untitled European Journal of Chemistry 6 (2) (2015) 225‐236 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2015 Atlanta Publishing House LLC ‐ All rights reserved ‐ Printed in the USA http://dx.doi.org/10.5155/eurjchem.6.2.225‐236.1246 European Journal of Chemistry Journal webpage: www.eurjchem.com Activation parameter changes as a mechanistic tool in SN2 reactions in solution Vladislav Mikhailovich Vlasov * Nikolay Nikolaevich Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russian Federation * Corresponding author at: Nikolay Nikolaevich Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russian Federation. Tel.: +7.383.3308833. Fax: +7.383.3309752. E‐mail address: vmvlasov@nioch.nsc.ru (V.M. Vlasov). REVIEW INFORMATION ABSTRACT DOI: 10.5155/eurjchem.6.2.225‐236.1246 Received: 21 January 2015 Received in revised form: 17 February 2015 Accepted: 21 February 2015 Published online: 30 June 2015 Printed: 30 June 2015 Recent applications of activation parameters variation approach to the elucidation of SN2 reaction mechanisms have led to further clarifications of structures of transition states involved in the concerted reaction pathway. SN2 reactions in solution are reviewed with special emphasis of activation parameter variation ΔX≠ (X = H, S and G) with substituents in the nucleophile, leaving and nonleaving groups applying linear free energy relationships in order to evaluate the resultant δΔX≠ reaction constants. The use of internal enthalpy reaction constants δΔH≠int as a mechanistic tool is stressed when the structure of transition state in SN2 reaction is changed. Variations of the activation parameters in SN2 reactions and their mechanisms were analyzed. KEYWORDS Transition state Substituent effects Charge development Reaction mechanisms Activation parameters SN2 reactions in solution Cite this: Eur. J. Chem. 2015, 6(2), 225‐236 1. Introduction A significant part of reactions carried out in organic and bioorganic chemistry involve the bimolecular nucleophilic reactions (BNRs) in solution [1,2]. These reactions play important role in organic synthesis [1,2]. Among them, bimolecular nucleophilic substitution at sp3 carbon (SN2) constitutes a fundamental reaction type [1‐4]. This reaction proceeds preferentially through backside nucleophile attack of the nucleophile at the carbon atom (SN2‐b) with concerted expulsion of the leaving group and with inversion of configuration at carbon. The latter is in general more efficient because it has a lower reaction barrier than the corresponding front side SN2‐f pathway, which goes with retention of configuration [1‐4]. The nature of the reactants or solvents influences both the kinetics and mechanism of SN2 reactions [5‐7]. Various experimental kinetic and theoretical studies have therefore been devoted to obtain a better understanding of the mechanisms of these processes [3‐5,8‐11]. Among traditional experimental methods, kinetic isotope effects [12‐ 15] and linear free energy relationships (LFER) [16‐19] have most frequently been used to study mechanisms of BNRs, in particular the nature of transition states (TSs) [20‐22]. Besides, the influence of the variations of substituents in reactants on activation parameters in BNRs including SN2 reactions was demonstrated [23‐27]. The effects of structural changes in the nucleophile, leaving and non‐leaving groups on the activation parameters of the SN2 reactions are quantitatively described using the Hammett or Hammett‐like substituent constants [16‐19,28‐ 30] for aromatic systems [31‐33]. Substituent effects are among the most important concepts of structural effects [31]. A search in the last 5 years using ISI Scifinder returned over 8700 papers containing the term “substituent effects” in the title or abstract. In this review recent advances in the detailed analysis of the relationship between the mechanisms and the activation parameter variations with substituents in the nucleophile, leaving and non‐leaving groups for the SN2 reactions in solution are surveyed. 2. Substituent effects on the activation parameters Generalized analysis of structural effects on the activation parameters of SN2 reactions implies separation of substituent effects into enthalpy and entropy contributions to the ρ value in the general Hammett equation (Equation (1)) [34‐41]. In Equation (1), the parameter σ is 226 Vlasov / European Journal of Chemistry 6 (2) (2015) 225‐236 ΔX≠ = δΔX≠σ + ΔX≠o (X = H, S, G) (1) substituent constant, the slope δΔX≠ determines the selectivity of the substituent effect on the activation parameters ΔX≠ (X = H, S and G), and the free term ΔX≠o is the corresponding activation parameter for unsubstituted compound. Therefore, the reaction constant δΔX≠ may be regarded as an analog of the Hammett ρ value. In keeping with the Hepler solvation theory [34,35], reaction constant δΔX≠ is the sum of internal (δΔX≠int) and external (δΔX≠ext) constituents related, respectively, to the chemical reaction and solvation processes (Equation (2)) [34‐ 41]. δΔX≠ = δΔX≠int + δΔX≠ext (X = H, S, G) (2) The changes in the δΔS≠ values caused by the variation of the remote substituent on the aromatic ring result from the changes in solvation of the external constant δΔS≠ext (Equation (3)). δΔS≠ = δΔS≠int + δΔS≠ext (3) Therefore, it is possible to believe that in the Equation (3) the internal constant δΔS≠int is independent of the substituent in the absence of steric effects (δΔS≠int ≈ 0) and δΔS≠ ≈ δΔS≠ext [34,35,42,43]. In this case, the magnitudes of δΔН≠ext (Equation (4)) and δΔS≠ can be δΔH≠ = δΔH≠int + δΔH≠ext (4) compensated to each other by Equation (5) [34,35,42,43]. As can be seen from the general δΔН≠ext = Tcomp δΔS≠ (5) compensation relationship given by Equation (6), the slope is the compensation temperature Tcomp δΔН≠ = δΔН≠int + Tcomp δΔS≠ (6) and the intercept is the internal enthalpy constant δΔН≠int for the given reaction series [34‐41]. Obviously, if the δ∆H≠int value is equal to zero, the δ∆H≠ value (δΔH≠ = δΔH≠ext) is determined by the solvation influence only. In another case when the compensation temperature is equal to zero, the δ∆H≠ value is governed by the magnitude of the δ∆H≠int constant. The equations (Equations (1‐6)) describing the influence of the substituents on the changes of the reaction constants δΔX≠ (X = H, S, G) are used for the analysis of SN2 reactions. 