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The rate constants of the title reactions have been measured at various amine concentrations. The second-order kinetic constant for the amino substitution increases in a hyperbolic way as a function of the nucleophile concentration. The k3Am/k-1 ratio for each catalysed system is not a monotonic function of the X substituent. This result has been rationalized in the framework of the SB-GA (Specific Base-General Acid) mechanism of base catalysis.

The protonation behaviour at 25 °C in aqueous sulphuric acid solution of some 3-, 4-, and 5-substituted thiophen-2-carboxamides has been investigated by u.v. spectrophotometry. pKBH+ Values were calculated by HA and Bunnett–Olsen methods using the multivariate analysis. A positive σα–s value was obtained indicating that the sulphur atom acts as an electron-withdrawing substituent. Plots of pKBH+ of 4- and 5-substituted thiophen-2-carboxamides and 3-substituted derivatives against σ were linear with the slope +1.10 and +1.28, respectively. A ρo/ρm,p ratio higher than unity (1.16) has been observed indicating a larger transmission of electronic effects between the 2- and 3-positions of the thiophen ring than between the 2- and 4- or 5-positions.

The rate constants of debromination of 2-bromo-3,5-dinitrothiopene by various meta- and para-substituted anilines have been measured in benzene at 25 °C. The reactions are mildly accelerated by increasing the amine concentration, showing ‘low’kB/k0 ratios (4.6–11 dm3 mol–1). However, the reactions are inferred to be genuinely base-catalysed on the grounds of the excellent Hammett-type relationships ollowed by both log kB and log k0 parameters.

The kinetics of the reactions of 2-methoxy-3-nitrothiophen (I) with pyrrolidine in methanol and benzene and with perhydroazepine in benzene have been studied as a function of amine concentration. The pyrrolidino-substitution of (I) in methanol is second-order overall whereas the corresponding piperidino-substitution is base-catalysed. The reactions of (I) with pyrrolidine, piperidine, and perhydroazepine in benzene are all catalysed by the nucleophile and by diazabicyclo[2.2.2]octane but the pattern of catalysis depends on the ring size of the cyclic amine. The data are most consistent with the specific base–general acid mechanism for base catalysis. The remarkable difference in behaviour between pyrrolidine and piperidine is suggested to stem from conformational effects concerning the amino-moieties in the transition state for the general acid-catalysed departure of methoxy-group.

The rates of piperidinodebromination of some N-substituted 2-bromo-4-R-5-nitrothiophene-3-carboxamides (R = H and Me) have been measured in methanol. The kinetic data obtained, as well as the investigation of the restricted rotation about the C–N bond of the amino group of some of the above carboxamides by dynamic n.m.r. spectroscopy, have shown the occurrence of steric interactions which force the 3-carboxamido group to rotate about its bond with the aromatic ring. This causes a reduced activation and a kinetic secondary steric effect.

The title reaction has been studied at various pS+ and buffer concentrations. Kinetic constants for uncatalysed and catalysed pathways have been calculated. A mechanism for the rearrangement is offered.

A 13C NMR study has been carried out in (CD3)2SO on the thiophene derivatives 5 and 7 and the related Meisenheimer adducts 6 and 8. The data obtained, and in particular the sums of the chemical-shift changes (ΣΔδ) at C-3, C-4 and C-5, accompanying the formation of the adducts, are compared with the corresponding data previously obtained for analogous substrates 1 and 3 and adducts 2 and 4. The four series of ΣΔδ values are then examined in the light of the already reported thermodynamic (Ke) and kinetic (k1) constants for the formation of the adducts. For a given X-substituent, log Ke values increase linearly as the corresponding absolute ΣΔδ values decrease. On these grounds, the smaller π-electron-density rearrangement accompanying the formation of gem-dimethoxy adducts emerges as an important factor, contributing to the larger observed Ke values. A further outcome is that, within a single series of adducts, a linear relationship of either log Ke or log k1 with Δδ holds only when excluding the terms with X = Ac or NO2. Such findings are interpreted on the basis of the two-component nature of the substituent –R effects: while for the nitro and the acetyl substituents the π-electron acceptor component is prevalent, the stabilizing effect of the other substituents is due mainly to a charge–dipole interaction. The analysis of some literature data for the benzene series fits the above conclusions.

