Attack at the a-Position

Similarly, carboxylic acid and ester groups tend to direct chlorination to the / and v positions, because attack at the a position is electronically disfavored. The polar effect is attributed to the fact that the chlorine atom is an electrophilic species, and the relatively electron-poor carbon atom adjacent to an electron-withdrawing group is avoided. The effect of an electron-withdrawing substituent is to decrease the electron density at the potential radical site. Because the chlorine atom is highly reactive, the reaction would be expected to have a very early transition state, and this electrostatic effect predominates over the stabilizing substituent effect on the intermediate. The substituent effect dominates the kinetic selectivity of the reaction, and the relative stability of the radical intermediate has relatively little influence. 

In fused ring systems, the positions are not equivalent and there is usually a preferred orientation even in the unsubstituted hydrocarbon. The preferred positions may often by predicted as for benzene rings. Thus it is possible to draw more canonical forms for the arenium ion when naphthalene is attacked at the a position than when it is attacked at the p position, and the a position is the preferred site of attack,though, as previously mentioned (p. 682), the isomer formed by substitution at the p position is thermodynamically more stable and is the product if the reaction is reversible and equilibrium is reached. Because of the more extensive delocalization of charges in the corresponding arenium ions, naphthalene is more reactive than benzene and substitution is faster at both positions. Similarly, anthracene, phenanthrene, and other fused polycyclic aromatic hydrocarbons are also substituted faster than benzene. 

The methyl groups on the pyridine ring result in a major difference in the reactivity of lutidines. In 3,5-lutidine the methyl groups act as electron donors tending to increase the stability of the tt-bonds, and activating the ring for electrophilic attack at the a-positions. The MOs in 3,5-lutidine show the it-levels pushed to lower energy... 

Nitration of anthraquinones has considerable industrial importance. Examples of compounds that may be nitrated are anthraquinone and the halo-, hydroxy-, amino-, and acylaminoanthraquinones. As a rule the nitro group attacks at the a-position choice of reaction conditions frequently permits mono- or dinitration. 

The effects of substituents upon the orientation of the entering phenyl radical and upon the reactivity of the pyridine nucleus have not received much attention. 4-Picoline is substituted by the 3-pyridyl radical (from the Gomberg-Hey reaction) to give a mixture containing 15% of the product of attack at the a-position (163) and 55% of product of attack at the /3-position (164). A very similar result was... 

It is important that the ring is opened at the / bond. Attack at the a position leads to irregularities and to asymmetric C inversion. 

Nitration of naphthalene gives 1-nitronaphthalene (12). Further substitution does not occur in the same ring and the main products of dinitration are 1,5- (13) and 1,8-dinitronaphthalenes (14). The initial nitro group deactivates that ring to further electrophilic substitution and attack at the a-positions of the other ring therefore takes place. 

But there are two of these stable contributing structures (I and II) for attack at the a-position and only one (IV) for attack at the jff-position. On this basis we would expect the carbonium ion resulting from attack at the a-position (and also the transition state leading to that ion) to be much more stable than the carbonium ion (and the corresponding transition state) resulting from attack at the jS-position, and that nitration would therefore occur much more rapidly at the a-position. 

However, it has been reported, and proved by mass spectrometry, that diethyl 1-methyl-1,2-epoxyethylphosphonate is attacked at the a-position by alcohols under acid-catalysis conditions (BF3Et2O or H2SO4) to give diethyl 1-alkoxy-l-methyl-2-hydroxyethylphosphonates. ... 

Intramolecnlar alkenylation at a furan a- or P-position by an alkyne occurs, with the formation of bicycUc derivatives, when promoted by mercury(II) acetate (or Hg(OAc)(OTf), generated in situ from mercuric acetate and scandinm triflate). In the case of closure onto a p-position, a spirocyclic intermediate from preferred attack at the a-position, may be involved, as shown. 

These cyclisations may proceed by direct electrophilic attack at the a-position, or by way of p-attack, then rearrangement. It may be significant that Mannich processes, as opposed to the alkylations discussed in Section 20.1.1.6, are reversible, which would allow a slower, direct a-substitution to provide the principal route to the a-substituted structure. 

Z-Substituted Allyl Anions—Dienolate Ions. Electrophilic attack on Z-substituted allyl anions is almost always selective for attack at the a position. The problem is to explain it. 

Pyrylium salts also react with hydrazine and its derivatives to give the N-aminoazonium salts (Eq. 3), although the reaction takes other courses in some cases.50,70,80-93 The reaction involves the formation of intermediate hydrazones by nucleophilic attack at the a-position of pyrylium rings. The hydrazones undergo ring closure followed by dehydration. This method has been utilized for the preparation of highly substituted pyridine AT-imines. 

In most electrophilic substitution reactions, pyrrole is preferentially attacked at the a-position. This regioselectivity, however, also depends on whether the reactions are carried out in solution or in the gas phase [35]. 

There is still controversy as to whether such cyclisations proceed by direct electrophilic attack at the a-position, or whether by way of P-attack then rearrangement. It may be significant that Mannich processes, as opposed to the alkylations discussed in section 17.1.6, are reversible, which would allow a slower, direct a-substitution to provide the principal route to the a-substituted structure. It has been shown that tryptamines carrying a 2-carboxylic acid group, which can be conveniently prepared (section 17.16.2) but are not easily decarboxylated, undergo cyclising Mannich condensation with aldehydes and ketones, with loss of the carbon dioxide in a final step and under much milder conditions. ... 

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