The retro-Diels–Alder reaction (rDA reaction) is the reverse of the
Diels–Alder (DA) reaction, a
+2cycloelimination. It involves the formation of a diene and dienophile from a
cyclohexene
Cyclohexene is a hydrocarbon with the formula C6H10. This cycloalkene is a colorless liquid with a sharp smell. It is an intermediate in various industrial processes. Cyclohexene is not very stable upon long term storage with exposure to light a ...
. It can be accomplished spontaneously with heat, or with acid or base mediation.
In principle, it becomes thermodynamically favorable for the Diels–Alder reactions to proceed in the reverse direction if the temperature is high enough. In practice, this reaction generally requires some special structural features in order to proceed at temperatures of synthetic relevance. For instance, the cleavage of cyclohexene to give butadiene and ethene has been observed, but only at temperatures exceeding 800 K. With an appropriate driving force, however, the Diels–Alder reaction proceeds in reverse under relatively mild conditions, providing diene and dienophile from starting cyclohexene derivatives. As early as 1929, this process was known and applied to the detection of cyclohexadienes, which released ethylene and aromatic compounds after reacting with acetylenes through a Diels–Alder/retro-Diels–Alder sequence. Since then, a variety of substrates have been subject to the rDA, yielding many different dienes and dienophiles. Additionally, conducting the rDA in the presence of a scavenging diene or dienophile has led to the capture of many transient reactive species.
Mechanism and stereochemistry
Prevailing mechanism
The retro-Diels–Alder reaction proper is the microscopic reverse of the Diels–Alder reaction: a concerted (but not necessarily synchronous), pericyclic, single-step process. Evidence for the retro-Diels–Alder reaction was provided by the observation of ''endo''-''exo'' isomerization of Diels–Alder adducts. It was postulated that at high temperatures, isomerization of kinetic ''endo'' adducts to more thermodynamically stable ''exo'' products occurred via an rDA/DA sequence. However, such isomerization may take place via a completely intramolecular,
,3sigmatropic (Cope) process. Evidence for the latter was provided by the reaction below—none of the "head-to-head" isomer was obtained, suggesting a fully intramolecular isomerization process.
''(2)''
Stereochemistry
Like the Diels–Alder reaction, the rDA preserves configuration in the diene and dienophile. Much less is known about the relative rates of reversion of ''endo'' and ''exo'' adducts, and studies have pointed to no correlation between relative configuration in the cyclohexene starting material and reversion rate.
Scope and limitations
A few rDA reactions occur spontaneously at room temperature because of the high reactivity or volatility of the emitted dienophile. Most, however, require additional thermal or chemical activation. The relative tendencies of a variety of dienes and dienophiles to form via rDA are described below:
Diene:
furan
Furan is a heterocyclic organic compound, consisting of a five-membered aromatic ring with four carbon atoms and one oxygen atom. Chemical compounds containing such rings are also referred to as furans.
Furan is a colorless, flammable, highly ...
,
pyrrole
Pyrrole is a heterocyclic aromatic organic compound, a five-membered ring with the formula C4 H4 NH. It is a colorless volatile liquid that darkens readily upon exposure to air. Substituted derivatives are also called pyrroles, e.g., ''N''-met ...
>
benzene
Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen ato ...
>
naphthalene
Naphthalene is an organic compound with formula . It is the simplest polycyclic aromatic hydrocarbon, and is a white crystalline solid with a characteristic odor that is detectable at concentrations as low as 0.08 ppm by mass. As an aromat ...
>
fulvene >
cyclopentadiene
Cyclopentadiene is an organic compound with the formula C5H6.LeRoy H. Scharpen and Victor W. Laurie (1965): "Structure of cyclopentadiene". ''The Journal of Chemical Physics'', volume 43, issue 8, pages 2765-2766. It is often abbreviated CpH beca ...
>
anthracene
Anthracene is a solid polycyclic aromatic hydrocarbon (PAH) of formula C14H10, consisting of three fused benzene rings. It is a component of coal tar. Anthracene is used in the production of the red dye alizarin and other dyes. Anthracene is ...
>
butadiene
1,3-Butadiene () is the organic compound with the formula (CH2=CH)2. It is a colorless gas that is easily condensed to a liquid. It is important industrially as a precursor to synthetic rubber. The molecule can be viewed as the union of two vin ...
Dienophile:
N2 >
CO2 >
naphthalene
Naphthalene is an organic compound with formula . It is the simplest polycyclic aromatic hydrocarbon, and is a white crystalline solid with a characteristic odor that is detectable at concentrations as low as 0.08 ppm by mass. As an aromat ...
