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einem, isomeren, methyl, octahydro, indolizin, 19375300106, harms, xxvi, isochinolin, entstehenden, 19365250107, 525, xxv, hydrazo, verbindungen, 157, 19355190113, 147, kech, xxiv, 146, 19355190112, 140, möller, xxiii, stilbazol, dicarbonester, 19355160104, 516, friedrichsen, xxii, c4o3, ihre, eignung, ein, neues, prinzip, dihydro, 155, 19345130109, xxi, verlauf, methylalkoholischer, lösung, 19345130108, 129, hydrazobenzol, 182, 19345110114, 168, 511, xix, primärprodukte, bei, 128, 19345100106, 510, 1933, xviii, chinolizins, indolizins, pseudolupinins, 150, 19335050109, 505, xvii, isochinolins, 19324980103, xvi, pyrazole, 19324980102, 294, 19314900113, 277, xiv, 276, 19314900112, 267, xiii, cumaline, 266, 19314900111, furans, 19314900110, cyclopentadiens, cyclo, hexadiens, butadiens, 242, 19314900109, 236, pyrrol, seinen, homologen, 225, 19314860112, 211, camphenilons, santens, 210, 19314860111, viii, anthracens, forme, 19314860110, 191, 1930, harren, ernst, petersen, 154, 19304780109, 137, 478, gerhard, stein, partiell, hydrierte, naphtho, anthrachinone, wasserstoff, bzw, stellung, winckler, 2372, 19290620872, 2337, tetrahydro, phthalsäure, stellungnahme, farmer, warren, eigenschaften, konjugierter, 2090, 19290620830, maleinsäure, anhydrid, arylierte, triene, fulvene, 19290620829, 2081, iii, terpenen, camphern, heterocyclischen, systemen, herren, wolfgang, lübbert, erich, naujoks, karl, röhl, harro, segeberg, 19294700106, 470, 562, 19290620318, anlagerungen, kohlenwasserstoffen, 19284600106, 460, behr, arno, homogeneous, 3527306732, 14356007, a18_215, minami, atsushi, oikawa, hideaki, 506, 30482282, 27301662, 500, antibiotics, advances, alderases, fluegel, lucas, 2444, 33492939, 8008985, chemrev, 0c00825, 2413, 121, rev, generation, cycloisomerization, tethered, triynes, baire, niu, willoughby, woods, 7419, 212, 23060191, 3538845, nature11518, 2012natur, 208h, 208, ahrendt, borths, macmillan, organocatalytic, 4244, ja000092s, 2000jachs, 4243a, 4243, versatile, 335, 10891050, ar960062n, 325, ryu, 2003, triflimide, 6390, 12785777, ja035393r, 6388, 125, shibata, lee, triflic, 3809, 11942799, ja025848x, 3808, loh, application, design, 8967, ja00023a066, 8966c, 8966, chapman, bisaha, acyloxazolidinones, 1256, ja00212a037, 1238e, 1238, james, shaw, subrata, diaminobicyclo, octane, scaffold, salen, 21462988, ol2007378, 2488, lett, tiekink, eveline, 5283, 239089361, 2066, 241097, ejoc, 202101107, 5275, hansen, yoshisada, ryoji, filippov, dmitri, marel, gijsbert, codée, jeroen, 3573, 33538169, 7901664, joc, 0c02955, 3565, openings, oxide, brinkhuis, francine, 1174, 32012430, 7187256, asia, 202000009, 1167, asian, alkali, cations, 1981, 232337915, 33759502, 1871, a0090b38, 9ab8, 4c32, 9d9a, b3d5de4e5ed3, 1c00016, 20106, 34499069, 8457343, d1cp02456f, 2021pccp, 2320095v
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e classical diels alder reaction subsection 2 1 other ring sizes 2 2 hetero diels alder 2 3 lewis acid activation 2 4 asymmetric diels alder 2 5 hexadehydro diels alder 3 applications and natural occurrence 4 history 5 applications in total synthesis 6 see also 7 references 8 bibliography 9 external links toggle the table of contents diels alder reaction 36 languages العربية azərbaycanca বাংলা bosanski català čeština deutsch ελληνικά español euskara فارسی suomi français עברית bahasa indonesia italiano 日本語 한국어 кыргызча latviešu македонски nederlands polski português română русский srpskohrvatski српскохрватски simple english српски srpski svenska türkçe українська oʻzbekcha ўзбекча tiếng việt 文言 中文 edit links article talk english read edit view history tools tools move to sidebar hide actions read edit view history general what links here related changes upload file permanent link page information cite this page get shortened url switch to legacy parser print export download as pdf printable version in other projects wikimedia commons wikidata item appearance move to sidebar hide from wikipedia the free encyclopedia redirected from diels alder reaction chemical reaction diels alder reaction reaction type cycloaddition identifiers organic chemistry portal diels alder reaction rsc ontology id rxno 0000006 diels alder reaction simplest example in organic chemistry the diels alder reaction is a chemical reaction between a conjugated diene and a substituted alkene commonly termed the dienophile to form a substituted cyclohexene derivative it is the prototypical pericyclic reaction with a concerted mechanism specifically it is a thermally allowed 4 2 cycloaddition with woodward hoffmann symbol π 4 s π 2 s simultaneously constructing two new carbon carbon bonds the diels alder reaction reliably forms six membered rings with good regio and stereochemical control 1 2 consequently it is a powerful tool widely applied to introduce chemical complexity in the synthesis of natural products and new materials 3 4 the reaction was first described by otto diels and kurt alder in 1928 for its discovery they were awarded the nobel prize in chemistry in 1950 the underlying concept has been generalized in several different directions in the hetero diels alder reaction π systems involving heteroatoms such as carbonyls and imines furnish the corresponding heterocycles diels alder like reactions occur for other ring sizes although none matched the 4 2 reaction in scope and versatility because δ h and δ s are negative for a typical diels alder reaction the reverse of a diels alder reaction becomes favorable at high temperatures this retro diels alder reaction is of synthetic importance for only a limited range of diels alder adducts generally with some special structural features 5 mechanism edit 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 diels alder reaction is governed by orbital symmetry considerations it