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

Kinetics studies for the coupling reactions of the 3-X-thiophene 1a-c (X�CH3, H and Br) with the electrophiles 2a and 3a-c have been investigated in acetonitrile at 20°C )e 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). )e 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(σ+p), 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.


Introduction
Nowadays, it has been shown that five-membered rings are very useful for various applications such as phosphor materials [1] and semiconductors [2][3][4]. As an example, the use of thiophene dicarboxylic acids has made it possible to prepare organometallic nanoarchitectures having very interesting optoelectronic properties [5].
e study of the reactivity of some mono-and bissubstituted thiophenes has attracted the attention of researchers because of their ability to react according to different processes and largely dependent on the substituent [6][7][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.

Supporting Information Available.
Tables S1-S3: kinetic data for reactions of thiophenes 1 with 4,6-dinitrotetrazolopyridine 2a and benzofuroxane 3a-c in an aqueous solution at 20°C. Table S4: 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.
Figures S1-S2: UV-visible spectrum of thiophenes 1a and 1b and the progressive evolution of the formation of the product 4A and 4B.

Kinetic Investigation.
e evolution of the kinetic constants of the coupling reaction between 3-X-thiophene 1a-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.
e 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 S X   Journal of Chemistry 5A-I adducts at wavelengths between 405 and 487 nm. A typical experiment is illustrated in Figure 1. e 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. A comparison of these values of λ max 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. ese high wavelengths translate a strong delocalization of the negative charge on the Z group (NO 2 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][11][12][13][14]. e analysis in Table S4 reveals that the σ-adducts 5A-C show an absorption maximum around 410 nm. is 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 SO 2 CF 3 group (Figure 2).
It is interesting to note that electrophiles 2a and 3a-c showed negligible absorption at the absorbance wavelengths λ max of the σ-adducts considered in this work (Figures 1, S1 Table 1: Second-order rate constants (k 1 /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.  Table 1). and S2). is observation made possible the kinetic study of the coupling reaction of thiophenes 1a-c with the various electrophiles 2a and 3a-c in acetonitrile. eoretically, the reactions proceed according to Scheme 3 and the bimolecular rate constant k 1 is related to the formation of the zwitterionic intermediate IZ ± while the monomolecular rate constants k −1 and k 2 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 ± . e various add adducts are the result of a two-step S E Ar process of the addition-elimination type. e graphs Ln (A e − A) as a function of time measured for a given interaction are linear (R 2 > 0.9998). From the slope of these lines, the constants k obsd were easily determined as follows: e straight lines k obsd 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 thiophenes 1a-c on the position 7 of the electrophiles 2a and 3a-c studied is then the determining step of the coupling reaction, which implies e values of the relative bimolecular rate constants k 1 for each electrophile studied are grouped in Table 1.

Nucleophilicities of
iophenes 1a-C. Based on the values measured in acetonitrile at 20°C of the bimolecular rate constants k 1 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 log k 1 /s as a function of the parameter E could be constructed. e situation is illustrated in Figure 3.
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][16][17].
e values of the parameters N and s relative to each 3-X-substituted thiophene 1a-c could thus be determined graphically. log In light of the values of N grouped in Table 2, 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 2phenylpropionitrile 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 1ac. 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].

Effect of Substituents on Reactivity.
e analysis of Table 2 clearly shows that the bimolecular rate constant k 1 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 Table 2: Second-order rate constants k 1 (M −1 ·s −1 ) and selectivity parameters (ρ and pK a ) of the reactions of 3-X-thiophene 1 with the electrophiles 2a and 3a-c. C-3 of the thiophenes 1a-c. Indeed, the constant k 1 decreases regularly when X � CH 3 , the most electro-donor substituent, and changes to X � Br, the most electroattracting substituent. is behavior is well illustrated in Figure 5, where the logarithm of the rate constant k 1 is a function of the Hammett constant σ + , reported in the literature, of the various X substituents [24].
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 thiophenes 1a-c on electrophiles 2a and 3a-c is the decisive stage of the reaction.
e negative values of the reaction constants ρ deduced from the slopes of the lines log k 1 � 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 k 1 observed Journal of Chemistry when passing from 3-methylthiophene 1a to 3-bromothiophene 1c.
It is interesting to note that the low values of ρ 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][26][27][28][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 log k 1 � f (σ + p ) 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 fivemembered heterocycles.
However, log k � f(σ p ) 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 2bromo-3-X-5-nitrothiophene with piperidine in methanol [31].

Reactivity-Acidity Relationship.
A comparison of electrophilic reactivity can be made using the linear freeenergy relation similar to that proposed by Brönsted [32,33]. e relation 4 relates the reactivity k to the thermodynamic acidity of the electrophile pK a . e constants A measure the reactivity of the family of electrophiles, and α El 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: However, at pK a > 3, the three electrophiles 3a-c define a linear Brönsted correlation according to equation (4). e slope values deduced from the linear straight lines in 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 Brönstedtype straight lines associated with the reactivity changes are characterized by a slope of β nuc -type since these changes are the structural variations of the nucleophile. However, in the present work, the α El 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 of α El obtained are in good agreement with a polar heteroaromatic electrophile substitution mechanism [36,37].

Effect of Substituant X on the Nucleophilicity N.
e 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 Table 3 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].
As can be seen, Figure 9 shows that a satisfactory linear line is obtained by carrying the values of N as a function of 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.

Conclusion
According to the free-energy relationship log k � 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 k 1 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 5position: hyperortho correlations.

Data Availability
e data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest
e authors confirm that this article content has no conflicts of interest.

Supplementary Materials
is is the UV-visible spectrum and the kinetics data of each thiophene 1a-c. Tables S1-S3: kinetics data for reactions of thiophene 1 with 4,6-dinitrotetrazolopyridine 2a and benzofuroxane 3a-c in aqueous solution at 20°C. Table S4: physical data for the formation of σ-adducts 4A-C and 5A-I derived from the reaction of 3-X-substituted thiophenes 1ac with the electrophiles 2a and 3a-c. Figures S1-S2: UVvisible spectrum of thiophenes 1a and 1b and the progressive evolution of the formation of the products 4A and 4B.