Substituent effect Diels-Alder reaction

Despite the concerted nature of most Diels-Alder reactions, substituent effects are evident. Electronic compatibility of the reaction partners is of paramount importance, therefore while a normal Diels-Alder reaction is characterized by the union of an electron-rich diene and an electron-poor dienophile, the Diels-Alder reaction with inverse electron demand features an electron-poor diene and electron-rich dienophile. 

It would be expected that substituents on the bridge that tend to hold the diene and dienophile closer to each other would enhance the rate of the intramolecular Diels-Alder reaction. This effect has been demonstrated quantitatively by Boeckman [18], who found that a gem-dimethyl substitution... 

So far the four metal ions have been compared with respect to their effect on (1) the equilibrium constant for complexation to 2.4c, (2) the rate constant of the Diels-Alder reaction of the complexes with 2.5 and (3) the substituent effect on processes (1) and (2). We have tried to correlate these data with some physical parameters of the respective metal-ions. The second ionisation potential of the metal should, in principle, reflect its Lewis acidity. Furthermore the values for Iq i might be strongly influenced by the Lewis-acidity of the metal. A quantitative correlation between these two parameters... 

Diels-Alder reactions, 4, 842 flash vapour phase pyrolysis, 4, 846 reactions with 6-dimethylaminofuKenov, 4, 844 reactions with JV,n-diphenylnitrone, 4, 841 reactions with mesitonitrile oxide, 4, 841 structure, 4, 715, 725 synthesis, 4, 725, 767-769, 930 theoretical methods, 4, 3 tricarbonyl iron complexes, 4, 847 dipole moments, 4, 716 n-directing effect, 4, 44 2,5-disubstituted synthesis, 4, 116-117 from l,3-dithiolylium-4-olates, 6, 826 electrocyclization, 4, 748-750 electron bombardment, 4, 739 electronic deformation, 4, 722-723 electronic structure, 4, 715 electrophilic substitution, 4, 43, 44, 717-719, 751 directing effects, 4, 752-753 fluorescence spectra, 4, 735-736 fluorinated derivatives, 4, 679 H NMR, 4, 731 Friedel-Crafts acylation, 4, 777 with fused six-membered heterocyclic rings, 4, 973-1036 fused small rings structure, 4, 720-721 gas phase UV spectrum, 4, 734 H NMR, 4, 7, 728-731, 939 solvent effects, 4, 730 substituent constants, 4, 731 halo... 

It has long been known that the Diels-Alder reaction is particularly efficient and rapid when the dienophile contains one or more electron-attracting groups. These substituent effects are illustrated by the data in Table 11.3. In the case of the diene, reactivity is increased by electron-releasing substituents. Some illustrative data are given in Table 11.4. 

More complete interpretations of Diels-Alder regioselectivity have been developed. MO results can be analyzed from an electrostatic perspective by calculating potentials at the various atoms in the diene and dienophile. These results give a more quantitatively accurate estimate of the substituent effects. Diels-Alder regioselectivity can also be accounted for in terms of HSAB theory (see Section 1.2.3). The expectation would be that the most polarizable (softest) atoms would lead to bond formation and that regioselectivity would reflect the best mateh between the diene and dienophile termini. These ideas have been applied using 3-2IG computations. The results are in agreement with the ortho rule for normal-electron-demand Diels-Alder reactions. ... 

Evans s bis(oxazolinyl)pyridine (pybox) complex 17, which is effective for the Diels-Alder reaction of a-bromoacrolein and methacrolein (Section 2.1), is also a suitable catalyst for the Diels-Alder reaction of acrylate dienophiles [23] (Scheme 1.33). In the presence of 5 mol% of the Cu((l )-pybox)(SbF5)2 catalyst with a benzyl substituent, tert-butyl acrylate reacts with cyclopentadiene to give the adduct in good optical purity (92% ee). Methyl acrylate and phenyl acrylate underwent cycloadditions with lower selectivities. 

For the ordinary Diels-Alder reaction the dienophile preferentially is of the electron-poor type electron-withdrawing substituents have a rate enhancing effect. Ethylene and simple alkenes are less reactive. Substituent Z in 2 can be e.g. CHO, COR, COOH, COOR, CN, Ar, NO2, halogen, C=C. Good dienophiles are for example maleic anhydride, acrolein, acrylonitrile, dehydrobenzene, tetracya-noethylene (TCNE), acetylene dicarboxylic esters. The diene preferentially is of the electron-rich type thus it should not bear an electron-withdrawing substituent. 

Equation 1.5) [13], Diels Alder reactions which are insensitive to the substituent effects in the diene and/or dienophile are classified as neutral (Equation 1.6) [14]. 

