Editing Diels–Alder reaction (section)

==Mechanism==
The reaction is an example of a concerted pericyclic reaction.<ref name=cb474>[[#Carey|Carey]], Part B., pp. 474–526</ref> It is believed to occur via a single, cyclic transition state,<ref name="AmChem1986">{{cite journal |last1=Dewar |first1=M. J. |last2=Olivella |first2=S. |last3=Stewart |first3=J. J. |year=1986 |title=Mechanism of the Diels-Alder reaction: Reactions of butadiene with ethylene and cyanoethylenes |journal=Journal of the American Chemical Society |volume=108 |issue=19 |pages=5771–5779 |doi=10.1021/ja00279a018 |pmid=22175326}}</ref> 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 [<sub>π</sub>4<sub>s</sub> + <sub>π</sub>2<sub>s</sub>] 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.<ref name=ca836>[[#Carey|Carey]], Part A., pp. 836–50</ref>

A consideration of the reactants' [[Frontier molecular orbital theory|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''<sub>2</sub> 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 electron-demand Diels–Alder reaction|inverse (reverse) electron-demand Diels–Alder reaction]], electron-withdrawing substituents on the diene lower the energy of its empty ''ψ''<sub>3</sub> 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.<ref name=ca836/>

[[File:FMO of Diels-Alder reaction.png|520x480 px|center|FMO analysis of the Diels–Alder reaction]]

The "prevailing opinion"<ref name=ca839>[[#Carey|Carey]], Part A., p. 839</ref><ref>{{cite journal |last1=Gajewski |first1=J. J. |last2=Peterson |first2=K. B. |last3=Kagel |first3=J. R. |year=1987 |title=Transition-state structure variation in the Diels–Alder reaction from secondary deuterium kinetic isotope effects: The reaction of a nearly symmetrical diene and dienophile is nearly synchronous |journal=Journal of the American Chemical Society |volume=109 |issue=18 |pages=5545–5546 |doi=10.1021/ja00252a052}}</ref><ref>{{cite journal |last1=Houk |first1=K. N. |last2=Lin |first2=Y. T. |last3=Brown |first3=F. K. |year=1986 |title=Evidence for the concerted mechanism of the Diels–Alder reaction of butadiene with ethylene |journal=Journal of the American Chemical Society |volume=108 |issue=3 |pages=554–556 |doi=10.1021/ja00263a059 |pmid=22175504}}</ref><ref>{{cite journal |last1=Goldstein |first1=E. |last2=Beno |first2=B. |last3=Houk |first3=K. N. |year=1996 |title=Density Functional Theory Prediction of the Relative Energies and Isotope Effects for the Concerted and Stepwise Mechanisms of the Diels−Alder Reaction of Butadiene and Ethylene |journal=Journal of the American Chemical Society |volume=118 |issue=25 |pages=6036–6043 |doi=10.1021/ja9601494}}</ref> 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<ref name="AmChem1986" /> (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]],<ref>{{cite journal |last1=Breslow |first1=R. |last2=Guo |first2=T. |year=1988 |title=Diels-Alder reactions in nonaqueous polar solvents. Kinetic effects of chaotropic and antichaotropic agents and of β-cyclodextrin |journal=Journal of the American Chemical Society |volume=110 |issue=17 |pages=5613–5617 |doi=10.1021/ja00225a003}}</ref> and even in water.<ref name="AmChem1980">{{cite journal |last1=Rideout |first1=D. C. |last2=Breslow |first2=R. |year=1980 |title=Hydrophobic acceleration of Diels-Alder reactions |journal=Journal of the American Chemical Society |volume=102 |issue=26 |pages=7816–7817 |doi=10.1021/ja00546a048}}</ref> The reaction of [[cyclopentadiene]] and [[butenone]] for example is 700 times faster in water relative to [[2,2,4-trimethylpentane]] as solvent.<ref name="AmChem1980" /> Several explanations for this effect have been proposed, such as an increase in effective concentration due to hydrophobic packing<ref>{{cite journal |last1=Breslow |first1=R. |last2=Rizzo |first2=C. J. |year=1991 |title=Chaotropic salt effects in a hydrophobically accelerated Diels–Alder reaction |journal=Journal of the American Chemical Society |volume=113 |issue=11 |pages=4340–4341 |doi=10.1021/ja00011a052}}</ref> or hydrogen-bond stabilization of the transition state.<ref>{{cite journal|last2=Engberts|first2=Jan B. F. N.|year=1992|title=Initial-State and Transition-State Effects on Diels–Alder Reactions in Water and Mixed Aqueous Solvents|journal=Journal of the American Chemical Society|volume=114|issue=13|pages=5440–5442|doi=10.1021/ja00039a074|last1=Blokzijl|first1=Wilfried}}</ref>

The geometry of the diene and dienophile components each propagate into stereochemical details of the product. For [[intermolecular]] reactions especially, the preferred [[constitutional isomer|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===
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<ref name="AshbyChao1973">{{cite journal |last1=Ashby |first1=E. C. |last2=Chao |first2=L.-C. |last3=Neumann |first3=H. M. |year=1973 |title=Organometallic reaction mechanisms. XII. Mechanism of methylmagnesium bromide addition to benzonitrile |journal=Journal of the American Chemical Society |volume=95 |issue=15 |pages=4896–4904 |doi=10.1021/ja00796a022}}</ref> provides a picture that is in good accord with the more straightforward analysis of the substituents' resonance effects, as illustrated below.

