Pyrroles acid stability

Particular attention has been paid to the oxidation of pyrrolecarboxylic acids, since it is related to the studies about the oxidative degradation of several natural pigments,67 which give mainly pyrrole acids among the identifiable products. Thus, the stability of the acids toward the oxidizing agents, and also hydrogen peroxide, has been tested.65... 

The synthons of porphyrin syntheses are the pyrroles, which in turn must be made from 1,4-difunctional synthons. These carbon skeletons are available by an aldol-type condensation of the enol of a 1,3-diketone with an a-nitrosylated acetoacetate (Knorr pyrrole synthesis. Scheme 1.3.4). The final reductive ring closure by Schiff base formation is again a reversible condensation reaction. After dehydration, however, a stable 7i-electron sextet is formed, which gives the resulting pyrrole aromatic stability. Hydrolysis of this enamine can now only occur in very strong acid. In water of modest acidity or basicity it is perfectly stable. 

Unsymmetrically substituted dipyrromethanes are obtained from n-unsubstitued pyrroles and fl(-(bromomethyl)pyiToIes in hot acetic acid within a few minutes. These reaction conditions are relatively mild and the o-unsubstituted pyrrole may even bear an electron withdrawing carboxylic ester function. It is still sufficiently nucleophilic to substitute bromine or acetoxy groups on an a-pyrrolic methyl group. Hetero atoms in this position are extremely reactive leaving groups since the a-pyrrolylmethenium( = azafulvenium ) cation formed as an intermediate is highly resonance-stabilized. 

Pyrrole is soluble in alcohol, benzene, and diethyl ether, but is only sparingly soluble in water and in aqueous alkaUes. It dissolves with decomposition in dilute acids. Pyrroles with substituents in the -position are usually less soluble in polar solvents than the corresponding a-substituted pyrroles. Pyrroles that have no substituent on nitrogen readily lose a proton to form the resonance-stabilized pyrrolyl anion, and alkaU metals react with it in hquid ammonia to form salts. However, pyrrole pK = ca 17.5) is a weaker acid than methanol (11). The acidity of the pyrrole hydrogen is gready increased by electron-withdrawing groups, eg, the pK of 2,5-dinitropyrrole [32602-96-3] is 3.6 (12,13). 

Pyrrole Carboxylic Acids and Esters. The acids are considerably less stable than benzoic acid and often decarboxylate readily on heating. However, electron-withdrawing substituents tend to stabilize them toward decarboxylation. The pyrrole esters are important synthetically because they stabilize the ring and may also act as protecting groups. Thus, the esters can be utilized synthetically and then hydrolyzed to the acid, which can be decarboxylated by heating. Often P-esters are hydrolyzed more easily than the a-esters. 

It is of interest to compare the stability of the protonated forms of benzo[u], benzo[Z>] and benzo[c] fused pyrroles, i.e. the cations derived from indolizines, indoles and isoindoles. Indolizine gives a stable pyridinium ion and does not polymerize in the presence of acid. 

It will be noted that pyrrole-3-carboxylic acid (154) is an appreciably weaker acid than benzoic acid and this is attributed to the stabilization of the undissociated acid by electron release from nitrogen. The 2-carboxylic acids of furan, thiophene, selenophene and tel-lurophene are all stronger acids than benzoic acid, tellurophene-2-carboxylic acid (pisTa 4.0) being the weakest acid in this series (77AHC(21)119). 

Poly(N-phenyl-3,4-dimethylenepyrroline) had a higher melting point than poly(N-phenyl-3,4-dimethylenepyrrole) (171° vs 130°C). However, the oxidized polymer showed a better heat stability in the thermogravimetric analysis. This may be attributed to the aromatic pyrrole ring structures present in the oxidized polymer, because the oxidized polymer was thermodynamically more stable than the original polymer. Poly(N-phenyl-3,4-dimethylenepyrroline) behaved as a polyelectrolyte in formic acid and had an intrinsic viscosity of 0.157 (dL/g) whereas, poly(N-pheny1-3,4-dimethylenepyrrole) behaved as a polyelectrolyte in DMF and had an intrinsic viscosity of 0.099 (dL/g). No common solvent for these two polymers could be found, therefore, a comparison of the viscosities before and after the oxidation was not possible. 

