C–N Coupling of 3‐Aminothiophene with Substituted Benzenediazonium Cations: Carbon Nucleophilicity, Hyper‐Ortho Effects, and Predictive Modeling of Structural Analogs

Abstract

This review has kinetically investigated the electrophilic attack of 3‐aminothiophene 1 by a series of para‐substituted benzenediazonium cations 7a–7h in 50% H₂O‐50% Me₂SO at 20 °C using stopped‐flow spectrophotometry. No kinetic isotope effect is observed with the 2‐deuterio‐3‐aminothiophene, confirming that the rate‐determining step is a carbon‐based electrophilic aromatic substitution (S_EAr) at the C–2 position. The Hammett plot with σ _p values shows nonlinearity due to electron‐donating substituents. However, a linear relationship is obtained using the Yukawa–Tsuno equation, highlighting the resonance contribution via the r(σ _p ⁺ − σ _p) term. An excellent linear correlation (R ² ≈ 0.9968) is observed between log k ₁ and the experimental electrophilicity parameter E of the diazonium cations, as defined in the Mayr–Patz equation, allowing the determination of the carbon nucleophilicity parameters of 3‐aminothiophene: N = 9.37 and s_N = 1.18. Importantly, a strong linear relationship is established between N and the Hammett σ ⁺ constants for 3‐substituted 3‐aminothiophenes (R ² = 0.9763), described by the equation: N = 6.72 – 2.01 σ ⁺. This correlation not only demonstrates the pronounced enaminic behavior of 3‐aminothiophenes but also enables the prediction of N values for unmeasured analogs, confirming that substituent–π‐system interactions govern nucleophilic reactivity via a hyper‐ortho electronic effect.

The nucleophilicity parameters of 3‐aminothiophene (N = 9.37; s_N = 1.18) are determined using the Mayr–Patz equation. A linear correlation with Hammett σ ⁺ constants (N = 6.72 – 2.01 σ ⁺) is established, enabling prediction of nucleophilic reactivity for 3‐substituted derivatives in 50% DMSO–50% H₂O at 20 °C.

1. Introduction

Although 3‐aminothiophene 1 and aniline display comparable amino basicities (pK_a = 3.38^{[ 1 ]} and 4.20^{[ 2 ]} in water, respectively), their nucleophilic reactivities toward electrophiles differ markedly. The reference reaction with 4,6‐dinitrobenzofuroxane (DNBF) 2, a well‐known super‐electrophile used to probe weak nucleophiles,^{[ 3} , ⁴ , ⁵ , ⁶ , ⁷ , ^{8 ]} highlights this difference. In the case of aniline, Buncel and coworkers^{[ 2 ]} showed that the first attack takes place at the nitrogen atom, giving the σ‐adduct 3 with a C—N bond, in line with the usual reactivity of amines. Since 3 is less stable than its carbon analog, it slowly dissociates and finally produces the more stable carbon‐bonded complex 4 with a C—C bond as the only final product. In contrast, Terrier and coworkers^{[ 1 ]} found that the reactions of 3‐aminothiophene 1 with 2 lead exclusively to C‐bonded σ‐adducts 5, while the expected nitrogen σ‐complex 6 was never observed under any experimental conditions, either in water or in H₂O–Me₂SO mixtures.

The nonreactivity of 3‐aminothiophene 1 towards nitrogen with various electrophilic motifs has also been observed by synthetic organic chemists.^{[ 9 ]} This property is indeed very important because the predominance of C‐nucleophilicity in 3‐aminothiophene 1 allows for the easy synthesis of numerous thiophene derivatives with interesting pharmacological properties.^{[ 10} , ^{11 ]} Fundamentally, this behavior appears to arise from the pronounced enaminic character of 3‐aminothiophene 1 and its structural analogs.