>
benzene
Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen ato ...
,
nitrile
In organic chemistry, a nitrile is any organic compound that has a functional group. The prefix '' cyano-'' is used interchangeably with the term ''nitrile'' in industrial literature. Nitriles are found in many useful compounds, including me ...
s >
methacrylate Methacrylates are derivatives of methacrylic acid.
* Methyl methacrylate
* Ethyl methacrylate
* Butyl methacrylate
* Hydroxyethyl methacrylate
* Glycidyl methacrylate
Glycidyl methacrylate (GMA) is an ester of methacrylic acid and glycidol. C ...
>
maleimides >
cyclopentadiene
Cyclopentadiene is an organic compound with the formula C5H6.LeRoy H. Scharpen and Victor W. Laurie (1965): "Structure of cyclopentadiene". ''The Journal of Chemical Physics'', volume 43, issue 8, pages 2765-2766. It is often abbreviated CpH beca ...
,
imine
In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bo ...
s,
alkene
In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond.
Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...
s >
alkyne
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Acetylene
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Propyne
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1-Butyne
In organic chemistry, an alkyne is an unsaturated hydrocarbon containing at least one carbon—carbon triple bond. The simplest acyclic alkynes with only one triple bond and no ...
s
All-carbon dienophiles
Because the Diels–Alder reaction exchanges two π bonds for two σ bonds, it is intrinsically thermodynamically favored in the forward direction. However, a variety of strategies for overcoming this inherent thermodynamic bias are known. Complexation of Lewis acids to basic functionality in the starting material may induce the retro-Diels–Alder reaction, even in cases when the forward reaction is intramolecular.
''(3)''
Base mediation can be used to induce rDA in cases when the separated products are less basic than the starting material. This strategy has been used, for instance, to generate aromatic cyclopentadienyl anions from adducts of cyclopentadiene. Strategically placed electron-withdrawing groups in the starting material can render this process essentially irreversible.
''(4)''
If isolation or reaction of an elusive diene or dienophile is the goal, one of two strategies may be used. Flash vacuum pyrolysis of Diels–Alder adducts synthesized by independent means can provide extremely reactive, short-lived dienophiles (which can then be captured by a unique diene). Alternatively, the rDA reaction may be carried out in the presence of a scavenger. The scavenger reacts with either the diene or (more typically) the dienophile to drive the equilibrium of the retro-DA process toward products. Highly reactive cyanoacrylates may be isolated from Diels–Alder adducts (synthesized independently) with the use of a scavenger.
''(5)''
Heteroatomic dienophiles
Nitriles may be released in rDA reactions of DA adducts of pyrimidines or pyrazines. The resulting highly substituted pyridines can be difficult to access by other means.
''(6)''
Release of isocyanates from Diels–Alder adducts of pyridones can be used to generate highly substituted aromatic compounds. The isocyanates may be isolated or trapped if they are the desired product.
''(7)''
Release of nitrogen from six-membered, cyclic diazenes is common and often spontaneous at room temperature. In this particular example, the epoxide shown undergoes rDA at 0 °C. The isomer with a ''cis'' relationship between the diazene and epoxide reacts only after heating to >180 °C.
''(8)''
The concerted release of oxygen via rDA results in the formation of
singlet oxygen
Singlet oxygen, systematically named dioxygen(singlet) and dioxidene, is a gaseous inorganic chemical with the formula O=O (also written as or ), which is in a quantum state where all electrons are spin paired. It is kinetically unstable at ambie ...
. Very high yields of singlet oxygen result from rDA reactions of some cyclic peroxides—in this example, a greater than 90% yield of singlet oxygen was obtained.
''(9)''
Carbon dioxide is a common dienophile released during rDA reactions. Diels–Alder adducts of alkynes and 2-pyrones can undergo rDA to release carbon dioxide and generate aromatic compounds.
''(10)''
Experimental conditions and procedure
Typical conditions
Internal energy is the only factor controlling the extent of rDA reactions, and temperature is usually the only variable cited for these reactions. Thus, there are no conditions which can be regarded as "typical." For rDA reactions that afford a volatile product, removal of this product may facilitate the reaction, although most of these reactions (nitrogen- and oxygen-releasing rDA, for instance) are irreversible without any extra inducement.
References
{{reflist, 35em
Cycloadditions
Tandem mass spectrometry
Name reactions