12 The origin of endo/ exo selectivity in DA reactions and the existence of SOIs has been debated, 13 with other types of interactions being invoked to explain endo-selective DA reactions, amongst them solvent effects, 14 electrostatic forces, 15 and pre-reaction van der Waals forces. Some cycloadditions, for example dimerizations of cyclopentadiene (CPD) and 1,3-butadiene (BD) exhibit bispericyclic TSs, whereupon the SH-type SOI becomes indistinguishable from one of the two σ-bonds being formed. 11 The former involves overlap of diene C2 with the carbonyl carbon of the dienophile substituent, and the latter involves overlap of diene C3 with the oxygen of the dienophile carbonyl substituent. Secondary orbital interactions (SOIs) are the most widely accepted cause, 9 and the two most common types are those proposed by Woodward and Hoffmann (WH SOI) 10 and by Salem and Houk (SH SOI). Various theoretical proposals have been advanced to explain the endo selectivity of DA reactions. 8 Often cited as the “Alder endo rule”, the endo mode of addition is favored by dienophiles bearing unsaturated groups in conjugation with the dienophile's reacting double bond ( i.e. Conversely, if only the diene does not satisfy this condition (as in 1,3-butadiene) then non-equivalent endo and exo-TSs are generated, but they deliver the same cycloadduct.Įarly experimental studies on endo/ exo stereoselectivity in Diels–Alder reactions by Alder and Stein led to the empirical rule of the “maximum accumulation of unsaturation”. ethylene) then endo- and exo-TSs are not possible. If the dienophile does not fulfil this requirement ( e.g. C1 and/or C4) and one of the two dienophile carbons must be different. Specifically, the substituents on at least one of the two ends of the diene ( i.e. A requirement for distinct endo and exo-stereoisomers is two different groups a reacting site in both diene and dienophile.Ĭertain structural requirements must be met in the diene and dienophile for the generation of endo and exo diastereomers. Scheme 1 Endo/ exo transition structures (TSs) and products in Diels–Alder (DA) reactions. These diastereomeric products result from two distinct transition state structures (TSs) in which a specific dienophile substituent is either closer to ( endo) or more distant from ( exo) C2 and C3 of the diene ( Scheme 1). 7Ī fundamental attribute of DA reactions between 1,3-butadienes and substituted olefinic dienophiles is the potential for the formation of endo and exo diastereomeric products. Indeed, synthetic chemistry would be unrecognizable without it.
6 The longevity of the DA reaction is unparalleled: it is as significant today as it was 50 years ago. 4 The reaction played a central role in the development of theories of organic reactivity, including the conservation of orbital symmetry 5 and frontier molecular orbital (FMO) theory. 3 The transformation has found wide application in chemical synthesis by virtue of its tolerance towards substitution and the inclusion of diverse functionality within the diene and dienophile. 2 The most well-known pericyclic reaction unites a diene and a dienophile through a concerted, thermally allowed 4 + 2 cycloaddition, which generates a new six membered ring, two new σ-bonds and up to four contiguous stereocenters. Introduction The Diels–Alder (DA) reaction 1 remains one of the most important reactions in chemical synthesis. Trends in behaviour are traced to steric and electronic effects in Diels–Alder transition structures, giving new insights into these fundamental processes. This work challenges the preconception of innate endo-selectivity by providing the first experimental evidence that the simplest Diels–Alder reactions are not endo-selective. CBS-QB3 calculations incorporating solvent and temperature parameters give endo : exo product ratios that are in near quantitative agreement with these and earlier experimental findings. Maleonitrile, butenolide, α-methylene γ-butyrolactone, and N-methylmaleimide behave differently, as does methyl vinyl ketone under Lewis acid catalysis. In contrast to expectations based upon this existing belief, the first experimental Diels–Alder reactions of a novel, deuterium-labeled 1,3-butadiene with commonly used mono-substituted alkenic dienophiles (acrolein, methyl vinyl ketone, acrylic acid, methyl acrylate, acrylamide and acrylonitrile) reveal kinetic endo : exo ratios close to 1 : 1. There is a widespread perception that the high level of endo selectivity witnessed in many Diels–Alder reactions is an intrinsic feature of the transformation.
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