The effect of the structure of the side chain both on the mechanism and the reactivity in mononuclear heterocyclic rearrangements has been studied by comparing the base-catalysed rearrangement of some 3-arylureines of 5-phenyl-1,2,4-oxadiazole with that of some arylhydrazones of 3-benzoyl-5-phenyl-1,2,4-oxadiazole. In acetonitrile and in benzene, in the presence of amines, on changing from the side chain CNN (arylhydrazones) to the side chain NCN (arylureines), a strong decrease of the reactivity has been observed (rate ratios ca. 103), but the reaction mechanism is the same for the two series of compounds. In contrast, in dioxane–water, the reactivity variation is much less (rate ratios ca. 25 in the pS+-dependent range) and a change of mechanism is observed. For arylureines and for arylhydrazones, specific- and general-base catalysis respectively has been shown. This is in keeping with the high acidity of arylureines, which in the presence of a strong base can be converted into the corresponding anions and then rearrange to the 1,2,4-triazolin-5-ones.

The rates of piperidinodebromination of some 2-bromo-3-X-5-nitrothiophens (I; X = Me, H, Br, CONH2, CO2Me, SO2Me, CN, or NO2) have been measured in methoanol. The logarithm of the rate constants gives an excellent straight line (except for X = Br) when plotted against σp– and against the logarithm of the rate constants of piperidnodebromination for the corresponding 2-bromo-3-nitro-5-X-thiophens (III). This confirms that a 3-substituent exerts an effect on the 2-position of the same kind (in this case extraconjugative) as that exerted from the 5-position. The ρ2,3 value (+4·02) and the ratio ρ2,3/ρ2,5(1·18) show there is a larger transmission of electronic effects between the 2- and 3-positions than between the 2- and 5-positions of the thiophen ring.

The rate constants for the reactions of some 2-L-3-nitro-5-X-thiophenes 1–4 with aniline and of compounds (4) with piperidine in methanol have been measured at various temperatures. By using the data obtained in this work as well as previously available data sets, a series of optimized ‘thiophene’σT values has been calculated. The susceptibility constants ρ(L)of the various sets have been analysed in the framework of the reactivity–selectivity principle.

The kinetic data obtained in the study of the title reaction reveal unusual substituent effects. A logarithmic plot of reactivity data versus substituent constants (σ and/or σ–) shows a ‘zigzag’ trend; it is suggested that this depends on a changeover of the mechanism and/or of the rate-determining step.

The rate constants for the reactions of 2-bromo-3-nitro-5-X-thiophens (X = H, Br, CONH2, CO2Me, Ac, SO2Me, CN, or NO2) with some substituted anilines YC6H4NH2(Y =p-OMe, p-Me, H, m-Cl, or p-CO2Me) have been measured in methanol at various temperatures. The sensitivity parameters, ρ(Y) and β(X), obtained from Hammett and Bronsted correlations are practically independent of the reactivity of the starting system. The relevance of these results to the reactivity–selectivity principle is discussed.

The kinetics of the title reaction have been measured at various pS+ values. The results show the occurrence of general base catalysis and furnish information about substituent effects on the studied reaction. A reaction mechanism analogous to that proposed for the rearrangement of the arylhydrazones of 3-benzoyl-5-phenyl-1,2,4-oxadiazole is suggested. The reactivity of isoxazole derivatives is much lower than that of 1,2,4-oxadiazole derivatives.

The rate constants of the decarboxylation reaction of compounds (Ib–f) have been measured in water over a range of proton activities, at various temperatures. The results obtained strongly support the unimolecular decarboxyprotonation mechanism.

The rate constants for the reactions of some 3-substituted 2-thenoyl chlorides (I; X = OMe, Me, SMe, H, I, Br, SOMe, and SO2Me) with aniline in benzene have been measured. A plot of the logarithm of the rate constants versus the –ΔpKa values of the corresponding acids furnishes an example of a non-linear free energy relationship, indicating the occurrence of different reaction mechanisms for 2-thenoyl chlorides with, respectively, electron-attracting and -repelling substituents at C-3.

The constants for ion-pair formation with 2,4-dinitrophenol in benzene (KB), and the pKa, values in water, of thirty-three amines have been measured. According to the class of amine, two different situations can be observed: for primary amines and secondary cyclic amines, the effects of structural variations on basicity are higher in water than in benzene; on the other hand, for tertiary amines these effects are similar in the two solvents. KB, Values of primary amines give a good correlation with σ*. The Taft and Hancock equation allows a unifying treatment of KB, values of the various classes of amines.

