In
organic chemistry, the DielsâAlder reaction is a chemical reaction between a
conjugateddiene and a substituted
alkene, commonly termed the
dienophile, to form a substituted
cyclohexene derivative. It is the prototypical example of a
pericyclic reaction with a
concerted mechanism. More specifically, it is classified as a thermally-allowed [4+2]
cycloaddition with
WoodwardâHoffmann symbol [Ï4s + Ï2s]. It was first described by
Otto Diels and
Kurt Alder in 1928. For the discovery of this reaction, they were awarded the
Nobel Prize in Chemistry in 1950. Through the simultaneous construction of two new carbonâcarbon bonds, the DielsâAlder reaction provides a reliable way to form six-membered rings with good control over the regio- and stereochemical outcomes.[1][2] Consequently, it has served as a powerful and widely applied tool for the introduction of chemical complexity in the synthesis of natural products and new materials.[3][4] The underlying concept has also been applied to Ï-systems involving
heteroatoms, such as
carbonyls and
imines, which furnish the corresponding
heterocycles; this variant is known as the hetero-DielsâAlder reaction. The reaction has also been generalized to other ring sizes, although none of these generalizations have matched the formation of six-membered rings in terms of scope or versatility. Because of the negative values of ÎH° and ÎS° for a typical DielsâAlder reaction, the microscopic reverse of a DielsâAlder reaction becomes favorable at high temperatures, although this is of synthetic importance for only a limited range of Diels-Alder adducts, generally with some special structural features; this reverse reaction is known as the
retro-DielsâAlder reaction.[5]
Mechanism
The reaction is an example of a concerted pericyclic reaction.[6] It is believed to occur via a single, cyclic transition state,[7] with no intermediates generated during the course of the reaction. As such, the DielsâAlder reaction is governed by orbital symmetry considerations: it is classified as a [Ï4s + Ï2s] cycloaddition, indicating that it proceeds through the
suprafacial/suprafacial interaction of a 4Ï electron system (the diene structure) with a 2Ï electron system (the dienophile structure), an interaction that leads to a transition state without an additional orbital symmetry-imposed energetic barrier and allows the DielsâAlder reaction to take place with relative ease.[8]
A consideration of the reactants'
frontier molecular orbitals (FMO) makes plain why this is so. (The same conclusion can be drawn from an orbital correlation diagram or a Dewar-Zimmerman analysis.) For the more common "normal" electron demand DielsâAlder reaction, the more important of the two HOMO/LUMO interactions is that between the electron-rich diene's Ï2 as the highest occupied molecular orbital (HOMO) with the electron-deficient dienophile's Ï* as the lowest unoccupied molecular orbital (LUMO). However, the HOMOâLUMO energy gap is close enough that the roles can be reversed by switching electronic effects of the substituents on the two components. In an
inverse (reverse) electron-demand DielsâAlder reaction, electron-withdrawing substituents on the diene lower the energy of its empty Ï3 orbital and electron-donating substituents on the dienophile raise the energy of its filled Ï orbital sufficiently that the interaction between these two orbitals becomes the most energetically significant stabilizing orbital interaction. Regardless of which situation pertains, the HOMO and LUMO of the components are in phase and a bonding interaction results as can be seen in the diagram below. Since the reactants are in their ground state, the reaction is initiated thermally and does not require activation by light.[8]
The "prevailing opinion"[9][10][11][12] is that most DielsâAlder reactions proceed through a concerted mechanism; the issue, however, has been thoroughly contested. Despite the fact that the vast majority of DielsâAlder reactions exhibit stereospecific, syn addition of the two components, a diradical intermediate has been postulated[7] (and supported with computational evidence) on the grounds that the observed stereospecificity does not rule out a two-step addition involving an intermediate that collapses to product faster than it can rotate to allow for inversion of stereochemistry.
