View source for Inverse electron-demand Diels–Alder reaction

[[File:DAinv mechanism with bonds labelled.svg|thumb|Prototypical DA<sub>INV</sub> reaction between an electron-poor diene ([[acrolein]]) and an electron-rich dienophile ([[methyl vinyl ether]]).  Bonds made and broken are labelled blue and red, respectively.|300px]]
The '''inverse electron demand Diels–Alder reaction''', or '''DA<sub>INV</sub>''' or '''IEDDA'''<ref>{{cite journal|last=Bodwell|first=Graham J.|author2=Zulan Pi|author3=Ian R. Pottie|title=Electron Deficient Dienes. 2. One Step Synthesis of a Coumarin-Fused Electron Deficient Diene and its Inverse Electron Demand Diels–Alder Reactions with Enamines|journal=Synlett|year=1999|volume=1999|issue=4|pages=477–479|doi=10.1055/s-1999-2645|url=http://faculty.msvu.ca/ianpottie/Papers/Synlett_1999.pdf|accessdate=31 March 2013|citeseerx=10.1.1.532.5783|archive-url=https://web.archive.org/web/20050825202046/http://faculty.msvu.ca/ianpottie/Papers/Synlett_1999.pdf|archive-date=25 August 2005|url-status=dead}}</ref>  is an organic chemical reaction, in which two new [[chemical bonds]] and a six-membered ring are formed. It is related to the [[Diels–Alder reaction]], but unlike the Diels–Alder (or DA) reaction, the DA<sub>INV</sub> is a [[cycloaddition]] between an electron-rich [[dienophile]] and an electron-poor [[diene]].<ref name=boger1>{{cite book|last=Boger|first=Dale|title=Progress in heterocyclic chemistry|year=1989|publisher=Pergamon|location=New York|isbn=978-0-08-037044-6|edition=1st}}</ref>   During a DA<sub>INV</sub> reaction, three [[pi-bonds]] are broken, and two [[sigma bonds]] and one new [[pi-bond]] are formed. A prototypical DA<sub>INV</sub> reaction is shown on the right.
DA<sub>INV</sub> reactions often involve [[heteroatoms]], and can be used to form [[heterocyclic compounds]]. This makes the DA<sub>INV</sub> reaction particularly useful in natural product syntheses, where the target compounds often contain heterocycles. Recently, the DA<sub>INV</sub> reaction has been used to synthesize a [[drug delivery|drug transport]] system which targets [[prostate cancer]].<ref name=weissler1>{{cite journal|last=Weissler|first=M|title=The Diels-Alder-Reaction with inverse-Electron-Demand, a very efficient versatile Click-Reaction Concept for proper Ligation of variable molecular Partners|journal=International Journal of Medical Sciences|year=2010|volume=7|issue=1|pages=19–28|url=http://www.medsci.org/v07p0019.pdf|doi=10.7150/ijms.7.19|pmid=20046231|pmc=2792734}}</ref>
==History==
The Diels–Alder reaction was first reported in 1928 by [[Otto Diels]] and [[Kurt Alder]]; they were awarded the [[Nobel Prize]] in chemistry for their work in 1950. Since that time, use of the Diels–Alder reaction has become widespread. Conversely, DA<sub>INV</sub> does not have a clear date of inception, and lacks the comparative prominence of the standard Diels-Alder reaction. DA<sub>INV</sub> does not have a clear date of discovery, because of the difficulty that chemists had in differentiating normal from inverse electron-demand Diels-Alder reactions before the advent of modern computational methods.<ref name="FleischhauerAsaad1981">{{cite journal|vauthors = Fleischhauer J, Asaad AN, Schleker W, Scharf HD|title=Zur Problematik der Einteilung von Diels-Alder-Reaktionen in "normale" und "inverse"|journal=Liebigs Annalen der Chemie|volume=1981|issue=2|year=1981|pages=306–311|issn=0170-2041|doi=10.1002/jlac.198119810214|language=German|trans-title=On the Difficulty of Classifying Diels-Alder-Reactions into “Normal” and “Inverse”}}</ref>   Much of the work in this area is attributed to [[Dale Boger]], though other authors have published numerous papers on the subject.<ref name=boger1/><ref name=sauer1/>
==Mechanism==
===Formal mechanism===
[[File:DAinv mechanism with bonds labelled correct.png|thumb|Arrow pushing mechanism of DA<sub>INV</sub>. Bonds broken are labelled in red; bonds made are labelled in blue.|300px]]