A series of 4- and 5-substituted 2-([3H]acetyl)thiophenes have been prepared and the kinetics of the hydroxide-catalysed detritiation studied at 25.0 °C. The second-order detritiation rate constants parallel those observed for the corresponding meta- and para-substituted acetophenones but as the reaction constant ρ is higher (1.61) the range of reactivity is much wider than that witnessed for the acetophenones.

The reactivity of some 2-L-3-nitro-4-R-5-X-thiophens (L = Br or SO2Ph; R = H or Me; X = H or NO2) with various nucleophiles (sodium methoxide and benzenethiolate, aliphatic, cyclic, and aromatic amines) has been measured in methanol. The results obtained have been interpreted in the light of the electronic and steric effects of the nucleophiles. The KH/KMe values calculated confirm the data previously obtained with piperidine, i.e., absence of a secondary steric effect (s.s.e). and presence of a small s.s.e. for bromine and phenylsulphonyl, respectively, as leaving groups. The special behaviour of N-methylaniline is discussed.

The 1H n.m.r. spectra of some 3- and 5-substituted thiophen-2-carboxamides in CDCl3 are reported. 3-Substituted thiophen-2-carboxamides show intramolecular hydrogen bonding between the N–H proton and the 3-substituent and also an intermolecular hydrogen bond, except for the 3-methyl derivative, which exhibits only intermolecular hydrogen bonding. 5-Substituted thiophen-2-carboxamides exhibit intermolecular hydrogen bonding. The chemical shifts for the 4-protons of 3-substituted thiophen-2-carboxamides correlate with σp(r= 0.962; ρ= 1.39). Correlation for the 4-protons of the 5-substituted amides is poor.The activation energies of rotation of the 3-substituted amides are higher than those of the corresponding 5-substituted derivatives. For 5-substituted amides the activation energies of rotation depend on the electronic nature of the substituents, and ΔG(Tc)/σp+ shows a linear relationship (r= 0.954; ρ= 1.77).

Kinetic data from the substitution of piperidine into some 2-substituted 3,5-dinitro-4-methyl-(IIa–d) and 3,5-dinitro-thiophens (Ia–d) show the occurrence of a small secondary steric effect (k(Id)/k(IId)= 8) only when the leaving group is SO2Ph. This effect seems to depend on the interaction of the groups at C-2, –3, and –4 of the thiophen ring, as the results obtained for other thiophens indicate.

The kinetics of piperidino-substitution of methyl 2-methoxy-3-nitrothiophen-5-carboxylate (lb) and of 5-acetyl-2-methoxy-3-nitrothiophen (lc) have been studied in methanol as a function of piperidine and methoxide ion concentrations. The reactions are catalysed by both piperidine and methoxide. Evidence is presented that the departure of the methoxy group is general-acid-catalysed, indicating a specific base-general acid mechanism for base catalysis.

The behaviour in alkaline media (water, water–dioxane, or water–dimethyl sulphoxide) of 2-phenylamino-1,3,4-oxadiazole (IH) has been studied, together with the title reaction. Chemical and kinetic evidence support the occurrence of a ring conversion through an intermediate cyclic compound (IV–), followed by the formation of an open-chain anion (V–) that cyclizes fast to the triazole derivative (III–).

The rate constants of the decarboxylation reaction of 5-amino-1,3,4-oxadiazole-2-carboxylic acid (I) have been measured in water, over a wide range of proton activities (from H0–0.95 to pH 4.77), at various temperatures, and the activation parameters have been determined. We present evidence for the occurrence of a decarboxyprotonation mechanism.

The protonation of some 3-substituted 2-(N,N-dialkylamino)-5-nitrothiophenes (3)–(4) and some 5-substituted 3-nitro-2-piperidinothiophenes (2) has been studied in aqueous perchloric and/or sulphuric acid. pKBH+ values have been calculated according to modified Hammett, Bunnett–Olsen, and Marziano–Yates–Cox methods and the data obtained related to the effect of the substituents. The results obtained have been discussed considering the different interactions that the dialkylamino (N,N-dimethylamino or piperidino) group at C-2 can give with the group (nitro-group or variable substituent) present at C-3 (an ortho-like position).

