Diels-Alder reaction



  The Diels-Alder reaction is an mass spectrometry.

Otto Paul Hermann Diels and Nobel Prize in Chemistry in 1950 for their work on this reaction.

The Diels-Alder reaction is generally considered the "Mona Lisa" of reactions in organic chemistry since it requires very little energy to create the very useful cyclohexene ring[4][5][6][7].

Reaction mechanism

The reaction occurs via a single pericyclic reaction.

Some thioketones).

The diene

The steric hindrance may influence the relative stabilities of the conformations. For simple cases, the barrier to rotation about the central bond is small and rotation to the less favourable but reactive s-cis conformation is rapid. Cyclic dienes that are permanently in the s-cis conformation are exceptionally reactive in Diels-Alder reactions (Danishefsky’s diene.

Dendralenes are a new class of experimental DA dienes.

Unstable dienes, such as o-quinodimethane, can be generated in situ. Aromatic stabilization in the product of a DA reaction using such a diene is, in some cases, the reason behind the very high reactivity and lack of stability of such diene. The use of such unstable dienes is advantageous, despite the trouble, in that the products will contain newly formed aromatic six-membered rings.

Benzenoid compounds rarely undergo DA reactions and often require very reactive dienophiles. One example of such rare reaction is the Wagner-Jauregg reaction.

The dienophile

In a typical Diels-Alder reaction, the dienophile has an electron-withdrawing group conjugated to the alkene. Though common, this feature is not exclusive of Diels-Alder dienophiles. There must be some extra conjugation, at least a phenyl group or niobium pentachloride.[10]

dichloromethane.

It is well known that it is possible to use heteroatom containing dienophiles for Diels-Alder reactions, for instance Aza Diels-Alder reaction.

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 not 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 alpha-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 cycloaddition), and therefore "masked functionality" approach has to be used.[11]

Other such functionalities are phosphonium substituents (yielding exocyclic double bonds after acetylene equivalents), and nitro groups (ketene equivalents).

Heterodienophiles

No major loss in reactivity of dienophile is seen when one, or both, of the carbons are substituted for another variety of atom.[12] transition state is favored in this case.

Nitroso compounds (N=O) react to form oxazine-like compounds (cyclic molecules with nitrogen and oxygen present in the six-membered ring).[13] Another group of dienophiles successfully used for DA reactions is alkaloid and other polycyclic compounds.

Stereoselectivity in DA Reactions

Diels-Alder reactions can lead to formation of a variety of structural diastereomers).[15] Identity of major products can usually be predicted, however.

In unsymmetrically substituted diene and dienophile, pseudo-LUMO of dienophile. Carbons that have the highest coefficients in two frontier orbitals will begin to bond; therefore these carbons will direct the orientation of substituents and thus identity of major product of a DA reaction.

Dealing with the actual frontier orbital coefficients can be avoided since the preferred orientation in product can be described in terms of partial positive and negative charges that exist in diene and dienophile. Carbon with a partial negative charge will interact most readily with carbon bearing a partial positive charge. Therefore those two carbons will start coming together, thus dictating the relative orientation of substituents. The existence of partial positive/negative charge can always be determined by drawing resonance contributors for diene and dienophile, taking their ERG and EWG into consideration.

Cis principle

 

According to the cis principle or the Alder-Stein rules formulated by Alder and Stein in 1937, the dienes. Trans,trans 1,4-substituents will end up on same side of the ring, whereas trans, cis 1,4-substituents will be oriented towards different faces of the ring.

Besides the ortho/meta/para-forming orientations, the diene, this would be the exo transition state.

Endo addition rule

  Using the 'cis principle' it is understood that cis-substituents on dienophile, for example, will end up on same side of the molecule. It is not obvious where the endo product. It is important to note that labels "exo" and "endo" relate to the orientation of diene and dienophile oriented toward the opposite sides of the newly formed ring.

 

Exo product can predominate, however, for some reactions. This can happen when the resulting endo product can easily dissociate back into the starting material. In such reactions, exo product predominates over extended reaction times because exo product is epimerize to exo product A in the following way:

 

In summary, diastereoselectivity is based on the postulation of transition state. For any given DA reaction, one can imagine one possible transition state being favored over the other due to steric, stereoelectronic, and complexing factors. Thus, predictions can be made on the identity of major product of a particular DA reaction by looking at the starting material available.