The mechanism of the DA<sub>INV</sub> reaction is controversial. While it is accepted as a formal [4+2] [[cycloaddition]], it is not well understood whether or not the reaction is truly [[concerted]]. The accepted view is that most DA<sub>INV</sub> reactions occur via an asynchronous mechanism. The reaction proceeds via a single transition state, but not all bonds are formed or broken at the same time, as would be the case in a [[concerted mechanism]].<ref name=boger1/>
The formal DA<sub>INV</sub> mechanism for the reaction of [[acrolein]] and [[methyl vinyl ether]] is shown in the figure to the right. Though not entirely accurate, it provides a useful model for the reaction. During the course of the reaction, three [[pi-bonds]] (labeled with red) are broken, and three new bonds are formed (labeled in blue): two [[sigma bonds]] and one new [[pi-bond]].<ref name=woodward2>{{cite journal|last=Woodward|first=R|title=The mechanism of the Diels-Alder reaction|journal=Tetrahedron|date=1 January 1959|volume=5|issue=1|pages=70–89|doi=10.1016/0040-4020(59)80072-7}}</ref>
===Transition state===
Like the standard DA, DA<sub>INV</sub> reactions proceed via a single boat [[transition state]], despite not being concerted. The single boat transition state is a simplification, but [[Density functional theory|DFT]] calculations suggest [[File:Boat ts for MVE and Acrolein.svg|thumb|left|The DA<sub>INV</sub> reaction proceeds through a boat transition state, with the diene and dienophile approaching on parallel planes.|500px]]that the time difference in bond scission and formation is minimal, and that despite potential asynchronicity, the reaction is concerted, with relevant bonds being either partially broken or partially formed at some point during the reaction.<ref name=rooshenas1>{{cite journal|last=Rooshenas|first=Parham |author2=Hof, Kira |author3=Schreiner, Peter R. |author4=Williams, Craig M.|title=1,2,4-Triazine vs. 1,3- and 1,4-Oxazinones in Normal- and Inverse-Electron-Demand Hetero-Diels-Alder Reactions: Establishing a Status Quo by Computational Analysis|journal=European Journal of Organic Chemistry|date=1 February 2011|volume=2011|issue=5|pages=983–992|doi=10.1002/ejoc.201001365}}</ref>  The near synchronicity of the DA<sub>INV</sub> means it can be treated similarly to the standard Diels-Alder reaction.<ref name=boger1/>
The reaction can be modeled using a closed, boat-like transition state, with all bonds being in the process of forming or breaking at some given point, and therefore must obey the [[Woodward–Hoffmann rules|Woodward–Hoffman]] general selection rules. This means that for a three component, six electron system, all components must interact in a [[suprafacial]] manner (or one suprafacial and two [[Antarafacial and suprafacial|antarfacial]]). With all components being suprafacial, the allowed [[transition state]] is boat-like; a chair-like transition state would result in three two-electron antarafacial components. The chair-like case is [[thermally disallowed]] by the Woodward-Hoffman rules.<ref name=woodward2/>
==Molecular orbital theory==
===Standard DA reactions===
In the standard Diels-Alder reaction, there are two components: the [[diene]], which is electron rich, and the [[dienophile]], which is electron poor. The relative electron-richness and electron deficiency of the reactants can best be described visually, in a [[molecular orbital diagram]]. In the standard Diels–Alder, the electron rich [[diene]] has molecular orbitals that are higher in energy than the orbitals of the electron poor [[dienophile]]. This difference in relative orbital energies means that, of the [[Frontier molecular orbital theory|frontier molecular orbitals]] the [[HOMO]] of the diene (HOMO<sub>diene</sub>) and the [[LUMO]] of the dienophile (LUMO<sub>dienophile</sub>) are more similar in energy than the HOMO<sub>dienophile</sub> and the LUMO<sub>diene</sub>.<ref name =boger1/><ref name=woodward1>{{cite journal|last=Hoffmann|first=Roald|author2=Woodward, Robert B.|title=Conservation of orbital symmetry|journal=Accounts of Chemical Research|date=1 January 1968|volume=1|issue=1|pages=17–22|doi=10.1021/ar50001a003}}</ref>  The strongest orbital interaction is between the most similar frontier molecular orbitals: HOMO<sub>diene</sub> and LUMO<sub>dienophile</sub>.