3. Reaction constants δΔH≠ and δΔS≠ Variations of the activation parameters δΔН≠ and δΔS≠ in the SN2 reactions with neutral and charged nucleophiles in various solvents in Table 1 reflect the sensitivity of activation parameters to substituent nature in the leaving groups, nucleophiles and nonleaving groups and strongly depend on solvation of reactants and TSs (Scheme 1) [24‐27,37‐40]. Negative values of δΔН≠ and δΔS≠ indicate enhanced solvation of the corresponding TS‐1 upon introduction of electron‐ withdrawing substituents R (entries 15‐17, 25‐28, 34‐36 in Table 1). At the same time, their positive values suggest stronger solvation of the initial reactants with electron‐ withdrawing groups R (entries 5, 10, 11, 19‐24, 29, 30, 37, 39‐ 42 in Table 1). In some cases, solvation of the initial reactants dominates which may lead to positive values of δΔS≠ and small negative values of δΔH≠ (entries 1‐4, 6‐9, 12, 13 in Table 1). There are three compensation relationships between δΔН≠ and δΔS≠ for SN2 reactions at saturated carbon atom including the changes of the substituents R in the leaving group (entries 1‐13 in Table 1), nonleaving group (entries 15‐29) and nucleophiles (entries 30‐42) (Figure 1). The lines II and III from Figure 1 combine a relatively fast reactions [50,53‐67] and the compensation relationships for these lines are tested at a confidence level of >95% [27,43]. The slopes of the lines II and III correspond to compensation temperatures Tcomp equaling 380 and 370 K, respectively. These values are higher than the mean experimental temperature Texp (entries 15‐42 in Table 1) and it must be concluded that the compensation relationships are not caused by experimental errors [68]. As for the exact physical‐chemical sense of the enthalpy‐entropy compensation, this is still a debated question [43,69‐71]. Nevertheless, when Tcomp > Texp, it is necessary to accept the existence of a real correlation between the values of δΔН≠ and δΔS≠ [68]. The line I from Figure 1 combines a more slower reactions (entries 1‐13 in Table 1) in a relatively narrow range of the values of δΔН≠ and δΔS≠. Therefore, the compensation equation for this line was tested at the >92% confidence level and the slope of the line I corresponds to compensation temperature Tcomp equaling 290 K. This temperature is lower than the middle experimental temperature Texp (entries 1‐13 in Table 1). The latter indicates some experimental errors upon the determination of the reaction rate constants leading to the existence of the compensation dependence between the values of δΔН≠ and δΔS≠ [43,68‐71]. There is the one deviation from line I (Figure 1) depicting the dependence of δΔН≠ versus δΔS≠ for the reactions of substituted N‐methylpyridinium salts with iodide ion (entry 14 in Table 1). These reactions are characterized by very low rate constants (k2 = 1×10‐12 ‐ 1×10‐9 dm3∙mol‐1∙s‐1) [50] and by a large negative value of δΔН≠ [24,27]. An analogous deviation from the dependence of δΔН≠ versus δΔS≠ for the line III (Figure 1) is connected with a large positive value of δΔS≠ for the reactions of N‐substituted anilines with benzyl bromide in methanol (entry 40 in Table 1). A lower rate constants characterize also these reactions in comparison with the same rate constants for the parent reactions of entry 41 in Table 1. The latter have a large positive value of δΔS≠. Obviously, the arrangement of lines I ‐ III and entries 14 and 40 on Figure 1 reflects the reactivity order of SN2 reactions with decreasing the values of δΔН≠ [24,27]. Figure 1. The plots of δΔН≠ versus δΔS≠ for SN2 reactions with the substituents R in the leaving group YCH2ZC6H4R (I), nonleaving group RC6H4ZCH2X (II) and nucleophile RC6H4Z‐ (RC6H4ZH) (III); values of δΔН≠ and δΔS≠ are taken from Table 1; line I, δΔН≠ = (‐8.0 ± 0.3) + (0.29 ± 0.03) δΔS≠, r = 0.950, s = 1.1, n = 13; line II, δΔН≠ = (‐1.5 ± 1.2) + (0.38 ± 0.03) δΔS≠, r = 0.973, s = 4.1, n = 11; line III, δΔН≠ = (11.4 ± 0.9) + (0.37 ± 0.02) δΔS≠, r = 0.990, s = 3.32, n = 12; the compensation equations for lines I – III are tested at the 92%, 95.7% and 97.6% confidence level, respectively [43]; the identity of the numbers is the entry number in Table 1. 4. SN2 Reactions with neutral nucleophiles The changes in the free energy of activation reaction constant, δΔG≠, in the SN2 reactions reflect the influence of the Vlasov / European Journal of Chemistry 6 (2) (2015) 225‐236 227 Table 1. Effects of the substituents R in the leaving groups YCH2ZC6H4R, nonleaving groups RC6H4ZCH2X and nucleophiles RC6H4Z‐ (RC6H4ZH) on the reaction constants δΔН≠ and δΔS≠ in SN2 reactions at saturated carbon atom YCH2‐X with neutral NuH (RC6H4ZH) and charged nucleophiles Nu‐ (RC6H4Z‐) in various solvents [24,27,44‐67]. Entry Reactants Solvent N(m) a Texp/ b K δΔH≠/ c kJ.mol‐1.σ‐1 δΔS≠/ c J.mol‐1.K‐1.σ‐1 Reference Substituents R are varied on leaving groups YCH2ZC6H4R 1 Me‐OSO2C6H4R + H2O H2O 6(3) 323 ‐2.1 11.3 24,27,44 2 Me‐OSO2C6H4R + EtOH EtOH 5(3) 343 ‐1.4 20.6 24,27,45,46 3 n‐Pr‐OSO2C6H4R + MeOH MeOH 6(3) 323 ‐2.4 16.0 24,27,47 4 n‐Pr‐OSO2C6H4R + EtOH EtOH 6(3) 323 ‐0.4 24.1 24,27,47 5 n‐Pr‐OSO2C6H4R + i‐PrOH i‐PrOH 6(3) 323 0.6 30.8 24,27,47 6 CH2=CH‐CH2‐SO2C6H4R + H2O H2O 4(3) 313 ‐7.5 1.3 24,27,48 7 CH2=CH‐CH2‐SO2C6H4R + H2O 90% Di‐oxane +10% H2O 4(3) 313 ‐6.4 8.6 24,27,48 8 CH2=CH‐CH2‐SO2C6H4R + MeOH MeOH 8(3) 313 ‐7.5 1.9 24,27,47 9 CH2=CH‐CH2‐SO2C6H4R + EtOH EtOH 8(3) 313 ‐4.6 14.0 24,27,47 10 CH2=CH‐CH2‐SO2C6H4R + i‐PrOH i‐PrOH 8(3) 313 0.2 31.8 24,27,47 11 СH≡C‐CH2‐OSO2C6H4R + MeOH MeOH 8(3) 323 0.5 28.6 24,27,49 12 СH≡C‐CH2‐SO2C6H4R + EtOH EtOH 8(3) 323 ‐6.0 8.3 24,27,49 13 СH≡C‐CH2‐OSO2C6H4R + i‐PrOH i‐PrOH 8(3) 323 ‐8.2 4.0 24,27,49 14 RC5H4N+‐Me + I‐ MeCN 5(4) 298 ‐29.0 16.1 24,27,50 Substituents R are varied on nonleaving group RC6H4ZCH2X 15 RC6H4CH2Cl + NH3 Liquid NH3 5(4) 298 ‐2.22 ‐9.06 51,52 16 RC6H4NHC(O)‐CH2Cl + PhNMe2 n‐Octanol 9(3) 440 ‐34.9 ‐69.0 24,27,53 17 RC6H4CH2Br + PhNH2 MeCN 5(3) 308 ‐2.0 ‐17.3 24,27,54 18 RC6H4CH2Cl + PhNH2 MeCN 5(3) 318 0.0 ‐9.6 24,27,54 19 RC6H4CH2Br + С5H5N MeOH 3(3) 298 17.5 50.2 24,27,55 20 RC6H4CH2Br + С5H5N DMF 3(3) 298 9.5 25.8 24,27,55 21 RC6H4CH2Cl + С5H5N MeOH 3(3) 298 31.2 89.3 24,27,55 22 RC6H4CH2Cl + С5H5N DMf 3(3) 298 19.4 56.8 24,27,55 23 RC6H4CH2Br + С5H5N MeCN 7(3) 290 12.6 36.8 24,27,56 24 RC6H4CH2Br + С5H5N Ionic liquid 7(3) 290 7.3 13.1 24,27,56 25 3‐NO2‐4‐C6H3C(O)CH2Br + HSСH2COOH MeOH 5(4) 303 ‐4.75 ‐8.93 57 26 3‐NO2‐4‐C6H3C(O)CH2Br + PhSH MeOH 5(4) 303 ‐4.66 ‐0.03 57 27 4‐C6H4C(O)CH2Br + PhSH MeOH 5(4) 303 ‐10.59 ‐16.24 57 28 RC6H4CH2Cl + PhSLi MeOH 5(3) 293 ‐11.6 ‐22.2 24,27,58 29 RC6H4CH(Me)Br + LiBr Acetone 5(3) 303 14.1 55.6 24,27,59 Substituents R are varied on nucleophiles RC6H4Z‐ (RC6H4ZH) 30 RC6H4NMe2 + MeI MeOH 8(4) 328 16.4 7.0 24,27,39,60 31 RC6H4NMe2 + MeI MeCN 5(4) 313 10.0 ‐14.2 24,27,39,61 32 RC6H4NMe2 + MeI Acetone 5(4) 313 9.8 ‐15.1 24,27,39,61 33 RC5H4N + MeI MeCN 5(4) 298 9.9 ‐10.7 24,27,39,50 34 RC6H4NH2 + CH2=CH‐CH2Br DMF 5(3) 303 ‐20.9 ‐88.8 24,27,62 35 RC6H4NH2 + PhCH2Br MeCN 4(3) 308 ‐1.9 ‐35.4 24,27,54 36 RC6H4NH2 + PhCH2Cl MeCN 5(3) 318 ‐0.6 ‐25.8 24,27,54 37 RC6H4NH2 + PhCH2Br EtOH 7(3) 303 8.0 7.9 24,27,63 38 RC6H4NH2 + PhCH2Br PhNO2 5(3) 303 7.7 ‐0.3 24,27,63 39 RC6H4NH2 + PhC(O)CH2Br EtOH 5(3) 308 23.4 40.0 64,65 40 RC6H4NHR + PhCH2Br MeOH 5(4) 303 46.5 278.0 66 41 RC6H4SO2Na + BrCH2СH=СHCN 50 vol% EtOH‐H2O 3(5) 318 41.2 78.4 27,67 42 RC6H4SO2Na + BrCH2СH=СHBr 50 vol% EtOH‐H2O 3(5) 318 67.6 150.3 27,67 a N is the number of reactions, and m is the number of rate constants at different temperatures. b The middle temperature of experiments; temperature range in which the reaction rate constants were determined is twenty. c The reaction constants δΔН≠ and δΔS≠ are estimated by Equation 1 using σ constants [28]. Scheme 1 substituent R in the leaving group (entries 1‐24 in Table 2), non‐leaving group (entries 25‐50) and nucleophile (entries 51‐79). The values of δΔG≠ are negative for the reaction series in which the substituent R is varied in the leaving group and, particularly, in the nonleaving group and nucleophile (entries 27, 28, 46‐50, 76, 78 in Table 2). On the other hand, reaction series in which change is only made to substituent R in the nucleophile (entries 51‐75, 77, 79) and in the nonleaving group (entries 25, 26, 29‐45) are characterized by positive values of δΔG≠. Such variations in the signs of the δΔG≠ values are common according to the Hammett‐like equation δΔG≠ = ‐ 2.303RTexpρ [16,38]. However, the dependence δΔG≠ versus ρ does not speak about peculiarities of the mechanisms of the SN2 reactions because the Hammett ρ values may depend on the contributions of the TS structure in the concerted mechanism or the formation of the complexes before forming the trigonal‐bipyramidal TS‐1 [24,27,40,41]. A lot of examples of the reaction constants δΔG≠ and δΔН≠int are presented in Table 2, where is clearly noted that these constants are approximately equal; therefore, linear dependence between δΔН≠int and δΔG≠ has been developed for entries 1‐13, 24, 29, 30, 36, 47‐49, 51‐54 and 57‐59 in Table 2 (Figure 2) [24]. Free term in this equation corresponds to the δΔG≠ext value and close to zero (δΔG≠ext = δΔН≠ext ‐ Texp δΔS≠ext ≈ 0 [24,27,36‐42]). 228 Vlasov / European Journal of Chemistry 6 (2) (2015) 225‐236 Table 2. Values of the reaction constants δΔG≠ and δΔH≠int, the Brønsted slopes βR, the Hammett reaction constants ρR, cross‐interaction constants ρRR in SN2 reactions at saturated carbon atom YCH2‐X with neutral nucleophiles in various solvents. Entry Reactants Solvent δΔG≠/ a kj.mol‐1 σ‐1 δΔH≠int/ b kJ.mol‐1.σ‐1 βR c ρR d ρRR e Reference Substituents R are varied on leaving groups YCH2ZC6H4R 1 Me‐OSO2C6H4R + H2O H2O ‐5.7 ‐5.7 ‐ 0.93 ‐ 24,27,44 2 Me‐OSO2C6H4R + EtOH EtOH ‐8.4 ‐7.9 ‐0.45 1.41 ‐ 24,27,45,46 3 n‐Pr‐OSO2C6H4R + MeOH MeOH ‐7.6 ‐7.5 ‐ 1.28 ‐ 24,27,47 4 n‐Pr‐OSO2C6H4R + EtOH EtOH ‐8.2 ‐8.1 ‐ 1.34 ‐ 24,27,47 5 n‐Pr‐OSO2C6H4R + i‐PrOH i‐PrOH ‐9.3 ‐9.3 ‐ 1.52 ‐ 24,27,47 6 CH2=CH‐CH2‐OSO2C6H4R + H2O H2O ‐7.9 ‐7.9 ‐ 1.31 ‐ 24,27,48 7 CH2=CH‐CH2‐OSO2C6H4R + H2O 90% dioxane + 10% H2O ‐9.1 ‐9.1 ‐ 1.52 ‐ 24,27,48 8 CH2=CH‐CH2‐OSO2C6H4R + MeOH MeOH ‐8.1 ‐8.1 ‐ 1.40 ‐ 24,27,47 9 CH2=CH‐CH2‐OSO2C6H4R + EtOH EtOH ‐9.0 ‐9.1 ‐0.51 1.51 ‐ 24,27,47 10 CH2=CH‐CH2‐OSO2C6H4R + i‐PrOH i‐PrOH ‐9.7 ‐10.0 ‐ 1.61 ‐ 24,27,47 11 СH≡C‐CH2‐OSO2C6H4R + MeOH MeOH ‐8.7 ‐8.6 ‐ 1.25 ‐ 24,27,49 12 СH≡C‐CH2‐OSO2C6H4R + EtOH EtOH ‐8.7 ‐8.7 ‐ 1.41 ‐ 24,27,49 13 СH≡C‐CH2‐OSO2C6H4R + i‐PrOH i‐PrOH ‐9.5 ‐9.5 ‐ 1.54 ‐ 24,27,49 14 Me‐OSO2C6H4R + PhNH2 MeOH ‐7.55 (‐7.9) ‐ (‐7.33) ‐0.39 1.16 0.30 72 15 Me‐OSO2C6H4R + PhNH2 MeCN ‐8.66 (‐8.13) ‐ (‐8.46) ‐0.45 1.33 0.32 72 16 Me‐OSO2C6H4R + PhNMe2 MeOH ‐7.07 (‐6.67) ‐ (‐6.85) ‐0.36 1.09 0.24 73 17 Me‐OSO2C6H4R + PhNMe2 MeCN ‐8.91 (‐8.43) ‐ (‐8.71) ‐0.46 1.38 0.25 73 18 CH2=CH‐CH2‐OSO2C6H4R + PhNH2 MeCN ‐7.55 (‐7.58) ‐ (‐7.33) ‐0.34 1.24 0.37 74 19 CH2=CH‐CH2‐OSO2C6H4R + PhNMe2 MeCN ‐7.87 (‐7.94) ‐ (‐7.95) ‐0.35 1.30 0.30 74 20 СH≡C‐CH2‐OSO2C6H4R + PhNH2 MeCN ‐7.23 (‐7.27) ‐ (‐7.01) ‐0.32 1.19 0.29 75 21 СH≡C‐CH2‐OSO2C6H4R + PhNMe2 MeCN ‐8.77 (‐8.79) ‐ (‐8.57) ‐0.39 1.44 0.25 75 22 PhCH2‐ OSO2C6H4R + 4‐MeC6H4NMe2 Acetone ‐12.27 (‐12.67) ‐ (‐12.10) ‐0.71 2.08 <0 76 23 PhCH2‐ OSO2C6H4R + PhNH2 MeOH ‐10.34 (‐8.13) ‐ (‐10.15) ‐0.45 1.33 ‐0.10 8,77 24 PhCH2‐ OSO2C6H4R + C5H5N Acetone ‐10.78 (‐11.64) ‐9.54 (‐11.64) ‐0.65 1.92 ‐ 78 Substituents R are varied on nonleaving group RC6H4ZCH2X 25 RC6H4CH2Cl + liquid NH3 Liquid NH3 0.48 (‐0.04) ‐ (0.77) ‐ 0 ‐ 51 26 RC6H4CH2Cl + C5H11N (R = 4‐Me, H, 4‐Cl, 4‐COOMe) Liquid NH3 1.52 (1.60) ‐ (1.82) ‐ ‐0.27 ‐ 52 27 RC6H4CH2Cl + C5H11N (R = 4‐COOMe, 4‐CN, 4‐NO2) Liquid NH3 ‐3.83 (‐4.11) ‐ (‐3.58) ‐ 0.67 ‐ 52 28 RC6H4NHC(O)‐CH2Cl + PhNMe2 n‐Octanol ‐4.5 ‐8.0 ‐ 0.49 ‐ 24,27,53 29 RC6H4CH2Br + PhNH2 MeCN 3.3 4.7 ‐ ‐0.55 ‐ 24,27,54 30 RC6H4CH2Cl + PhNH2 MeCN 3.1 3.7 ‐ ‐0.51 ‐ 24,27,54 31 RC6H4CH2Br + С5H5N MeOH 2.5 ‐2.1 ‐ ‐0.66 ‐ 24,27,55 32 RC6H4CH2Br + С5H5N DMF 1.8 ‐0.6 ‐ ‐0.31 ‐ 24,27,55 33 RC6H4CH2Cl + С5H5N MeOH 4.6 ‐3.6 ‐ ‐0.78 ‐ 24,27,55 34 RC6H4CH2Cl + С5H5N DMF 2.5 ‐2.7 ‐ ‐0.49 ‐ 24,27,55 35 RC6H4CH2Br + С5H5N MeCN 1.9 ‐1.4 ‐ ‐0.32 ‐ 24,27,56 36 RC6H4CH2Br + С5H5N Ionic liquid 3.5 2.3 ‐ ‐0.56 ‐ 24,27,56 37 RC6H4CH2Cl + PhNH2 MeOH 3.99 (3.91) ‐ (4.32) ‐ ‐0.65 ‐0.75 79 38 RC6H4CH2Cl + PhNH2 (R = 4‐MeO, 4‐Me, H) EtOH 27.6 (27.1) ‐ (28.2) ‐ ‐4.46 ‐0.93 80 39 RC6H4CH2Cl + PhNH2 (R = H, 4‐Cl, 4‐NO2) EtOH 2.40 (2.39) ‐ (2.71) ‐ ‐0.40 ‐0.93 80 40 RC6H4CH2Br + PhNH2 (R = 4‐Me, H, 4‐Cl, 4‐NO2) MeOH 4.36 (4.46) ‐ (4.69) ‐ ‐0.74 ‐0.78 81 41 RC6H4CH2Br + PhNH2 (R = H, 4‐Cl, 4‐NO2) MeOH 3.45 (3.49) ‐ (3.77) ‐ ‐0.58 ‐0.78 81 42 RC6H4CH2Br + PhNMe2 Acetone 6.71 (6.28) ‐ (7.07) ‐ ‐1.04 ‐1.14 82 43 PhCH2‐OTs + PhNMe2 MeCN 11.67 (11.94) ‐ (12.08) ‐ ‐1.97 ‐ 83 44 RC6H4CH(Me)Br + С5H5N (R = 4‐MeO, 4‐MeS, 4‐PhO, 4‐MeO‐3‐Cl) MeCN 30.1 (29.9) ‐ (30.7) ‐ ‐4.92 ‐ 84 45 RC6H4CH(Me)Br + С5H5N MeCN 8.0 (8.2) ‐ (8.4) ‐ ‐1.36 ‐ 84 46 4‐RC6H4C(O)CH2Br + HSCH2COOH MeOH ‐7.20 (‐7.45) ‐ (‐6.98) ‐ 1.22 ‐ 57 47 3‐NO2‐ 4‐RC6H3C(O)CH2Br + HSСH2COOH MeOH ‐2.33 (‐2.41) ‐1.36 (‐2.06) ‐ 0.39 ‐ 57 48 4‐RC6H4C(O)CH2Br + PhSH MeOH ‐5.67 (‐5.94) ‐4.42 (‐5.44) ‐ 0.97 ‐ 57 49 3‐NO2‐ 4‐RC6H3C(O)CH2Br + PhSH MeOH ‐4.65 (‐4.84) ‐4.65 (‐4.41) ‐ 0.79 ‐ 57 50 4‐RC6H4C(O)CH2Br + PhNH2 MeOH ‐6.28 (‐6.30) ‐ (‐6.05) ‐ 1.03 0.11 85 Substituents R are varied on nucleophiles RC6H4ZH 51 RC6H4NMe2 + MeI MeOH 14.1 13.8 0.45 ‐2.10 ‐ 24,27,39,60 52 RC6H4NMe2 + MeI MeCN 14.4 15.3 ‐ ‐2.43 ‐ 24,27,39,61 53 RC6H4NMe2 + MeI Acetone 14.6 15.4 ‐ ‐2.40 ‐ 24,27,39,61 54 RC5H4N + MeI MeCN 13.1 13.9 0.38 ‐2.27 ‐ 24,27,39,50 55 RC6H4NH2 + CH2=CH‐CH2Br DMF 6.0 12.0 0.43 ‐1.17 ‐ 24,27,62 56 RC6H4NH2 + PhCH2Br MeCN 9.0 11.2 0.31 ‐1.47 ‐ 24,27,54 57 RC6H4NH2 + PhCH2Cl MeCN 7.9 8.9 0.26 ‐1.23 ‐ 24,27,54 58 RC6H4NH2 + PhCH2Br EtOH 5.6 5.1 ‐ ‐0.89 ‐ 24,27,63 59 RC6H4NH2 + PhCH2Br PhNO2 7.8 7.8 ‐ ‐1.63 ‐ 24,27,63 60 RC6H4NH2 + PhC(O)CH2Br EtOH 11.1 8.6 ‐ ‐1.86 ‐ 64,65 61 RC6H4NH2 + PhC(O)CH2Br MeOH 11.1 (11.0) ‐ (11.5) 0.66 ‐1.81 0.11 85 62 RC6H4NH2 + PhCH2Br EtOH 8.61 (8.47) ‐ (9.0) 0.49 ‐1.40 <0 80 63 RC6H4NH2 + PhCH2Cl EtOH 5.36 (5.25) ‐ (5.70) 0.31 ‐0.87 ‐0.93 80 64 RC6H4NH2 + Me‐OSO2Ph MeOH 10.61 (9.63) ‐ (11.0) 0.60 ‐1.59 0.30 72 65 RC6H4NH2 + Me‐OSO2Ph MeCN 11.65 (10.90) ‐ (12.05) 0.65 ‐1.80 0.32 72 66 RC6H4NMe2 + Me‐OSO2Ph MeOH 15.05 (14.0) ‐ (15.5) 0.66 ‐2.31 0.24 73 67 RC6H4NMe2 + Me‐OSO2Ph MeCN 14.66 (13.45) ‐ (15.10) 0.62 ‐2.22 0.25 73 68 RC6H4NH2 + CH2=CH‐CH2‐OSO2Ph MeCN 11.15 (10.61) ‐ (11.55) 0.66 ‐1.75 0.37 74 69 RC6H4NMe2 + CH2=CH‐CH2‐OSO2Ph MeCN 12.67 (12.30) ‐ (13.09) 0.57 ‐2.03 0.30 74 Vlasov / European Journal of Chemistry 6 (2) (2015) 225‐236 229 Table 2. (Continued). Entry Reactants Solvent δΔG≠/ a kj.mol‐1 σ‐1 δΔH≠int/ b kJ.mol‐1.σ‐1 βR c ρR d ρRR e Reference 70 RC6H4NH2 + СH≡C‐CH2‐OSO2Ph MeCN 10.55 (10.05) ‐ (10.95) 0.63 ‐1.66 0.29 75 71 RC6H4NMe2 + СH≡C‐CH2‐OSO2Ph MeCN 12.53 (12.18) ‐ (12.94) 0.57 ‐2.01 0.25 75 72 RC6H4NMe2 + PhCH2‐ OSO2C6H4Cl‐4 Acetone 13.73 (14.13) ‐ (14.16) 0.49 ‐2.33 <0 76 73 RC6H4NH2 + PhCH2‐ OSO2Ph MeOH 4.97 (5.07) ‐ (5.31) 0.29 ‐0.84 ‐0.10 8,77 74 RC6H4NH2 + PhCH2Cl MeOH 9.08 (9.32) ‐ (9.46) 0.55 ‐1.54 ‐0.75 79 75 RC6H4NH2 + PhCH2Br MeOH 8.31 (8.53) ‐ (8.68) 0.46 ‐1.41 ‐0.78 81 76 PhCH2NHR + PhCH2Br (tert‐Bu, i‐Pr, n‐Bu, Et, Me) MeOH ‐37.77 (‐39.50) ‐ (‐37.86) ‐10.2 6.49 ‐ 66 77 PhCH2NHR + PhCH2Br (Me, H, Ph) MeOH 10.11 (10.42) ‐ (10.50) 3.38 ‐1.72 ‐ 66 78 4‐RC6H4SH + 3‐NO2C6H4C(O)CH2Br MeOH ‐5.77 (‐6.06) ‐ (‐5.54) 0.41 0.99 0 57 79 RC6H4NMe2 + PhCH2Br Acetone 5.49 (5.43) ‐ (5.83) ‐ ‐0.90 ‐1.14 82 a Calculated by Eyring equation; values in parentheses are calculated by the Hammett‐like equation δΔG≠ = ‐2.303RTexpρ [16,38]. b Calculated by Equation 6; values in parentheses are calculated by Equation: δΔH≠int = (0.29 ± 0.12) + (1.01 ± 0.01) δΔG≠ (Figure 2). c Calculated by Brønsted equation; the calculations use the values of pK for methyl transfer [46] in entries 2, 9, 14 – 24, substituted N,N‐dimethyl anilines in 50% water EtOH [86] in entries 51, 66, 67, 69, 71, 72, substituted pyridines in MeCN [87] in entry 54, substituted anilines in H2O in entries 76 and 77 [66] and 55, 61‐64, 73‐75 [88], in MeCN in entries 56, 57, 65 and substituted benzenethiols in entry 78 [57]. d Calculated by Hammett equation; σ constants are taken from [28]; σ* constants are used in entries 76 and 77 and taken from [28]. e Calculated by Equation log (kRR’/kHH) = ρRσR + ρR’σR’ + ρRR’σRσR’ in entries 14‐23, 37‐42, 49, 50, 61‐75, 78, 79. Figure 2. The plots of δΔН≠int versus δΔG≠ for SN2 reactions of entries 1‐13, 24, 29, 30, 36, 47‐49, 51‐54 and 57‐59 in Table 2: δΔН≠int = (0.29 ± 0.12) + (1.01 ± 0.01) δΔG≠, r = 0.998, s = 0.61, n = 27; the identity of the numbers is the entry number in Table 2. The latter means that the dependence of the changes of the free energy of activation is governed mainly by the changes in the internal enthalpy of activation in the SN2 reactions: δΔG≠ ≈ δΔН≠int [24,27,36‐42]. The dependence δΔН≠int versus δΔG≠ (Figure 2) is used to calculate the reaction constant δΔН≠int on the basis of the values of δΔG≠. The latter may be obtained by the Eyring equation [6] using the reaction rate constants at single temperature for entries 14‐23, 25‐27, 37‐46, 50, 61‐79 in Table 2. It was shown that the values of δΔG≠ calculated by the Eyring equation and the Hammett‐like equation between the δΔG≠ and ρR values coincide practically for these entries. It is obvious that the majority of the SN2 reactions follow through TS‐1 according to the dependence δΔН≠int versus δΔG≠ (Figure 2). However, there are the deviations from the dependence depicted in Figure 2 for the SN2 reactions of entries 28, 31‐35, 55, 56 and 60 in Table 2. The deviations of entries 28 and 60 can be explained by the formation of the complexes 1 and 2 before forming the distorted trigonal‐bipyramidal TS‐2 or TS‐ 3, respectively (Scheme 2) [24,41]. The latter leads to an increase in the magnitudes of δΔG≠ and a decrease of the δΔН≠int values for these reactions. The assumption of the formation of the complexes 1 and 2 is supported by recent DFT computations of phenacyl bromides with pyridines [41]. It is necessary to emphasize that the SN2 reactions of phenacyl derivatives with benzenethiol (entries 48 and 49 in Table 2) do not lead to the deviations from the dependence between δΔН≠int and δΔG≠ (Figure 2). It is obvious that these reactions follow through TS‐1 according to the low positive values of ρ constants [57]. The increase in the magnitudes of δΔG≠ takes place also for the Menschutkin reactions of benzyl halides with pyridine (entries 31‐35 in Table 2) (Figure 2), possibly, due to a change of TS‐1 to the distorted trigonal‐bipyramidal TS‐4 by the influence of the