# Quantification of the Nucleophilicities of 3-X-Thiophenes: Highlighting the Hyperortho Correlation

Authors: W. Gabsi; T. Boubaker; R. Goumont
Journal: Journal of Chemistry
 (2020)

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## Abstract

Kinetics studies for the coupling reactions of the 3-X-thiophene1a-c (X = CH3, H and Br) with the electrophiles 2a and 3a-c have been investigated in acetonitrile at 20°C The second-order rate constants have been employed to determine the nucleophilicity parameters N and s of the thiophene 1 according the Mayr equation log k (20°C) = s (E + N). The nucleophilic-specific parameters N and s quantified in this work have been derived and compared with the reactivity of other C nucleophiles. Based on the linear correlations log k1 = f(E) and log k1 = f(σp+), we have shown that the mechanism of interactions occurs by a unique process: electrophilic heteroaromatic substitution of an α-carbon position of substituted 3-X-thiophenes 1 known hyperortho correlation.


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## Body

## 1. Introduction

Nowadays, it has been shown that five-membered rings are very useful for various applications such as phosphor materials [1] and semiconductors [2–4]. As an example, the use of thiophene dicarboxylic acids has made it possible to prepare organometallic nanoarchitectures having very interesting optoelectronic properties [5].The study of the reactivity of some mono- and bis-substituted thiophenes has attracted the attention of researchers because of their ability to react according to different processes and largely dependent on the substituent [6–8]. Indeed, Mayr and coworkers [6] showed that benzhydrylium ions react very easily with 3-methoxythiophene to form C-substituted derivatives in acetonitrile, which further confuses the idea that the position of α-carbon of aminothiophenes has a high potential for nucleophilic carbon reactivity [9]. In this regard, to provide more information concerning the behavior of these types of heterocycles, we report, in this paper, on the results of a kinetic investigation of the α-carbon reactivity of the 3-X-thiophenes 1a-c with a series of superelectrophiles 2a and 3a-c in acetonitrile.


## 2. Experimental Section

### 2.1. Materials

3-X-thiophene1 used in this study (Aldrich products) was of the highest quality commercially available. The electrophiles 2 and 3 have been synthesized by the team of Professor Régis GOUONT at the Versailles laboratory. Acetonitrile (for HPLC, ≥99.9%) was available of the highest quality and used without further purification.


### 2.2. Rate Measurements

Kinetic measurements were performed using a conventional spectrophotometer (Shimadzu UV-visible model 1650) equipped with a thermoelectrically temperature controlled cell holder (model TCC-240 A) which was maintained at 20 ± 0.1°C.All the reactions were carried out at 20°C under pseudo-first-order conditions with a thiophene concentration of approximately 5 × 10−3 mol·dm−3 and oxygen-nucleophile concentrations in the range 1 × 10−1–1 mol·dm−3. The pseudo-first-order rate constants, kobsd, measured were found to be reproducible to ±3–5%. Concentrations and the measured rate constants, kobsd, for the individual kinetic experiments values, are given in Tables S1–S3 in Supplementary Material.


### 2.3. Supporting Information Available

TablesS1–S3: kinetic data for reactions of thiophenes 1 with 4,6-dinitrotetrazolopyridine 2a and benzofuroxane 3a-c in an aqueous solution at 20°C.TableS4: physical data for the formation of σ-adducts 4A-C and 5A-I derived from the reaction of 3-X-substituted thiophenes 1a-c with the electrophiles 2a and 3a-c.FiguresS1-S2: UV-visible spectrum of thiophenes 1a and 1b and the progressive evolution of the formation of the product 4A and 4B.


## 2.1. Materials

3-X-thiophene1 used in this study (Aldrich products) was of the highest quality commercially available. The electrophiles 2 and 3 have been synthesized by the team of Professor Régis GOUONT at the Versailles laboratory. Acetonitrile (for HPLC, ≥99.9%) was available of the highest quality and used without further purification.