[[File:MO diagram for da standard.svg|thumb|center|Generic [[molecular orbital]] diagram for the standard DA reaction. The HOMO<sub>diene</sub> and LUMO<sub>dienophile</sub> are the closest pair of [[Frontier molecular orbital theory|frontier molecular orbitals]], and that those two interact to form the new orbital in the transition state.|300px]]
===[4+2] dimerization reactions===
Dimerization reactions are neither normally or inversely accelerated, and are usually low yielding. In this case, two [[monomers]] react in a DA fashion. Because the orbital energies are identical, there is no preference for interaction of the HOMO or the LUMO of either the diene or dienophile. The low yield of dimerization reactions is explained by second-order [[perturbation theory]]. The LUMO and HOMO of each species are farther apart in energy in a dimerization than in either normally or inversely accelerated Diels–Alder. This means that the orbitals interact less, and there is a lower thermodynamic drive for dimerization.<ref name=boger1/>
[[File:MO diagram for da dimerization of acrolein.svg|thumb|center|FMO diagram for the DA dimerization of [[acrolein]]. The FMO overlap is relatively poor, due to the large difference in orbital energies.|300px]]
===Diels–Alder with inverse electron demand===
In the dimerization reactions, the diene and dienophile were equally electron rich (or equally electron poor). If the diene becomes any less electron rich, or the dienophile any more so, the possible [4+2] cycloaddition reaction will then be a DA<sub>INV</sub> reaction. In the DA<sub>INV</sub> reaction, the LUMO<sub>diene</sub> and HOMO<sub>dienophile</sub> are closer in energy than the HOMO<sub>diene</sub> and LUMO<sub>dienophile</sub>. Thus, the LUMO<sub>diene</sub> and HOMO<sub>dienophile</sub> are the frontier orbitals that interact the most strongly, and result in the most energetically favourable bond formation.<ref name=boger1/><ref name=rooshenas1/><ref name=dang1>{{cite journal|last=Dang|first=Anh-Thu|author2=Miller, David O. |author3=Dawe, Louise N. |author4=Bodwell, Graham J. |title=Electron-Deficient Dienes. 5. An Inverse-Electron-Demand Diels−Alder Approach to 2-Substituted 4-Methoxyxanthones and 3,4-Dimethoxyxanthones|journal=Organic Letters|date=1 January 2008|volume=10|issue=2|pages=233–236|doi=10.1021/ol702614b |pmid=18092790}}</ref>
[[File:MO diagram for DAinv.svg|thumb|center|In DA<sub>INV</sub>, the LUMO<sub>diene</sub> and HOMO<sub>dienophile</sub> are very close in energy, which results in a strong bonding interaction between the two.|300px]]
==Regiochemistry and stereochemistry of DA<sub>INV</sub>==
===Regiochemistry===
Regiochemistry in DA<sub>INV</sub> reactions can be reliably predicted in many cases. This can be done one of two ways, either by electrostatic (charge) control, or orbital control.<ref name=boger1/><ref name=rooshenas1/><ref name=dang1/> To predict the regiochemistry via charge control, one must consider the resonance forms of the reactants. These resonance forms can be used to assign partial charges to each of the atoms. Partially negative atoms on the diene will bond to partially positive atoms on the dienophile, and vice versa.