[[File:Resonance of diene and dienophile.png|500x500px|center|Resonance structures of normal-demand dienes and dienophiles|alt=]]

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.

[[File:Diels-Alder regiochemistry.png|600x600px|center|Regioselectivity in normal (1 and 2) and inverse (3 and 4) electron demand Diels-Alder reactions|alt=]]

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.<ref name="ca836" /> In a more sophisticated treatment, three types of substituents ('''Z''' ''withdrawing'': HOMO and LUMO lowering (CF<sub>3</sub>, NO<sub>2</sub>, CN, C(O)CH<sub>3</sub>), '''X''' ''donating'': HOMO and LUMO raising (Me, OMe, NMe<sub>2</sub>), '''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.<ref>{{Cite book|title=Frontier Orbital and Organic Chemical Reactions|last=Fleming|first=I.|publisher=Wiley|year=1990|isbn=978-0471018193|location=Chichester, UK}}</ref> However, cases where the resonance argument and the matching of largest orbital coefficients disagree are rare.

===Stereospecificity and stereoselectivity===

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:<ref name="KirmseMönch1991">{{cite journal |last1=Kirmse |first1=W. |last2=Mönch |first2=D. |year=1991 |title=Umlagerungen von 1,4,4- und 2,2,5-Trimethylbicyclo[3.2.1]oct-6-yl-Kationen |journal=Chemische Berichte |volume=124 |issue=1 |pages=237–240 |doi=10.1002/cber.19911240136}}</ref><ref>{{cite journal |last1=Bérubé |first1=G. |last2=DesLongchamps |first2=P. |year=1987 |title=Stéréosélection acyclique-1,5: Synthèse de la chaîne latérale optiquement active de la vitamine E |journal=Bulletin de la Société Chimique de France |volume=1 |pages=103–115}}</ref>
[[File:Diels-alder-stereospecificity.png|center|frameless|500x500px]] [[File:Secondary orbitals.png|300x300px|''Endo'' and ''exo'' transition states for cyclopentadiene adding to [[acrolein]]; ''endo''/''exo'' product ratio for this and various other dienophiles|alt=|thumb]]

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-exo isomerism|''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 [[acrylate]]s and [[crotonate]]s, selectivity is not very pronounced.<ref>{{cite journal |last1=Houk |first1=K. N. |last2=Luskus |first2=L. J. |year=1971 |title=Influence of steric interactions on endo stereoselectivity |journal=Journal of the American Chemical Society |volume=93 |issue=18 |pages=4606–4607 |doi=10.1021/ja00747a052}}</ref>
[[File:Endo-TS.png|center|frameless|400x400px|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 [[electric dipole|dipolar]] and [[Van der Waals force|van der Waals]] attractions may play a part as well, and solvent can sometimes make a substantial difference in selectivity.<ref name="cb474" /><ref>{{cite journal |last1=Kobuke |first1=Y. |last2=Sugimoto |first2=T. |last3=Furukawa |first3=J. |last4=Fueno |first4=T. |year=1972 |title=Role of attractive interactions in endo–exo stereoselectivities of Diels–Alder reactions |journal=Journal of the American Chemical Society |volume=94 |issue=10 |pages=3633–3635 |doi=10.1021/ja00765a066}}</ref><ref>{{cite journal |last1=Williamson |first1=K. L. |last2=Hsu |first2=Y.-F. L. |year=1970 |title=Stereochemistry of the Diels–Alder reaction. II. Lewis acid catalysis of syn-anti isomerism |journal=Journal of the American Chemical Society |volume=92 |issue=25 |pages=7385–7389 |doi=10.1021/ja00728a022}}</ref> The secondary orbital overlap explanation was first proposed by Woodward and Hoffmann.<ref>{{Cite book|title=The conservation of orbital symmetry|last1=Woodward|first1=R. B.|last2=Hoffmann|first2=R.|isbn=9781483282046|location=Weinheim|oclc=915343522|date = 2013-10-22}}</ref> 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.<ref>{{Cite journal|last1=Wannere|first1=Chaitanya S.|last2=Paul|first2=Ankan|last3=Herges|first3=Rainer|last4=Houk|first4=K. N.|last5=Schaefer|first5=Henry F.|last6=Schleyer|first6=Paul Von Ragué|date=2007|title=The existence of secondary orbital interactions|journal=Journal of Computational Chemistry|language=en|volume=28|issue=1|pages=344–361|doi=10.1002/jcc.20532|pmid=17109435|s2cid=26096085|issn=1096-987X|doi-access=}}</ref>
[[File:Cyclopentadiene dimerization endo ts.jpg|center|frameless|400x400px]]
Often, as with highly substituted dienes, very bulky dienophiles, or [[reversible reaction]]s (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 Diels–Alder reaction can be either open-chain or cyclic, and it can host many different types of substituents.<ref name=cb474/> It must, however, be able to exist in the s-''cis'' conformation, since this is the only conformer that can participate in the reaction.<!--[[File:S-cis-s-trans conformation.png|thumbnail|right|s-''cis'' and s-''trans'' conformations of butadiene]]--> Though butadienes are typically more stable in the s-''trans'' conformation, for most cases energy difference is small (~2–5 kcal/mol).<ref>[[#Carey|Carey]], Part A, p. 149</ref>

