Regioselectivity electron-donating substituents

Regioselective substitutions in di- and tri-halogenopyrimidine derivatives can in many cases be achieved. Chloro, bromo, and iodo substituents undergo aminolysis at approximately the same rates whereas a fluoro substituent reacts 60-200 times faster. 4(6)-Halo substituents react up to 10 times faster than 2-halo substituents. Electron-donating substituents (e.g., Me, Ph, OMe, NMe2) decrease the rate of aminolysis whereas electron-withdrawing substituents (Cl, CF3, N02) have the opposite effect (B-94MI602-01). 

Addition to simple, unstrained alkenes is usually quite slow, but these reactions become more useful when electron-withdrawing and electron-donating substituents are present on the double bond. On the other hand, the reactivity of diazo compounds is reduced when they bear conjugating substituents (e.g. aryl or carbonyl groups). Acceleration of these reactions by high pressure has been reported.9 The initial cycloaddition is generally stereospecific and is considered to be concerted. The regioselectivity of these... 

In benzene derivatives, electron-donating substituents direct into the ortho-and para-positions, while in the case of the electron-withdrawing substituents considerable meta-addition is observed (Table 3.1) otherwise a more equal distribution is established [reactions (6)-(9) and Table 3.1]. In agreement with the pronounced regioselectivity, ipso-addition at a bulky substituent such as the chlorine substituent in chlorobenzene is disfavored. Evidence for this is the low HC1 yield in the case of chlorobenzene, the low yield of para adduct in 4-methyl-phenol (Table 3.1), or the decarboxylation in the case of benzoic acid [reactions (6) and (10)]. 

Pyridines undergo radical substitution reactions preferentially at the 2-position. Yields and regioselectivity are generally higher if the reaction is carried out in an acid medium. The presence of a strongly electron-donating substituent (OH, OR, NR2) on the pyridine ring can alter the reactivity pattern of electrophilic and radical substitution. 

The diaryl substituted systems (139) have been shown to undergo regioselective cleavage of the cyclopropene o-bond bearing the more electron donating substituent under direct photolysis 116). 

Since perfluoroalkyl-substituted olefins and alkynes possess low-lying frontier orbitals, [4 + 2] cycloaddition reactions to oxazoles and thiazoles without strongly electron-donating substituents are unfavorable. On the other hand, five-membered heteroaromatic compounds possessing an electron-rich diene substructure, like furans, thiophenes, and pyrroles, should be able to add perfluoroalkyl-substituted olefins as well as alkynes in a normal Diels-Alder process. A reaction sequence consisting of a Diels-Alder reaction with perfluoroalkyl-substituted alkynes as dienophile, and a subsequent retro-Diels-Alder process of the cycloadduct initially formed, represents a preparatively valuable method for regioselective introduction of perfluoroalkyl groups into five-membered heteroaromatic systems. 

When substituents are present, they may influence the regioselectivity of the Birch reduction. The product is determined by the site of the first protonation, since the second protonation is nearly always opposite (para to) the first. Electron-donating substituents such as ethers and alkyl groups favour protonation at an unoccupied site meta to the substituent whereas electron-attracting substituents such as carboxyl favour para protonation. This can be explained by the stability of the intermediates 6.29 and 6.30 formed in both cases. 

The molybdenum-catalyzed asymmetric allylic alkylation can also be carried out under non-inert conditions with microwave activation (eq 5). In comparison to the thermally promoted reaction, reaction times are shorter (5 min vs 4 h). Nevertheless, high yields (87%) and ee (98%) are obtained, the regioselectivity is lower in the microwave reactions (19 1). This can be improved (41 1) by introducing an electron-donating substituent (4-methoxypyridine derivative) into the title ligand. ... 

In contrast to the thorough studies of the Diels-Alder reactions of oxa- and aza-butadienes, the [4 + 2] cycloaddition reactions of 1-thia-1,3-butadienes have not been studied extensively.Although the general participation of thiabutadienes in LUMOdiene-controlled [4 + 2] cycloaddition reactions has been recognized and experimentally verified, most investigations have detailed their 4rr participation in HOMOdiene-controlled reactions with typical electron-deficient dienophiles. In such instances, the complementary C-2 or C-4 addition of electron-donating substituents to the 1-thia-1,3-butadiene increases the rate and regioselectivity of its Ait participation in HOMOdiene-controlled Diels-Alder reactions. With notable exceptions, the LUMOdiene-controlled Diels-Alder reactions provide the expected 2-substituted 3,4-dihydro-2//-thiopyrans and, unlike simple 1-oxa-1,3-butadienes, the HOMOdiene-controlled Diels-... 

In fact, because most Diels-Alder reactions proceed by the reaction of nucleophilic dienes with electrophilic dienophiles, the following rule can be formulated as follows Diels-Alder reactions proceed to put the most electron donating substituent on the diene and the most electron withdrawing substituent on the dienophile either ortho or para to one another. This ortho-para rule misuses the terms ortho and para, which really apply only to benzene rings, but it allows one to remember the regioselectivity of these reactions fairly easily. 

Note the chemoselectivity between the two alkenes in the cyclohexadiene 160. This is the expected selectivity as Danishefsky s diene, with two electron-donating substituents is obviously electron rich and prefers to react with the electron-deficient alkene. The next two steps are the planned iodolactonisation and elimination with the usual reagents. There is chemoselectivity here too as iodine will attack the more nucleophilic double bond in 158, regioselectivity in that the carboxylate anion attacks the nearer end of the alkene 163, and stereoselectivity in that the anion can reach only the bottom face of the alkene. 

This reaction pathway is usually favoured when an aromatic moiety and an alkene bear electron-withdrawing and electron-donating substituents, respectively (or vice versa). This addition involves a charge transfer and the course of the reaction is sensitive to the solvent polarity. Such a mechanism may resemble that of [2 + 2] photocycloaddition of alkenes to aji-unsaturated carbonyl compounds (Section 6.3.2). Scheme 6.81 shows examples of two intermolecular processes and one intramolecular [2 + 2] photocycloaddition reaction (a) crotononitrile (196) is added to anisole (197) to yield several stereoisomers of 198 in 38% chemical yield and with high regioselectivity, which is linked to bond polarization in the exciplex 818 (b) hexafluorobenzene (199) reacts with 1-ethynylbenzene (200) to form the bicyclo[4.2.0]octa-2,4,7-triene 201 in 86% yield 819 and (c) irradiation of 202 in methanol leads to the single photoproduct 203. 820... 

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