is classified as a π 4 s π 2 s cycloaddition indicating that it proceeds through the suprafacial suprafacial interaction of a 4π electron system the diene structure with a 2π electron system the dienophile structure an interaction that leads to a transition state without an additional orbital symmetry imposed energetic barrier and allows the diels alder 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 diels alder reaction the more important of the two homo lumo interactions is that between the electron rich diene s ψ 2 as the highest occupied molecular orbital homo with the electron deficient dienophile s π as the lowest unoccupied molecular orbital lumo however the homo lumo 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 diels alder reaction electron withdrawing substituents on the diene lower the energy of its empty ψ 3 orbital and electron donating substituents on the dienophile raise the energy of its filled π 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 fmo analysis of the diels alder reaction additional phenomena beyond the frontier orbital interactions also affect the reaction rate one simple way to deduce this is to note that the homo lumo interactions detailed above apply to all donor acceptor complexes even though not all donor acceptor complexes undergo the diels alder reaction in practice most of the other phenomena are captured in the reaction enthalpy and the orbital interaction can be estimated from geometry and ionization energies an empirical formula for the reaction rate of an uncatalyzed reaction is log k mol s 290 10 60 8 2 8 å 1 r ev i d e a 5 05 0 39 mol kj δ h 28 2 displaystyle log k cdot textrm mol cdot textrm s left 290 pm 10 60 8 pm 2 8 text å 1 cdot r right frac textrm ev i_ d e_ a 5 05 pm 0 39 frac textrm mol textrm kj cdot delta h 28 2 where k is the reaction rate r is the distance between the two ends of the diene i d is the ionization potential of the diene e a is the electron affinity of the dienophile and δ h is the reaction enthalpy 9 the prevailing opinion 10 11 12 13 is that most diels alder reactions proceed through a concerted mechanism the issue however has been thoroughly contested despite the fact that the vast majority of diels alder 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 diels alder reactions are carried out in polar organic solvents such as dimethylformamide and ethylene glycol 14 and even in water 15 the reaction of cyclopentadiene and butenone for example is 700 times faster in water relative to 2 2 4 trimethylpentane as solvent 15 several explanations for this effect have been proposed such as an increase in effective concentration due to hydrophobic packing 16 or hydrogen bond stabilization of the transition state 17 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 diels alder cycloaddition reactions the conformational stability of the structure of the transition state can be an overwhelming influence regioselectivity edit frontier molecular orbital theory has also been used to explain the regioselectivity patterns observed in diels alder reactions of substituted systems calculation of the energy and orbital coefficients of the components frontier orbitals 18 provides a picture that is in good accord with the more straightforward analysis of the substituents resonance effects as illustrated below resonance structures of normal demand dienes and dienophiles in general the regioselectivity found for both normal and inverse electron demand diels alder 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 regioselectivity in normal 1 and 2 and inverse 3 and 4 electron demand diels alder reactions 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 z withdrawing homo and lumo lowering cf 3 no 2 cn c o ch 3 x donating homo and lumo raising me ome nme 2 c conjugating 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 19 however cases where the resonance argument and the matching of largest orbital coefficients disagree are rare stereospecificity and stereoselectivity edit diels alder 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 20 21 endo and exo transition states for cyclopentadiene adding to acrolein endo exo product ratio for this and various other dienophiles diels alder 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 diels alder 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 π 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 diels alder 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 22 the endo rule applies when there the electron withdrawing groups on the dienophile are all on one side the most widely accepted explanation for the origin of this effect is a favorable interaction between the π 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 23 24 the secondary orbital overlap explanation was first proposed by woodward and hoffmann 25 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 β carbons both participate when molecular geometry allows 26 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 edit the diene component of the diels alder 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 2 5 kcal mol 27 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 28 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 28 dienes with bulky terminal substituents c1 and c4 decrease the rate of reaction presumably by impeding the approach of the diene and dienophile 29 an especially reactive diene is 1 methoxy 3 trimethylsiloxy buta 1 3 diene otherwise known as danishefsky s diene 30 it has particular synthetic utility as means of furnishing α β unsaturated 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 31 and 1 dialkylamino 3 trimethylsiloxy 1 3 butadienes rawal dienes 32 the increased reactivity of these and similar dienes is a result of synergistic contributions...
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