Rate constants have been determined for the chlorine-isotopic exchange reactions in sulpholane solution between lithium chloride-36 and compounds containing two non-equivalent exchangeable chlorine substituents, viz. 2,5-dichloro-3-nitrothiophene, 1,3-dichloro-2,4-dinitrobenzene, and 4-chloro-3,5-dinitrobenzenesulphonyl chloride.

The reactivity of 2,3-dihalogeno-4-R-5-nitrothiophens [R = H (I) and Me (II); halogen = Cl (b) and I (c)] with piperidine and sodium benzenethiolate has been studied in methanol at various temperatures. The results obtained together with previous data concerning 2,3-dibromo-4-R-5-nitrothiophens [R = H (I) and Me (II)] and 2-halogeno-5-nitrothiophens [(IV); halogen = Br (a), Cl (b), and I (c)] have shown that the activating effect of the 3-halogen substituent is largely affected by the nature of both halogen and nucleophile, and furnished further examples of weak activation by a meta-methyl group.

The acid dissociation constants of some 3-substituted thiophen-2-carboxylic acids (I; X = OMe, Me, SMe, H, I, Br, SOMe, or SO2Me) in water, at 25 °, have been measured. The data obtained furnish a good linear free energy relationship of the Yukawa–Tsuno type (ρ+1.34, r+ 0.57, R 0.996) emphasizing the large difference, probably linked to the geometry of the five-membered ring, from the situation observed for ortho-substituted benzoic acids. A ρ2,3/ρ2,5 ratio higher than unity (1.37) has been observed.

The kinetics of the title reactions have been measured at various piperidine concentrations. The results obtained show that in all the solvents studied the rearrangements occur through a bimolecular reaction pathway involving one molecule of piperidine (kII). However, depending on the solvent used more catalysed steps contribute to the overall reaction. Thus, in methanol, catalysis (kMeO) by methoxide ion, derived from the basic ionization of piperidine in methanol, has also been observed and in dioxan or in ethyl acetate, besides the uncatalysed (ku) and kII steps, the overall mechanism involves a small contribution from catalysis by two molecules of piperidine (kIII). The results obtained in this work together with those previously obtained in benzene allow exclusion of the addition of piperidine to the C(5)–N(4) bond of the 1,2,4-oxadiazole ring. The kIII step is likely to arise from catalysis of catalysis.

The rates of piperidino-substitution of 2,4-dinitrophenyl 4-nitrophenyl ether (1) and of 2,4-dinitrophenyl phenyl sulphone (2) in benzene at various piperidine concentrations and in the presence of some additives (dioxan, tetrahydrofuran, pyridine, acetonitrile, α-pyridone, methanol, and diazabicyclo [2.2.2]octane) indicate the possibility of catalytic decomposition of the reaction intermediate; e.g. clear evidence of catalysis has been obtained in the cases of piperidine and of α-pyridone. In other cases the additives seem to influence the reaction rates by affecting the nature of the solvent (tetrahydrofuran, pyridine, and acetonitrile) or giving rise to opposite, balancing effects (methanol). Dioxan does not affect the reactivity.

The rate and equilibrium constants for the formation of the Meisenheimer-type adduct from 2-methoxy-5-methyl-3-nitrothiophene (1a) and sodium methoxide in methanol have been measured at 20 °C. The adduct (2a) is nine times more stable and is formed about three times faster than the ‘unsubstituted’ adduct (2b), confirming the unusual role that a methyl substituent can play in reactions where it is necessary to delocalize a negative charge. 13C N.m.r. chemical shifts of (1a) and (2a) have also been determined. An interpretation of all the results is offered on the basis of polarity variation of the methyl group.

The susceptibility constants measured for the reaction of 3-bromo-(Ia) and 3-methoxy-2-thenoyl (Ic) chlorides with some meta- and para-substituted anilines in benzene at 25°C have confirmed the occurrence of two different mechanisms for the anilinodechlorination of 3-substituted 2-thenoyl chlorides: (i) the classical AE mechanism and (ii) the IP mechanism (unusual for reactions with anilines in nonpolar aprotic solvents) which can operate when electron-releasing substituents are present in the thiophen ring.

The rate constants for the alkaline hydrolysis of some methyl 3-substituted thiophen-2-carboxylates (I)(substituents OMe, Me, SMe, H, I, Br, SOMe, and SO2Me) in methanol–water (80% v/v) have been determined. The logarithms of the rate constants give an excellent straight line when plotted against the pKa values of the corresponding acids (slope 1.91) and obey an equation of the Yukawa–Tsuno type (ρ+ 2.77, r+ 0.44, R 0.996), confirming the marked difference in behaviour between ortho-like substituted thiophen and benzene derivatives.