[[File:Charge control of regiochemistry.svg|thumb|center|Using the DA<sub>INV</sub> reaction of [[acrolein]] and [[methyl vinyl ether]] as an example, the regiochemical outcome of the DA<sub>INV</sub> reaction can often be predicted. Resonance contributors of each molecule can be used to assign partial positive charges. The preferred reaction pathway connects the partially negative atoms to the partially positive ones. |400px]]
Predicting the regiochemistry of the reaction via orbital control requires one to calculate the relative orbital coefficients on each atom of the reactants.<ref name=rooshenas1/> The HOMO of the dienophile reacts with the LUMO of the diene. The relative orbital size on each atom is represented by orbital coefficients in the [[Frontier molecular orbital theory]] (FMO). Orbitals will align to maximize the bonding interactions, and minimize the anti-bonding interactions.
[[File:FMO control of regiochemistry.svg|thumb|center|The orbitals with the largest coefficients in the reactive FMO's will overlap most strongly, and bond. Qualitatively, the largest FMO coefficients of the diene and dienophile are on gamma-carbon of acrolein and the terminal CH<sub>2</sub> of the methyl vinyl ether, respectively.|400px]]
===Alder–Stein principle===
[[File:Diels-Alder sample.png|thumb|right|Because there is a single transition state, and all modes of attack are suprafacial, stereochemistry in this reaction is retained. R<sup>4</sup> and R<sup>5</sup> are [[Cis–trans isomerism|cis]] in the dienophile, and [[syn addition|syn]] in the product. Conversely, R<sup>3</sup> and R<sup>5</sup> are [[:wikt:trans-|trans]] in the dienophile, and [[anti addition|anti]] in the product. In addition, R<sup>1</sup> and R<sup>2</sup>share the same starting chemistry both in the diene, and the product.]]
The Alder–Stein principle states that the stereochemistry of the reactants is maintained in the stereochemistry of the products during a Diels–Alder reaction. This means that groups which were cis in relation to one another in the starting materials will be syn to one another in the product, and groups that were trans to one another in the starting material will be anti in the product.
The Alder–Stein principle has no bearing on the relative orientation of groups on the two starting materials. One cannot predict, via this principle, whether a substituent on the diene will be syn or anti to a substituent on the dienophile. The Alder–Stein principle is only consistent across the self-same starting materials. The relationship is only valid for the groups on the diene alone, or the groups on the dienophile, alone. The relative orientation of groups between the two reactants can be predicted by the ''endo selection rule''.
===Endo selection rule===
[[File:Endo-exo for dainv.svg|thumb|left|In the endo transition state, the methoxy group is "inside" the boat; where in the exo transition state, it is "outside".]]
Similarly to the standard Diels–Alder reaction, the DA<sub>INV</sub> also obeys a general endo selection rule. In the standard Diels–Alder, it is known that [[electron withdrawing group]]s on the dienophile will approach endo, with respect to the diene. The exact cause of this selectivity is still debated, but the most accepted view is that endo approach maximizes secondary orbital overlap.<ref name="GarcíaMayoral2005">{{cite journal|vauthors = García JI, Mayoral JA, Salvatella L|title=The Source of the endoRule in the Diels−Alder Reaction: Are Secondary Orbital Interactions Really Necessary?|journal=European Journal of Organic Chemistry|volume=2005|issue=1|year=2005|pages=85–90|issn=1434-193X|doi=10.1002/ejoc.200400424}}</ref>
The DA<sub>INV</sub> favors an endo orientation of electron donating substituents on the dienophile. Since all Diels–Alder reactions proceed through a boat [[transition state]], there is an "inside" and an "outside" of the transition state (inside and outside the "boat"). The substituents on the dienophile are considered "endo" if they are 'inside' the boat, and "exo" if they are on the outside.