## 2.2. Rate Measurements

Kinetic measurements were performed using a conventional spectrophotometer (Shimadzu UV-visible model 1650) equipped with a thermoelectrically temperature controlled cell holder (model TCC-240 A) which was maintained at 20 ± 0.1°C.All the reactions were carried out at 20°C under pseudo-first-order conditions with a thiophene concentration of approximately 5 × 10−3 mol·dm−3 and oxygen-nucleophile concentrations in the range 1 × 10−1–1 mol·dm−3. The pseudo-first-order rate constants, kobsd, measured were found to be reproducible to ±3–5%. Concentrations and the measured rate constants, kobsd, for the individual kinetic experiments values, are given in Tables S1–S3 in Supplementary Material.


## 2.3. Supporting Information Available

TablesS1–S3: kinetic data for reactions of thiophenes 1 with 4,6-dinitrotetrazolopyridine 2a and benzofuroxane 3a-c in an aqueous solution at 20°C.TableS4: physical data for the formation of σ-adducts 4A-C and 5A-I derived from the reaction of 3-X-substituted thiophenes 1a-c with the electrophiles 2a and 3a-c.FiguresS1-S2: UV-visible spectrum of thiophenes 1a and 1b and the progressive evolution of the formation of the product 4A and 4B.


## 3. Results and Discussion

### 3.1. Kinetic Investigation

The evolution of the kinetic constants of the coupling reaction between 3-X-thiophene1a-c and the various electrophiles 2a (Scheme 1) and 3a-c (Scheme 2) requires a preliminary study by UV-visible spectrophotometry to determine the wavelengths of these reagents and their σ-adducts 4 and 5. The addition of a solution of 3-X-substituted thiophene 1a-c on electrophiles 2a and 3a-c in acetonitrile gives rise to absorbents 4A-C and 5A-I adducts at wavelengths between 405 and 487 nm. A typical experiment is illustrated in Figure 1. The spectral data for the σ-adducts 4 and 5 considered in this work (the absorption maxima and the corresponding molar extinction coefficients in acetonitrile) are collated in Table S4.Scheme 1Scheme 2Figure 1
UV-visible spectrum of thiophene1c and the progressive evolution of the formation of the product 4C in acetonitrile at 20°C with [1c] = 1 mol·L−1 and [2a] = 5.10−5 mol·L−1.A comparison of these values ofλmax makes it possible to obtain information on the structure of the various adducts. Indeed, the spectra of all the adducts 4 A-C and 5 D-I have a very high absorption maximum up to 465–487 nm. These high wavelengths translate a strong delocalization of the negative charge on the Z group (NO2 or CN) of the carbocyclic. In this respect, it should also be noted that the strong electro-deficient character of the carbocycles of electrophiles 2a, 3b, and 3c is known to promote the formation of the σ−anionic complexes [10–14].The analysis in TableS4 reveals that the σ-adducts 5A-C show an absorption maximum around 410 nm. This hypochromic effect observed with respect to the σ-complexes resulting from the coupling reaction between the electrophiles 2a, 3b, and 3c with thiophenes 1a-c suggests that a very high negative charge density is preferentially localized on the carbon bearing the SO2CF3 group (Figure 2).Figure 2It is interesting to note that electrophiles2a and 3a-c showed negligible absorption at the absorbance wavelengths λmax of the σ-adducts considered in this work (Figures 1, S1, and S2). This observation made possible the kinetic study of the coupling reaction of thiophenes 1a-c with the various electrophiles 2a and 3a-c in acetonitrile.Theoretically, the reactions proceed according to Scheme3 and the bimolecular rate constant k1 is related to the formation of the zwitterionic intermediate IZ± while the monomolecular rate constants k−1 and k2 are associated with the decomposition processes of the intermediate IZ± with, respectively, a return to the starting reagents or rearomatization of the thiophenic entity. So, as can be seen, the proposed mechanism is the result of an electrophilic aromatic substitution of the α-carbon position of the thiophenes 1a-c with formation of a zwitterionic intermediate IZ±. The various add adducts are the result of a two-step SEAr process of the addition-elimination type.Scheme 3The graphs Ln (Ae − A) as a function of time measured for a given interaction are linear (R2 > 0.9998). From the slope of these lines, the constants kobsd were easily determined as follows:(1)LnAe−A=−kobst+LnAe−Ao.The straight lineskobsd as a function of the concentration of thiophenes 1a-c have proved to be linear and are characterized by a zero origin ordinate.It follows that the nucleophilic attack of the various thiophenes1a-c on the position 7 of the electrophiles 2a and 3a-c studied is then the determining step of the coupling reaction, which implies(2)kobsd=k13−X−thiophene.The values of the relative bimolecular rate constantsk1 for each electrophile studied are grouped in Table 1.Table 1
Second-order rate constants (k1/M−1·s−1) and electrophilicity parameters (E) of the reactions of 3-X-thiophene 1 with the electrophiles 2a and 3a-c in acetonitrile at 20°C.
Electrophile
Ea
Nucleophile
k
1 (M−1s−1)
−4.58
1a
4.08 × 10−3
1b
1.28 × 10−3
1c
3.41 × 10−4
−4.74
1a
2.67 × 10−3
1b
7.18 × 10−4
1c
2.22 × 10−4
−5.06
1a
1.23 × 10−3
1b
3.39 × 10−4
1c
1.08 × 10−4
−6.41
1a
4.10 × 10−5
1b
1.35 × 10−5
1c
4.36 × 10−6
aRef [7].