Based on these results, it became clear that additional information on the behavior of aminothiophene 1 was needed. Specifically, its reactivity with other electrophiles had to be investigated to allow for kinetic quantification. As a result, we conducted a detailed study of the C–N coupling reaction between aminothiophene 1 and various para‐R‐benzenediazonium cations 7a–7h in a 50% H₂O‐50% Me₂SO mixture at 20 °C (Scheme  1 ). This study provided the kinetic data required to quantify its carbon nucleophilicity and to assess the influence of substituent effects on reaction rates through Hammett‐type analysis. By combining our data with previously reported results by Terrier and coworkers on other 3‐substituted aminothiophenes, we established a strong linear correlation between the nucleophilicity parameter N and the Hammett σ ⁺ constants of C‐3 substituents. As we will see, the relationship established between the nucleophilicity parameter N and the σ ⁺ constants of C‐3 substituents revealed a hyperortho electronic effect arising from substituent–π‐system interactions and further enabled the prediction of N values for structurally related analogs within the thiophene series.

Scheme 1.

Carbon‐nitrogen coupling reactions of 3‐aminothiophene 1 with para‐R‐substituted benzenediazonium cations 7 in a 50% H₂O‐50% Me₂SO mixture. Products 8 are represented in the (E)‐configuration, which has recently been reported as the thermodynamically most stable form.^{[ 12 ]}

2. Results and Discussion

2.1. Kinetic Investigations: Reactions of 3‐Aminothiophene 1 with Cations 2

The diazo C‐adducts 8a–8 h, generated by the in situ coupling of benzenediazonium cations 7a–7h with 3‐aminothiophene 1, display UV–vis absorption maxima in the 439–498 nm range. As an illustrative case, Figure  1 shows the absorption spectrum recorded at the end of the reaction for the 3‐aminothiophene–benzenediazonium systems 7a, 7c, and 7g at pH = 1. Notably, Terrier and coworkers^{[ 1 ]} reported similar absorption maxima (λ _max ≈ 480 nm) for the σ‐adducts 5 formed between 4,6‐dinitrobenzofuroxan 2 and 3‐aminothiophene 1 in 50:50 v/v Me₂SO‐H₂O, which fall within the same spectral region (≈439–498 nm). Despite differences in their π‐systems, the C‐adducts and σ‐adducts exhibit visible absorption in a similar range, allowing convenient monitoring of the reaction by UV–vis spectroscopy.

Figure 1.

UV–vis absorption spectra at the end of the reaction for the 3‐aminothiophene–benzenediazonium systems 7a, 7c, and 7g at pH = 1 in 50% H₂O‐50% Me₂SO v/v at 20 °C.

In most cases, our experiments were conducted using a stopped‐flow spectrophotometer. To simplify the kinetic equations, all measurements were performed with concentrations of 3‐aminothiophene 1 (ranging from 10⁻³ to 2.80 × 10⁻² mol L⁻¹) significantly higher than those of the cations 7a–7h (≈5 × 10⁻⁵ mol L⁻¹) in the Me₂SO‐H₂O 50%‐50% v/v medium. This allowed us to operate under pseudo‐first‐order conditions, favorable for the analysis of the kinetic data collected. The reactions were studied at 20 °C at pH = 2 and pH = 1, using hydrochloric acid solutions. The ionic strength of the medium was kept constant at 0.1 mol L⁻¹ by adding potassium chloride.

In all experiments conducted, spectroscopic monitoring revealed a single relaxation process. By analogy with the coupling mechanism proposed in the literature for the reactions of various carbon nucleophiles with superelectrophiles,^{[ 12} , ¹³ , ¹⁴ , ¹⁵ , ^{16 ]} it is reasonable to assume that the diazo adducts 8a–8h formed with 3‐aminothiophene 1 result from an electrophilic aromatic substitution (S_EAr) occurring at the C‐2 position of the nucleophile, via the formation of a Wheland‐type σ‐complex intermediate. As depicted in Scheme  2 , the diazo adducts 8a–8h arise from a two‐step S_EAr pathway involving an initial addition step followed by elimination. Kinetically, the bimolecular rate constant k ₁ corresponds to the addition of benzenediazonium salts 7a–7h to aminothiophene 1, while the unimolecular rate constants k ₋₁ and k ₂ describe the decomposition of the σ‐complex intermediate I ⁺ , either by reversion to the starting materials or by re‐aromatization of the thiophene ring to yield the final products.

Scheme 2.

Carbon‐nitrogen coupling reactions of 3‐aminothiophene 1 with para‐R‐substituted benzenediazonium cations 2 in 50% H₂O‐50% Me₂SO v/v.