The exo pathway would be favored by sterics, so a different explanation is needed to justify the general predominance of endo products. Frontier molecular orbital theory can be used to explain this outcome. When the substituents of the dienophile are exo, there is no interaction between those substituents and the diene. However, when the dienophile substituents are endo, there is considerable orbital overlap with the diene. In the case of DA<sub>INV</sub> the overlap of the orbitals of the electron withdrawing substituents with the orbitals of the diene create a favorable [[bonding interaction]], stabilizing the transition state relative to the exo transition state.<ref name=rooshenas1/> The reaction with the lower activation energy will proceed at a greater rate.<ref name=rooshenas1/>
== Common dienes ==
The [[diene]]s used in Inverse electron demand Diels-Alder are relatively electron-deficient species; compared to the standard Diels-Alder, where the diene is electron rich. These electron-poor species have lower [[molecular orbital]] energies than their standard DA counterparts. This lowered energy results from the inclusion of either: A) electron withdrawing group, or B) electronegative heteroatoms. Aromatic compounds can also react in DA<sub>INV</sub> reactions, such as [[triazine]]s and [[tetrazine]]s. Other common classes of dienes are oxo- and [[Aza-|aza]]- butadienes.<ref name=dang1/><ref name=pottie1>{{cite journal|last=Pottie|first=Ian |author2=Nandaluru, Penchal |author3=Bodwell, Graham|title=An Inverse Electron-Demand Diels-Alder-Based Total Synthesis of Urolithin M7|journal=Synlett|date=30 August 2011|volume=2011|issue=15|pages=2245–2247|doi=10.1055/s-0030-1261203|title-link=Urolithin M7 }}</ref>
The key quality of a good DA<sub>INV</sub> diene is a significantly lowered HOMO and LUMO, as compared to standard DA dienes. Below is a table showing a few commonly used DA<sub>INV</sub> dienes, their HOMO and LUMO energies, and some standard DA dienes, along with their respective MO energies.<ref name=boger1/><ref name=flemming1>{{cite book|last=Flemming|first=Ian|title=Molecular Orbitals and Organic Chemical Reactions|year=2010|publisher=Wiley|location=Great Britain|isbn=978-0-470-74658-5}}</ref><ref name=figeys1>{{cite journal|last=Figeys|first=H.P.|author2=Mathy, A.|title=Diels-alder reactions with inverse electron demand. II. The reaction of benzamidine with π-deficient heteroaromatic compounds.|journal=Tetrahedron Letters|date=1 January 1981|volume=22|issue=15|pages=1393–1396|doi=10.1016/S0040-4039(01)90330-2}}</ref><ref name=palasz1/>
{|class="wikitable sortable"
|-
! scope="col" class="unsortable" | Diene
! scope="col" class="unsortable" | Name
! scope="col" | HOMO Energy (eV)
! scope="col" | LUMO Energy (eV)
! scope="col" class="unsortable" | Reaction Pathway (DA/DA<sub>INV</sub>)
|-
|[[File:Picture 1 for table.svg|center|80px]]
|2-cyclohexylidene-3-oxo-3-phenylpropanenitrile
| -9.558
|2.38
|DA<sub>INV</sub>
|-
|[[File:Picture 2 for table.svg|center|25px]]
|Acrolein
| -14.5
|2.5
|DA<sub>INV</sub>
|-
|[[File:Picture 3for table.svg|center|90px]]
|5-cyclopentylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione
| -10.346
|1.879
|DA<sub>INV</sub>
|-
|[[File:Picture 4 for table.svg|center|25px]]
|Butadiene
| -10.346
|1.879
|DA or DA<sub>INV</sub>
|-
|[[File:Picture 5 for table.svg|center|75px]]
|1-Methoxy-butadiene
| -8.21
|3.77
|DA
|-
|[[File:Picture 6 for table.svg|center|55px]]
|2,3-dimethyl-butadiene
| -8.76
|2.18
|DA
|}
==Common dienophiles==