Certain lead(II) complexes were shown to display reversible redox behavior on the CV scale. Examples are Pb(II) complexes of 2(o-hydroxyphenyliminomethyl)-pyrrole and 2(o-hydroxyphenyliminomethyl)-thiophene. Their stability constants were also determined by polarography140. Anodic exchange reactions of extracted metal chelates were carried out with 1-pyrrolidinecarbodithioic acid in isobutyl methyl ketone141. 

It is possible to protonate pyrrole using a strong acid, but even then the protonation occurs on C-2 and not on the nitrogen. Although this still destroys aromaticity, there is some favourable resonance stabilization in the conjugate acid. Protonation on C-3 is not as favourable, in that there is less resonance stabilization in the conjugate acid. It turns out that, as opposed to acting as a base, pyrrole is potentially an... 

Imidazole (pATa 14.2) is also more acidic than pyrrole (pATa 17.5) this, again, is a feature conferred by symmetry and the enhanced resonance stabilization in the conjugate base. 

These compounds are less common than indole (benzo[ ]pyrrole). In the case of benzo[i>]furan the aromaticity of the heterocycle is weaker than in indole, and this ring is easily cleaved by reduction or oxidation. Electrophilic reagents tend to react with benzo[Z ]furan at C-2 in preference to C-3 (Scheme 7.21), reflecting the reduced ability of the heteroatom to stabilize the intermediate for 3-substitution. Attack in the heterocycle is often accompanied by substitution in the benzenoid ring. Nitration with nitric acid in acetic acid gives mainly 2-nitrobenzo[Z ]furan, plus the 4-, 6- and 7-isomers. When the reagent is in benzene maintained at 10 °C, both 3- and 2-nitro[ ]furans are formed in the ratio 4 1. Under Vilsmeier reaction conditions (see Section 6.1.2), benzo[Z ]furan gives 2-formylbenzo[6]furan in ca. 40% yield. 

The differences in aromaticity follow the results of theoretical analyses on the acidity of the NH proton of the pyrrole fragment of furo[ ]pyrroles <2000PJC207> and are nicely reflected in the observed stability of both systems. The total energy difference between methyl 4f/-furo[3,2- ]pyrrole-5-carboxylate 8a and methyl 6f/-furo[2,3- ]pyr-role-5-carboxylate 31a is rather small (—7.2 kj mol ) indicating the higher stability of the former system. However, if the increase of energy of the appropriate anions is compared (relative to the parent molecules), then it indicates that formation of 67/-furo[2,3-7]pyrrole-5-carboxylate anion is much easier (by —22.5 kJ mol ) than formation of 4//-furo[3,2- ]pyrrole-5-carboxylate anion. 

We can now make sensible guesses as to the order of rate constant for water replacement from coordination complexes of the metals tabulated. (With the formation of fused rings these relationships may no longer apply. Consider, for example, the slow reactions of metal ions with porphyrine derivatives (20) or with tetrasulfonated phthalocyanine, where the rate determining step in the incorporation of metal ion is the dissociation of the pyrrole N-H bond (164).) The reason for many earlier (mostly qualitative) observations on the behavior of complex ions can now be understood. The relative reaction rates of cations with the anion of thenoyltrifluoroacetone (113) and metal-aqua water exchange data from NMR studies (69) are much as expected. The rapid exchange of CN " with Hg(CN)4 2 or Zn(CN)4-2 or the very slow Hg(CN)+, Hg+2 isotopic exchange can be understood, when the dissociative rate constants are estimated. Reactions of the type M+a + L b = ML+(a "b) can be justifiably assumed rapid in the proposed mechanisms for the redox reactions of iron(III) with iodide (47) or thiosulfate (93) ions or when copper(II) reacts with cyanide ions (9). Finally relations between kinetic and thermodynamic parameters are shown by a variety of complex ions since the dissociation rate constant dominates the thermodynamic stability constant of the complex (127). A recently observed linear relation between the rate constant for dissociation of nickel complexes with a variety of pyridine bases and the acidity constant of the base arises from the constancy of the formation rate constant for these complexes (87). 

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