### 3.2. Nucleophilicities of Thiophenes1a-C

Based on the values measured in acetonitrile at 20°C of the bimolecular rate constantsk1 associated with the coupling reaction between thiophenes 1a-c and electrophiles 2a and 3a-c which are grouped in Table 1 with the values of the parameters E of the various electrophiles 2a and 3a-c reported in the literature [7], the plots logk1/s as a function of the parameter E could be constructed. The situation is illustrated in Figure 3.Figure 3
Plots of logk1 versus E for the reactivity of thiophenes 1a-c with the reference electrophiles 2a and 3a-c in acetonitrile at 20°C (the identity of points is given in Table 1).As can be seen, satisfactory lines of equal slope or near unity have been obtained in accordance with Mayr’s rearranged equation (equation (3) [15–17]. The values of the parameters N and s relative to each 3-X-substituted thiophene 1a-c could thus be determined graphically.(3)logk1s=E+N.In light of the values of N grouped in Table2, we have undertaken to compare the reactivity of our thiophenes 1a-c with that of other nucleophiles. Figure 4 reveals that the N parameters for 3-X-substituted thiophenes 1a-c are located on over a reactivity range of nearly 3 orders of magnitude. As can be seen, the reactivity of the most reactive thiophene 1d (N = 3.96) [19] is approximately 13 units above the reactivity of tetraethylsilane 6 (N = −6.50) [20] and tris-p-tolylmethane 7 (N = −8.80) [20], but it remains significantly lower (25 units) than that of the 2-phenylpropionitrile anion 8 (N = 28.95) [21] considered to be the nucleophile more reactive encrypted to date. Another important observation is that the nucleophilic reactivity of the pyrroles 9a and 9b [22] and the furans 10a and 10b [6] is higher than that of the thiophene series 1a-c. Moreover, the nucleophilicity of the thiophenes 1e and 1d is at the level of that of the indoles 11b and 11c [23]. Regarding the nucleophilicity of the three less-reactive thiophenes 1a-c, we find that their ranking on the universal scale N of Mayr is about 4 units higher than that of naphthalenes 12 and 13 [20].Table 2
Second-order rate constantsk1 (M−1·s−1) and selectivity parameters (ρ and pKa) of the reactions of 3-X-thiophene 1 with the electrophiles 2a and 3a-c.
Thiophene
Ν/s
σ
+b
k
1 (M−1s−1)
2a
3a
3b
3c
2.38/1.09
−0.31
4.08 × 10−3
2.76 × 10−3
1.23 × 10−3
4.10 × 10−5
1.79/1.06
0.00
1.28 × 10−3
7.18 × 10−4
3.39 × 10−4
1.35 × 10−5
1.20/1.03
0.15
3.41 × 10−4
2.22 × 10−4
1.08 × 10−4
4.36 × 10−6
ρ
−2.23
−2.27
−2.22
−2.03
pKa
0.30
2.95
3.75
5.86
bRef [18].Figure 4
Ranking the carbon reactivity of the 3-X-substituted thiophene1 on the Mayr N universal N scale.


