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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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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 from donor groups at c1 and c3 raising the homo significantly above that of a comparable monosubstituted diene 3 general form of danishefsky brassard and rawal dienes 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 diels alder 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 33 the dienophile edit in a normal demand diels alder 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 10 dienophiles can be chosen to contain a masked functionality the dienophile undergoes diels alder 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 ch 2 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 ch 2 c o which would produce same product in one da step the problem is that ketene itself cannot be used in diels alder reactions because it reacts with dienes in unwanted manner by 2 2 cycloaddition and therefore masked functionality approach has to be used 34 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 variants on the classical diels alder reaction edit other ring sizes edit in trimethylenemethane cycloaddition and 1 3 dipolar cycloaddition the eponymous synthon replaces the diene in 4 3 cycloaddition an allyl cation replaces the dienophile hetero diels alder edit an example of a hetero diels alder reaction which results in the synthesis of a bicyclic heterocycle diels alder reactions involving at least one heteroatom are also known and are collectively called hetero diels alder reactions 35 carbonyl groups for example can successfully react with dienes to yield dihydropyran rings a reaction known as the oxo diels alder reaction and imines can be used either as the dienophile or at various sites in the diene to form various n heterocyclic compounds through the aza diels alder reaction nitroso compounds r n o can react with dienes to form oxazines chlorosulfonyl isocyanate can be utilized as a dienophile to prepare vince lactam 6 36 lewis acid activation edit lewis acids such as zinc chloride boron trifluoride tin tetrachloride or aluminium chloride can catalyze diels alder 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 37 38 39 recent studies however have shown that this rationale behind lewis acid catalyzed diels alder reactions is incorrect 40 41 42 43 it is found that lewis acids accelerate the diels alder 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 diels alder reaction barrier in addition the lewis acid catalyst also increases the asynchronicity of the diels alder reaction making the occupied π 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 44 this working catalytic mechanism is known as pauli lowering catalysis 45 which is operative in a variety of organic reactions 46 47 48 the original rationale behind lewis acid catalyzed diels alder reactions is incorrect 40 49 50 51 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 diels alder reactions and making this not the active mechanism behind lewis acid catalyzed diels alder reactions asymmetric diels alder edit many methods have been developed for influencing the stereoselectivity of the diels alder reaction such as the use of chiral auxiliaries catalysis by chiral lewis acids 52 and small organic molecule catalysts 6 evans oxazolidinones 53 oxazaborolidines 54 55 56 bis oxazoline copper chelates 57 imidazoline catalysis 58 and many other methodologies exist for effecting diastereo and enantioselective diels alder reactions hexadehydro diels alder edit in the hexadehydro diels alder 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 59 60 applications and natural occurrence edit asymmetric diels alder reaction is one step in the biosynthesis of the statin lovastatin 61 the retro diels alder reaction is used in the industrial production of cyclopentadiene cyclopentadiene is a precursor to various norbornenes which are common monomers the diels alder reaction is also employed in the production of vitamin b6 typical route for production of ethylidene norbornene from cyclopentadiene through vinyl norbornene 62 history edit the reaction discovered by diels and alder in 1928 the diels alder reaction was the culmination of several intertwined research threads some near misses and ultimately the insightful recognition of a general principle by otto diels and kurt alder their seminal work detailed in a series of 28 articles published in the justus liebigs annalen der chemie and berichte der deutschen chemischen gesellschaft from 1928 to 1937 established the reaction s wide applicability and its importance in constructing six membered rings the first 19 articles were authored by diels and alder while the later articles were authored by diels and various other coauthors 63 64 however the history of the reaction extends further back revealing a fascinating narrative of discoveries missed and opportunities overlooked 65 several chemists working independently in the late 19th and early 20th centuries encountered reactions that in retrospect involved the diels alder process but remained unrecognized as such 65 theodor zincke performed a series of experiments between 1892 and 1912 involving tetrachlorocyclopentadienone a highly reactive diene analogue 66 67 68 69 in 1910 sergey lebedev systematically investigated thermal polymerization of three conjugated dienes butadiene isoprene and dimethylbutadiene a process now recognized as a diels alder self reaction providing a detailed analysis of the dimerization products and recognizing the importance of the conjugated system in the process 70 five years earlier carl harries studied the degradation of natural rubber leading him to propose a cyclic structure for the polymer 71 hermann staudinger s work with ketenes published in 1912 covered both 2 2 cycloadditions where one molecule of a ketene reacted with an unsaturated compound to form a four membered ring and importantly 4 2 cycloadditions in the latter case two molecules of ketene combined with one molecule of an unsaturated compound such as a quinone to yield a six membered ring 72 while not a classic diels alder reaction in the typical sense of a conjugated diene and a separate dienophile staudinger s observation of this 4 2 process forming a six membered ring foreshadowed the later work of diels and alder however his focus remained primarily on the more common 2 2 ketene cycloaddition hans von euler chelpin and k o josephson investigating isoprene and butadiene reactions in 1920 both observed products consistent with diels alder cycloadditions but didn t go on to research it further 73 perhaps the most striking near miss came from walter albrecht in early 1900s working in johannes thiele s laboratory albrecht investigated the reaction of cyclopentadiene with para benzoquinone his 1902 doctoral dissertation clearly describes the formation of the diels alder adduct even providing incorrect structural assignments 74 however influenced by thiele s focus on conjugation and partial valence albrecht in his 1906 publication 75 interpreted the reaction as a 1 4 addition followed by a 1 2 addition completely overlooking the cycloaddition aspect while these observations hinted at the possibility of a broader class of cycloaddition reactions they remained isolated incidents their significance not fully appreciated at the time with none of the researchers even trying to generalize their findings 65 it fell to diels and alder to synthesize these disparate threads into a coherent whole unlike the earlier researchers they recognized the generality and predictability of the diene and dienophile combining to form a cyclic structure through their systematic investigations exploring various combinations of dienes and dienophiles they firmly established the diene synthesis as a powerful new synthetic method their meticulous work not only demonstrated the reaction s scope and versatility but also laid the groundwork for future theoretical developments including the woodward hoffmann rules which would provide a deeper understanding of pericyclic reactions including the diels alder applications in total synthesis edit the diels alder reaction was one step in an early preparation of the steroids cortisone and cholesterol 76 the reaction involved the addition of butadiene to a quinone diels alder in the total synthesis of cortisone by r b woodward diels alder reactions were used in the original synthesis of prostaglandins f2α and e2 77 the diels alder reaction establishes the relative stereochemistry of three contiguous stereocenters on the prostaglandin cyclopentane core activation by lewis acidic cupric tetrafluoroborate was required a diels alder reaction was used in the synthesis of disodium prephenate 78 a biosynthetic precursor of the amino acids phenylalanine and tyrosine a synthesis of reserpine uses a diels alder reaction to set the cis decalin framework of the d and e rings 79 in another synthesis of reserpine the cis fused d and e rings was formed by a diels alder reaction intramolecular diels alder 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 80 a pyranone was similarly used as the dienophile in the total synthesis of taxol 81 the intermolecular reaction of the hydroxy pyrone and α β unsaturated ester shown below suffered from poor yield and regioselectivity however when directed by phenylboronic acid 82 the desired adduct could be obtained in 61 yield after cleavage of the boronate w...