There is a notable rate enhancement when certain DielsâAlder reactions are carried out in polar organic solvents such as
dimethylformamide and
ethylene glycol,[13] and even in water.[14] The reaction of
cyclopentadiene and
butenone for example is 700 times faster in water relative to
2,2,4-trimethylpentane as solvent.[14] Several explanations for this effect have been proposed, such as an increase in effective concentration due to hydrophobic packing[15] or hydrogen-bond stabilization of the transition state.[16]
The geometry of the diene and dienophile components each propagate into stereochemical details of the product. For
intermolecular reactions especially, the preferred
positional and stereochemical relationship of substituents of the two components compared to each other are controlled by electronic effects. However, for
intramolecular DielsâAlder cycloaddition reactions, the conformational stability of the structure of the
transition state can be an overwhelming influence.
Regioselectivity
Frontier molecular orbital theory has also been used to explain the regioselectivity patterns observed in DielsâAlder reactions of substituted systems. Calculation of the energy and orbital coefficients of the components' frontier orbitals[17] provides a picture that is in good accord with the more straightforward analysis of the substituents' resonance effects, as illustrated below.
In general, the regioselectivity found for both normal and inverse electron-demand DielsâAlder reaction follows the ortho-para rule, so named, because the cyclohexene product bears substituents in positions that are analogous to the ortho and para positions of disubstituted arenes. For example, in a normal-demand scenario, a diene bearing an electron-donating group (EDG) at C1 has its largest HOMO coefficient at C4, while the dienophile with an electron withdrawing group (EWG) at C1 has the largest LUMO coefficient at C2. Pairing these two coefficients gives the "ortho" product as seen in case 1 in the figure below. A diene substituted at C2 as in case 2 below has the largest HOMO coefficient at C1, giving rise to the "para" product. Similar analyses for the corresponding inverse-demand scenarios gives rise to the analogous products as seen in cases 3 and 4. Examining the canonical mesomeric forms above, it is easy to verify that these results are in accord with expectations based on consideration of electron density and polarization.
In general, with respect to the energetically most well-matched HOMO-LUMO pair, maximizing the interaction energy by forming bonds between centers with the largest frontier orbital coefficients allows the prediction of the main regioisomer that will result from a given diene-dienophile combination.[8] In a more sophisticated treatment, three types of substituents (Zwithdrawing: HOMO and LUMO lowering (CF3, NO2, CN, C(O)CH3), Xdonating: HOMO and LUMO raising (Me, OMe, NMe2), Cconjugating: HOMO raising and LUMO lowering (Ph, vinyl)) are considered, resulting in a total of 18 possible combinations. The maximization of orbital interaction correctly predicts the product in all cases for which experimental data is available. For instance, in uncommon combinations involving X groups on both diene and dienophile, a 1,3-substitution pattern may be favored, an outcome not accounted for by a simplistic resonance structure argument.[18] However, cases where the resonance argument and the matching of largest orbital coefficients disagree are rare.
Stereospecificity and stereoselectivity
DielsâAlder reactions, as concerted cycloadditions, are
stereospecific. Stereochemical information of the diene and the dienophile are retained in the product, as a syn addition with respect to each component. For example, substituents in a cis (trans, resp.) relationship on the double bond of the dienophile give rise to substituents that are cis (trans, resp.) on those same carbons with respect to the cyclohexene ring. Likewise, cis,cis- and trans,trans-disubstituted dienes give cis substituents at these carbons of the product whereas cis,trans-disubstituted dienes give trans substituents:[19][20]
DielsâAlder reactions in which adjacent stereocenters are generated at the two ends of the newly formed single bonds imply two different possible stereochemical outcomes. This is a
stereoselective situation based on the relative orientation of the two separate components when they react with each other. In the context of the DielsâAlder reaction, the transition state in which the most significant substituent (an electron-withdrawing and/or conjugating group) on the dienophile is oriented towards the diene Ï system and slips under it as the reaction takes place is known as the endo transition state. In the alternative exo transition state, it is oriented away from it. (There is a more general usage of the terms
endo and exo in stereochemical nomenclature.)