### 3.3. Effect of Substituents on Reactivity

The analysis of Table2 clearly shows that the bimolecular rate constant k1 associated with the coupling reaction of thiophenes 1a-c with the superelectrophiles 2a and 3a-c is very sensitive to the nature of the substituent X located in position C-3 of the thiophenes 1a-c. Indeed, the constant k1 decreases regularly when X = CH3, the most electro-donor substituent, and changes to X = Br, the most electro-attracting substituent.This behavior is well illustrated in Figure5, where the logarithm of the rate constant k1 is a function of the Hammett constant σ+, reported in the literature, of the various X substituents [24].Figure 5
Hammett correlations: influence of the nature of the substituent X on the constantk1 relating to the coupling reaction of thiophenes 1a-c with electrophiles 2a and 3a-c in acetonitrile at 20°C.It is interesting to note that obtaining such correlations means the same reaction mechanism despite the variation of the substituent and confirms that the addition step of thiophenes1a-c on electrophiles 2a and 3a-c is the decisive stage of the reaction.The negative values of the reaction constantsρ deduced from the slopes of the lines log k1 = f (σ+), as shown in Table 2, indicate a development of a positive charge on the thiophenic entity in the transition state that means a decrease in electron density on the C-2 carbon atom of thiophene (Figure 6). It is noted that the more the substituent X is an electron donor, the more this charge is positive, and therefore the corresponding transition state is stabilized, which confirms the decrease in k1 observed when passing from 3-methylthiophene 1a to 3-bromothiophene 1c.Figure 6
Proposed transitional state structures forσ-adducts 4 and 5 in acetonitrile.It is interesting to note that the low values ofρ obtained can also be interpreted in terms of a large delocalization of the negative charge in the carbocyclic of electrophiles 2a and 3a-c. In addition, our values (−2.23 < ρ < −2.03) are similar to the values measured by several authors [18, 25–29]. El Guesmi and coworkers have shown that the aromatic nucleophilic substitution reactivity of triflone 2,4,6-tris (trifluoromethanesulfonyl) anisole with various anilines in acetonitrile at 15°C is characterized by a value of ρ equal to −1.80 [25].Moreover, the existence of linear correlations logk1 = f (σp+) and result of the study of the variation of the reactivity according to the structural variations of the nucleophilic pattern (thiophene) exhibits the phenomenon known as “Hyper-Ortho Correlation” [10, 30]. Currently, such a situation has never been encountered in the context of five-membered heterocycles.However, logk = f(σp) correlations were obtained in thiophenic series, but in these cases, the reactivity variations were made from structural variations in the electrophilic motif [18, 30]. In this regard, we note that Spinelli and coworkers were the first to identify a hyperortho effect in the case of the coupling reaction of various thiophenes such as 2-bromo-3-X-5-nitrothiophene with piperidine in methanol [31].


### 3.4. Reactivity-Acidity Relationship

A comparison of electrophilic reactivity can be made using the linear free-energy relation similar to that proposed by Brönsted [32, 33]. The relation 4 relates the reactivity k to the thermodynamic acidity of the electrophile pKa. The constants A measure the reactivity of the family of electrophiles, and αEl is the sensitivity of the reaction to the variations of acidity of the electrophile. As can be seen, an examination of Figure 7 leaves no doubt that the Brönsted type graphs for the three thiophenes 1a-c have a curvilinear appearance:(4)logk=A+αElpKa.Figure 7
Bronsted nonlinear correlations: influence of electrophilic acidity2a and 3a-c on bimolecular rate constants, k1, related to the coupling reaction of the thiophene 1a-c with the electrophiles 2a and 3a-c in acetonitrile at 20°C.However, at pKa > 3, the three electrophiles 3a-c define a linear Brönsted correlation according to equation (4). The slope values deduced from the linear straight lines in Figure 8 (αEl1a = −0.64, αEl1b = −0.61, αEl1c = −0.60) suggest that the formation of the carbon-carbon and thus the transfer of the charge of the nucleophile (thiophene) to the electrophile (benzofuraxanes 3a-c) is almost 60% carried out in the state of transition.Figure 8
Brönsted linear correlations for the coupling reaction of the thiophenes1a-c with the electrophiles 3a-c in acetonitrile at 20°C.Numerous electrophilic substitution studies exist in the literature in which the variations in reactivity have been studied from structural variations in the nucleophilic motif [34, 35]. Challis and coworkers, for example, investigated the reaction of 4,6-dinitrobenzofuraxane 3b with 5-X substituted indoles 11 [34]. In these systems, the Brönsted-type straight lines associated with the reactivity changes are characterized by a slope of βnuc-type since these changes are the structural variations of the nucleophile. However, in the present work, the αEl values reveal the structural variations of the electrophile and we have not found in the literature values of the same type that we could compare to our system.On the other hand, it remains that our values ofαEl obtained are in good agreement with a polar heteroaromatic electrophile substitution mechanism [36, 37].