substituents R and solvation [40]. The latter has been confirmed by DFT computations of TS‐4 in the reactions of benzyl bromides with pyridine in solutions showing a significant change of their geometry in comparison with a standard structure TS‐1 (Scheme 3) [40]. At the same time the variation of the solvent in the Menschutkin reaction of benzyl bromide with pyridine from acetonitrile to ionic liquid (entries 35 and 36 in Table 2) does not give the deviation from the dependence δΔН≠int versus δΔG≠ (Figure 2). The origin of that is a lower interaction of ionic liquid with the incipient charges in TS‐1 leading to the change in the entropy of the system (entries 23 and 24 in Table 1) [56]. The variation of the activation parameters ΔН≠ and ΔS≠ in this Menschutkin reaction depends also on the structure of the ionic liquid cation. The importance of accessibility of the charge centre on the cation and the ability for generalized electrostatic interactions between the nucleophile and the cation of the ionic liquid are responsible for any change in rate constants [89]. The deviations from the dependence δΔН≠int versus δΔG≠ for entries 55 and 56 (Figure 2) are connected with the decrease in the magnitudes of δΔG≠ (Table 2) due to a change in the reaction mechanisms. It was shown that the reactions of allyl and benzyl bromides with anilines involve, possibly, the formation of the four‐membered cyclic TS‐5 or TS‐6, respectively, with frontside attack by nucleophiles (Scheme 4) [8,12,90,91]. Usually the formation of the cyclic TSs with frontside attack by nucleophiles is accompanied by the lower values of activation entropy [90,92]. Taking into account the Hammett‐like equation δΔG≠ = ‐ 2.303RTexpρ [16,38] and considering the relationship between δΔН≠int and δΔG≠ (Figure 2), a correlation between δΔН≠int and ρ for SN2 reactions carrying out through TS‐1 also takes place (entries 1‐13, 24, 29, 30, 36, 47‐49, 51‐54, 57‐59 in Table 2) (Figure 3) [24]. The intercept in this equation is close to zero and the slope reflects a sensitivity of δΔН≠int to a change of ρ equaling 2.303RTexp. Realization of this dependence becomes possible, as magnitudes of ρ for these SN2 reactions characterize charge development in TS‐1 [16‐19, 93‐96]. It is obvious that the δΔН≠int reaction constants characterize also the degree of developing negative charge in TS‐1. The large positive and negative values of δΔН≠int indicate essential charge development in TS‐1 for the reactions of entries 10, 24, 59 and 60 in Table 2. 230 Vlasov / European Journal of Chemistry 6 (2) (2015) 225‐236 C N H N Cl H H 1 C TS-2 = TS-3 CH3H3C C N H N Cl H H C CH3H3C O = C N Ph Br H H 2 C HH O C N Ph Br H H C HH O R R R R PhC(O)CH2NHC6H4R + HBrPhC(O)CH2Br + RC6H4NH2 k2 2 k-1 k1 TS-3 Scheme 2 Scheme 3 Figure 3. The plots of δΔН≠int versus ρ for SN2 reactions of entries 1‐13, 24, 29, 30, 36, 47‐49, 51‐54 and 57‐59 in Table 2: δΔН≠int = (0.27 ± 0.17) ‐ (6.08 ± 0.01) ρ, r = 0.995, s = 0.89, n = 27; the identity of the numbers is the entry number in Table 2. The linearity between the magnitudes of δΔН≠int and ρ over a wide range of their values (Figure 3) furthermore supports the assumption that there is no change in the mechanism of the SN2 reactions carried out through TS‐1 with the variation of the substituents R in the leaving and nonleaving groups and neutral nucleophile. Therefore, the deviations from the correlation δΔН≠int versus ρ give a possibility of offering alternative ways for such SN2 reactions. For instance, some dissociative (ρ < 0) and associative SN2 reactions (ρ > 0) in which the substituent R is varied in the nonleaving group (entries 28, 31‐35 in Table 2) and nucleophiles (entries 55, 56 and 60 in Table 2) [8,12,97] deviate from the linear dependence δΔН≠int versus ρ (Figure 3). Though this dependence describes normal SN2 reactions in solution proceeding through TS‐1, the deviations of entries 28 and 60 (Table 2) from it are connected with the formation of the complexes 1 and 2, TS‐2 and TS‐3 on the reaction coordinate, respectively (Scheme 2) [24,41]. Therefore, the magnitudes of ρ is equal to ρ = ρeq (k1/k‐1) + ρnuc(k2). The magnitudes of ρnuc are calculated by equation δΔН≠int versus ρ (Figure 3) using the δΔН≠int values (entries 28 and 60 in Table 2), respectively [24]. The deviations of entries 55 and 56 in Table 2 from the dependence δΔН≠int versus ρ (Figure 3) are connected with the formation of TS‐5 and TS‐6, respectively, due to front side attack by nucleophiles (Scheme 4). The large charge development in these transition states leads to the small negative values of ρ [8,12,54]. On the other hand, the deviations of entries 31 – 35 in Table 2 (Figure 3) with a distortion of TS‐1 to TS‐4 give the increase of the negative values of ρ indicating the less charge development in TS‐4 [40]. Vlasov / European Journal of Chemistry 6 (2) (2015) 225‐236 231 Table 3. Values of the reaction constants δΔG≠ and δΔH≠int, the Brønsted slopes βR, the Hammett reaction constants ρR, cross‐interaction constants ρRR in SN2 reactions at saturated carbon atom YCH2‐X with charged nucleophiles in various solvents. Entry Reactants Solvent δΔG≠ a kJ.mol‐1.σ‐1 δΔH≠int b kj.mol‐1.σ‐1 βR c ρR d ρRR e Reference Substituents R are varied on leaving groups YCH2ZC6H4R 1 RC5H4N+‐Me + I‐ MeCN ‐33.8 ‐33.9 ‐0.95 5.95 ‐ 24,27,50 Substituents R are varied on nonleaving group RC6H4ZCH2X 2 RC6H4CH2Cl + PhSLi MeOH ‐5.1 ‐3.0 ‐ 0.58 ‐0.62 24,27,58 3 RC6H4CH2Cl + PhONa Liquid NH3 ‐6.31 (‐5.69) ‐ (‐7.79) ‐ 1.11 0 52 4 RC6H4CH(Me)Br + LiBr Acetone ‐2.7 ‐7.0 ‐ 1.13 ‐ 24,27,59 5 CH2=CH‐CH2‐OSO2C6H4R + sodium 1,2,4‐triazolate Liquid NH3 ‐5.11 (‐4.41) ‐ (‐7.44) ‐ 0.89 ‐ 52 Substituents R are varied on nucleophiles RC6H4Z‐ 6 BrCH2CH = CHCN + RC6H4SO2Na 50 vol% EtOH‐H2O 16.7 12.2 ‐ ‐ 2.62 ‐ 27,67 7 BrCH2CH = CHBr + RC6H4SO2Na 50 vol% EtOH‐H2O 19.5 12.0 ‐ ‐ 3.25 ‐ 24,67 8 PhCH2Cl + RC6H4SLi MeOH 2.80 (4.23) ‐ (0.86) 0.28 ‐0.58 ‐0.62 8,58,99 9 PhCH2Cl + RC6H4ONa Liquid NH3 10.22 (11.08) ‐ (5.895) 0.42 ‐1.79 0 52 a Calculated by Eyring equation; values in parentheses are calculated by the Hammett‐like equation δΔG≠ = ‐2.303RTexpρ [16,38]. b Calculated by Equation 6; values in parentheses are calculated by Equation 7. c Calculated by Brønsted equation; the calculations use the values of pK for substituted pyridines in MeCN [87] in entry 1, substituted benzenethiols in MeOH [57] in entry 8 and substituted phenols in liquid NH3 in entry 9 [52]. d Calculated by Hammett equation; σ constants are taken from [28]; σ* constants are used in entries 76 and 77 and taken from [28]. e Calculated by Equation 9: log (kRR’/kHH) = ρRσR + ρR’σR’ + ρRR’σRσR’ in entries 2, 3, 8, 9. Scheme 4 It is obvious that the deviations from the dependence between δΔН≠int and δΔG≠ or δΔН≠int and ρ can be interpreted in terms of a change of transition state structures. 