The [[dienophile]]s used in inverse electron demand Diels-Alder reactions are, unlike in the standard DA, very electron rich, containing one or more [[electron donating group]]s. This results in higher orbital energies, and thus more orbital overlap with the LUMO of the diene. Common classes of dieneophiles for DA<sub>INV</sub> reaction include vinyl ethers and vinyl acetals, imine, enamines, alkynes and highly strained olefins.<ref name=pottie1/><ref name=palasz1>{{cite journal|last=Pałasz|first=Aleksandra|author2=Pałasz, Tadeusz|title=Knoevenagel condensation of cyclic ketones with benzoylacetonitrile and N,N′-dimethylbarbituric acid. Application of sterically hindered condensation products in the synthesis of spiro and dispiropyrans by hetero-Diels–Alder reactions|journal=Tetrahedron|date=18 February 2011|volume=67|issue=7|pages=1422–1431|doi=10.1016/j.tet.2010.12.053}}</ref>
The most important consideration in choice of dienophile is its relative orbital energies. Both HOMO and LUMO impact the rate and selectivity of the reaction. A table of common DA<sub>INV</sub> dienophiles, standard DA dienophiles, and their respective MO energies can be seen below.<ref name=boger1/><ref name=rooshenas1/><ref name=flemming1/>
{|class="wikitable sortable"
|-
! scope="col" class="unsortable" | Dienophile
! scope="col" class="unsortable" | Name
! scope="col" | HOMO Energy (eV)
! scope="col" | LUMO Energy (eV)
! scope="col" class="unsortable" | Reaction Pathway (DA/DA<sub>INV</sub>)
|-
|[[File:Ethyl vinylether.svg|center|75px]]
|ethyl vinyl ether
| -9.006
|5.313
|DA<sub>INV</sub>
|-
|[[File:Methylidine pyran.svg|center|60px]]
|2-methylenetetrahydro-2H-pyran
| -8.939
|5.140
|DA<sub>INV</sub>
|-
|[[File:Bis cyclopentilidene.svg|center|60px]]
|1,1'-bis(cyclopentilidene)
| -8.242
|4.749
|DA<sub>INV</sub>
|-
|[[File:Acrolein for table.svg|center|75px]]
|Acrolein
| -14.5
|2.5
|DA
|-
|[[File:Cyclohexene for table.svg|center|50px]]
|Cyclohexene
| -8.94
|2.1
|DA
|-
|[[File:Propylene skeletal.svg|center|70px]]
|Propene
| -9.13
|1.8
|DA
|-
|[[File:Ethylene for table.svg|center|50px]]
|Ethylene
| -10.52
|1.5
|DA
|}
A second table shows how electron richness in the dienophiles affects the rate of reaction with a very electron poor diene, namely [[hexachlorocyclopentadiene]]. The more electron rich the dienophile is, the higher the rate of the reaction will be. This is very clear when comparing the relative rates of reaction for [[styrene]] and the less electron rich [[p-nitrostyrene]]; the more electron rich styrene reactions roughly 40% faster than p-nitrostyrene.<ref name=sauer1>{{cite journal|last=Sauer|first=J.|author2=Wiest, H.|title=Diels-Alder-Additionen mit "inversem" Elektronenbedarf|journal=Angewandte Chemie|date=21 May 1962|volume=74|issue=10|pages=353|doi=10.1002/ange.19620741006|bibcode=1962AngCh..74..353S}}</ref>
{|class="wikitable sortable"
|-
!Dienophile
!Relative reaction rate with
[[hexachlorocyclopentadiene]]
|-
|Cyclopentadiene
|15200
|-
|p-Methoxystyrene
|1580
|-
|Styrene
|750
|-
|p-Nitrostyrene
|538
|-
|2,3-Dihydrofuran
|333
|-
|Norbornene
|70.8
|-
|Cyclopentene
|59.0
|-
|Maleic anhydride
|29.1
|-
|Cyclohexene
|3.0
|}
==Scope and applications==
DA<sub>INV</sub> reactions provide a pathway to a rich library of synthetic targets,<ref name=rooshenas1/><ref name=pottie1/> and have been utilized to form many highly functionalized systems, including selectively protected sugars, an important contribution to the field of sugar chemistry.<ref name=bogersugar>{{cite journal|last=Boger|first=Dale L.|author2=Robarge, Kirk D.|title=Divergent de novo synthesis of carbohydrates based on an accelerated inverse electron demand Diels-Alder reaction of 1-oxa-1,3-butadienes|journal=The Journal of Organic Chemistry|date=1 November 1988|volume=53|issue=24|pages=5793–5796|doi=10.1021/jo00259a040}}</ref>  In addition, DA<sub>INV</sub> reactions can produce an array of different products from a single starting material, such as tetrazine.<ref name=boger1/><ref name=figeys1/>
