Pyridinium salts electrophilic substitution

Typically, pyridinium salts are prepared through reaction of an intact pyridine with electrophiles. Marazano el al. used a three-component process as entry into 3-substituted pyridinium salts for the preparation of 49 as shown below <06TL5503>. 

Studies on reactions of fused tetrazoles with electrophilic agents are few, presumably due to the capability of these compounds to enter into various transformations <1998JPR687>. It was found <1999JST(477)119> that tetra-zolo[l,5- ]pyridine 13 and its substituted derivatives undergo alkylation with dimethyl sulfate to give the iV -methyl compounds 229 as the prevailing isomer. Only when R = H is a small amount of the iVz-methyltetrazolo[l,5-tf]-pyridinium salt obtained (Equation 33) <1999JST(477)119>. 

Heterocyclic cations will not easily react with electrophiles unless substituted by strongly electron-releasing groups. Alternatively, the reaction conditions are chosen in such a way that a reactive anhydro base or pseudobase intermediate is formed. Thus the thiazolo cation (336) can be nitrated at C-3 (78ZOR216) possibly via the ylide (337). The 6(8)-nitro-2,3-dihydrothiazolo[3,2-a]pyridinium salts (338) and (340) are readily brominated in hydroxylic solvents the regioselectivity and the ease of reaction are consistent with pseudobase intermediates (339) and (341) <81H(15)1349). 

The consequence of this replacement gives pyridine a reduced susceptibility to electrophilic substitution compared to benzene, while being more susceptible to nucleophilic attack. An avenue of chemistry not possible with benzene is the formation of pyridinium salts by donation of the nitrogen lone pair electrons. The resultant salts are still aromatic, however they are much more polarized. This is reflected by the apparent acidity of the corresponding conjugate acid (pK, 5.2) compared to the acidity of the corresponding conjugate acid of piperidine (pK, 11.1). 

The formal replacement of a CH in benzene by N leads to far-reaching changes in typical reactivity pyridines are much less susceptible to electrophilic substitution than benzene and much more susceptible to nucleophilic attack. However, pyridine undergoes a range of simple electrophilic additions, some reversible, some forming isolable products, each involving donation of the nitrogen lone pair to an electrophile, and thence the formation of pyridinium salts which, of course, do not have a counterpart in benzene chemistry at all. The ready donation of the pyridine lone pair in this way does not destroy the aromatic... 

Pyridinium salts show the properties that have been discussed above, but in extreme, thus they are highly resistant to electrophilic substitution but, conversely, nucleophiles add very easily. Especially useful are the adducts formed from iV" -C02R salts with alkyl- or aryllithiums (see above). The hydrogens of pyridinum a- and y-alkyl side-chains are further acidified compared with an uncharged alkyl pyridine. 

Straightforward electrophilic or radical substitutions at ring positions are unknown. Controlled oxidations, like those of pyridinium salts to 2-pyridones, are likewise not known in pyrylium chemistry. 

Practically all the reactions of quinolizinium ions are similar to those of pyridinium salts, thus they are resistant to electrophilic attack, but readily undergo nucleophilic addition, the initial adducts undergoing spontaneous electrocyclic ring opening to afford, finally, 2-substituted pyridines however the susceptibility of the cations to nucleophiles is not extreme - Uke simpler pyridinium salts they are stable to boiling water. 

For the unsubstituted pyridinium cation, reaction at the 2- and at the 4-position is predicted according to the theory. Indeed, reaction of protonated pyridine with the tcrt-butyl radical at low conversions (<30%) afforded selectively the ortho- and para-substituted derivatives without any alkylation at the meta position [16], It turned out that the ortho-para ratio is highly solvent dependent. If the reaction is conducted in H2O, the para product is formed as the major compound (see 10, ortho. para — 23 77). The same reaction in benzene afforded mainly the ortho compound [ortho-.para = 11 29). The reversal of the selectivity can be explained by assuming a reversible initial radical addition, especially if the reaction is conducted in H2O [16]. Similar results were obtained for the reaction with the tetrahydrofuryl radical [16]. The alkylations are generally stopped at low conversions. Since the alkylated pyridinium cations are only slightly less electrophilic than the starting pyridinium cations, overalkylation competes at higher conversion. For example, ethylation of the pyridinium cation at 100% conversion afforded a mixture of mono-, double- and tri-ethylated pyridinium salts (—> 11a e) [17]. 

Benzyl bromide is a good electrophile and it reacts well with alkoxides to make ethers. With neutral alcohols however the substitution is very slow, so only the more nucleophilic (and more basic) pyridine nitrogen is attacked, to make a pyridinium salt. 

---