In cases where the dienophile has a single electron-withdrawing / conjugating substituent, or two electron-withdrawing / conjugating substituents cis to each other, the outcome can often be predicted. In these "normal demand" DielsâAlder scenarios, the endo transition state is typically preferred, despite often being more sterically congested. This preference is known as the Alder endo rule. As originally stated by Alder, the transition state that is preferred is the one with a "maximum accumulation of double bonds." Endo selectivity is typically higher for rigid dienophiles such as
maleic anhydride and
benzoquinone; for others, such as
acrylates and
crotonates, selectivity is not very pronounced.[21]
The most widely accepted explanation for the origin of this effect is a favorable interaction between the Ï systems of the dienophile and the diene, an interaction described as a secondary orbital effect, though
dipolar and
van der Waals attractions may play a part as well, and solvent can sometimes make a substantial difference in selectivity.[6][22][23] The secondary orbital overlap explanation was first proposed by Woodward and Hoffmann.[24] In this explanation, the orbitals associated with the group in conjugation with the dienophile double-bond overlap with the interior orbitals of the diene, a situation that is possible only for the endo transition state. Although the original explanation only invoked the orbital on the atom α to the dienophile double bond, Salem and Houk have subsequently proposed that orbitals on the α and ÎČ carbons both participate when molecular geometry allows.[25]
Often, as with highly substituted dienes, very bulky dienophiles, or
reversible reactions (as in the case of
furan as diene), steric effects can override the normal endo selectivity in favor of the exo isomer.
The diene
The
diene component of the DielsâAlder reaction can be either open-chain or cyclic, and it can host many different types of substituents.[6] It must, however, be able to exist in the s-cis conformation, since this is the only conformer that can participate in the reaction. Though butadienes are typically more stable in the s-trans conformation, for most cases energy difference is small (~2â5 kcal/mol).[26]
A bulky substituent at the C2 or C3 position can increase reaction rate by destabilizing the s-trans conformation and forcing the diene into the reactive s-cis conformation. 2-tert-butyl-buta-1,3-diene, for example, is 27 times more reactive than simple butadiene.[6][27] Conversely, a diene having bulky substituents at both C2 and C3 is less reactive because the steric interactions between the substituents destabilize the s-cis conformation.[27]
Dienes with bulky terminal substituents (C1 and C4) decrease the rate of reaction, presumably by impeding the approach of the diene and dienophile.[28]
An especially reactive diene is 1-methoxy-3-trimethylsiloxy-buta-1,3-diene, otherwise known as
Danishefsky's diene.[29] It has particular synthetic utility as means of furnishing α,ÎČâunsaturated
cyclohexenone systems by elimination of the 1-methoxy substituent after deprotection of the enol silyl ether. Other synthetically useful derivatives of Danishefsky's diene include 1,3-alkoxy-1-trimethylsiloxy-1,3-butadienes (Brassard dienes)[30] and 1-dialkylamino-3-trimethylsiloxy-1,3-butadienes (Rawal dienes).[31] The increased reactivity of these and similar dienes is a result of synergistic contributions from donor groups at C1 and C3, raising the HOMO significantly above that of a comparable monosubstituted diene.[3]
Unstable (and thus highly reactive) dienes can be synthetically useful, e.g. o-
quinodimethanes can be generated in situ. In contrast, stable dienes, such as
naphthalene, require forcing conditions and/or highly reactive dienophiles, such as
N-phenylmaleimide.