5. SN2 Reactions with charged nucleophiles The changes of the reaction constants δΔG≠, δΔН≠int and ρ of the SN2 reactions with charged nucleophiles are presented in Table 3. The linear dependences δΔН≠int versus δΔG≠ and δΔН≠int versus ρ have been developed for entries 1, 2, 4, 6, 7 in Table 3 (Equations 7 and 8). The degrease of the slopes in these equations in comparison with that of the analogous equations for the reactions with neutral nucleophiles (Figures 2 and 3) follows from the difference in the values of δΔG≠ and δΔН≠int for entries 2, 4, 6, 7 in Table 3. δΔH≠int = (‐3.0 ± 1.4) + (0.87 ± 0.07 δΔG≠ r = 0.990, s = 3.1, n = 5 (7) δΔH≠int = (‐2.11 ± 0.97) ‐ (5.12 ± 0.29)ρ r = 0.995, s = 2.17, n = 5 (8) The origin of the differences between δΔG≠ and δΔН≠int for the reactions of entry 4 in Table 3 is, possibly, the formation of the complex 3 before forming the distorted trigonal‐ bipyramidal TS‐7 ( (Scheme 5) [24,27]. The latter leads to an increase of the δΔG≠ value. The assumption is supported by DFT computations of complexes of 1‐aryl‐1‐bromoethanes with bromide ion [40]. The large magnitudes of δΔG≠ in comparison with the δΔН≠int values for the reactions of entries 6 and 7 in Table 3 can be explained by the formation of the distorted trigonal‐ bipyramidal TS‐8 [27]. The Br‐C‐S angle deviates from 180 degrees and the longer C – S bond leads to an increase of the δΔS≠ values (entries 41 and 42 in Table 1) on passing to the electron‐withdrawing substituent R in nucleophile (Scheme 6) [67]. It is worth noting that the differences in the magnitudes of the reaction constants δΔG≠ and δΔН≠int for SN2 reactions with the charged nucleophiles in entries 4, 6 and 7 in Table 3 give a possibility to elucidate some peculiarities of the changes of the transition state structure. It is very interesting that the SN2 reaction of charged nucleophile with an ionic electrophile in the medium of the ionic liquid shows a linear dependence of the reaction rate constant upon nucleophile concentration. Such dependence is absent for this reaction proceeding in the molecular solvents. The linear kinetic behavior seen in the ionic liquid solutions clearly indicates that the reactions are not progressing via ion pairs, but via free solvated ions which are considerably less reactive than the ion pairs forming in the molecular solvents. Thus the ionic liquids are extremely dissociating solvents [98]. 232 Vlasov / European Journal of Chemistry 6 (2) (2015) 225‐236 Scheme 5 Scheme 6 Scheme 7 6. Mechanistic criteria for SN2 reactions on the basis of the Brønsted and Hammett equations The concept of the linear free energy relationship developed on the basis of the kinetic researches in the frameworks of the Brønsted and Hammett equations is used most frequently to study the substituent effects into the product relation and the reaction rate for the reaction mechanism [16‐19]. Therefore, the analysis of the kinetic data is important to elucidate a properties of the transition state for the SN2 reactions with the rate‐determining step kc [8,10,73,75,91,92,97,99]. The magnitudes of the Brønsted slopes βR for the reactions with neutral and charged nucleophiles when the substituents R are varied in benzene derivatives of the leaving group and nucleophile are equal to ‐0.95÷‐0.32 and 0.28÷0.66, respectively (entries 2, 9, 14‐24, 51, 54‐57, 61‐78 in Table 2; entries 1, 8, 9 in Table 3). These values reflect the SN2 reactions with the mechanism proceeding via TS‐1 [8,10,73,75,92,99]. However, there are the reaction series in which the substituent R in the nucleophile is varied in α‐ position to the reaction center (entries 76 and 77 in Table 2). In these cases, the values of the Brønsted slope βR are changed from ‐10.2 up to 3.38 for electron‐donating and electron‐ withdrawing substituents R, respectively [66]. It is obvious that a curved Brønsted plot for these reactions can arise from the variable TS‐9 (Scheme 7) [20]. At the same time, the sign and magnitude of the Hammett‐ like cross‐interaction constants ρRR’ where R and R’ are the substituents in the leaving and nonleaving groups and nucleophile, respectively, provide mechanistic criteria for the SN2 reactions [10,73,75,91,92,97,100]. log (kRR’/kHH) = ρRσR + ρR’σR’ + ρRR’σRσR’ (9) The magnitude ρRR’ is positive for more active nucleophile and nucleofuge at the variation of the substituent in nucleophile and leaving group. The latter leads to the early TS‐ 1 on the reaction coordinate with a low degree of the formation and breakdown of the bond (entries 14‐21, 61‐71 in Table 2). On the contrary, the more late TS‐1 is formed at negative values of ρRR’ (entries 22, 23, 62, 63, 72‐75, 79 in Table 2) [8,12,91]. Therewith, the larger negative values of ρRR’ indicate the formation of TS‐5 or TS‐6 as a result of the frontside nucleophile‐substrate interaction [8,12,90‐92]. Further, the magnitude of ρRR’ is negative and almost constant (ρRR’ = ‐0.70 ± 0.08) upon change of the substituent in nucleophile and nonleaving group. The latter characterizes close degree of the bond formation in TS‐1 (entries 37‐42, 63, 74, 75, 79 in Table 2; entries 2, 8, 9 in Table 3) [8]. So, the analysis of the cross‐interaction constants ρRR’ gave an opportunity to determine the properties of the transition state for the SN2 reactions in solution including both the backside and frontside attacks by the nucleophile onto the reaction centre. 