Attack at the 3-Position

Dimethylpyrazole 1.4- Dimethyl-3-nitropyrazole The attack at the 3- and 5-positions occurs on the free base. Standard rates 1,4-dimethylpyrazole (attack at the 3-position), log /co = 3.55, l,4-dimethyl-3-nitropyrazole (attack at the 5-position), log /c = -4.73 (deactivating effect of the nitro group) 75JCS(P2)1632... 

Protonation of the enolate ion is chiefly at the oxygen, which is more negative than the carbon, but this produces the enol, which tautomerizes. So, although the net result of the reaction is addition to a carbon-carbon double bond, the mechanism is 1,4 nucleophilic addition to the C=C—C=0 (or similar) system and is thus very similar to the mechanism of addition to carbon-oxygen double and similar bonds (see Chapter 16). When Z is CN or a C=0 group, it is also possible for Y to attack at this carbon, and this reaction sometimes competes. When it happens, it is called 1,2 addition. 1,4 Addition to these substrates is also known as conjugate addition. The Y ion almost never attacks at the 3 position, since the resulting carbanion would have no resonance stabilization " ... 

However, attack at the 3 position has been reported when the 4 position contains one or two carbanion-stabilizing groups such as SiMe3 Klumpp, G.W. Mierop, A.J.C. Vrielink, J.J. Brugman, A. Schakel, M. J. Am. Chem. Soc., 1985, 107, 6740. 

The ease with which furans react with electrophiles is forcibly demonstrated by the reaction (in CHC13 at 25°C) of 2,4-dimethylfuran with trichloroacetyl isocyanate to give the amide 56a.129 Attack at the 3-position is not easy, but still the azide of 3-(2-furyl)propenoic acid at 230°C gives an isocyanate that... 

The polar effect was at first invoked to explain various directive effects observed in aliphatic systems. Methyl radicals attack propionic acid preferentially at the a-position, ka/kp = 7.8 (per hydrogen), whereas chlorine " prefers to attack at the /3-position, ka/kp = 0.03 (per hydrogen). In an investigation of f-butyl derivatives, a semiquanti-tative relationship was observed between the relative reactivity and the polar effect of the substituents, as evidenced by the pK, of the corresponding acid. In the case of meta- and / ara-substituted toluenes, it has been observed that a very small directive effect exists for some atoms or radicals. When treated by the Hammett relation it is observed that p = —0.1 for H , CeHs , P-CH3C6H4 and CHs . On the contrary, numerous radicals with an appreciable electron affinity show a pronounced polar effect in the reaction with the toluenes. Compilation of Hammett reaction constants and the type of substituent... 

Pyridinones and quinolinones undergo electrophilic attack at the (3 -position (12,13) fairly easily and disubstitution is well known in the pyridine series. Pyridinones are more easily halogenated than benzene, but the highly acidic conditions used for nitration and sulfonation makes these less easy reactions. Electrophiles also attack at the oxygen (14), but this is considered as a substituent reaction and therefore will be dealt with in Chapter 2.06. 

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 3 position, and the a position is the preferred site of attack,59 though, as previously mentioned (p. 508), 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. 

Although there appear to be no examples of the specific acid-catalyzed rearrangement of 3-substituted indoles to give the 2-substituted indoles, electrophilic substitution of 3-substituted indoles is known to proceed via the attack at the 3-position to give the... 

The synthesis of the heteroarylcarboxylic acid chlorides is fraught with difficulties. When isolated, the acid chlorides are generally unstable and readily produce bisheteroaryl ketones (see Section 3.05.1.2.9). Using standard preparative procedures the increase in the acidity of the reaction medium can cause polymerization, whilst the addition of a base can result in the formation of compounds of the type (403) and (404). Attempts to prepare indole-2 -carboxylic acid chloride using thionyl chloride result in the isolation of sulfur-containing derivatives, which arise from electrophilic attack at the 3-position (64JOC178). 

Methylindole with DMAD in acetonitrile, which had been redistilled from phosphorus pentoxide, gave173,174 the azepine 261 which is formed by electrophilic attack at the 3-position of the indole to give 258, cyclization to 259 and opening of the four-membered ring as is well... 

In the case of nitrosation, l-phenyl-2-pyrazoline gives either attack at the 3-position or in the phenyl ring (05LAI85), and diazo coupling has... 

Lithium or magnesium derivatives react readily and in predictable ways but the allyl system (94) surprisingly leads to attack at the 3-position, (Scheme 54) [115-117],... 

The position 3 is so much preferred in electrophilic substitution, that it is the site for primary attack even when it is already substituted. Jackson and co-workers255 have provided a considerable body of evidence that electrophilic substitution at the 2-position of 3-substituted indoles is an indirect process involving prior attack at the 3-position to give an indolenine derivative (30), which subsequently rearranges to a 2,3-disubstituted indole. 

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... 

Electrophilic attack on pyridine at the 2-position gives an unstable intermediate, with one of the resonance structures showing a positive charge and only six electrons on nitrogen. In contrast, electrophilic attack at the 3-position gives a more stable intermediate with the positive charge spread over three carbon atoms and not on nitrogen. 

The observation that carbenoids are capable of electrophilic attack at the 3-position of A -BOC-pyrrole may shed light on other carbenoid reactions that have stood out as rather unusual transformations. For example, a very useful [3- -2]-annulation between diazodimedone 1071 and ethyl 177-pyrrole-l-carboxylate leading to the tricyclic product 1072 was discovered (Scheme 208) <1995JOC2112>. It was proposed that the reactions occurred through initial cyclopropanation followed by ring opening of the pyrrolocyclopropane 1073 to a zwitterionic intermediate 1074. 

Clearly, attack at the (3-position maximises the influence of fluorine substituents. These same approaches can be used to account for the orientation of substitution in other systems (Figure 9.29). 

While attack at the 3-position is still much slower than for benzene, no canonical form places positive charges on adjacent atoms and so the intermediate is less destabilized than those arising from ortho and para attack. Hence meta attack is the preferred reaction, as illustrated in Figure 2.3. For example, nitration of nitrobenzene gives 88% of 1,3-dinitrobenzene and only 8% and 1% of the 1,2- and 1,4-isomers, respectively. The reaction occurs at a relative rate of 6 x 10 to that of benzene. 

---