Nucleophilic rings

A nitro group behaves the same way m both reactions it attracts electrons Reaction is retarded when electrons flow from the aromatic ring to the attacking species (electrophilic aromatic substitution) Reaction is facilitated when electrons flow from the attacking species to the aromatic ring (nucleophilic aromatic substitution) By being aware of the connection between reactivity and substituent effects you will sharpen your appreciation of how chemical reactions occur... 

Onium ions of small and large heterocyclics are usually produced by electrophilic attack on a heteroatom. In three- and four-membered rings nucleophilic attack on an adjacent carbon follows immediately, in most cases, and ring opening stabilizes the molecule. In large rings the onium ion behaves as would its acyclic analog, except where aromaticity or transannular reactions come into play (each with its electronic and steric pre-conditions). A wide diversity of reactions is observed. 

A recent review entitled Pyridine Ring Nucleophilic Recyclizations (81T3423) gives a comprehensive treatment of Type D behaviour. 

Nucleophilic aromatic substitutions Pyridine is more reactive than benzene towards nucleophilic aromatic substitutions because of the presence of electron-withdrawing nitrogen in the ring. Nucleophilic aromatic substitutions of pyridine occur at C-2 (or C-6) and C-4 positions. 

Unsaturated fluorocarbons are much more reactive toward nucleophiles than then hydrocarbon counterparts owing to fluorine s ability to both stabilize carban ions and inductively increase the electrophihcity of multiple bonds and aromauc rings Nucleophilic attack dominates the chemistry of unsaturated fluorocarbons, and the role of fluoride ion in fluorocarbon chemistry is analogous to that of the proton in hydrocarbon chemistry [729] Lake the related electrophilic reactions for hydrocarbons, there are fluoride-promoted isomenzations and dimerizations (equation 9), oligomerizations (equation 10), additions (equation 11), and amomc Fnedel-Crafts alkylations (equation 12) that all proceed via carbamomc intermediates [729 141]... 

Because H " is not a good leaving group, nucleophilic displacements on unsubstituted aromatics rarely occur. However, if there is a suitable leaving group on the ring, nucleophilic aromatic substitution may take place by one of three mechanisms. 

The functionalization of electron rich aromatics rings is often accomplished by electrophilic aromatic substitution. However, electrophilic substitutions require stringent conditions or fail entirely with electron deficient aromatic rings. Nucleophilic aromatic substitutions are commonly used but must usually be conducted under aprotic conditions. In contrast, nucleophilic radicals can add to electron deficient aromatic rings under very mild conditions. 

The reason for the particular ease of formation of 1, l-di-(2-cyclopropyl-5-pyrryl)ethane (98a) evidently consists in the high electron-donor ability of cyclopropyl, which increases the pyrrole ring nucleophilicity. 

Two other irreversible inhibitors are penicillin G (4.18), a /3-lactam antibiotic, and orlistat (Xenical or Alii, 4.19), an antiobesity drug (Figure 4.19). Penicillin G inhibits cell wall synthesis in bacteria, while orlistat inhibits the breakdown of fats in the small intestine.16 Both drugs contain acid derivatives in a strained four-membered ring. Nucleophiles in the active sites of the inhibited enzymes attack the reactive carbonyl groups and open the strained ring in an energetically favorable, irreversible process. 

It was established that the Pd(II) complexes of bmpa were more reactive than those of dien, and the aqua-complexes were much more reactive than the chloro-complexes. The most reactive nucleophile of the five-membered rings is triazole, while pyridazine is the most reactive six-membered ring nucleophile. This could be understood in terms of nitrogen donor atoms in the 1,2-positions rather than in other configurations. As noted earlier, 260 for a given complex, the reactivity is related to the basicity of the... 

Isomerization of the double bond of geranyl pyrophosphate from to 7 produces neryl pyrophosphate. As shown in Figure 28.3, the carbocation that is formed from neryl pyrophosphate can cyclize to a new carbocation that contains a six-membered ring. Nucleophilic addition of water to this carbocation produces a-terpenol, whereas loss of a proton produces limonene, a monoterpene with a lemonlike odor that occurs in citrus fruits. Further transformations lead to other monoterpenes, such as menthol,... 

During the base catalyzed epimerization of various penicillins, the formation of thiazepinones, Vl/81, was observed. It has been suggested that the unsaturated /3-lactam VI/80 is formed as a key intermediate by opening of the sulfur containing ring. Nucleophilic attack by the newly freed mercapto group in VI/80 led to VI/81 [57], Scheme VI/17. 

Nucleophilic attack on azirines at the C=N double bond is useful for the preparation of substituted aziridines. The C=N bond is more electrophilic than a normal imine due to the strain of the three-membered ring. Nucleophilic additions to 3-alkoxy- and 3-amino-2//-azirines are especially well studied, e.g., Scheme 36. Many of these reactions involve assistance by protonation of the nitrogen. 

A set of resonance structures drawn for benzimidazole show similar features as far as amphoteric nature is concerned, but imply that electrophilic attack will be either at N-3 or in the benzene ring nucleophilic attack at C-2 is predicted (see Scheme 2). Qualitatively the same trends can be noted as are obtained by applications of MO methods. 

Oxidation and reduction procedures have little effect on 1-aryl substituents which are also very difficult to remove. When, however, there are strongly electron-withdrawing groups present in the benzene ring, nucleophiles are effective in promoting dearylation. Thus, a 2,4-dinitrophenyl group at N-1 of histidine is cleaved by alkaline hydrolysis, aminolysis or hydrazinolysis. On the other hand, l-(2-pyridyl)imidazole is cleaved neither by 2M sodium hydroxide nor by 2M hydrochloric acid. 

Because of the deactivated ir-deficient nature of the ring, nucleophilic attack can readily occur on tetrazoles. Nucleophilic replacement of halogens at the C-5 position has been widely used for the synthesis of disubstituted tetrazoles, e.g. (56). Kinetic studies of the reaction between 5-bromo-l-methyltetrazole and the 2-methyl isomer with piperidine have shown the 1-methyl compound to be considerably more reactive. Comparison of these kinetics with similar reactions for a series of azoles has suggested that two to three deactivating doubly bound nitrogens (—N=) are required to overcome the electron release from one pyrrole-type nitrogen atom in these systems <67JCS(B)64l>. 

This result is reminiscent of the opening of epoxide rings with acids HZ (Z = a nucleophile), which we encountered in Section 9.15B. As in the opening of an epoxide ring, nucleophilic attack occurs at the more substituted carbon end of the bridged halonium ion because that carbon is better able to accommodate a partial positive charge in the transition state. 

Epoxidation of cyclohexene adds an O atom from either above or below the plane of the double bond to form a single achiral epoxide, so only one representation is shown. Opening of the epoxide ring then occurs with backside attack at either C—O bond. Because the epoxide is drawn above the plane of the six-membered ring, nucleophilic attack occurs from below the plane. This reaction is a specific example of the opening of epoxide rings with strong nucleophiles, first presented in Section 9.15. 

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