[[File:Tetrazine explosion diagram for DAinv.svg|thumb|center|500px]]
DA<sub>INV</sub> reactions have been utilized for the synthesis of several natural products, including (-)-CC-1065, a parent compound in the [[Duocarmycin]] series, which found use as an anticancer treatment. Several drug candidates in this series have progress into clinical trials. The DA<sub>INV</sub> reaction was used to synthesise the PDE-I and PDE-II sections of (-)-CC-1065. The first reaction in the sequence is a DA<sub>INV</sub> reaction between the [[tetrazine]] and [[vinyl acetal]], followed by a [[retro-Diels–Alder reaction]] to afford a 1,2-[[diazine]] product. After several more steps, an [[Intramolecular reaction|intramolecular]] DA<sub>INV</sub> reaction occurs, followed again by a retro Diels-Alder in situ, to afford an [[indoline]] product. This indoline is a converted into either PDE-I or PDE-II in a few synthetic steps.
[[File:DAinv use in synthesis of PDE I and II.png|thumb|center|The synthesis of PDE-I and PDE-II contained two distinct uses of the DA<sub>INV</sub> reaction. The first DA<sub>INV</sub> reaction noccurs between a substituted [[tetrazine]] and a vinyl acetal. After several more steps, ad second DA<sub>INV</sub> reaction is used to close one of the ring systems. The two PDE pieces were then coupled to form [[(-)-CC-1065]]. |500px]]
DA<sub>INV</sub> reaction between 2,3,4,5-tetrachlorothiophene-1,1-dioxide (diene) and [[4,7-dihydroisoindole]] derivative (dienophile) afforded a new precursor for tetranaphthoporphyrins (TNP) bearing perchlorinated aromatic rings. This precursor can be transformed into corresponding porphyrins by [[Lewis acids and bases|Lewis acid]]-catalyzed condensation with aromatic aldehydes and further oxidation by [[2,3-Dichloro-5,6-dicyano-1,4-benzoquinone|DDQ]]. Polychlorination of the TNP system has a profound favorable effect on its solubility. Heavy aggregation and poor solubility of the parent tetranaphthoporphyrins severely degrade the usefulness of this potentially very valuable porphyrin family. Thus, the observed effect of polychlorination is very welcome. Besides the effect on the solubility, polychlorination also turned out to improve substantially the stability of these compounds towards [[Photo-oxidation of polymers|photooxidation]], which has been known to be another serious drawback of tetranaphthoporphyrins.<ref>{{ cite journal |author1=Filatov, M.A. |author2=Cheprakov, A. V. | title = The synthesis of new tetrabenzo- and tetranaphthoporphyrins via the addition reactions of 4,7-dihydroisoindole |journal = [[Tetrahedron (journal)|Tetrahedron]] | year = 2011 | volume = 67 | issue = 19 | pages = 3559–3566 | doi = 10.1016/j.tet.2011.01.052 }}</ref>
[[File:Synthesis of polychlorinated naphthoporphyrin.png|thumb|center|Use of inverse electron-demand reaction between 2,3,4,5-tetrachlorothiophene-1,1-dioxide and 4,7-dihydroisoindole derivation in the synthesis of polychlorinated tetranaphthoporphyrin. |500px]]
==See also==
*[[Diels–Alder reaction]]
*[[Cycloaddition]]
*[[Pericyclic]] reaction
*[[Molecular orbital theory]]
*[[Boger pyridine synthesis]]
==External links==
*[https://web.archive.org/web/20120424230107/http://orgsyn.org/orgsyn/pdfs/CV9P0335.pdf Organic Syntheses Preparation]
==References==
{{Reflist}}
{{DEFAULTSORT:Inverse electron-demand Diels-Alder reaction}}
[[Category:Cycloadditions]]
[[Category:Name reactions]]