### 3.5. Effect of Substituant X on the Nucleophilicity N

The aim of this part is to verify if the C-2 carbon nucleophilicity of the 3-X-substituted thiophenes measured by the parameter N is dependent on the electronic effect of the substituent X in position 3. In this context, we have grouped in Table3 the values of the parameter N of the thiophenes 1a-c quantified in this work as well as that of 3-methoxythiophene 1d reported by Berionni and coworkers [6] and the constants of Hammett σ of various groups used in this study [24].Table 3
Nucleophilicity parameters N of 3-X-substituted thiophenes in acetonitrile at 20°C.
σ
+
N
Reference
OCH3
−0.78
3.06
[6]
OC2H5
−0.81
3.69
[16]
CH3
−0.31
2.38
This work
H
0.00
1.79
This work
Br
0.15
1.20
This work
NH2
−1.30
4.62
Estimated
CF3
0.61
0.23
Estimated
CN
0.66
0.13
Estimated
NO2
0.79
−0.17
EstimatedAs can be seen, Figure9 shows that a satisfactory linear line is obtained by carrying the values of N as a function of Hammett constants σ. Equation (5) describes this linear dependence:(5)N=1.65−2.28⋅σ+,R2=0.9663.Figure 9
Correlation N =f(σ+) of a series of 3-X-substituted thiophenes in acetonitrile at 20°C.We note that obtaining the correlation (5) informs us about the exceptional α-carbon nucleophilic reactivity of 3-X-substituted thiophenes. Also, it can be used for a direct estimation of N values that are not easily measurable.