In this context, the observed pseudo‐first‐order rate constant (k _obsd) for the formation of diazo adducts 8a–8h at a given pH can be determined by applying the quasi‐steady‐state assumption to the intermediate complex I ⁺ , a thermodynamically unstable species. This approach leads to the following relation (1).^{[ 1 ]}

(1)

In agreement with this expression, excellent linear correlations were observed at each pH studied when the pseudo‐first‐order rate constants (k _obsd) were plotted as a function of the total concentration of aminothiophene 1, as illustrated in Figure  2 . Additional kinetic data obtained under various conditions are provided in Table S1–S11 and Figure S1–S9, Supporting Information.

Figure 2.

Influence of the total concentration of 3‐aminothiophene 1 and pH on the pseudo‐first‐order rate constants (k _obsd) for its addition to benzenediazonium salts 7d and 7e in 50% H₂O–50% Me₂SO v/v at 20 °C. Reactions were monitored at pH 1 and 2.

Table  1 summarizes the values of the second‐order rate constants k, along with those obtained from a series of experiments involving 2‐deuteriated‐3‐aminothiophene. Notably, the data presented in Table 1 show that isotopic substitution at C‐2 does not significantly affect the rate of formation of adducts 8a–8h. Indeed, the measured k ^H/k ^D ratios are found in the range 0.96–1.14, indicating that the nucleophilic addition is the rate‐determining step, i.e., k ₂ >> k ₋₁ in Scheme 2. Accordingly, the observed pseudo‐first‐order rate constant (k _obsd) reduces to the simplified expression given in Equation (2), from which the values of k ₁ for the addition of 1 to the benzenediazonium cations 7a–7h were determined at each pH (see Table 1).

(2)

Table 1.

Effect of pH and substituent nature on the bimolecular rate constants (k) and relative rate constants (k ₁) for the coupling of 3‐aminothiophene 1 with benzenediazonium cations 7a–7h in 50% H₂O–50% Me₂SO v/v at 20 °C and I = 0.1 mol L⁻¹.

		k a) M−1 s−1	k 1 b) M−1 s−1	k a) M−1 s−1	k 1 b) M−1 s−1	σ p d)	σ p + d)	E e)
		pH = 2		pH = 1
7a	R = OCH3	5.30 × 10−1 (4.90 × 10−1)c)	1.33 × 101 (1.23 × 101)c)	6.00 × 10−2 (5.30 × 10−2)c)	1.45 × 101 (1.30 × 101)c)	−0.27	−0.78	−8.4
7b	R = CH3	2.78	6.95 × 101	2.40 × 10−1	5.88 × 101	−0.17	−0.31	−7.7
7c	R = H	1.71 × 101 (1.79 × 101)c)	4.27 × 102 (4.45 × 102)c)	1.93 (1.67)c)	4.65 × 102 (4.12 × 102)c)	0	0	−7.2
7d	R = F	4.12 × 101	1.03 × 103	4.19	1.01 × 103	0.06	−0.07	–
7e	R = Cl	8.46 × 101	2.11 × 103	8.54	2.06 × 103	0.23	0.11	−6.7
7f	R = CF3	1.03 × 103	2.57 × 104	1.07 × 102	2.58 × 104	0.54	0.61	−5.7
7g	R = CN	1.38 × 103 (1.21 × 103)c)	3.44 × 104 (3.02 × 104)c)	1.29 × 102 (1.31 × 102)c)	3.10 × 104 (3.21 × 104)c)	0.66	0.66	−5.5
7h	R = NO2	3.83 × 103	9.55 × 104	3.45 × 102	8.32 × 104	0.78	0.79	−5.1

^a)Values of k were determined in this work from the slope of plots of k _obsd vs. [1]_o in 50% H₂O–50% Me₂SO v/v (for details, see Table S1–S7, Supporting Information).

^b)Rate constants k ₁ were calculated in this work by using k, [H₃O⁺], and the K_a = 10^−3.38 for aminothiophene 1 taken from ref. [1].

^c)Value for the corresponding 2‐deuterio‐3‐aminothiophene.

^d) σ _p and σ _p ⁺ values were taken from ref. [33].