Anthracene, being less aromatic (and therefore more reactive for DielsâAlder syntheses) in its central ring can form a 9,10 adduct with
maleic anhydride at 80 °C and even with
acetylene, a weak dienophile, at 250 °C.[32]
The dienophile
In a normal demand DielsâAlder reaction, the dienophile has an electron-withdrawing group in conjugation with the alkene; in an inverse-demand scenario, the dienophile is conjugated with an electron-donating group.[9] Dienophiles can be chosen to contain a "masked functionality". The dienophile undergoes DielsâAlder reaction with a diene introducing such a functionality onto the product molecule. A series of reactions then follow to transform the functionality into a desirable group. The end product cannot be made in a single DA step because equivalent dienophile is either unreactive or inaccessible. An example of such approach is the use of
α-chloroacrylonitrile (CH2=CClCN). When reacted with a diene, this dienophile will introduce α-chloronitrile functionality onto the product molecule. This is a "masked functionality" which can be then hydrolyzed to form a
ketone. α-Chloroacrylonitrile dienophile is an equivalent of
ketene dienophile (CH2=C=O), which would produce same product in one DA step. The problem is that ketene itself cannot be used in DielsâAlder reactions because it reacts with dienes in unwanted manner (by [2+2] cycloaddition), and therefore "masked functionality" approach has to be used.[33] Other such functionalities are
phosphonium substituents (yielding exocyclic double bonds after
Wittig reaction), various
sulfoxide and
sulfonyl functionalities (both are acetylene equivalents), and
nitro groups (ketene equivalents).[6]
Lewis acids, such as
zinc chloride,
boron trifluoride,
tin tetrachloride, or
aluminium chloride, can catalyze DielsâAlder reactions by binding to the dienophile. Traditionally, the enhanced Diels-Alder reactivity is ascribed to the ability of the Lewis acid to lower the LUMO of the activated dienophile, which results in a smaller normal electron demand HOMO-LUMO orbital energy gap and hence more stabilizing orbital interactions.[36][37][38]
Recent studies, however, have shown that this rationale behind Lewis acid-catalyzed DielsâAlder reactions is incorrect.[39][40][41][42] It is found that Lewis acids accelerate the DielsâAlder reaction by reducing the destabilizing steric Pauli repulsion between the interacting diene and dienophile and not by lowering the energy of the dienophile's LUMO and consequently, enhancing the normal electron demand orbital interaction. The Lewis acid binds via a donor-acceptor interaction to the dienophile and via that mechanism polarizes occupied orbital density away from the reactive C=C double bond of the dienophile towards the Lewis acid. This reduced occupied orbital density on C=C double bond of the dienophile will, in turn, engage in a less repulsive closed-shell-closed-shell orbital interaction with the incoming diene, reducing the destabilizing steric Pauli repulsion and hence lowers the DielsâAlder reaction barrier. In addition, the Lewis acid catalyst also increases the asynchronicity of the DielsâAlder reaction, making the occupied Ï-orbital located on the C=C double bond of the dienophile asymmetric. As a result, this enhanced asynchronicity leads to an extra reduction of the destabilizing steric Pauli repulsion as well as a diminishing pressure on the reactants to deform, in other words, it reduced the destabilizing activation strain (also known as distortion energy).[43] This working catalytic mechanism is known as Pauli-lowering catalysis,[44] which is operative in a variety of organic reactions.[45][46][47]
The original rationale behind Lewis acid-catalyzed DielsâAlder reactions is incorrect,[39][48][49][50] because besides lowering the energy of the dienophile's LUMO, the Lewis acid also lowers the energy of the HOMO of the dienophile and hence increases the inverse electron demand LUMO-HOMO orbital energy gap. Thus, indeed Lewis acid catalysts strengthen the normal electron demand orbital interaction by lowering the LUMO of the dienophile, but, they simultaneously weaken the inverse electron demand orbital interaction by also lowering the energy of the dienophile's HOMO. These two counteracting phenomena effectively cancel each other, resulting in nearly unchanged orbital interactions when compared to the corresponding uncatalyzed DielsâAlder reactions and making this not the active mechanism behind Lewis acid-catalyzed DielsâAlder reactions.
In the
hexadehydro DielsâAlder reaction,
alkynes and
diynes are used instead of alkenes and dienes, forming an unstable
benzyne intermediate which can then be trapped to form an aromatic product. This reaction allows the formation of heavily functionalized aromatic rings in a single step.[58][59]
Applications and natural occurrence
The retro-DielsâAlder reaction is used in the industrial production of
cyclopentadiene. Cyclopentadiene is a precursor to various
norbornenes, which are common
monomers. The DielsâAlder reaction is also employed in the production of
vitamin B6.