Retro Diels-Alder reactions

DA reactions are reversible and in a retro Diels-Alder reaction the diene and alkene are reformed. One representative reaction is the Rickert-Alder reaction[16] in which, thanks to favorable rearomatization, the oxidized cycloadduct of anthraquinone.

Asymmetric DA reactions

In asymmetric Diels-Alder reactions only one of two possible enantiomers is formed. acrolein:[17]

Diels-Alder reactions also lend themselves to ee.

electrophilic and more reactive toward the diene. This increases the rate and often the stereoselectivity of a DA reaction.

References

  1. ^ Diels, O.; Alder, K. (1928). "Synthesen in der hydroaromatischen Reihe". Liebigs Annalen der Chemie 460 (1): 98 - 122. doi:10.1002/jlac.19284600106.
  2. ^ Synthesis of the hydro aromatic sequence, Ann. 1929, 470, 62.
  3. ^ Synthesis in the hydroaromatic series, IV. Announcement: The rearrangement of malein acid anhydride on arylated diene, triene and fulvene, Diels, O.; Alder, K. Ber. 1929, 62, 2081 & 2087.
  4. ^ Kloetzel, M. C. Org. React. 1948, 4, 1-59. (Review)
  5. ^ Holmes, H. L. Org. React. 1948, 4, 60-173. (Review)
  6. ^ Catalytic asymmetric Diels Alder reactions, Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92, 1007-1019. (Review)doi:10.1021/cr00013a013
  7. ^ The Diels-Alder Reaction in Total Synthesis Angew. Chem. Int. Ed. 2002, 41, 1668-1698. (Review) doi:10.1002/1521-3773(20020517)41:10<1668::AID-ANIE1668>3.0.CO;2-Z 10.1002/1521-3773(20020517)41:10<1668::AID-ANIE1668>3.0.CO;2-Z
  8. ^ Kozmin, S. A.; He, S.; Rawal, V. H. Organic Syntheses, Coll. Vol. 10, p.442 (2004); Vol. 78, p.160 (2002). (Article)
  9. ^ Hershberg, E. B.; Ruhoff, J. R. Organic Syntheses, Coll. Vol. 2, p.102 (1943); Vol. 17, p.25 (1937). (Article)
  10. ^ Niobium Pentachloride Activation of Enone Derivatives: Diels-Alder and Conjugate Addition Products Mauricio Gomes Constantino, Valdemar Lacerda Júnior and Gil Valdo José da Silva Molecules 2002, 7, 456–465. (Article)
  11. ^ Ranganathan Synthesis 1977, 289.
  12. ^ Weinreb, S. M. Comp. Org. Syn. 1991, 5, 513-550. (Review)
  13. ^ Streith, J.; DeFoin, A. Synthesis 1994, 1107-1117.
  14. ^ Greico, P.; Larsen, S. D. Organic Syntheses, Coll. Vol. 8, p.31 (1993); Vol. 68, p.206 (1990). (Article)
  15. ^ Diastereofacial Selectivity in the Diels-Alder Reaction Coxon, J. M. et al. Advances in Detailed Reaction Mechanisms 1994, 3, 131-166. (Review)
  16. ^ Alder, K.; Stein, G.; Pries, P.; Winckler, H. Ber. Dtsch. Chem. Ges.1929, 62B, 2337-72.
  17. ^ New Strategies for Organic Catalysis: The First Highly Enantioselective Organocatalytic Diels-Alder Reaction Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc.; (Communication); 2000; 122(17); 4243-4244. doi:10.1021/ja000092s
  18. ^ A fully-telescoped, aqueous, auxiliary-mediated asymmetric transformation Mathew P. D. Mahindaratne, Brian A. Quiñones, Antonio Recio III, Eric A. Rodriguez, Frederick J. Lakner, and George R. Negrete Arkivoc(EJ-1566C) pp 321-328 2005. (Article)
 
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