^e)Electrophilicity parameters E taken from ref. [24].

2.2. Electronic Effects: Insights from Hammett and Yukawa–Tsuno Correlations

Analysis of the data presented in Table 1 clearly reveals a strong influence of the para‐substituent R on the reactivity of benzenediazonium salts toward 3‐aminothiophene 1. The bimolecular rate constants (k ₁) decrease markedly as the electron‐withdrawing ability of R diminishes. For example, at pH = 1, k ₁ decreases from 8.32 × 10⁴ M⁻¹ s⁻¹ for R = NO₂ to 1.45 × 10¹ M⁻¹ s⁻¹ for R = OCH₃. This trend highlights the crucial role of electronic effects in modulating the electrophilic character of the diazonium salts.

To quantify this influence, we first examined the correlation between the logarithm of the rate constants (log k ₁) and the Hammett substituent constants. As depicted in Figure  3 , the plot of log k ₁ versus σ _p shows substantial deviation from linearity, particularly for electron‐donating substituents such as CH₃ and OCH₃ , which exhibit significantly lower reactivities than predicted by their σ _p values. This observation indicates that classical inductive effects alone are insufficient to account for the observed substituent‐dependent reactivity. In contrast, a significantly improved linear correlation is observed when using the σ _p ⁺ constants (Figure 3), which incorporate both inductive and resonance contributions. The best‐fit regression line is described by Equation (3).

$$\text{log\hspace{0.17em}}{k}_1=2.91+2.48{\sigma }_{\mathrm{p}}^{+}(R^2=0.9879)$$ (3)

Figure 3.

Hammett plots of log k₁ for the coupling reactions of 3‐aminothiophene 1 with benzenediazonium salts 7a–7h in 50% H₂O–Me₂SO v/v at 20 °C using a) σ _p and b) σ _p ⁺ Hammett constants.

The high Hammett reaction constant (ρ = 2.48) reflects a strong sensitivity of the reaction rate to the electronic nature of para‐substituents on the electrophilic partner. This substantial ρ value clearly indicates significant positive charge development on the nucleophilic moiety already in the transition state. Interestingly, this value is comparable to that reported for the C–N coupling of 3‐methoxythiophene with benzenediazonium salts (ρ = 2.11),^{[ 15 ]} a well‐documented reaction that is highly responsive to substituent effects. These findings support a mechanism in which the rate‐determining step involves nucleophilic attack on an electron‐deficient diazonium center, with the process being strongly accelerated by electron‐withdrawing groups through inductive stabilization of the transition state.

To further assess the role of resonance effects in modulating the reactivity of benzenediazonium salts, the experimental data were analyzed using the Yukawa–Tsuno formalism.^{[ 17} , ^{18 ]} While the classical Hammett plot^{[ 19 ]} shows notable deviations from linearity, the corresponding Yukawa–Tsuno correlation provided a satisfactory linear fit (Figure  4 ), yielding a reaction constant ρ = 2.11 and a resonance parameter r = 1.54.

Figure 4.

Yukawa–Tsuno correlation for reactions of 3‐aminothiophene 1 with benzenediazonium salts 7a–7h in 50% H₂O–50% Me₂SO v/v at 20 °C. The σ _p and σ _p ⁺ values were taken from ref. [33].

These results indicate a significant contribution of resonance effects, particularly for electron‐donating substituents such as 4‐methoxy and 4‐methyl, which show negative deviations from the Hammett line. This behavior can be attributed to ground‐state stabilization via mesomeric interactions of the methoxy group and hyperconjugative effects of the methyl group with the diazonium moiety.^{[ 20} , ²¹ , ^{22 ]} This interpretation is supported by the satisfactory Yukawa–Tsuno linear fit, which explicitly includes a resonance parameter (r) to quantify the contribution of substituent conjugation to the observed reactivity trend.