7. Relationship between the mechanism of SN2 reactions and the changes of the activation parameters The activation parameters ΔН≠, ΔS≠ and ΔG≠ are widely used for characterizing the structures of transition states in solution SN2 reactions [6,16,52,58,92,100]. It was found that the solvolysis of benzyl‐ and benzhydryl halides follows the SN2 and SN1 mechanisms, respectively, as SN2 reactions show more negative values of ΔS≠ [101,102]. Vlasov / European Journal of Chemistry 6 (2) (2015) 225‐236 233 Scheme 8 It was also shown that the interaction of 4,4’‐ dichlorobenzhydryl bromide with morpholine in DMSO leads to the alkylation product through the SN2 and SN1 mechanisms with the ratio of 70, respectively, at more negative value of ΔS≠ for the SN2 pathway through TS‐1 with backside attack by the nucleophile onto the substrate [103]. The less values of ΔG≠ and ρR are characteristic of the SN2 reactions than the SN1 one’s (entry 43 in Table 2) due to the charge decrease in the transition state [83]. Usually, the SN2 reactions are characterized by the magnitudes of ΔН≠ and ΔS≠ equaling 8.0 ÷ 100.8 kJ.mol‐1 and ‐2.3 ÷ ‐277 J.mol‐1.K‐1, respectively [23,104]. These limit magnitudes for the activation parameters can be used to determine the properties of the transition state structure for the SN2 reactions. For instance, the low values of ΔН≠ and the larger negative values of ΔS≠ characterize the SN2 reactions with the frontside attack by nucleophile at the α‐carbon of the substrate with the formation of the cyclic transition states TS‐5 or TS‐6 [90,92]. Considering the values of ΔG≠ and ρR , it is seen that the SN2 reactions with neutral nucleophiles are characterized by the less values of these magnitudes than the analogous reactions with charged nucleophiles (entries 25‐27 in Table 2; entries 3, 5 in Table 3). The comparison confirms that there is the small charge onto the α‐carbon atom in the TS‐1 for the SN2 reactions with neutral nucleophiles. At the same time, the large sensitivity to a change of substituents in the aromatic ring for these reactions with charged nucleophiles affords to increase a negative charge in the TS‐1 [52]. When electron‐donating and electron‐withdrawing substituents are introduced to the same central carbon at the reaction centre of Menschutkin‐type SN2 reaction, the π – π*, σ – π* and π – σ* interactions among these substituents in the transition state cooperatively accelerate this reaction by stabilizing its transition state [105]. However, when electron‐ donating and electron‐withdrawing substituents are varied in α‐position to the reaction centre of neutral nucleophile (entries 76, 77 in Table 2), there is a curved Brønsted plot for the SN2 reactions (Scheme 7) [66] due to the variable TS‐9 [20]. The analysis of the influence of structural changes on the barriers of SN2 reactions of alkyl halides with cyanide ion in acetonitrile revealed quantitatively the contribution of different substituents to the ΔG≠ value [106]. For instance, α‐ and β‐ methylation of the substrate increases the ΔG≠ by 8 and 4 kJ.mol‐1, respectively. Benzyl and carbonyl substituents decrease significantly the reaction barriers of SN2 reactions (up to 20‐28 kJ.mol‐1) [106]. It is noting that the same influence of the substituent variation in α‐ and β‐positions in alkyl halides on the energetic barrier of SN2 reactions revealed in the gas phase [106,107]. Therewith, in according with Galabov’s work [108], substrate‐nucleophile electrostatic interactions in the SN2 transition state rather than π‐ conjugation lower net activation barriers and enhance reaction rates unaltered by solvation effects. The energetic barriers and the transition state structure of the gas phase SN2 reactions of para‐substituted phenoxides with halomethanes are thermodynamically controlled. Furthermore, the energetics barriers display good linear correlations with the substituent constants σ in the nucleophile [100,109]. The increase of the chlorine atoms by substitution of hydrogen atoms in methyl chloride leads to the lowest free energy activation barrier for the reaction with OH‐ in aqueous solution due to both the solvation effects and the solvent‐ induced polarization effect [110]. The solvent effect on the activation free energy of the Finkelstein reaction between methyl iodide and Cl‐ ions depends linearly on the reaction free energy [111]. It was found that the effects of the microsolvation of water in the I‐ + CH3I → ICH3 + I‐ SN2 reaction can effectively inhibit this reaction increasing the barrier height [112]. The intramolecular hydrogen bonding in alkoxide anions acting as a good model system for studying of intramolecular mictosolvation on nucleophilicity increases the intrinsic barrier height of SN2 reactions of alkoxides with methyl chloride by ~ 12.5 kJ.mol‐1 [113]. It was shown that the structure of the TS‐1 in the SN2 reaction between n‐butyl chloride and thiophenoxide ion is slightly changed in both methanol and DMSO when the reacting nucleophile is the solvent‐separated ion‐pair and the free ion, respectively. However, the reaction rate in MeOH is significantly lower than in DMSO in the presence of sodium nitrate due to the solvation leading to the tighter transition state [114]. The effect of the substituents γ for the reactions of trans‐γ‐ substituted allyl chlorides γCH=CHCH2Cl with Cl‐ and LiCl has been studied. It was shown that the computed reaction barriers give reasonable correlations with the Hammett σp constants leading to ρ = ‐8.3 and +18.8, respectively. It is obvious that ionic and ion pair reactions give ρ values of opposite signs [115]. The Hammett correlations for the reactions of benzylic chlorides with ethoxide ion and sodium ethoxide ion pairs give also the ρ values of 2.2 and ‐0.6 with opposite signs, respectively [116]. Note that an ionic structure of the transition state is stabilized by electrostatic polarization of the double bond than π‐conjugation [108]. At the same time, the significant charge delocalization takes place for the ion pair structure of the transition state. In general, ion pair reactions are less favorable than the corresponding ionic reactions [115]. The steric effect in SN2 reactions of alkyl chloronitriles with chloride ion was quantitatively estimated (Scheme 8). The magnitude of the steric effect, however, is not significantly different in the gas phase and in solution [117]. Moreover, the solvation energy of the SN2 transition state TS‐10 does not depend on the size of the substituent R. The weak size dependence results from the compensation between a direct shielding effect of the substituent and an indirect ionic solvation effect, which arises from the geometric perturbations introduced by the substitution [117]. The influence of microsolvation on the Cl‐ + RCl SN2 reaction, with R being methyl, ethyl, i‐propyl, and tert‐butyl, has been investigated in the presence of 0‐4 water molecules, and 0‐2 molecules of methanol, acetonitrile, acetone, dimethyl ether and propane by the calculations, using B3LYP/6‐31 + G* level with the polarizable continuum model (PCM) [118,119]. 