The DielsâAlder reaction was one step in an early preparation of the steroids
cortisone and
cholesterol.[64] The reaction involved the addition of butadiene to a quinone.
DielsâAlder reactions were used in the original synthesis of
prostaglandinsF2α and
E2.[65] The DielsâAlder reaction establishes the relative stereochemistry of three contiguous stereocenters on the prostaglandin cyclopentane core. Activation by Lewis acidic
cupric tetrafluoroborate was required.
A synthesis of
reserpine uses a DielsâAlder reaction to set the
cis-decalin framework of the D and E rings.[67]
In another synthesis of reserpine, the cis-fused D and E rings was formed by a DielsâAlder reaction. Intramolecular DielsâAlder of the
pyranone below with subsequent extrusion of carbon dioxide via a retro [4+2] afforded the bicyclic
lactam. Epoxidation from the less hindered α-face, followed by epoxide opening at the less hindered C18 afforded the desired stereochemistry at these positions, while the cis-fusion was achieved with hydrogenation, again proceeding primarily from the less hindered face.[68]
A pyranone was similarly used as the dienophile in the
total synthesis of taxol.[69] The intermolecular reaction of the hydroxy-pyrone and α,ÎČâunsaturated
ester shown below suffered from poor yield and regioselectivity; however, when directed by
phenylboronic acid[70] the desired adduct could be obtained in 61% yield after cleavage of the
boronate with
neopentyl glycol. The stereospecificity of the DielsâAlder reaction in this instance allowed for the definition of four stereocenters that were carried on to the final product.
A DielsâAlder reaction is a key step in the synthesis of (-)-furaquinocin C.[71]
Tabersonine was prepared by a DielsâAlder reaction to establish cis relative stereochemistry of the alkaloid core. Conversion of the cis-aldehyde to its corresponding
alkene by Wittig olefination and subsequent
ring-closing metathesis with a
Schrock catalyst gave the second ring of the alkaloid core. The diene in this instance is notable as an example of a 1-amino-3-siloxybutadiene, otherwise known as a Rawal diene.[72]
(+)-Sterpurene can be prepared by asymmetric D-A reaction[73] that featured a remarkable intramolecular DielsâAlder reaction of an
allene. The
[2,3]-sigmatropic rearrangement of the thiophenyl group to give the sulfoxide as below proceeded enantiospecifically due to the predefined stereochemistry of the propargylic alcohol. In this way, the single allene isomer formed could direct the DielsâAlder reaction to occur on only one face of the generated 'diene'.
The tetracyclic core of the antibiotic
(-)-tetracycline was prepared with a DielsâAlder reaction. Thermally initiated, conrotatory opening of the benzocyclobutene generated the o-quinodimethane, which reacted intermolecularly to give the tetracycline skeleton. The dienophile's free hydroxyl group is integral to the success of the reaction, as hydroxyl-protected variants did not react under several different reaction conditions.[74]
Takemura et al. synthesized
cantharidin in 1980 by DielsâAlder reaction, utilizing high pressure.[75]
Synthetic applications of the DielsâAlder reaction have been reviewed extensively.[76][77][78][79][80]
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Diels, O.; Alder, K. (1930). "Synthesen in der hydroaromatischen Reihe, VII. Mitteilung. (Mitbearbeitet von den Harren Ernst Petersen und Franz Querberitz.)". Justus Liebigs Annalen der Chemie. 478: 137â154.
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Diels, O.; Alder, K. (1931). "Synthesen in der hydroaromatischen Reihe, IX. Mitteilung: Synthese des Camphenilons und des Santens". Justus Liebigs Annalen der Chemie. 486: 202â210.