2.3. Quantifying the C‐Nucleophilicity of 3‐Aminothiophene

To investigate the influence of electrophilic strength on the reactivity of cations 7a–7h, we apply the Mayr–Patz Equation (4)^{[ 23 ]} to quantify the nucleophilicity at C‐2 position of 3‐aminothiophene 1, based on its second‐order rate constants with a series of reference diazonium salts of known electrophilicity^{[ 24 ]} (see Table 1).

$$\text{log\hspace{0.17em}}k={\mathrm{s}}_{\mathrm{N}}(E+N)$$ (4)

In this equation, N and s_N are nucleophile‐specific parameters, and E is an electrophile parameter. As shown in Figure  5 , an excellent linear correlation was obtained by plotting log k ₁ against the electrophilicity values E of benzenediazonium salts 7a–7h, in accordance with Equation  (5).

$$\text{log\hspace{0.17em}}{k}_1=11.06+1.18E (R^2=0.9968)$$ (5)

Figure 5.

Plot of the rate constants (log k ₁) for the reactions of 3‐amonothiophene 1 with reference electrophiles 7a–7h in 50% H₂O–50% Me₂SO v/v at 20 °C versus their electrophilicity parameters E.

From the slope and intercept, the nucleophilicity parameters of 3‐aminothiophene were determined to be N  = 9.37 and s_N = 1.18. These values indicate that 3‐aminothiophene behaves as a relatively strong carbon nucleophile, exhibiting moderate sensitivity to changes in the electrophilic nature of the reaction partner.

The experimentally determined s_N = 1.18 for 3‐aminothiophene reflects a moderate to high sensitivity to the electrophilic partner, indicating a notable degree of polarizability at the nucleophilic site. This value places 3‐aminothiophene in a similar range as conjugated carbon nucleophiles such as 3‐methoxythiophene (s_N = 1.19, acetonitrile),^{[ 25 ]} 5‐methoxyindole (s_N = 1.12, dichloromethane),^{[ 13 ]} and 1,3‐dimethoxybenzene (s_N = 1.09, dichloromethane).^{[ 26 ]} The observed similarity indicates that the conjugation between the NH₂ group and the thiophene ring efficiently stabilizes the charge development in the transition state, which in turn increases the site's electronic reactivity.

Compared with other π‐rich heterocycles such as pyrrole (s_N = 1.00),^{[ 27 ]} and N‐methylpyrrole^{[ 26 ]} (s_N = 1.03), 3‐aminothiophene displays slightly greater sensitivity, which likely arises from more efficient delocalization of the amino lone pair into the thiophene ring. In contrast, cyclic enamines such as 1‐(N‐piperidino)cyclohexene (s_N = 0.83),^{[ 28 ]} and 1‐(N ‐morpholino) cyclohexene (s_N = 0.81)^{[ 28 ]} show significantly lower sensitivities.

2.4. Validation and Comparative Nucleophilicity Analysis

The nucleophilicity parameter (N) of 3‐aminothiophene 1 was validated by reference to the well‐established nucleophilic aromatic substitution of 4,6‐dinitrobenzofuroxan (DNBF, 2), previously investigated in detail by Terrier and coworkers.^{[ 1 ]} The corresponding second‐order rate constant under comparable conditions was analyzed using Equation (4), with the electrophilicity parameter of DNBF (E = −5.06).^{[ 29 ]} The value obtained is summarized in Table  2 . Importantly, the N value estimated for 3‐aminothiophene 1 (N = 9.59) closely matches the experimentally determined value (N = 9.37), thus providing strong support for the reliability of the nucleophilicity parameter derived in this work.

Table 2.

Comparative study of nucleophilicity parameters N in 50% H₂O–50% Me₂SO v/v for selected C‐nucleophiles including pyrroles 11 and 12, indoles 13 and 14, and 3‐aminothiophenes 1, 9, and 10. The reference electrophile is 4,6‐dinitrobenzofuroxan 2 with E = –5.06.^{[ 29 ]}

Nucleophile	k (M −1 s−1)a)	Nucleophilicity parameter Nb)
3‐Aminothiophene	3.37 × 104	9.59 (9.37)c)
3‐(Methylamino)thiophene	2.58 × 105	10.47
3‐(Dimethylamino)thiophene	9.03 × 104	10.02
1,2,3‐Trimethylpyrrole	2.40 × 104	9.44
N‐Methylpyrrole	1.00 × 102	7.06
N‐Methylindole	3.51 × 103	8.61
Indole	5.55 × 102	7.80

^a)Second‐order rate constants k were taken from ref. [1].