## 3.1. Kinetic Investigation

The evolution of the kinetic constants of the coupling reaction between 3-X-thiophene1a-c and the various electrophiles 2a (Scheme 1) and 3a-c (Scheme 2) requires a preliminary study by UV-visible spectrophotometry to determine the wavelengths of these reagents and their σ-adducts 4 and 5. The addition of a solution of 3-X-substituted thiophene 1a-c on electrophiles 2a and 3a-c in acetonitrile gives rise to absorbents 4A-C and 5A-I adducts at wavelengths between 405 and 487 nm. A typical experiment is illustrated in Figure 1. The spectral data for the σ-adducts 4 and 5 considered in this work (the absorption maxima and the corresponding molar extinction coefficients in acetonitrile) are collated in Table S4.Scheme 1Scheme 2Figure 1
UV-visible spectrum of thiophene1c and the progressive evolution of the formation of the product 4C in acetonitrile at 20°C with [1c] = 1 mol·L−1 and [2a] = 5.10−5 mol·L−1.A comparison of these values ofλmax makes it possible to obtain information on the structure of the various adducts. Indeed, the spectra of all the adducts 4 A-C and 5 D-I have a very high absorption maximum up to 465–487 nm. These high wavelengths translate a strong delocalization of the negative charge on the Z group (NO2 or CN) of the carbocyclic. In this respect, it should also be noted that the strong electro-deficient character of the carbocycles of electrophiles 2a, 3b, and 3c is known to promote the formation of the σ−anionic complexes [10–14].The analysis in TableS4 reveals that the σ-adducts 5A-C show an absorption maximum around 410 nm. This hypochromic effect observed with respect to the σ-complexes resulting from the coupling reaction between the electrophiles 2a, 3b, and 3c with thiophenes 1a-c suggests that a very high negative charge density is preferentially localized on the carbon bearing the SO2CF3 group (Figure 2).Figure 2It is interesting to note that electrophiles2a and 3a-c showed negligible absorption at the absorbance wavelengths λmax of the σ-adducts considered in this work (Figures 1, S1, and S2). This observation made possible the kinetic study of the coupling reaction of thiophenes 1a-c with the various electrophiles 2a and 3a-c in acetonitrile.Theoretically, the reactions proceed according to Scheme3 and the bimolecular rate constant k1 is related to the formation of the zwitterionic intermediate IZ± while the monomolecular rate constants k−1 and k2 are associated with the decomposition processes of the intermediate IZ± with, respectively, a return to the starting reagents or rearomatization of the thiophenic entity. So, as can be seen, the proposed mechanism is the result of an electrophilic aromatic substitution of the α-carbon position of the thiophenes 1a-c with formation of a zwitterionic intermediate IZ±. The various add adducts are the result of a two-step SEAr process of the addition-elimination type.Scheme 3The graphs Ln (Ae − A) as a function of time measured for a given interaction are linear (R2 > 0.9998). From the slope of these lines, the constants kobsd were easily determined as follows:(1)LnAe−A=−kobst+LnAe−Ao.The straight lineskobsd as a function of the concentration of thiophenes 1a-c have proved to be linear and are characterized by a zero origin ordinate.It follows that the nucleophilic attack of the various thiophenes1a-c on the position 7 of the electrophiles 2a and 3a-c studied is then the determining step of the coupling reaction, which implies(2)kobsd=k13−X−thiophene.The values of the relative bimolecular rate constantsk1 for each electrophile studied are grouped in Table 1.Table 1
Second-order rate constants (k1/M−1·s−1) and electrophilicity parameters (E) of the reactions of 3-X-thiophene 1 with the electrophiles 2a and 3a-c in acetonitrile at 20°C.
Electrophile
Ea
Nucleophile
k
1 (M−1s−1)
−4.58
1a
4.08 × 10−3
1b
1.28 × 10−3
1c
3.41 × 10−4
−4.74
1a
2.67 × 10−3
1b
7.18 × 10−4
1c
2.22 × 10−4
−5.06
1a
1.23 × 10−3
1b
3.39 × 10−4
1c
1.08 × 10−4
−6.41
1a
4.10 × 10−5
1b
1.35 × 10−5
1c
4.36 × 10−6
aRef [7].


## 3.2. Nucleophilicities of Thiophenes1a-C

Based on the values measured in acetonitrile at 20°C of the bimolecular rate constantsk1 associated with the coupling reaction between thiophenes 1a-c and electrophiles 2a and 3a-c which are grouped in Table 1 with the values of the parameters E of the various electrophiles 2a and 3a-c reported in the literature [7], the plots logk1/s as a function of the parameter E could be constructed. The situation is illustrated in Figure 3.Figure 3
Plots of logk1 versus E for the reactivity of thiophenes 1a-c with the reference electrophiles 2a and 3a-c in acetonitrile at 20°C (the identity of points is given in Table 1).As can be seen, satisfactory lines of equal slope or near unity have been obtained in accordance with Mayr’s rearranged equation (equation (3) [15–17]. The values of the parameters N and s relative to each 3-X-substituted thiophene 1a-c could thus be determined graphically.(3)logk1s=E+N.In light of the values of N grouped in Table2, we have undertaken to compare the reactivity of our thiophenes 1a-c with that of other nucleophiles. Figure 4 reveals that the N parameters for 3-X-substituted thiophenes 1a-c are located on over a reactivity range of nearly 3 orders of magnitude. As can be seen, the reactivity of the most reactive thiophene 1d (N = 3.96) [19] is approximately 13 units above the reactivity of tetraethylsilane 6 (N = −6.50) [20] and tris-p-tolylmethane 7 (N = −8.80) [20], but it remains significantly lower (25 units) than that of the 2-phenylpropionitrile anion 8 (N = 28.95) [21] considered to be the nucleophile more reactive encrypted to date. Another important observation is that the nucleophilic reactivity of the pyrroles 9a and 9b [22] and the furans 10a and 10b [6] is higher than that of the thiophene series 1a-c. Moreover, the nucleophilicity of the thiophenes 1e and 1d is at the level of that of the indoles 11b and 11c [23]. Regarding the nucleophilicity of the three less-reactive thiophenes 1a-c, we find that their ranking on the universal scale N of Mayr is about 4 units higher than that of naphthalenes 12 and 13 [20].Table 2
Second-order rate constantsk1 (M−1·s−1) and selectivity parameters (ρ and pKa) of the reactions of 3-X-thiophene 1 with the electrophiles 2a and 3a-c.
Thiophene
Ν/s
σ
+b
k
1 (M−1s−1)
2a
3a
3b
3c
2.38/1.09
−0.31
4.08 × 10−3
2.76 × 10−3
1.23 × 10−3
4.10 × 10−5
1.79/1.06
0.00
1.28 × 10−3
7.18 × 10−4
3.39 × 10−4
1.35 × 10−5
1.20/1.03
0.15
3.41 × 10−4
2.22 × 10−4
1.08 × 10−4
4.36 × 10−6
ρ
−2.23
−2.27
−2.22
−2.03
pKa
0.30
2.95
3.75
5.86
bRef [18].Figure 4
Ranking the carbon reactivity of the 3-X-substituted thiophene1 on the Mayr N universal N scale.