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Diels, O.; Alder, K. (1931). "Synthesen in der hydroaromatischen Reihe, X. Mitteilung: "Dien-Synthesen"ïž mit Pyrrol und seinen Homologen". Justus Liebigs Annalen der Chemie. 486: 211â225.
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Diels, O.; Alder, K. (1931). "Synthesen in der hydroaromatischen Reihe, XI. Mitteilung. ("Dien-Synthesen"ïž des Cyclopentadiens, Cyclo-hexadiens und Butadiens mit Acetylen-dicarbonsĂ€ure und ihren Estern". Justus Liebigs Annalen der Chemie. 490: 236â242.
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Diels, O.; Alder, K. (1931). "Synthesen in der hydroaromatischen Reihe, XII. Mitteilung. ("Dien-Synthesen"ïž sauerstoffhaltiger Heteroringe. 2. Dien-Synthesen des Furans.)". Justus Liebigs Annalen der Chemie. 490: 243â257.
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Diels, O.; Alder, K. (1931). "Synthesen in der hydroaromatischen Reihe, XIII. Mitteilung. ("Dien-Synthesen"ïž sauerstoffhaltiger Heteroringe. 3. Dien-Synthesen der Cumaline.)". Justus Liebigs Annalen der Chemie. 490: 257â266.
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Diels, O.; Alder, K. (1931). "Synthesen in der hydroaromatischen Reihe, XIV. Mitteilung. ("Dien-Synthesen"ïž stickstoffhaltiger Heteroringe. 2. Dien-Synthesen der Pyrrole mit Acetylen-dicarbonsĂ€ure und mit ihren Estern.)". Justus Liebigs Annalen der Chemie. 490: 267â276.
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Diels, O.; Alder, K. (1931). "Synthesen in der hydroaromatischen Reihe, XV. Mitteilung. ("Dien-Synthesen"ïž stickstoffhaltiger Heteroringe. 3. Dien-Synthesen der Indole.)". Justus Liebigs Annalen der Chemie. 490: 277â294.
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Diels, O.; Alder, K. (1932). "Synthesen in der hydroaromatischen Reihe, XVI. Mitteilung. ("Dien-Synthesen"ïž stickstoffhaltiger Heteroringe. 4. Dien-Synthesen der Pyrrole, Imidazole und Pyrazole.)". Justus Liebigs Annalen der Chemie. 498: 1â15.
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Diels, O.; Alder, K. (1934). "Synthesen in der hydroaromatischen Reihe, XIX. "Dien-Synthesen"ïž stickstoffhaltiger Heteroringe. 7. Zur Kenntnis der PrimĂ€rprodukte bei den Dien-Synthesen des Pyridins, Chinolins und Chinaldins". Justus Liebigs Annalen der Chemie. 510: 87â128.
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Diels, O.; Reese, J. (1934). "Synthesen in der hydroaromatischen Reihe, XX. Ăber die Anlagerung von Acetylen-dicarbonsĂ€ureester an Hydrazobenzol". Justus Liebigs Annalen der Chemie. 511: 168â182.
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Diels, O.; Meyer, R. (1934). "Synthesen in der hydroaromatischen Reihe, XXI. "Dien-Synthesen"ïž stickstoffhaltiger Heteroringe. 8. Ăber den Verlauf der Dien-Synthese des Pyridins in methylalkoholischer Lösung". Justus Liebigs Annalen der Chemie. 513: 129â145.
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Diels, O.; Friedrichsen, W. (1934). "Synthesen in der hydroaromatischen Reihe, XXII. Ăber die AnthracenâC4O3-Addukte, ihre Eignung zu Dien-Synthesen und ein neues Prinzip zur Synthese von PhtalsĂ€uren und Dihydro-phtalsĂ€uren". Justus Liebigs Annalen der Chemie. 513: 145â155.
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External links
[1] English Translation of Diels and Alder's seminal 1928 German article that won them the Nobel prize. English title: 'Syntheses of the hydroaromatic series'; German title "Synthesen in der hydroaromatischen Reihe".