^b)Nucleophilicity parameters N were estimated in this work from Equation (4) by using k, E, and s_N  = 1.

^c)Experimental N value determined in this work (Figure 5).

Six nucleophiles were selected, covering a representative set of π‐activated C‐nucleophiles, namely pyrroles, indoles, and aminothiophenes (see Table 2 for full structural and kinetic data). As illustrated in Table 2, 3‐aminothiophenes 1, 9, and 10 display markedly higher nucleophilic reactivity than both pyrroles 11–12 and indoles 13–14. This enhanced reactivity stems from the strong electron‐donating effect of the amino substituent at the 3‐position, which increases the electron density at the adjacent carbon and facilitates the formation of a Meisenheimer‐type σ‐complex^{[ 6} , ⁷ , ⁸ , ³⁰ , ³¹ , ^{32 ]} during nucleophilic attack. In contrast, in pyrroles and indoles, the nitrogen lone pair is delocalized into the aromatic sextet, stabilizing aromaticity but reducing its availability for nucleophilic activation. This delocalization lowers the electron density at the reactive carbons, thus diminishing nucleophilicity. Collectively, these findings confirm the pronounced enamine‐like character of 3‐aminothiophenes, where the amino lone pair conjugates effectively with the thiophene π‐system, strongly enhancing nucleophilic activation at C‐2, as depicted in resonance structures I and II.^{[ 1} , ^{9 ]}

2.5. Quantitative Prediction of Nucleophilicity and Hyper‐Ortho Reactivity in 3‐Aminothiophenes Using Hammett σ ⁺ Constants

A significant feature emerging from Table 2 is the behavior of the three 3‐substituted aminothiophenes, 3‐aminothiophene 1 (X = NH₂), 3‐(dimethylamino)thiophene 10 (X = N(CH₃)₂), and 3‐(methylamino)thiophene 9 (X = NHCH₃), which possess substituents at the 3‐position with progressively increasing electron‐donating abilities. This trend is reflected in their decreasing constants Hammett (σ ⁺), which are −1.30 for NH₂, −1.70 for N(CH₃)₂, and –1.81 for NHCH₃, respectively.^{[ 33 ]} The systematic variation in electronic properties is directly correlated with their experimental nucleophilicity parameters (N): 9.37 for compound 1, 10.02 for 10, and 10.47 for 9. The direct relationship between the nucleophilicity N of 3‐aminothiophenes and their σ ⁺ constants is illustrated in Figure  6 , where N is plotted as a function of σ ⁺. A good linear correlation is observed and is described by Equation (6).

$$N=6.72-2.01{\sigma }^{+} (R^2=0.9763)$$ (6)

Figure 6.

Correlation of N values with Hammett σ ⁺ constants for aminothiophenes 1, 9, and 10 in 50% H₂O–50% Me₂SO v/v, highlighting the enaminic behavior and the hyper‐ortho relationship.

This high correlation coefficient (R ² = 0.9763) emphasizes the strong influence of the substituent's electronic effects on nucleophilicity. Moreover, this correlation not only highlights the pronounced enaminic behavior of 3‐aminothiophene^{[ 1} , ⁹ , ^{13 ]} but also suggests that the nucleophilic reactivity within this series is governed by a hyper‐ortho electronic effect,^{[ 34} , ^{35 ]} whereby substituent–π‐system interactions at the 3‐position play a decisive role.

This empirical relationship further enabled the extrapolation of N values for structurally related 3‐substituted thiophenes for which no direct kinetic measurements are available. Using the Hammett σ ⁺ constants of –0.78, –0.31, and 0.00^{[ 33 ]} for thiophenes 15 (OCH₃), 16 (CH₃), and 17 (H), the corresponding N values were estimated as 8.29, 7.34, and 6.72 in 50% H₂O–50% Me₂SO v/v.

These predictions demonstrate the quantitative applicability of the N versus σ ⁺ relationship within the thiophene series and further support the hypothesis that substituent effects at the 3‐position directly modulate nucleophilic reactivity through electronic delocalization and resonance donation into the π‐system of the thiophene ring.