## 3.3. Effect of Substituents on Reactivity

The analysis of Table2 clearly shows that the bimolecular rate constant k1 associated with the coupling reaction of thiophenes 1a-c with the superelectrophiles 2a and 3a-c is very sensitive to the nature of the substituent X located in position C-3 of the thiophenes 1a-c. Indeed, the constant k1 decreases regularly when X = CH3, the most electro-donor substituent, and changes to X = Br, the most electro-attracting substituent.This behavior is well illustrated in Figure5, where the logarithm of the rate constant k1 is a function of the Hammett constant σ+, reported in the literature, of the various X substituents [24].Figure 5
Hammett correlations: influence of the nature of the substituent X on the constantk1 relating to the coupling reaction of thiophenes 1a-c with electrophiles 2a and 3a-c in acetonitrile at 20°C.It is interesting to note that obtaining such correlations means the same reaction mechanism despite the variation of the substituent and confirms that the addition step of thiophenes1a-c on electrophiles 2a and 3a-c is the decisive stage of the reaction.The negative values of the reaction constantsρ deduced from the slopes of the lines log k1 = f (σ+), as shown in Table 2, indicate a development of a positive charge on the thiophenic entity in the transition state that means a decrease in electron density on the C-2 carbon atom of thiophene (Figure 6). It is noted that the more the substituent X is an electron donor, the more this charge is positive, and therefore the corresponding transition state is stabilized, which confirms the decrease in k1 observed when passing from 3-methylthiophene 1a to 3-bromothiophene 1c.Figure 6
Proposed transitional state structures forσ-adducts 4 and 5 in acetonitrile.It is interesting to note that the low values ofρ obtained can also be interpreted in terms of a large delocalization of the negative charge in the carbocyclic of electrophiles 2a and 3a-c. In addition, our values (−2.23 < ρ < −2.03) are similar to the values measured by several authors [18, 25–29]. El Guesmi and coworkers have shown that the aromatic nucleophilic substitution reactivity of triflone 2,4,6-tris (trifluoromethanesulfonyl) anisole with various anilines in acetonitrile at 15°C is characterized by a value of ρ equal to −1.80 [25].Moreover, the existence of linear correlations logk1 = f (σp+) and result of the study of the variation of the reactivity according to the structural variations of the nucleophilic pattern (thiophene) exhibits the phenomenon known as “Hyper-Ortho Correlation” [10, 30]. Currently, such a situation has never been encountered in the context of five-membered heterocycles.However, logk = f(σp) correlations were obtained in thiophenic series, but in these cases, the reactivity variations were made from structural variations in the electrophilic motif [18, 30]. In this regard, we note that Spinelli and coworkers were the first to identify a hyperortho effect in the case of the coupling reaction of various thiophenes such as 2-bromo-3-X-5-nitrothiophene with piperidine in methanol [31].


