Nucleophilic aromatic substitution reactivity

Indeed the order of leaving group reactivity m nucleophilic aromatic substitution is the... 

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... 

The most common types of aryl halides m nucleophilic aromatic substitutions are those that bear o ox p nitro substituents Among other classes of reactive aryl halides a few merit special consideration One class includes highly fluormated aromatic compounds such as hexafluorobenzene which undergoes substitution of one of its fluorines on reac tion with nucleophiles such as sodium methoxide... 

Bromo 1 3 dimethylbenzene is inert to nucleophilic aromatic substitution on treatment with sodium amide in liquid ammonia It is recovered unchanged even after extended contact with the reagent Suggest an explanation for this lack of reactivity... 

Several chemical methods have been devised for identifying the N terminal ammo acid They all take advantage of the fact that the N terminal ammo group is free and can act as a nucleophile The a ammo groups of all the other ammo acids are part of amide linkages are not free and are much less nucleophilic Sanger s method for N terminal residue analysis involves treating a peptide with 1 fluoro 2 4 dimtrobenzene which is very reactive toward nucleophilic aromatic substitution (Chapter 23)... 

I > Br > Cl > F. In nucleophilic aromatic substitution, the formation of the addition intermediate is usually the rate-determining step so the ease of C—X bond breaking does not affeet the rate. When this is the ease, the order of reactivity is often F > Cl > Br > I. This order is the result of the polar effeet of the halogen. The stronger bond dipoles assoeiated with the more eleetronegative halogens favor the addition step and thus inerease the overall rate of reaetion. 

The compound 1-fluoro-2,4-dinitrobenzene is exceedingly reactive toward nucleophilic aromatic substitution and was used in an imaginative way by Frederick Sanger (Section 27.11) in his determination of the structure of insulin. 

Nucleophilic aromatic substitution of hydrogen in heteroaromatic compounds, reactivity and reaction mechanisms 94MI2. 

The difference in reactivity is not as much as is generally observed in nucleophilic aromatic substitution in solution by an addition-elimination mechanism (ref. 25). Substituents with electron withdrawing capabilities enhance the rate of the reaction therefore decabromobiphenyl ether reacts nearly 2 times faster than 1,2,3,4-tetrabromodibenzodioxin. 

The ease of dehalogenation of C H X by Ni(ll)/ IMes HCl 1/NaO Pr decreased in the order 1 > Br > Cl F. Subsequent work showed that a 1 1 combination of Ni and NHC in the presence of NaOCHEt resulted in enhanced reactivity towards aryl fluorides [6], Again, the A-mesityl substituted ligand IMes HCl 1 imparted the highest level of catalytic activity. Table 8.2 illustrates that hydrodefluorination is sensitive to both the nature of the substituents on the aromatic ring and the specific regioisomer. Thus, 2- or 4-fluorotoluene (Table 8.2, entry 2) proceeded to only 30% conversion after 15 h, whereas quantitative conversion of 2-fluoroanisole (Table 8.2, entry 3) and high conversion of 3-fluoropyridine (Table 8.2, entry 5) was achieved in only 2-3.5 h. The reactivity of 2-fluoropyridine was compromised by more efficient nucleophilic aromatic substitution. 

The addition of a nucleophile to an aromatic ring, followed by elimination of a substituent, results in nucleophilic substitution. The major energetic requirement for this mechanism is formation of the addition intermediate. The addition step is greatly facilitated by strongly electron-attracting substituents, and nitroaromatics are the best reactants for nucleophilic aromatic substitution. Other EWGs such as cyano, acetyl, and trifluoromethyl also enhance reactivity. 

Aromatic nitro compounds undergo nucleophilic aromatic substitutions with various nucleophiles. In 1991 Terrier s book covered (1) SNAr reactions, mechanistic aspects (2) structure and reactivity of anionic o-complexes (3) synthetic aspects of intermolecular SNAr substitutions (4) intramolecular SNAr reactions (5) vicarious nucleophilic substitutions of hydrogen (VNS) (6) nucleophilic aromatic photo-substitutions and (7) radical nucleophilic aromatic substitutions. This chapter describes the recent development in synthetic application of SNAr and especially VNS. The environmentally friendly chemical processes are highly required in modem chemical industry. VNS reaction is an ideal process to introduce functional groups into aromatic rings because hydrogen can be substituted by nucleophiles without the need of metal catalysts. 

Some theoretical aspects of thiophene reactivity and structure have also been discussed, for example the kinetics of proton transfer from 2,3-dihydrobenzo[6]thiophenc-2-onc <06JOC8203>, the configuration of imines derived from thiophenecarbaldehydes <06JOC7165>, and the relative stability of benzo[c]thiophene <06T12204>. The kinetics of nucleophilic aromatic substitution of some 2-substituted-5-nitrothiophenes in room temperature ionic liquids have also been investigated <06JOC5144>. 

It is more difficult to interpret micellar effects upon reactions of azide ion. The behavior is normal , in the sense that k /kw 1, for deacylation, an Sn2 reaction, and addition to a carbocation (Table 4) (Cuenca, 1985). But the micellar reaction is much faster for nucleophilic aromatic substitution. Values of k /kw depend upon the substrate and are slightly larger when both N 3 and an inert counterion are present, but the trends are the same. We have no explanation for these results, although there seems to be a relation between the anomalous behavior of the azide ion in micellar reactions of aromatic substrates and its nucleophilicity in water and similar polar, hydroxylic solvents. Azide is a very powerful nucleophile towards carboca-tions, based on Ritchie s N+ scale, but in water it is much less reactive towards 2,4-dinitrohalobenzenes than predicted, whereas the reactivity of other nucleophiles fits the N+ scale (Ritchie and Sawada, 1977). Therefore the large values of k /kw may reflect the fact that azide ion is unusually unreactive in aromatic nucleophilic substitution in water, rather than that it is abnormally reactive in micelles. 

Pyridine, on the other hand, is more reactive than benzene towards nucleophilic aromatic substitution. This is effectively reaction towards the C=N imine function, as described above. Attack is... 

Relative Reactivity of Pyridyl Derivatives in Nucleophilic Aromatic Substitutions... 

Halopyridines and other re-deficient nitrogen heterocycles are excellent reactants for nucleophilic aromatic substitution.112 Substitution reactions also occur readily for other heterocyclic systems, such as 2-haloquinolines and 1-haloisoquinolines, in which a potential leaving group is adjacent to a pyridine-type nitrogen. 4-Halopyridines and related heterocyclic compounds can also undergo substitution by nucleophilic addition-elimination but are somewhat less reactive. 

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. 

Nucleophilic aromatic substitutions 1,3-azoles are more reactive than pyrrole, furan or thiaphene towards nucleophilic attack. Some examples of nucleophilic aromatic substitutions of oxazole, imidazole and thiazoles and their derivatives are given below. In the reaction with imidazole, the presence of a nitro-group in the reactant can activate the reaction because the nitro-group can act as an electron acceptor. 

Nucleophilic aromatic substitutions Pyrimidine is more reactive than pyridine towards nucleophilic aromatic substitution, again due to the presence of the second electron-withdrawing nitrogen in the pyrimidine ring. Leaving groups at C-2, C-4 or C-6 positions of pyrimidine can be displaced by nucleophiles. 

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