Inner-outer-ring dienes are very useful in the synthesis of polycyclic molecules. Their reactivity in the Diels-Alder reaction depends on the type of ring (carbo-cyclic, heterocyclic, aromatic) that bears the ethenyl group or on the electronic effects of substituents at the diene moiety [30]. 

Styrenes may act as 2n and 4n components of the Diels-Alder reaction depending on the substitution site and the electronic effects of the substituent. Electron-donating groups at the a-carbon of the olefinic double bond enhance the dienic reactivity of styrenes [30]. 

The substituents at C-2, C-3 within diene 97 and those at C-1, C-2 within dienophiles 98-100 are electronically and/or sterically equivalent with respect to diene and dienophile reaction centers, respectively, and therefore cycloaddition should not display regiochemical bias in the absence of orientational effects. The Diels-Alder reactions of 97 prepared in situ with 98-100 gave an excess of 101 (Scheme 4.19) [70b], which are the expected regioisomers if the reagents react in their preferred orientations within a mixed micelle with an ammonium head group at the aggregate-water interface and the remainder in the micelle interior. 

Keywords imines derived from formylphosphonate undergo Diels-Alder reactions only in those cases which carry a strongly electron-withdrawing N-substituent. Lewis acidity, solvent effect, lithium perchlorate in diethyl ether... 

Kuzuya M., Noguchi A. The Nature of Substituent Effects on Tautomeric Equilibria of 2-Pyridones and Their Reactions Trends Org. Chem. 1991 2 73-92 Keywords chemo- and regiochemistry of Diels-Alder reactions with benzyne,... 

Jung M. E. Substituent and Solvent Effects in Intramolecular Diels-Alder Reactions Synlett 1990 186-190... 

In another aspect of the mechanism, the effects of electron-donating and electron-withdrawing substituents (p. 1065) indicate that the diene is behaving as a nucleophile and the dienophile as an electrophile. However, this can be reversed. Perchlorocyclopentadiene reacts better with cyclopentene than with maleic anhydride and not at all with tetracyanoethylene, though the latter is normally the most reactive dienophile known. It is apparent, then, that this diene is the electrophile in its Diels-Alder reactions. Reactions of this type are said to proceed with inverse electron demand ... 

Ab initio calculation of Diels-Alder reactions of a series of 5-heteroatom substituted cyclopentadienes Cp-X (65 X = NH, 50 X = NH, 64 X = NH3, 67 X = O", 54 X = OH, 68 X = OH3% 69 X = PH, 51 X = PH, 70 X = PH3% 71 X = S, 55 X = SH, 72 X = SH/) with ethylene at HF/6-31++G(d)//HF/6-31-i i-G(d) level by BumeU and coworkers [37] provided counterexamples of the Cieplak effect. The calculation showed that ionization of substituents has a profound effect on the n facial selectivity deprotonation enhances syn addition and protonation enhances anti addition. The transition states for syn addition to the deprotonated dienes are stabilized relative to those of the neutral dienes, while those for anti addition are destabilized relative to those of the neutral dienes. On the other hand, activation energies for syn addition to the protonated dienes are similar to those of the neutral dienes, but those for anti addition are very much lowered relative to neutral dienes (Table 6). 

Overman, Hehre and coworkers reported anti rr-fadal selectivity in Diels-Alder reactions of vinylcyclopenten 73, 74 and 4,5-dihydro-3-etliynylthiophen S-oxide 75 [38] (Scheme 31). These results are not in agreement with the Cieplak effect, at least in Diels-Alder reactions of the dienes having unsymmetrical rr-plane. Yadav and coworkers reported that the reactions between the vinylcyclohexene 76 and dienophiles favor the reactions syn to oxygen, while 77 and 78 favor the reaction anti to oxygen substituents [39], They discuss the Cieplak effect but the reactions are not suitable. 

The choice of the acyl substituent X for Diels-Alder reactions of l-N-acylamino-l,3-butadicnes depends on the particular synthetic problem. The acyl substituent has a moderate effect on the cycloaddition reactivity of these dienes, and also determines what amine unmasking procedures are required. As a result of their stability and the variety of amine deprotection procedures available, " the diene carbamates are the components of choice in most cases. A particularly attractive aspect of the diene synthesis detailed here is the ability to tailor the amino-protecting group... 

Aromatic thioureas were more active than alkyl (octyl, cyclohexyl) derivatives. Thioureas with trilluoromethyl substituents were even more effective. The same group also showed that these organocatalysts can act as weak Lewis acids and are thus able to alter the stereochemistry of the Diels-Alder reaction between cyclopentadiene and chiral acrylamide derivatives (Scheme 49) [167]. 

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