A 13C n.m.r. study in (CD3)2SO has been carried out on 5-cyano-(5), 5-methoxycarbonyl-(6), 5-carbamoyl-(7), and 5-acetyl-3-nitro-2-X-thiophenes (8) in order to investigate the 2-X-substituent effect on the C(α) chemical shifts of the different 5-probes. The results obtained show that, unlike the case of the acetyl group, the α-carbon chemical shifts of the cyano, methoxycarbonyl, and carbamoyl groups are not appreciably affected by through-conjugation with the 2-X-substituents, π-polarization being the more important outcome of the substituent effect on the probe group. The analysis of both the C(5) and C(α) chemical-shift variations in the series (5)–(8), by means of a gradual modification of the electron-releasing power of the substituents, reveals a trend which has been interpreted as a useful indicator of the electronic effects in play on the distribution of the π-electron densities in the corresponding Meisenheimer adducts (1)–(4).

The kinetics of the reactions of some 2-methoxy-3-nitro-5-X-thiophenes (Ia–g; X = H, CONH2, CO2Me, Ac, SO2Me, CN, or NO2) with piperidine and with n-butylamine in benzene have been measured in the range 20–40 °C. The reactions with piperidine are catalysed by piperidine, being third-order overall (second-order in amine). The electronic effects of the 5-substituent on the ‘catalytic’ constants are shown to be most consistent with the SB-GA mechanism of base catalysis in benzene.

To obtain information on the influence of a leaving group with high steric requirements on the possibility of obtaining ortho-linear free energy correlations in SNAr reactions of five-membered ring derivatives, the rates of piperidinosubstitution of some 3-X-5-nitro-2-thienyl phenyl sulphones (II; X = Me, H, Br, CONH3, CO2Me, SO2Me, CN, and NO2) have been measured in methanol solution. The logarithm of the rate constants gives a straight line when plotted against σp– or against the logarithm of the rate constants of piperidino-substitution for the para-isomers(IV) except for X = Me, Br, and SO2Me. The ρ2,3 value (+4.60) and the ratio ρ2,3 : ρ2,5(1.15) compare well with those obtained for the corresponding piperidinodebromination reactions, thus confirming that an ortho-substituent affects the position of the rate-determining transition state along the reaction co-ordinate more than a para-substituent.

In order to study primary steric effects (p.s.e.) in nucleophilic substitutions of five-membered rings, the rate of piperidino and benzenethiolate substitution of some 2-L-5-nitrothiophens (Ia—d) and 2-L-3-methyl-5-nitrothiophens (IIa—d) have been measured in methanol. The rate ratios (kH/kMe) obtained show an absence of p.s.e. in piperidino substitutions when the leaving group is halogen but not when L = SO2Ph. Benzenethiolate substitution data show the presence of a large Reinheimer–Bunnett effect.

The kinetics of the title reaction have been measured in the presence of primary, secondary, and tertiary amines and of primary diamines. The following relationships have been observed: kA=kIV[B]3 with primary amines and with 1,6-diaminohexane, kA=kIII[B]2 with secondary cyclic amines and the other primary diamines, and kA=kII[B] with diazabicyclo[2.2.2]octane (DABCO). The reaction has also been studied in the presence of pairs of amines [butylamine (piperidine) and triethylamine (DABCO)], in which case ‘mixed’ terms such as k′IV[BuA][DABCO]2 and k′III[PIP][DABCO] also occur. On the basis of the results the kinetic laws observed have been ascribed to catalysis of catalysis which depends on the nature and the structure of the amine used.

The rates of piperidino-debromination of some 2-bromo-3-nitro-5-X-thiophens and 2-bromo-4-methyl-3-nitro-5-X-thiophens in methanol have been measured. The results indicate that the Hammett relationship can be applied to the tetrasubstituted as well as to the trisubstituted compounds. The kinetic data for 2-bromo-4-methyl-3-nitro-5-X-thiophens represent the first good fit of the Hammett equation for a series of ortho-tetrasubstituted compounds. This is possible with fully substituted thiophens because the geometry of the 5-membered ring lowers steric interactions which in a 6-membered ring (e.g. benzene) are known to be very large.