Electron withdrawal

Both precursors can be used as reactants in an aldol condensation. It has to be emphasized that the chlorine atom in 4 has to be considered as a representative for any electron-withdrawing group in particular, in the case presented here, it would best be taken as an OEt group. In order to verify this proposal, a reaction substructure search is initiated in the Chcmlnform reaction database of 1997. 

Diels-Alder reactions can be divided into normal electron demand and inverse electron demand additions. This distinction is based on the way the rate of the reaction responds to the introduction of electron withdrawing and electron donating substituents. Normal electron demand Diels-Alder reactions are promoted by electron donating substituents on the diene and electron withdrawii substituents on the dienophile. In contrast, inverse electron demand reactions are accelerated by electron withdrawing substituents on the diene and electron donating ones on the dienophile. There also exists an intermediate class, the neutral Diels-Alder reaction, that is accelerated by both electron withdrawing and donating substituents. 

Hydrogen bonding of water to the activating group of (for normal-electron demand Diels-Alder reactions) the dienophile constitutes the second important effect". Hydrogen bonds strengthen the electron-withdrawing capacity of this functionality and thereby decrease the HOMO-LUMO gap... 

Note that the Diels-Alder reaction works best when there is an electron-withdrawing group (here CC>2Et) on the olefinic component. 

A cyclohexene with an electron-withdrawing group on the other side of the ring to the double bond ... 

Analysis The central ring has the electron-withdrawing substituents so all we have to do is to adjust the oxidation level ... 

Alkyllithium bases are generally less suitable for deprotofiation of compounds with strongly electron-withdrawing groups such as C=0, COOR and CsN. In these cases lithium dialkylamides, especially those with bulky groups (isopropyl, cyclohexyl), are the reagents of choice. They are very easily obtained from butyllithium and the dialkylamine in the desired solvent. 

Cumulenic anions, C=C=C and C=C=C=C, without strongly electron-withdrawing substituents are much stronger bases than acetylides, "CsC- and are therefore also stronger nucleophiles. In view of the poor stability of the cumulenic anions at normal temperatures this is a fortunate circumstance the usual functionalization reactions such as alkylation, trimethylsilylation and carboxylation in most cases proceed at a sufficient rate at low temperatures, provided that the... 

The electrophilicity of C = C double bonds conjugated with electron withdrawing groupings leads to a -synthons. This is an important example of the vinyiogous principle ... 

If alkyl groups are attached to the ylide carbon atom, cis-olefins are formed at low temperatures with stereoselectivity up to 98Vo. Sodium bis(trimethylsilyl)amide is a recommended base for this purpose. Electron withdrawing groups at the ylide carbon atom give rise to trans-stereoselectivity. If the carbon atom is connected with a polyene, mixtures of cis- and rrans-alkenes are formed. The trans-olefin is also stereoseiectively produced when phosphonate diester a-carbanions are used, because the elimination of a phosphate ester anion is slow (W.S. Wadsworth, 1977). 

The high nucleophilicity of sulfur atoms is preserved, even if it is bound to electron withdrawing carbonyl groups. Thiocarboxylales, for example, substitute bromine, e.g. of a-bromo ketones. In the presence of bases the or-acylthio ketones deprotonate and rearrange to episulfides. After desulfurization with triphenylphosphine, 1,3-diketones are formed in good yield. Thiolactams react in the same way, and A. Eschenmoser (1970) has used this sequence in his vitamin B]2 synthesis (p. 261). 

If a Michael reaction uses an unsymmetrical ketone with two CH-groups of similar acidity, the enol or enolate is first prepared in pure form (p. llff.). To avoid equilibration one has to work at low temperatures. The reaction may then become slow, and it is advisable to further activate the carbon-carbon double bond. This may be achieved by the introduction of an extra electron-withdrawing silyl substituent at C-2 of an a -synthon. Treatment of the Michael adduct with base removes the silicon, and may lead as well to an aldol addition (G. Stork, 1973, 1974 B R.K. Boeckman, Jr., 1974). 

Unsymmetrically substituted dipyrromethanes are obtained from n-unsubstitued pyrroles and fl(-(bromomethyl)pyiToIes in hot acetic acid within a few minutes. These reaction conditions are relatively mild and the o-unsubstituted pyrrole may even bear an electron withdrawing carboxylic ester function. It is still sufficiently nucleophilic to substitute bromine or acetoxy groups on an a-pyrrolic methyl group. Hetero atoms in this position are extremely reactive leaving groups since the a-pyrrolylmethenium( = azafulvenium ) cation formed as an intermediate is highly resonance-stabilized. 

A mild procedure which does not involve strong adds, has to be used in the synthesis of pure isomers of unsymmetrically substituted porphyrins from dipyrromethanes. The best procedure having been applied, e.g. in unequivocal syntheses of uroporphyrins II, III, and IV (see p. 251f.), is the condensation of 5,5 -diformyldipyrromethanes with 5,5 -unsubstituted dipyrromethanes in a very dilute solution of hydriodic add in acetic acid (A.H. Jackson, 1973). The electron-withdrawing formyl groups disfavor protonation of the pyrrole and therefore isomerization. The porphodimethene that is formed during short reaction times isomerizes only very slowly, since the pyrrole units are part of a dipyrromethene chromophore (see below). Furthermore, it can be oxidized immediately after its synthesis to give stable porphyrins. 

From the perspective of laboratory practice, the sensitivity of many indoles to acids, oxygen and light prescribes the use of an inert atmosphere for most reactions involving indoles and the avoidance of storage with exposure to light. This sensitivity is greatly attenuated by electron-withdrawing (EW) substituents. 

A decrease of a- and tt-electronic density in both adjacent positions. For the a system this decrease is approximately the same at the 2- and 4-positions, which expresses an equivalent electron withdrawing from nitrogen in both positions. On the other hand, the decrease in tr-electronic density is twice as large at C-2 as at C-4. 

The frequencies of suite I (related to the Wj mode of thiazole) increase under the influence of electron-withdrawing substituents, whatever their positions on the ring the frequencies increase similarly for suite II, but only when the substituent is in the 2-position. 

In agreement with the theory of polarized radicals, the presence of substituents on heteroaromatic free radicals can slightly affect their polarity. Both 4- and 5-substituted thiazol-2-yl radicals have been generated in aromatic solvents by thermal decomposition of the diazoamino derivative resulting from the reaction of isoamyl nitrite on the corresponding 2-aminothiazole (250,416-418). Introduction in 5-position of electron-withdrawing substituents slightly enhances the electrophilic character of thiazol-2-yl radicals (Table 1-57). 

The electronic influence of the 4-substituent corresponds to a relative increase in the kinetic acidity of the C-5 proton when an electron-withdrawing group (R=Ph) is situated at the 4-position and to a relative increase in the kinetic acidity of the 2-methyl group when an electron-donating group (R = Me) is at the same position (Table 1-59). 

The interaction between a substituent and the ring carbon to which it is bonded could be related to some electronic characteristics of the unsubstituted ring and especially to the net charge of its various sites. In that respect the rr-net charges diagram discussed in Section 1.5 indicates that the electron-withdrawing power of the ring-carbon atoms will decrease in the order, 2>4>5. 

Aldehydes are more generally prepared by electrolytic reduction of amides, the reduction of carboxylic adds being possible only when they are activated by a strongly electron-withdrawing group (58). 

All the halogenothiazoles, depending on the electron-withdrawing power of the halosubstituent, together with the electron-withdrawing power of the azasubstituent, are only slightly susceptible to electrophilic substitution reactions such as nitration, sulfonation, and so on, while the polyhalogenatjon reaction can take place. 

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