## 3.4. Reactivity-Acidity Relationship

A comparison of electrophilic reactivity can be made using the linear free-energy relation similar to that proposed by Brönsted [32, 33]. The relation 4 relates the reactivity k to the thermodynamic acidity of the electrophile pKa. The constants A measure the reactivity of the family of electrophiles, and αEl is the sensitivity of the reaction to the variations of acidity of the electrophile. As can be seen, an examination of Figure 7 leaves no doubt that the Brönsted type graphs for the three thiophenes 1a-c have a curvilinear appearance:(4)logk=A+αElpKa.Figure 7
Bronsted nonlinear correlations: influence of electrophilic acidity2a and 3a-c on bimolecular rate constants, k1, related to the coupling reaction of the thiophene 1a-c with the electrophiles 2a and 3a-c in acetonitrile at 20°C.However, at pKa > 3, the three electrophiles 3a-c define a linear Brönsted correlation according to equation (4). The slope values deduced from the linear straight lines in Figure 8 (αEl1a = −0.64, αEl1b = −0.61, αEl1c = −0.60) suggest that the formation of the carbon-carbon and thus the transfer of the charge of the nucleophile (thiophene) to the electrophile (benzofuraxanes 3a-c) is almost 60% carried out in the state of transition.Figure 8
Brönsted linear correlations for the coupling reaction of the thiophenes1a-c with the electrophiles 3a-c in acetonitrile at 20°C.Numerous electrophilic substitution studies exist in the literature in which the variations in reactivity have been studied from structural variations in the nucleophilic motif [34, 35]. Challis and coworkers, for example, investigated the reaction of 4,6-dinitrobenzofuraxane 3b with 5-X substituted indoles 11 [34]. In these systems, the Brönsted-type straight lines associated with the reactivity changes are characterized by a slope of βnuc-type since these changes are the structural variations of the nucleophile. However, in the present work, the αEl values reveal the structural variations of the electrophile and we have not found in the literature values of the same type that we could compare to our system.On the other hand, it remains that our values ofαEl obtained are in good agreement with a polar heteroaromatic electrophile substitution mechanism [36, 37].


## 3.5. Effect of Substituant X on the Nucleophilicity N

The aim of this part is to verify if the C-2 carbon nucleophilicity of the 3-X-substituted thiophenes measured by the parameter N is dependent on the electronic effect of the substituent X in position 3. In this context, we have grouped in Table3 the values of the parameter N of the thiophenes 1a-c quantified in this work as well as that of 3-methoxythiophene 1d reported by Berionni and coworkers [6] and the constants of Hammett σ of various groups used in this study [24].Table 3
Nucleophilicity parameters N of 3-X-substituted thiophenes in acetonitrile at 20°C.
σ
+
N
Reference
OCH3
−0.78
3.06
[6]
OC2H5
−0.81
3.69
[16]
CH3
−0.31
2.38
This work
H
0.00
1.79
This work
Br
0.15
1.20
This work
NH2
−1.30
4.62
Estimated
CF3
0.61
0.23
Estimated
CN
0.66
0.13
Estimated
NO2
0.79
−0.17
EstimatedAs can be seen, Figure9 shows that a satisfactory linear line is obtained by carrying the values of N as a function of Hammett constants σ. Equation (5) describes this linear dependence:(5)N=1.65−2.28⋅σ+,R2=0.9663.Figure 9
Correlation N =f(σ+) of a series of 3-X-substituted thiophenes in acetonitrile at 20°C.We note that obtaining the correlation (5) informs us about the exceptional α-carbon nucleophilic reactivity of 3-X-substituted thiophenes. Also, it can be used for a direct estimation of N values that are not easily measurable.


## 4. Conclusion

According to the free-energy relationship logk = s (N + E), the nucleophile-specific parameters N and s of 3-X-thiophenes 1 have been evaluated and compared with the reactivity of other C-nucleophiles in acetonitrile. On the other hand, the satisfactory Hammett correlations (log k1 vs. σ−) obtained confirms that a 3-X substituent exerts an effect on the 2-position of the same type as that exerted from the 5-position: hyperortho correlations.



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