The linear correlation observed here between the nucleophilicity parameter (N) and the Hammett σ ⁺ constants for 3‐substituted thiophenes is consistent with findings reported for other aromatic and heterocyclic compounds.^{[ 36} , ³⁷ , ^{38 ]} For instance, Gabsi and coworkers reported a strong linear relationship between N and σ _p ⁻ values for para‐substituted phenoxide anions in water (N = 9.21 − 2.51σ _p ⁻ ; R ² = 0.9763).^{[ 37 ]} Similarly, Ghabi and coworkers showed that the nucleophilicity of para‐substituted anilines in methanol correlates well with their σ _p constants (N = 12.46 – 5.89 σ _p ; R ² = 0.9982).^{[ 36 ]}

These examples support the general idea that electronic substituent effects, as measured by Hammett constants, can be used to predict and compare nucleophilic reactivity in a wide range of systems. Our results with aminothiophenes add to this growing body of evidence and confirm the usefulness of such correlations for understanding and anticipating structure–reactivity relationships.

It is noteworthy that the nucleophilicity parameters N of thiophenes 15–17 are applicable for predicting rate constants of their reactions with other electrophiles. Kinetic data for the reactions of 15–17 with 4,6‐dinitrobenzotriazole 18 ^{[ 38} , ^{39 ]} in 50% H₂O‐50% Me₂SO v/v at 20 °C are summarized in Table  3 and detailed in Table S12 and Figure S10, Supporting Information confirming this applicability.

Table 3.

Experimental and calculated second‐order rate constants for the reactions of 4,6‐dinitrobenzotriazole 18 with a series of thiophenes 15‐17 in 50% H₂O–50% Me₂SO v/v at 20 °C.

Electrophile	Nucleophile	N b)	Rate constants [mol−1 L s−1]
			k 1 exp b)	k 1 calcd c)	k 1 exp/k 1 calcd
E = −9.56a)		8.29	4.51 × 10−1	5.37 × 10−2	8.4
		7.34	9.38 × 10−2	6.03 × 10−3	15.6
		6.72	1.60 × 10−2	1.46 × 10−3	11.1

^a)Electrophilicity parameter E value taken from Ref. [38, 39]

^b)This work.

^c) k ₁ ^calcd values calculated using Equation (4) with the nucleophilicity parameters N (and s_N = 1) of thiophenes 15–17 in 50% H₂O–50% Me₂SO v/v as given in this Table, and the electrophilicity parameter E of 4,6‐dinitrobenzotriazole 18.

As shown in Table 3, the predicted and experimental rate constants remain within a factor of 8.4–15.6, which falls well inside the confidence limits of Mayr's approach (factor 10–100).^{[ 40} , ⁴¹ , ^{42 ]} This validation strongly supports the use of these N values, together with those of thiophenes 1, 9, and 10, as a reliable reference set for quantifying the reactivity of other electrophiles, including super‐electrophiles.

3. Conclusion

The electrophilic substitution occurs at the C–2 position of 3–aminothiophene, and the rate‐determining step is not influenced by deuterium substitution at C–3, confirming a classical S_EAr mechanism. The curvature observed in the Hammett plot is attributed to the pronounced resonance effects exerted by electron‐donating substituents. This interpretation is supported by the Yukawa–Tsuno analysis (ρ = 2.11, r = 1.54), which underscores the dominant role of resonance stabilization over inductive contributions in governing the reactivity of substituted diazonium cations. 3–Aminothiophene exhibits high nucleophilicity (N = 9.37 and s_N = 1.18) in 50% H₂O–50% Me₂SO v/v, comparable to conjugated enamines, and reacts rapidly with a range of electrophiles in π‐type S_EAr reactions. A strong linear relationship was found between the nucleophilicity N and the Hammett σ ⁺ constants of substituents at the C‐3 position of 3‐aminothiophenes, expressed as N = 6.72 – 2.01 σ ⁺. This equation highlights the role of hyper ortho electronic effects, i.e., direct substituent–π‐system interactions, on nucleophilic reactivity and reinforces the enaminic nature of 3‐aminothiophenes. The N vs. σ ⁺ correlation enables extrapolation to other 3‐substituted thiophenes. For example, predicted N values are 8.29 (OCH₃), 7.34 (CH₃), and 6.72 (H), consistent with their electronic properties. This predictive model is useful for designing nucleophilic heterocycles in synthetic and mechanistic studies.