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.<ref name=cb474/><ref name="Ditertiobutylbutadiène">{{cite journal |last=Backer |first=H. J. |year=1939 |title=Le 2,3-Ditertiobutylbutadiène |journal=Recueil des Travaux Chimiques des Pays-Bas |volume=58 |issue=7 |pages=643–661 |doi=10.1002/recl.19390580712}}</ref> 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.<ref name="Ditertiobutylbutadiène"/>

Dienes with bulky terminal substituents (C1 and C4) decrease the rate of reaction, presumably by impeding the approach of the diene and dienophile.<ref>{{cite journal |last1=Craig |first1=D. |last2=Shipman |first2=J. J. |last3=Fowler |first3=R. B. |year=1961 |title=The Rate of Reaction of Maleic Anhydride with 1,3-Dienes as Related to Diene Conformation |journal=Journal of the American Chemical Society |volume=83 |issue=13 |pages=2885–2891 |doi=10.1021/ja01474a023}}</ref>

An especially reactive diene is 1-methoxy-3-trimethylsiloxy-buta-1,3-diene, otherwise known as [[Danishefsky's diene]].<ref>{{cite journal |last1=Danishefsky |first1=S. |last2=Kitahara |first2=T. |year=1974 |title=Useful diene for the Diels–Alder reaction |journal=Journal of the American Chemical Society |volume=96 |issue=25 |pages=7807–7808 |doi=10.1021/ja00832a031}}</ref> 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)<ref>{{cite journal |last1=Savard |first1=J. |last2=Brassard |first2=P. |year=1979 |title=Regiospecific syntheses of quinones using vinylketene acetals derived from unsaturated esters |journal=Tetrahedron Letters |volume=20 |issue=51 |pages=4911–4914 |doi=10.1016/S0040-4039(01)86747-2}}</ref> and 1-dialkylamino-3-trimethylsiloxy-1,3-butadienes (Rawal dienes).<ref>{{cite journal |last1=Kozmin |first1=S. A. |last2=Rawal |first2=V. H. |year=1997 |title=Preparation and Diels−Alder Reactivity of 1-Amino-3-siloxy-1,3-butadienes |journal=Journal of Organic Chemistry |volume=62 |issue=16 |pages=5252–5253 |doi=10.1021/jo970438q}}</ref> 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.<ref name="AngChem2002">{{cite journal |last1=Nicolaou |first1=K. C. |last2=Snyder |first2=S. A. |last3=Montagnon |first3=T. |last4=Vassilikogiannakis |first4=G. |year=2002 |title=The Diels-Alder Reaction in Total Synthesis |journal=Angewandte Chemie International Edition |volume=41 |issue=10 |pages=1668–1698 |doi=10.1002/1521-3773(20020517)41:10<1668::AID-ANIE1668>3.0.CO;2-Z|pmid=19750686 }}</ref>
[[File:Named dienes.png|400px|center|General form of Danishefsky, Brassard, and Rawal dienes]]

Unstable (and thus highly reactive) dienes can be synthetically useful, e.g. ''o''-[[quinodimethane]]s can be generated in situ.  In contrast, stable dienes, such as [[naphthalene]], require forcing conditions and/or highly reactive dienophiles, such as [[N-Phenylmaleimide|''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&nbsp;°C and even with [[acetylene]], a weak dienophile, at 250&nbsp;°C.<ref>Margareta Avram (1983). ''Chimie organica'' p. 318-323. Editura Academiei Republicii Socialiste România</ref>

===The dienophile===
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.<ref name=ca839/> 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<sub>2</sub>=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<sub>2</sub>=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.<ref name="RanganathanRanganathan1977">{{cite journal |last1=Ranganathan |first1=S. |last2=Ranganathan |first2=D. |last3=Mehrotra |first3=A. K. |year=1977 |title=Ketene Equivalents |journal=Synthesis |volume=1977 |issue=5 |pages=289–296 |doi=10.1055/s-1977-24362|s2cid=260335918 }}</ref> Other such functionalities are [[phosphonium]] substituents (yielding exocyclic double bonds after [[Wittig reaction]]), various [[sulfoxide]] and [[sulfonyl]] functionalities (both are acetylene equivalents), and [[nitro group]]s (ketene equivalents).<ref name=cb474/>