234 Vlasov / European Journal of Chemistry 6 (2) (2015) 225‐236 Scheme 9 The calculated barrier heights increase with the number of solvent molecules and the size of the R substituent. Microsolvation causes only small changes in the TS geometries for the methyl, ethyl, and i‐propyl substituents, whereas the tert‐butyl TS becomes significantly looser [118]. Microsolvation decreases the steric effect of the substituent R depending on the dielectric constant of the solvent. The decrease in steric effect of the substituent is due to an increased solvation of the TS mediated by the electron donating effect of the methyl groups at the central carbon. The latter leads to an increased interaction with the solvent [118,119]. It should be noted that the variation of the activation parameters for SN2 reactions depend on the reacting species and solvents [120‐126]. For instance, the activation parameters ΔН≠ and ΔS≠ for the reaction of sodium 4‐ nitrophenoxide and iodomethane in acetone‐water mixtures at 25‐35 °C form the compensation dependence reflecting electrostatic and specific interactions between a nucleophile and a solvent mixture [120]. However, a Menschutkin reaction between 2‐amino‐1‐methylbenzimidazole and iodomethane in acetonitrile at 20‐50 °C leads to non‐Arrhenius behavior of the kinetic data steming from the conjunction of a nucleophile with a dipolar aprotic solvent that is protophobic [121]. Recently, a new concept based on selective solvation of the TS‐11 by double hydrogen bonding in the reaction of the cyanide ion with ethyl chloride in carbon tetrachloride solution in the presence of 1,4‐benzenedimethanol (BDM) was proposed (Scheme 9) [122,123]. The high stability of the BDM‐ cyanide complex induces a substantial rate acceleration effect leading to lower activation barrier [122,123]. The SN2 reactions using alkali metal salts MX (M+ = Cs+, K+; X = F‐, Br‐, I‐, CN‐) as nucleophile agents and C3H7OSO2CH3 as a substrate in the presence of n‐oligoethylene glycols demonstrate a new concept for elucidating the promoting effects: the nucleophiles react as ion pairs, whose metal cation is coordinated by the oxygen atoms in oligoethylene glycols acting as Lewis base to reduce the unfavorable electrostatic effects of M+ on X‐. The calculated SN2 barriers of various nucleophiles (F‐ > CN‐ > Br‐ > I‐) were in agreement with experimental observations [125, 126]. The effect of counterion on the reactivity of ion pairs along the backside and frontside reactions Nu‐ + CH3X → CH3Nu + X‐ (X = F, Cl, Br; Nu‐ = X‐, Li+X‐, Na+X‐, K+X‐) in solvent media shows that the calculated energy barriers increase with decreasing the size of counterion [124]. The analysis of the potential energy surfaces of various model SN2 reactions of Cl‐ + CR3Cl and Cl‐ + SiR3Cl (R = H, Me, Et, OMe) shows that the central SN2 @C barrier is retained by the interplay of steric and electronic effects between nucleophile and substrate. However, the central SN2 @Si barrier disappears because there is less steric congestion. Such a comparison of the mechanisms of the SN2 @C and SN2 @Si reactions gives the possibility to elucidate the steric nature of the SN2 barrier [127]. The comparison of the potential energy surfaces of the backside as well as frontside SN2 reactions of X‐ + CH3Y with X, Y = F, Cl, Br, and I, using DFT at ZORA‐OLYP/TZ2P provides that backside SN2‐b barriers increase along the nucleophiles F‐ > Cl‐ > Br‐ > I‐ and decrease along the substrates CH3F > CH3Cl > CH3Br > CH3I. Frontside SN2‐f barriers show the same trends but are in all cases much higher (~ 42 ÷ 250 kJ.mol‐1) because of more steric repulsion between the nucleophile and leaving group [128,129]. Therewith, the frontside substitution becomes gradually more competitive when the substitution in the substrate becomes bigger and the leaving group / nucleophile become better [9]. However, the solvation of the SN2 reaction in water of Cl‐ + CH3Cl leads into unimodal reaction profile via one single barrier TS‐1 to the product [130]. The significant increase of the energetic barrier by over 63‐71 kJ mol‐1 for the SN2 reactions of CN‐ + CH3I and CN‐ + C2H5I occurs in protic and aprotic solvents in comparison with the gas phase. The magnitudes of the electrostatic attraction between the partial negative charges on the nucleophiles in the transition state and the partial positive charge on the α carbon are much larger in the gas phase than in solvent where solvation will reduce these interactions between ions in the transition state [131]. 8. Conclusions The parameters from the linear free energy relationships providing mechanistic criteria for the SN2 reactions in solution allow one to determine the peculiarities in the mechanism of these reactions. Compensation relationships between the changes of the activation parameters δΔН≠ and δΔS≠ give a possibility to estimate the changes of the internal enthalpy δΔН≠int. These reaction constants give rise to two linear dependences with the values of the reaction constants δΔG≠ or the Hammett values ρ for SN2 reactions in solution with neutral and charged nucleophiles. Furthermore, the different deviations from these dependences indicate the alternative TS structures in comparison with the standard structure of TS‐1 on the ground of their activation parameter variations. Computations with the PCM method give a possibility to evaluate the influence of solvation as microsolvation onto the activation parameters in the SN2 reactions in solution. Moreover, microsolvation can offer greater insight into the role of the hydrogen bonding, conjugation and steric hindrance in these reactions. 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