4. Experimental Section

4.1.

4.1.1.

Materials

3‐Aminothiophene 1 used in this study was prepared and characterized according to a previously reported procedure.^{[ 1} , ^{9 ]}

All para‐R‐substituted benzenediazonium tetrafluoroborate salts (para‐R‐C₆H₄N₂ ⁺·BF₄₋) 7a–7h were freshly prepared by diazotization of the corresponding para‐R‐anilines in a 50% aqueous solution of fluoroboric acid (HBF₄) at 0 °C, as described in the literature.^{[ 15} , ^{43 ]}

Dimethyl sulfoxide (Me₂SO, Aldrich, ≥99.9%, HPLC grade) was used as received, without further purification.

Kinetics Measurements

Kinetic measurements were conducted using a Shimadzu UV‐Vis spectrophotometer (Model 1650) and a Biologic Stopped‐Flow Spectrophotometer (Model SFM‐X00/Q). Temperature control was ensured using a thermoelectrically regulated cell holder (Model TCC‐240 A), maintaining a stable temperature of 20.0 ± 0.1 °C. Pseudo‐first‐order rate constants k _obsd were calculated using Equation (7),^{[ 1} , ¹³ , ^{15 ]} where A _∞ refers to the absorbance measured at the equilibrium state of the reaction between diazonium salt 7a–7h and aminothiophene 1, A _o refers to the absorbance at zero time, and A _t refers to the absorbance at time t. Correlation coefficients of the linear regressions were usually higher than 0.97. The variations of the observed rate constants k _obsd as a function of the concentrations of the carboxylic acids are shown in Figure S1–S9 and Table S1–S11, Supporting Information.

$$\text{ln}\hspace{0.17em}(A_{\infty }-A_t)\hspace{0.17em}=\hspace{0.17em}-k_{\text{obsd}}t\hspace{0.17em}+\hspace{0.17em}ln\hspace{0.17em}(A_{\infty }-A_o)$$ (7)

Supporting Information

Figures S1–S6: Effects of the total concentration of 3‐aminothiophene 1 and pH on the pseudo‐first‐order rate constants (k _obsd) for its addition reactions with benzenediazonium salts 7a–7c and 7f–7h in 50% H₂O–50% Me₂SO (v/v) mixture at 20 °C. Measurements were conducted at pH 1 and 2.

Figures S7–S9: Effects of the total concentration of 2‐deuterio‐3‐aminothiophene and pH on the pseudo‐first‐order rate constants (k _obsd) for its addition reactions with benzenediazonium salts 7a, 7c and 7g in 50% H₂O–50% Me₂SO (v/v) at 20 °C. Measurements were conducted at pH 1 and 2.

Tables S1–S8: Concentrations and observed rate constants (kobsd) from individual kinetic experiments of the reactions between 3‐aminothiophene 1 and benzenediazonium salts 7a–7h in 50% H₂O–50% Me₂SO (v/v) mixture at 20 °C.

Tables S9–S11: Concentrations and observed rate constants (k _obsd) from individual kinetic experiments of the reactions between 2‐deuterio‐3‐aminothiophene and benzenediazonium salts 7a, 7c and 7g in 50% H₂O–50% Me₂SO (v/v) at 20 °C.

Kinetic studies: Reaction of 4,6‐dinitrobenzotriazole 18 with thiophenes 15–17 in 50% H₂O–50% Me₂SO (v/v) mixture at 20 °C.

Conflict of Interest

The authors declare no conflict of interest.

Author Contributions

R. El Abed: data curation (equal); investigation (lead); and writing—original draft (equal). T. Slama: data curation (equal); software (equal); and visualization (equal). F. Mahdhaoui: data curation (equal); software (equal); and visualization (equal). T. Boubaker: conceptualization (equal); investigation (equal); supervision (lead); and writing—review and editing (equal).

Supporting information

Supplementary Material

El Abed R., Slama T., Mahdhaoui F., Boubaker T., ChemPhysChem, 2025, 26, e202500553. 10.1002/cphc.202500553

Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.