the maximization of gains in sigma bond energy during reaction. However, there are several exceptions that include multistep reaction pathways.
When the dipolarophiles are alkenes or alkynes, the dominant force in dictating direction of addition are substituents effects, primarily steric.
Molecular Orbitals
The reaction goes through a symmetry-allowed Huckel aromatic molecular orbital in the transition state.The allyl anion-type orbital of the dipole is involved in the reaction, where the terminal centers are both nucleophilic and electrophilic, depending on the resonance structures.
In an FMO consideration of 1,3-cycloadditions, both combinations of HOMO-LUMO considerations contribution to the interaction energies. These reactions can be categorized into three major types based on the conjugated substituents.
- Type I: Electron-withdrawing groups favor reaction by stabilizing the dipolarophiles LUMO and decreasing the HOMO-LUMO gap. Electron-donating groups will deactivate dipolarophiles.
- Type II: Electron-withdrawing groups lower the orbital energies of the dipolarophiles. Electron-releasing substituents raise the dipolarophiles orbital energies. In both cases, one HOMO-LUMO gap is decreased more than the other is increased, so the overall result is an increase in reaction rate.
- Type III: Electron-donating groups increase the dipolarophiles HOMO to better interact with the 1,3-dipole LUMO. Electron-withdrawing groups will deactivate the dipolarophiles.
Classes of 1,3-dipoles
Huisgen and others investigated a range of 1,3-dipoles and dipolarophiles. These included:- AzideAzideAzide is the anion with the formula N3−. It is the conjugate base of hydrazoic acid. N3− is a linear anion that is isoelectronic with CO2 and N2O. Per valence bond theory, azide can be described by several resonance structures, an important one being N−=N+=N−...
s and alkyneAlkyneAlkynes are hydrocarbons that have a triple bond between two carbon atoms, with the formula CnH2n-2. Alkynes are traditionally known as acetylenes, although the name acetylene also refers specifically to C2H2, known formally as ethyne using IUPAC nomenclature...
s react in the Azide alkyne Huisgen cycloadditionAzide alkyne Huisgen cycloadditionThe Azide-Alkyne Huisgen Cycloaddition is a 1,3-dipolar cycloaddition between an azide and a terminal or internal alkyne to give a 1,2,3-triazole. Rolf Huisgen was the first to understand the scope of this organic reaction. American chemist K...
. - Diazo compounds are 1,3-dipoles in the Diazoalkane 1,3-dipolar cycloadditionDiazoalkane 1,3-dipolar cycloadditionThe Diazoalkane 1,3-dipolar cycloaddition is a 1,3-dipolar cycloaddition between a 1,3-dipole diazo compound and a dipolarophile. When the dipolarphile is an alkene, the reaction product is a pyrazoline....
. - NitroneNitroneA nitrone is the N-oxide of an imine and a functional group in organic chemistry. The general structure is R1R2C=NR3+O- where R3 is different from H.A nitrone is 1,3-dipole in 1,3-dipolar cycloadditions...
s react with alkenes to form isoxazolidines. - Nitrile oxides react with alkenes to form isoxazolines.
- OzonolysisOzonolysisOzonolysis is the cleavage of an alkene or alkyne with ozone to form organic compounds in which the multiple carbon–carbon bond has been replaced by a double bond to oxygen...
begins with a 1,3-dipolar cycloaddition of ozoneOzoneOzone , or trioxygen, is a triatomic molecule, consisting of three oxygen atoms. It is an allotrope of oxygen that is much less stable than the diatomic allotrope...
. This is followed by a retro-1,3-dipolar cycloaddition and then a 1,3-dipolar cycloaddition of the fragments. - FullerenesFullereneA fullerene is any molecule composed entirely of carbon, in the form of a hollow sphere, ellipsoid, or tube. Spherical fullerenes are also called buckyballs, and they resemble the balls used in association football. Cylindrical ones are called carbon nanotubes or buckytubes...
and nanotubesCarbon nanotubeCarbon nanotubes are allotropes of carbon with a cylindrical nanostructure. Nanotubes have been constructed with length-to-diameter ratio of up to 132,000,000:1, significantly larger than for any other material...
can undergo a 1,3-dipolar cycloaddition with an azomethine ylide in the Prato reactionPrato reactionThe Prato reaction in fullerene chemistry describes the functionalization of fullerenes and nanotubes with azomethine ylides in a 1,3-dipolar cycloaddition...
.
External links
- Click Chemicals. A new site featuring in depth discussion, faq's and links to key papers surround 1,3 dipolar cycloadditions