Reactions with electrophilic reagents

In reactions which involve bond formation using the lone pair of electrons on the ring nitrogen, such as protonation and quaternisation, pyridines behave just like tertiary aliphatic or aromatic amines. When a pyridine reacts as a base or a nucleophile it forms a pyridinium cation in which the aromatic sextet is retained and the nitrogen acquires a formal positive charge. 

Pyridines form crystalline, frequently hygroscopic, salts with most protic acids. Pyridine itself, with pATa 5.2 in water, is a much weaker base than saturated aliphatic amines which have pATa values mostly between 9 and 11. Since the gas-phase proton affinity of pyridine is actually very similar to those of aliphatic amines, the observed solution values reflect relatively strong solvation of aliphatic ammonium cations this difference may in turn be related to the mesomerically delocalised charge in pyridinium ions and the consequent reduced requirement for external stabilisation via solvation. 

Electron-releasing substituents generally increase the basic strength 2-methyl-(pKa 5.97), 3-methyl (5.68) and 4-methylpyridine (6.02) illustrate this. The basicities of pyridines carrying groups which can interact mesomerically as well as inductively vary in more complex ways, for example 2-methoxypyridine (3.3) is a weaker, but 4-methoxypyridine (6.6) a stronger base than pyridine the effect of inductive 

Large 2- and 6-substituents impede solvation of the protonated form 2,6-di-t-butylpyridine is less basic than pyridine by one pA a unit and 2,6-di(tri-i-propylsilyl)pyridine will not dissolve even in 6N hydrochloric acid.  

This occurs readily by reaction of pyridines with nitronium salts, such as nitronium tetrafluoroborate. Protic nitrating agents such as nitric acid of course lead exclusively to iV-protonation. 

6-Triphenylpyrylium undergoes exchange at the 3- and 5-positions in hot deuterioacetic acid, but the process probably involves, not protonation of the pyrylium cation, but formation of an equilibrium concentration of an adduct, with acetate added to C-2, allowing enol ether protonation and thus exchange.  

Heterocyclic Chemistry 5th Edition John Joule and Keidi Mills 2010 Blackwell Publishing Ltd 

Nitration of 2,4,6-triphenylpyrylium proceeds on the benzene rings no nitrations of pyrylinm rings are known. 

Many synthetic pyridine derivatives are important as therapeutic agents, for example Isoniazide is a major antituberculosis agent, Sulphapyridine is one of the sulfonamide antibacterials, Prialdoxime is an antidote for poisoning by organophosphates, and Lacidipine is one of several antihypertensive 1,4-dihy-dropyridines. Some herbicides (Paraquat) and fungicides (Davicil) are also pyridine derivatives. 

Electron-releasing substituents generally increase the basic strength  

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Section 12 1 On reaction with electrophilic reagents compounds that contain a ben zene ring undergo electrophilic aromatic substitution Table 12 1 m Section 12 1 and Table 12 3 m this summary give examples... 

Carboxylic acid derivatives on pyridopyrimidine rings appear to undergo normal reactions with electrophilic reagents, e.g. the 6-amide (70) is dehydrated to the 6-nitrile with phosphorus oxychloride. 

The high reactivity of pyrroles to electrophiles is similar to that of arylamines and is a reflection of the mesomeric release of electrons from nitrogen to ring carbons. Reactions with electrophilic reagents may result in addition rather than substitution. Thus furan reacts with acetyl nitrate to give a 2,5-adduct (33) and in a similar fashion an adduct (34) is obtained from the reaction of ethyl vinyl ether with hydrogen bromide. 

Mesomeric shifts of the types shown in structures (82) and (83) increase the electron density on the nitrogen atom and facilitate reaction with electrophilic reagents. However, the heteroatom Z also has an adverse inductive effect the pK, of NH2OH is 6.0 and that of N2H4 is 8.0, both considerably lower than that of NH3 which is 9.5. 

The reactivity of Ce, C7, Cg aromatics is mainly associated with the benzene ring. Aromatic compounds in general are liable for electrophilic substitution. Most of the chemicals produced directly from benzene are obtained from its reactions with electrophilic reagents. Benzene could be alkylated, nitrated, or chlorinated to important chemicals that are precursors for many commercial products. 

Sulfinyl and sulfonyl groups were involved in early studies of the directive effects of substituents in nitration and other reactions with electrophilic reagents. Thus Twist and Smiles (in 1925) showed that nitration of phenyl methyl sulfone gave exclusively 3-nitrophenyl methyl sulfone. The results of bromination and sulfonation were analogous, so S02Me was established, like NO2, as a mefa-directing group. 

Butadiene shows 1,4-addition reactions with electrophilic reagents other than HC1. 

These reactions may be considered to be a method of obtaining 1,3,2,5-dioxaborataphosphoniarinanes with different substituents at carbon and phosphorus atoms of the ring. Comparing the properties of cyclic oxyalkyl-phosphines and boryloxyalkylphosphines, it should be noted that in both cases the reaction with alkyl halides results in the formation of a tertiary phosphonium salt. The reaction with electrophilic reagents such as diphe-nylchlorophosphine and diphenylchloroborane proceeded quite differently [Eq. (100)]. 

Thus, metalation of cyclic nitrones, followed by successive reactions with electrophilic reagents serves as a synthetic method toward a-heteroatom substituted nitrones, which are inaccessible by other methods. It is noteworthy that these reactions can take place only with cyclic nitrones with E -configuration of the aldonitrone group. 

Reactions of cyclophosphines may be divided into three types (a) those that involve retention of the initial ring size, (b) those in which a P-P bond is cleaved and (c) those that result in a change in ring size, i.e. ring expansion or ring contraction. The former type (a) is observed for reactions with electrophilic reagents in which the lone pairs on the phosphorus(III) centres provide the nucleophilic site. These may involve simple adduct formation or oxidation to phosphorus(V) in some cases this oxidation may be accompanied by ring... 

All of the parent heterocycles possess some degree of aromaticity, as based upon chemical behavior such as their proclivity to undergo substitution reactions with electrophilic reagents. Quantification of the relative aromaticities of these heterocycles is less easily achieved. The wide range of potential criteria available for this purpose has been surveyed in Section 2.2.4.2. 

Reactions with electrophilic reagents. Reactions of nucleic acids with the simplest electrophile, the proton, have been considered in Section A2. Somewhat similar are the reactions by which metal ions bind at many sites on both the bases and the phosphate groups of the backbone.550... 

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